KR100937134B1 - Benzofuran and bezothiophene derivatives substituted by amide, process for the preparation thereof, and pharmaceutical compositions containing the same - Google Patents

Abstract

The present invention relates to a benzofuran and a benzothiophene derivative substituted with an amide of Formula 1, a preparation method thereof, and a pharmaceutical composition comprising the same, wherein the benzofuran and benzothiophene derivative substituted with an amide of the present invention are ischemic cell death. Since it can be significantly reduced, the composition containing it as an active ingredient can be usefully used as an agent for preventing and treating ischemic diseases or long-term protection mediated by ischemic cell death.

Where

R ¹ , B, n, Y, Z, X, W and A are as defined in the specification.

Description

Benzofuran and benzothiophene derivatives substituted with amides, methods for preparing the same, and pharmaceutical compositions comprising the same. {BENZOFURAN AND BEZOTHIOPHENE DERIVATIVES SUBSTITUTED BY AMIDE, PROCESS FOR THE PREPARATION THEREOF, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME}

The present invention relates to benzofuran and benzothiophene derivatives substituted with amides, preparation methods thereof, and pharmaceutical compositions comprising the same.

Ischemia refers to a reduced state of blood supply to body organs, tissues or sites caused by contraction or blockage of blood vessels. After ischemia, even if reperfusion of blood occurs, nerve cells are damaged and cause various sequelae. Such ischemia is often associated with coronary artery disease, cardiovascular disease, angina pectoris, headache or other vascular symptoms, and ultimately leads to irreversible damage, ie necrosis of cells and tissues.

Ischemic diseases such as myocardial infarction, arrhythmia, and insufficiency caused by cellular damage and deterioration during ischemia / reperfusion have high prevalence, mortality, and difficulty in cure. See Wang, QD et al., Cardiovasc. Res. 55: 25-37, 2002). Ischemia / reperfusion injury involves various physiological mechanisms such as metabolism, changes in immune response and ionic constant, oxygen free radicals, and therefore, research is being conducted in various fields such as immunomodulators, apoptosis-related substances, and ion channel regulators. Hearse, DJ et al., Mol. Cell. Biochem. 186: 177-184, 1998). To date, there have been active researches on the development of therapeutic agents and surgical procedures with new action points, but the techniques for protecting cardiomyocytes from ischemia / reperfusion have not been commercialized clinically. Therefore, there is a need for development of a prophylactic or therapeutic agent for ischemic heart disease or a cardioprotective agent that can slow the progression of cardiomyocyte damage due to ischemia and alleviate reperfusion injury.

It is also increasingly clear that when ischemia is eliminated by the return of blood flow, the production of reactive oxygen species (ROS) is accelerated, which leads to a much more pronounced decrease in glutathione leading to the development of more serious diseases. have. Similar diseases are observed upon implantation of various organs such as the heart, liver, lungs, pancreas and blood vessels, and upon stopping or returning blood flow. The disease is also a problem in the incision and removal of organs. Free radicals and reactive free radicals that are believed to cause disease are detected in both the cytoplasmic cells and organelles that make up tissues, especially the mitochondria that produce ATP, which contributes to the cell's main energy source. In mitochondria, it has been observed that the respiratory chain is the main source of these reactive molecules and their concentrations rise significantly during ischemia and reperfusion.

In ischemic diseases, apoptosis or cell necrosis is caused by ischemia. Especially, apoptosis after reperfusion is a major cause of tissue damage. Ischemic cell death is caused by cerebral ischemia, cardiac ischemia, diabetic vascular heart disease, heart failure, cardiomyopathy, and retina. Causes of the development of various ischemic diseases, including ischemia, ischemic colitis and ischemic acute renal failure.

In the case of ischemic disease, cerebral ischemia, depletion of energy source causes depletion of energy source, and ischemic cell death is excessively activated. Cellular receptors are excessively activated, glutamic acid is accumulated outside the cell and calcium is accumulated inside the cell. It involves a variety of biochemical changes, such as damaging lipids, proteins and nucleic acids, resulting in damage to brain tissue (Liu, PK, J. Biomed. Sci. 10: 4-13, 2003; Lipton, P., Physiol. Rev. 79: 1431-1568, 1999; and Renolleau, S. et al., Stroke 29: 1454-1460, 1998).

In the case of ischemic heart disease, myocardial infarction, arrhythmia and heart failure, it is known that lipid membrane activation causes cell membrane damage, pH changes and calcium migration, resulting in ischemic cell death (Ferrari, R. Rev. Port. Cardiol. 5: 7-20, 2000; Webster, KA et al., J. Clin. Invest. 104: 239-252, 1999; Katz, AM et al., J. Mol. Cell.Cardiol. 2: 11- 20, 1985; and Vandeplassche, G. et al. Basic Res. Cardiol. 85: 384-391, 1990), and ischemic cell death associated with glutamate-mediated retinal cell death in retinal ischemia. Is known (see Napper, GA et al., Vis. Neurosci. 16: 149-158, 1999), and ischemic cell death occurs due to insufficient blood flow to the large intestine, and the necrosis of the arteries and fluids are caused by cell necrosis. It is known that ischemic colitis, an ischemic disease, is described above (Saegesser, F. et al., Pathobiol. Annu. 9: 303 -337, 1979).

In addition, minocycline, a tetracycline-based antibiotic that inhibits ischemic cell death, is known to have cerebral infarction (see Yrjanheikki, J. et al., Proc. Natl. Acad. Sci. USA 96: 13496-13500, 1999), myocardial infarction ( See Scarabelli, TM et al., J. Am. Coll. Cardiol. 43: 865-874 , 2004) and ischemic acute renal failure (Wang, J. et al., J. Biol. Chem. 279: 19948-19954, 2004) is also effective in the treatment of ischemic diseases, it is understood that ischemic cell death is the cause of the disease.

In addition, damage or death of neurons caused by ischemia is known to be a major cause of various neurological diseases, including stroke, brain trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma and diabetic neurosis (GJ Zoppo et. al. , Drugs 54 , 9 (1997); I. Sziraki et al. , Neurosci. 85 , 1101 (1998)).

Therefore, the present inventors are trying to develop a compound that exhibits a pharmacological effect against the ischemic disease, and the ischemic cell death is mediated by ischemic cell death by inhibiting ischemic cell death of benzofuran and benzothiophene derivatives substituted with new amides. Prevention of ischemic diseases such as cardiac ischemia, diabetic vascular heart disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, brain trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma and diabetic neurosis And by confirming that it can be used as a therapeutic or long-term protective agent.

Accordingly, it is an object of the present invention to inhibit ischemic cell death, thereby ischemia, cardiac ischemia, diabetic vascular heart disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, brain trauma, It is to provide a benzofuran and benzothiophene derivatives having a prophylactic and therapeutic effect of Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma and diabetic neuropathy, and a preparation method thereof.

Another object of the present invention to provide a pharmaceutical composition containing the compound as an active ingredient.

In order to achieve the above object, the present invention provides benzofuran and benzothiophene derivatives or pharmaceutically acceptable salts thereof substituted with amides of the general formula:

Formula 1

Where

이며, 이때 R²는 서로 독립적으로 H, 또는 C₁ 내지 C₆의 직쇄, 측쇄 또는 사이클릭 알킬이고;R ¹ is —CO ₂ R ² , or

Where R ² is independently of each other H, or C ₁ To C ₆ straight, branched or cyclic alkyl;

B is H, phenyl unsubstituted or substituted with halogen or C ₁ -C ₃ alkyl;

n is an integer from 0 to 2;

Y is S;

Z is H or halogen;

X is O or S;

W is H or halogen;

A and G are independently of each other CH or N.

The present invention also provides a method for preparing benzofuran and benzothiophene derivatives substituted with the amide of Formula 1.

The present invention also provides a composition for the prevention and treatment of ischemic diseases containing benzofuran and benzothiophene derivatives or pharmaceutically acceptable salts thereof substituted with the amide of Formula 1 as an active ingredient.

In another aspect, the present invention provides a composition for long-term protection containing benzofuran and benzothiophene derivatives or pharmaceutically acceptable salts thereof substituted with the amide of the formula (1) as an active ingredient.

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

The present invention relates to a benzofuran and a benzothiophene derivative substituted with the amide of Formula 1, a preparation method thereof, and a composition for preventing or treating ischemic disease containing the same as an active ingredient.

Among the benzofuran and benzothiophene derivatives substituted with amides according to the present invention, preferred ones in the general formula (1),

이며, 이때 R²는 서로 독립적으로 H, 메틸 또는 에틸이고;R ¹ is -CO ₂ R ² , or

Wherein R ² is, independently from each other, H, methyl or ethyl;

B is H, phenyl unsubstituted or substituted with halogen or C ₁ -C ₃ alkyl;

n is 0 or 1;

Y is S;

Z is H or halogen;

X is O or S;

W is H or halogen;

A and G are independently of each other CH or N.

Further preferred compounds as the benzofuran and benzothiophene derivatives substituted with the amide of Formula 1 according to the present invention are

1) 3- (2-phenylsulfanyl-acetylamino) -benzofuran-2-carboxylic acid methyl ester

2) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -benzofuran-2-carboxylic acid methyl ester

3) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -4-chloro-benzofuran-2-carboxylic acid methyl ester

4) 3- [3- (4-Bromo-phenylsulfanyl) -propionylamino] -benzofuran-2-carboxylic acid methyl ester

5) 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -benzofuran-2-carboxylic acid

6) 4-Chloro-3- (3- (pyridin-2-ylsulfanyl) -propionylamino] -benzofuran-2-carboxylic acid methyl ester

7) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -furo [2,3- b ] pyridine-2-carboxylic acid methyl ester

8) 3- (3- (pyridin-2-ylsulfanyl) -propionylamino] -furo [2,3- b ] pyridine-2-carboxylic acid methyl ester

9) 3- [2- (4-bromo-phenylsulfanyl) -2-phenyl-acetylamino] -benzofuran-2-carboxylic acid methyl ester

10) 2- (4-Bromo-phenylsulfanyl) -N- [2- (4,5-dihydro-oxazol-2-yl) -benzofuran-3-yl] -2-phenyl-aceta mid

11) 3- (2-phenylsulfanyl-acetylamino) -benzo [b] thiophene-2-carboxylic acid methyl ester

12) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -benzo [b] thiophene-2-carboxylic acid methyl ester

13) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -4-chloro-benzo [b] thiophene-2-carboxylic acid methyl ester

14) 3- (3-phenylsulfanyl-propionylamino] -benzo [b] thiophene-2-carboxylic acid methyl ester

15) 3- [3- (4-bromo-phenylsulfanyl) -propionylamino] -benzo [b] thiophene-2-carboxylic acid methyl ester

16) 4-chloro-3- (3- (pyridin-2-ylsulfanyl) -propionylamino] -benzo [ b ] thiophene-2-carboxylic acid methyl ester

17) 3- [2- (4-bromo-phenylsulfanyl) -2-phenyl-acetylamino] -benzo [b] thiophene-2-carboxylic acid methyl ester

18) 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -thieno [2,3- b ] pyridine-2-carboxylic acid methyl ester

19) 3- (3- (pyridin-2-ylsulfanyl) -propionylamino] -thieno [2,3- b ] pyridine-2-carboxylic acid methyl ester.

The structural formulas of the compounds according to the present invention are as shown in Table 1 below.

The benzofuran and benzothiophene derivatives substituted with the amides of Formula 1 according to the present invention include not only pharmaceutically acceptable salts thereof, but also all possible solvates, hydrates and stereoisomers that may be prepared therefrom.

Pharmaceutically acceptable salts of benzofuran and benzothiophene derivatives substituted with the amides of Formula 1 according to the present invention may include acid addition salts formed by pharmaceutically acceptable free acid. The free acid may be an organic acid or an inorganic acid, and an organic acid may be citric acid, acetic acid, maleic acid, fumaric acid, glucoic acid, methanesulfonic acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, Galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid and the like can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid and the like can be used, and methanesulfonic acid and hydrochloric acid are preferable.

Acid addition salt according to the present invention is dissolved in a conventional method, that is, benzofuran and benzothiophene derivatives substituted with the amide of the formula (1) in a water miscible organic solvent such as acetone, methanol, ethanol, acetonitrile and the like It can be prepared by addition, or by addition of an acidic aqueous solution of an inorganic acid followed by precipitation or crystallization, evaporation of the solvent or excess acid from the mixture, followed by drying or suction filtration of the precipitated salt.

In addition, the present invention provides a method for preparing benzofuran and benzothiophene derivatives substituted with the amide of Chemical Formula 1.

The benzofuran and benzothiophene derivatives substituted with the amide represented by the following formula (1) according to the present invention may be substituted with the benzofuran and benzothiophene derivatives substituted with the amide of the following formula (2) in the presence of a suitable solvent and base. It can manufacture by reacting with.

Formula 1

Wherein R ¹ , B, n, Y, z, G, X, W and A are as defined in Formula 1, and L is a leaving group.

In Formula 1, when R ¹ is an ester, a compound of Formula 2a having a leaving group L is reacted with a compound of Formula 3 in the presence of a suitable solvent and a base to a nucleophilic substitution reaction to an amide of Formula 1a. Substituted benzofurans and benzothiophene derivatives can be prepared.

Formula 3

Wherein, B, n, Y, z, G, X, W and A are as defined in Formula 1,

R ² is preferably H, methyl or ethyl;

L is a halide group, a mesylate group or a tosylate group as a leaving group.

At this time, the base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5,4,0] de-7-cene (DBU), or NaOH, Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO _3, etc. may be used in equivalent or excess amounts.

As the reaction solvent, ether solvents such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide and the like may be used alone or in combination. Is the boiling point of the solvent at 0 ° C.

Meanwhile, as shown in Scheme 1, a compound represented by Formula 2aa through a nucleophilic substitution reaction, a cyclization reaction, and an amide formation reaction using a substituted benzonitryl derivative of Formula 5 as a starting material (of Formula 2a Where L is Br in the compound). At this time, the substituted benzonitrile compound of Formula 5 is o-fluorobenzonitrile, 6-chloro-2-nitrobenzonitrile or 2-chloro-3-pyridinecarbonitrile (for example, commercially available from Sigma Aldrich Korea) Etc. can be used.

In which R ² , B, n, X, W and A are as defined in Formula 1a, G is F or NO ₂ And D is OH, Br or Cl.

In the nucleophilic substitution reaction and cyclization reaction of Scheme 1, the compound of Formula 6 may be prepared by reacting with methyl substituted benzonitrile compound of Formula 5 in the presence of methyl glycolate or methyl thio glycolate and a base. . At this time, the base is an inorganic base such as sodium hydride, potassium t -butoxide, sodium methoxide, K ₂ CO ₃ , NaOAc, KOAc, NaOH, KOH, Na ₂ CO ₃ , BaCO ₃ or Cs ₂ CO ₃ Alternatively, the solvent may be used in an excess amount, and as the reaction solvent, an ether solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, DMF, or dimethyl sulfoxide may be used alone or in combination. The reaction temperature is up to the boiling point of the solvent.

In the amide formation reaction of Scheme 1, when D is a bromide group (Br) or a chloride group (Cl), the amide compound of Formula 2aa may be prepared from the compound of Formula 6 in the presence of a base, and the base used And reaction conditions are the same as in the substitution reaction in the preparation of the compound of Formula 1a. When D is a hydroxy group, 1,3-dicyclohexylcarbodimide (DCC), 1,3-diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-ethylcarbodi An amide compound of Formula 2aa may be prepared using a condensing agent such as mid (EDC) or 1,1-carbonyldiimidazole (CDI), wherein the reaction solvent is dichloromethane, chloroform, tetrahydrofuran Or DMF, and the like, and the reaction temperature is from room temperature to the boiling point of the solvent.

Meanwhile, when n is 1 in the benzofuran and benzothiophene derivatives substituted with the amide of Formula 1a, it may also be prepared by the following method. That is, benzofuran and benzothiophene derivatives substituted with amides of formula 1aa by 1,4-addition reaction of a compound of formula 4 having a double bond with an equivalent or excess of a compound of formula 3 in the presence of a suitable solvent and a base Can be obtained. In this case, the base and reaction conditions used are the same as those used in the preparation of the compound of Formula 1a.

Formula 3

Wherein R ² , B, Y, z, G, X, W and A are as defined in Formula 1a.

The compound of Formula 4 is prepared by removing the leaving group L by reacting the compound of Formula 2a (when n is 1) with an equivalent or excess of base, or the compound represented by Formula 6 of Scheme 1 and acryloyl The halide can be prepared by the amide formation reaction.

In addition, as shown in Scheme 2, the following various derivatives may be prepared through modification of the ester group from the benzofuran and benzothiophene derivatives substituted with the amide of Formula 1a.

Wherein R ² , B, n, Y, z, G, X, W and A are as defined in Formula 1a.

As shown in Scheme 2, the carboxylic acid derivative of Chemical Formula 1b may be prepared by hydrolyzing an ester group of benzofuran and a benzothiophene derivative substituted with an amide of Chemical Formula 1a with a base. In this case, the solvent may be used alone or mixed with an alcohol solvent such as methanol or an ether solvent such as tetrahydrofuran, dioxane, etc., and base may be used as a sodium hydroxide or potassium hydroxide, Silver can be used in 1 to 5 equivalents, the reaction temperature is from 0 ℃ to the boiling point of the solvent.

 In the amide forming reaction of Scheme 2, the carboxylic acid derivative of Chemical Formula 1b is reacted with a condensing agent such as DCC, DIC, EDC, and CDI, and then 2-chloroethylamine hydrochloride is reacted under an excess of base. Benzofuran and benzothiophene derivatives substituted with amides thereof may be prepared, and the reaction solvent may be an ether solvent such as tetrahydrofuran, dioxane, dichloromethane or 1,2-dimethoxyethane, DMF, dimethyl sulfoxide, or the like. May be used alone or in combination, the base may be used in equivalent or excess amounts, and the reaction temperature is from 0 ° C. to the boiling point.

In addition, in Scheme 2, the benzofuran and benzothiophene derivatives substituted with the amide of Formula 1c are subjected to an oxazolidine heterocyclic formation reaction in the presence of a base, and the benzofuran and benzothiophene derivatives substituted with the amide of Formula 1d. Can be prepared. In this case, DBU may be used as a base, and tetrahydrofuran, benzene, or toluene may be used as the solvent. The reaction temperature is from room temperature to the boiling point of the solvent.

On the other hand, the present invention provides a composition for the prevention or treatment of ischemic diseases, and a composition for long-term protection, containing benzofuran and benzothiophene derivatives substituted with amides or pharmaceutically acceptable salts thereof as an active ingredient.

The benzofuran and benzothiophene derivatives substituted with the amide according to the present invention and pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the same can be administered orally or parenterally during clinical administration and used in the form of general pharmaceutical preparations. If formulated, it may be prepared using diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants commonly used.

Solid preparations for oral administration are prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose or gelatin, with one or more aminopyrazole derivatives according to the invention. can do. In addition to simple excipients, lubricants such as magnesium stearate or talc may also be used.

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

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations or suppositories. The non-aqueous solvent or suspension may be a vegetable oil such as propylene glycol, polyethylene glycol, or olive oil, or an injectable ester such as ethyl oleate. The base of the suppository may be utopsol, macrogol, tween 61, Cacao butter, laurin butter, glycerol or gelatin and the like can be used.

In addition, the dosage to the human body of benzofuran and benzothiophene derivatives substituted with the amides of the present invention and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same may be determined by the age, weight, sex, dosage form, Depending on the state of health and degree of disease, based on an adult patient weighing 70 kg, it is generally 0.1 to 1000 mg / day, preferably 1 to 500 mg / day, 1 at regular time intervals It may be administered in divided doses once or several times a day.

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

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

Since the benzofuran and benzothiophene derivatives substituted with the amide of the present invention can significantly reduce ischemic cell death, the composition containing the same as an active ingredient is cerebral ischemia, cardiac ischemia, diabetic vascular heart disease, and heart failure mediated by ischemic cell death. It can be useful for the prevention and treatment of ischemic diseases such as myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, brain trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma and diabetic neurosis have.

In the present invention, the molecular structure of the compounds was confirmed by infrared spectroscopy, nuclear magnetic resonance spectra, mass spectroscopy, liquid chromatography, X-ray structure determination, photoluminescence measurement or elemental analysis of representative compounds and comparison of actual values.

Production Example

Preparation Example 1 3-Amino-benzofuran-2-carboxylic acid methyl ester

Dissolve 0.22 g (1.18 mmol) of o-fluorobenzonitrile in 5 ml of N, N-dimethylformamide, add 0.16 ml (2.18 mmol) of methyl glyconate and 0.62 g (4.54 mmol) of potassium carbonate at room temperature for 12 hours. Heat to reflux. After the reaction was completed, the reaction solution was diluted with 10 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and separated and purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1). Compound (0.10 g, 48% yield) was obtained.

¹ H NMR (300MHz, DMSO-d6): δ 3.97 (s, 3H), 4.98 (s, 2H), 7.23-7.28 (m, 1H), 7.44-7.47 (m, 2H), 7.56 (d, 1H)

Mass (m / e, M ⁺ ): 192

Preparation Example 2 3- (2-Bromo-acetylamino) -benzofuran-2-carboxylic acid methyl ester

0.75 g (3.92 mmol) of the compound obtained in Preparation Example 1 was dissolved in 5 ml of tetrahydrofuran, and 1.09 g (7.84 mmol) of bromoacetic acid and 1.21 ml (7.84 mmol) of 1,3-diisopropyl carbodiimide were stored at room temperature. After addition, it is reacted for 5 hours. After the reaction was completed, the reaction solution was diluted with 10 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and separated and purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1). (0.96 g, 79% yield) was obtained.

¹ H NMR (300MHz, DMSO-d6): δ 4.04 (s, 2H), 4.12 (s, 3H), 7.49-7.52 (m, 3H), 7.32-7.36 (m, 3H), 8.38 (d, 1H) , 10.18 (s, 1H)

Mass (m / e, M ⁺ ): 312, 314

Preparation Example 3: 3-Amino-4-chloro-benzofuran-2-carboxylic acid methyl ester

After using 513 mg (2.81 mmol) of 6-chloro-2-nitrobenzonitrile as a starting material, the reaction was carried out in the same manner as in Preparation Example 1, followed by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1). The obtained compound was obtained 222 mg (35.0%).

¹ H NMR (300 MHz, CDCl 3): δ 3.97 (s, 3H), 5.51 (brs, 2H), 7.17 (t, J = 4.2 Hz, 1H), 7.34-7.35 (m, 2H)

MS (m / e, M ⁺ ): 224

Preparation Example 4 4-Chloro-3- (2-chloro-acetylamino) -benzofuran-2-carboxylic acid methyl ester

200 mg (0.89 mmol) of the compound obtained in Preparation Example 3 was dissolved in 3 ml of tetrahydrofuran, 0.37 ml (2.67 mmol) of triethylamine and 0.18 ml (2.23 mmol) of chloro acetyl chloride were added dropwise, and the reaction mixture was purged with nitrogen. Stir for 2 hours under atmosphere. After distilling off the solvent under reduced pressure, the obtained crystal compound was washed with ether, filtered and dried to obtain 195 mg (73%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 3.94 (s, 3H), 4.43 (s, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H ), 7.81 (d, J = 7.8 Hz, 1H), 10.37 (brs, 1H).

MS (m / e, M ⁺ ): 302

Preparation Example 5 3-Acryloylamino-benzofuran-2-carboxylic acid methyl ester

640 mg (3.35 mmol) of the compound obtained in Preparation Example 1 was dissolved in 3 ml of tetrahydrofuran, 1.48 ml (10.05 mmol) of triethylamine and 0.54 ml (6.70 mmol) of acryloyl chloride were added dropwise thereto, and then the reaction mixture was added. Stirred under nitrogen atmosphere for 1 hour. The solvent was distilled off under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 4: 1), to obtain 590 mg (yield 72%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): δ 4.03 (s, 3H), 5.88 (d, 1H), 6.36 (m, 2H), 7.29 (m, 1H), 7.49 (d, 2H), 8.51 (d , 1H), 9.57 (Br, NH)

MS (m / e, M ⁺ ): 245

Preparation Example 6 3- (3-Bromo-propionylamino) -4-chloro-benzofuran-2-carboxylic acid methyl ester

241 mg (1.33 mmol) of the compound obtained in Preparation Example 3 was dissolved in 5 ml of N, N-dimethylformamide, and 0.27 ml (2.66 mmol) of 3-bromopropionyl chloride was added dropwise, and the reaction mixture was added under nitrogen atmosphere. Stir for 1 hour. After distilling off the solvent under reduced pressure, the obtained crystal compound was washed with ether, filtered and dried to obtain 372 mg (78%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 3.05 (t, J = 6.6 Hz, 2H), 3.74 (t, J = 6.6 Hz, 2H), 3.89 (s, 3H), 7.42 (d, J = 7.5 Hz, 1H), 7.55 (t, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 10.09 (brs, 1H)

MS (m / e, M ⁺ ): 360

Preparation Example 7 3-Acryloylamino-4-chloro-benzofuran-2-carboxylic acid methyl ester

200 mg (0.56 mmol) of the compound obtained in Preparation Example 6 was dissolved in 3 ml of N, N-dimethylformamide, 0.23 ml (1.67 mmol, 3.0eq) of triethylamine was added dropwise, and the reaction mixture was added under a nitrogen atmosphere for 2 hours. Was stirred. After distilling off the solvent under reduced pressure, the obtained crystal compound was washed with ether, filtered and dried to obtain 140 mg (90.9%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 3.91 (s, 3H), 5.80 (d, J = 9.9 Hz, 1H), 6.25 (d, J = 17.1 Hz, 1H), 6.47-6.56 (m , 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 10.13 (brs, 1H)

Preparation Example 8 3-Amino-Puro [2,3, -b ] pyridine-2-carboxylic acid methyl ester

After reacting in the same manner as in Preparation Example 1 using 600 mg (4.33 mmol) of 2-chloro-3-pyridinecarbonitrile as a starting material, silica gel column chromatography (hexane: ethyl acetate = 3: 1) The obtained compound was obtained 105 mg (yield 13%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): δ 3.97 (s, 3H), 5.07 (brs, 2H), 7.24-7.28 (m, 2H), 7.96 (dd, J = 7.8, 1.8 Hz, 1H), 8.51 (dd, J = 4.8, 1.8 Hz, 1H)

MS (m / e, M ⁺ ): 192

Preparation Example 9 3- (2-Chloro-acetylamino) -furo [2,3, -b ] pyridine-2-carboxylic acid methyl ester

200 mg (1.0 mmol) of the compound obtained in Preparation Example 8 was dissolved in 5 ml of N, N-dimethylformamide, and 0.17 ml (2.1 mmol, 2.0 eq) of chloro acetyl chloride was added dropwise, and the reaction mixture was added under nitrogen atmosphere for 1 hour. Was stirred. After distilling off the solvent under reduced pressure, the obtained crystal compound was washed with ether, filtered and dried to obtain 241 mg (86.4%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 3.94 (s, 3H), 4.53 (s, 2H), 7.50 (dd, J = 8.1, 4.5 Hz, 1H), 8.40 (dd, J = 8.1, 1.8 Hz, 1H), 8.57 (dd, J = 4.5, 1.8 Hz, 1H), 10.47 (brs, 1H)

MS (m / e, M ⁺ ): 268

Preparation Example 10 3-acryloyl-furo [2,3, -b ] pyridine-2-carboxylic acid methyl ester

531 mg (2.76 mmol) of the compound obtained in Preparation Example 8 were used to react in the same manner as in Preparation Example 5, whereby 208 mg (yield 31%) of the title compound was obtained.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 3.93 (s, 3H), 5.90 (dd, J = 10.2, 1.2 Hz, 1H), 6.37 (d, J = 16.8 Hz, 1H), 6.62 (dd , J = 16.8, 10.2, Hz, 1H), 7.47 (dd, J = 8.1, 4.8 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 8.77 (dd, J = 4.8, 0.9 Hz, 1H ), 10.32 (brs, 1H)

MS (m / e, M ⁺ ): 246

Preparation Example 11 3- (2-Bromo-2-phenyl-acetylamino) -benzofuran-2-carboxylic acid methyl ester

2.00 g (10.46 mmol) of the compound obtained in Preparation Example 1 were dissolved in 40 ml of dichloromethane, and 6.75 g (31.38 mmol) of bromo phenylacetic acid and 4.86 ml (31.38 mmol) of 1,3-diisopropyl carbodiimide were added at room temperature. After reacting for 24 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and separated and purified using silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the target compound (1.75). g, 43% yield).

¹ H NMR (300 MHz, DMSO): δ 4.02 (s, 3H), 5.62 (s, 1H), 7.25-7.27 (m, 1H), 7.39-7.49 (m, 5H), 7.52 (d, 2H), 8.37 (d, 1 H), 10.29 (br, NH)

Preparation Example 12 3- [2- (4-Bromo-phenylsulfanyl) -2-phenyl-acetylamino] -benzofuran-2-carboxylic acid

1.70 g (3.42 mmol) of the compound obtained in Example 9 were dissolved in 30 ml of tetrahydrofuran and 2.57 ml (5.13 mmol, 1.5eq) of 2N sodium hydroxide solution was added dropwise, and the reaction mixture was heated and stirred for 24 hours under a nitrogen atmosphere. It was. After acidification with 1 N hydrochloric acid solution, the mixture was extracted with ethyl acetate and brine, and the resulting impure compound was purified by silica gel column chromatography (10% methanol / dichloromethane) to obtain 0.75 g (yield 45%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ); δ 5.11 (s, 1H), 7.25-7.41 (m, 9H), 7.49-7.60 (m, 4H), 8.36 (d, 1H), 10.33 (br, NH)

Preparation Example 13 3- [2- (4-Bromo-phenylsulfanyl) -2-phenyl-acetylamino] -benzofuran-2-carboxylic acid (2-chloro-ethyl) -amide

700 mg (1.45 mmol) of the compound obtained in Preparation 12 were dissolved in 15 ml of tetrahydrofuran, and 471 mg (2.18 mmol) of di (2-pyridyl) carbonate and 18 mg (0.15 mmol) of 0.1 equivalent of dimethylaminopyridine were added dropwise. Thereafter, the reaction mixture was stirred for 1 hour under a nitrogen atmosphere, and then 0.60 ml (4.35 mmol) of triethylamine and 510 mg (4.35 mmol) of 2-chloroethylamine hydrochloride were added thereto, and the reaction mixture was stirred for 24 hours under a nitrogen atmosphere. . The solvent was distilled off under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 4: 1), to obtain 663 mg (yield 84%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ); δ 3.76 (t, 2H), 3.88 (t, 2H), 5.05 (s, 1H), 6.84 (t, 1H), 7.27 (d, 1H), 7.34-7.43 (m, 8H), 7.56 (d, 2H) ), 8.41 (d, 1 H), 10.93 (br, NH)

Preparation Example 14 3-Amino-benzo [ b ] thiophene-2-carboxylic acid methyl ester

Dissolve 0.90 ml (8.26 mmol) of o -fluorobenzonitrile in 6 ml of N, N-dimethylformamide, add 0.90 ml (9.91 mmol) of methyl thioglyconate and 3.42 g (24.78 mmol) of potassium carbonate at room temperature. Heat reflux for a time. After the reaction was completed, the reaction solution was diluted with 10 ml of ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and separated and purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1). (1.53 g, 89% yield) was obtained.

¹ H NMR (300 MHz, CDCl 3); δ 3.90 (s, 3H), 5.87 (br, 2H), 7.35 (t, 1H), 7.45 (t, 1H), 7.63 (d, 1H), 7.72 (d, 1H)

MS (m / e, M ⁺ ): 207

Preparation Example 15 3- (2-Bromo-acetylamino) -benzo [ b ] thiophene-2-carboxylic acid methyl ester

500 mg (2.42 mmol) of the compound obtained in Preparation Example 14 were reacted in the same manner as in Preparation Example 2, followed by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain 356 mg of the target compound ( 45.0%).

¹ H NMR (300 MHz, CDCl 3); δ 3.97 (s, 3H), 4.27 (s, 2H), 7.39 (t, 1H), 7.47 (t, 1H), 7.77 (d, 1H), 7.99 (d, 1H), 10.14 (br, NH)

MS (m / e, M ⁺ ): 327

Preparation Example 16 3-Amino-4-chloro-benzo [ b ] thiophene-2-carboxylic acid methyl ester

350 mg (1.92 mmol) of 6-chloro-2-nitrobenzonitrile were dissolved in 5 ml of N, N-dimethylformamide, 0.17 ml (1.92 mmol, 1.0 eq) of methyl thioglyconate and 192 mg (3.43 mmol) of potassium hydroxide , 1.8 eq) was added dropwise at 0 ° C., and the reaction mixture was stirred at 0 ° C. under nitrogen atmosphere for 1 hour. Ice water was poured into the reaction mixture, and the resulting crystals were filtered to obtain 404 mg (87.3%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): δ 3.86 (s, 3H), 6.85 (brs, 2H), 7.28-7.35 (m, 2H), 7.60 (dd, J = 7.5, 0.8 Hz, 1H)

MS (m / e, M ⁺ ): 241

Preparation Example 17 3- (2-Chloro-acetylamino) -4-chloro-benzo [ b ] thiophene-2-carboxylic acid methyl ester

241 mg (1.0 mmol) of the compound obtained in Preparation Example 16 was used to react in the same manner as in Preparation Example 4, whereby 117 mg (yield 37%) of the title compound was obtained.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 3.87 (s, 3H), 4.37 (s, 2H), 7.54-7.58 (m, 2H), 8.05-8.10 (m, 1H), 10.28 (brs, 1H)

MS (m / e, M ⁺ ): 317

Preparation Example 18 3-Acryloylamino-benzo [ b ] thiophene-2-carboxylic acid methyl ester

176 mg (0.85 mmol) of the compound obtained in Preparation Example 14 was dissolved in 3 ml of N, N-dimethylformamide, and 0.10 ml (1.02 mmol) of 3-bromopropionyl chloride was added dropwise, and the reaction mixture was added under nitrogen atmosphere. Stir for hours. The solvent was distilled off under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 6: 1), to obtain 68 mg (yield 31%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): δ 3.88 (s, 3H), 5.87 (dd, 1H), 6.39 (m, 2H), 7.41 (t, 1H), 7.47 (t, 1H), 7.76 (d , 1H), 8.17 (d, 1H), 9.81 (br, NH)

MS (m / e, M ⁺ ): 261

Preparation Example 19 3- (3-Bromo-propionylamino) -4-chloro-benzo [ b ] thiophene-2-carboxylic acid methyl ester

241 mg (1.0 mmol) of the compound obtained in Preparation Example 16 was dissolved in 5 ml of N, N-dimethylformamide, and 0.20 ml (2.02 mmol) of 3-bromopropionyl chloride was added dropwise, and the reaction mixture was stirred for 24 hours under a nitrogen atmosphere. Was stirred. After distilling off the solvent under reduced pressure, the obtained crystal compound was washed with ether, filtered and dried to obtain 285 mg (75.8%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 3.04 (t, J = 6.6 Hz, 2H), 3.73 (t, J = 6.6 Hz, 2H), 3.91 (s, 3H), 7.51-7.61 (m , 2H), 8.06 (d, J = 6.3, 2.7 Hz, 1H), 10.07 (brs, 1H)

Preparation Example 20 3-Acryloylamino-4-chloro-benzo [ b ] thiophene-2-carboxylic acid methyl ester

Using 458 mg (1.22 mmol) of the compound obtained in Preparation Example 19, the reaction was carried out in the same manner as in Preparation Example 7, to obtain 266 mg (yield 63%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 3.84 (s, 3H), 5.80 (d, J = 10.2 Hz, 1H), 6.25 (d, J = 17.1 Hz, 1H), 6.52 (dd, J = 17.1, 10.2 Hz, 1H), 7.51-7.58 (m, 2H), 8.07 (dd, J = 6.6, 2.1 Hz, 1H), 10.13 (brs, 1H)

Preparation Example 21 3- (2-Bromo-2-phenyl-acetylamino) -benzo [ b ] thiophene-2-carboxylic acid methyl ester

350 mg (1.69 mmol) of the compound obtained in Preparation Example 14 were used to react in the same manner as in Preparation Example 11, to obtain 232 mg (34%) of the title compound.

¹ H NMR (300 MHz, DMSO): δ 3.95 (s, 3H), 5.64 (s, 1H), 7.34 (m, 5H), 7.65 (m, 2H), 7.76 (d, 1H), 7.78 (d, 1H), 8.37 (d, 1H), 10.33 (br, NH)

MS (m / e, M ⁺ ): 405, 403

Preparation Example 22 3-Amino-thiophene [2,3, -b ] pyridine-2-carboxylic acid methyl ester methyl acid methyl ester

After using 560 mg (3.07 mmol) of 2-chloro-3-pyridinecarbonitrile as a starting material, the reaction was carried out in the same manner as in Preparation Example 14, and the solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate and brine. The solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The crystal compound was washed with ether, filtered and dried to obtain 343 mg (40.6%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): δ 3.91 (s, 3H), 5.93 (brs, 2H), 7.31 (dd, J = 8.2, 4.6 Hz, 1H), 7.93 (dd, J = 8.2, 1.6 Hz , 1H), 8.69 (dd, J = 4.6, 1.6 Hz, 1H)

MS (m / e, M ⁺ ): 208

Preparation 23: 3- (2-Chloro-acetylamino) -thiophene [2,3, -b ] pyridine-2-carboxylic acid methyl ester

208 mg (1.0 mmol) of the compound obtained in Preparation Example 22 was reacted in the same manner as in Preparation Example 9, the solvent was distilled off under reduced pressure, and the obtained crystal compound was washed with ether, filtered and dried to give 266 mg. (93.7%) of the title compound was obtained.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 3.90 (s, 3H), 4.51 (s, 2H), 7.58 (dd, J = 8.4, 4.5 Hz, 1H), 8.27 (dd, J = 8.4, 1.8 Hz, 1H), 8.79 (dd, J = 4.5, 1.8 Hz, 1H), 10.69 (brs, 1H)

MS (m / e, M ⁺ ): 284

Preparation Example 24 3-acryloylamino-thiophene [2,3, -b ] pyridine-2-carboxylic acid methyl ester

After 150 mg (0.72 mmol) of the compound obtained in Preparation Example 22, the reaction was carried out in the same manner as in Preparation Example 18, the solvent was distilled off under reduced pressure, and the obtained crystal compound was washed with ether, filtered and dried to give 266 mg. (93.7%) of the title compound was obtained.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 3.87 (s, 3H), 5.87 (dd, J = 10.2, 1.8 Hz, 1H), 6.33 (dd, J = 17.1, 1.8 Hz, 1H), 6.62 (dd, J = 17.1, 10.2, Hz, 1H), 7.55 (dd, J = 8.4, 4.8 Hz, 1H), 8.20 (dd, J = 8.4, 1.5 Hz, 1H), 8.77 (dd, J = 4.8, 1.5 Hz, 1H), 10.47 (brs, 1H)

Example

Example 1: 3- (2-phenylsulfanyl-acetylamino) -benzofuran-2-carboxylic acid methyl ester

0.20 g (0.64 mmol) of the compound obtained in Preparation Example 2 were dissolved in 4 ml of tetrahydrofuran, and 0.079 ml (0.77 mmol) of benzenethiol and 0.13 ml (0.96 mmol) of triethylamine were added dropwise, and the reaction mixture was dried under a nitrogen atmosphere. Stir for hours. The solvent was distilled off under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 4: 1), to obtain 0.18 g (yield 80%) of the title compound.

¹ H NMR (300 MHz, DMSO-d6) δ 3.86 (s, 3H), 4.07 (s, 2H), 7.24 (t, 2H), 7.29-7.47 (m, 4H), 7.53 (t, 1H), 7.69 ( t, 2H), 10.36 (s, 1H)

Mass (m / e, M ⁺ ): 342

Example 2: 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -benzofuran-2-carboxylic acid methyl ester

0.22 g (0.64 mmol) of the compound obtained in Preparation Example 2 was dissolved in 4 ml of tetrahydrofuran, 0.15 g (0.77 mmol) of 4-bromobenzenethiol and 0.13 ml (0.96 mmol) of triethylamine were added dropwise, followed by reaction mixture. Was stirred for 5 h under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 4: 1), to obtain 0.22 g (yield 84%) of the title compound.

¹ H NMR (300MHz, DMSO-d ₆ ) δ 3.73 (s, 3H), 3.94 (s, 2H), 7.18 (t, 2H), 7.28 (d, 2H), 7.38-7.43 (m, 2H), 7.53 (d, 2H), 10.23 (s, 1H)

Mass (m / e, M ⁺ ) : 412, 399

Example 3: 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -4-chloro-benzofuran-2-carboxylic acid methyl ester

0.14 g (0.46 mmol) of the compound obtained in Preparation Example 4, and 129 mg (0.88 mmol) of 4-bromo benzenethiol were reacted in the same manner as in Example 2, after which the solvent was distilled off under reduced pressure to obtain a crystalline compound The obtained product was washed with ether, filtered and dried to obtain 0.13 g (62.7%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 3.82 (s, 3H), 3.98 (s, 2H), 7.35-7.49 (m, 3H), 7.50-7.55 (m, 3H), 7.72 (d, J = 7.8 Hz, 1H), 10.25 (brs, 1H)

MS (m / e, M ⁺ ): 455

Example 4: 3- [3- (4-Bromo-phenylsulfanyl) -propionylamino] -benzofuran-2-carboxylic acid methyl ester

0.10 g (0.41 mmol) of the compound obtained in Preparation Example 5 and 93 mg (0.49 mmol) of 4-bromo benzenethiol were reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 0.13 g (yield 75%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.79 (t, 2H), 3.30 (t, 2H), 4.01 (s, 3H), 7.27 (m, 3H), 7.41 (d, 2H), 7.48 (d , 2H), 8.36 (d, 1H), 9.36 (br, NH)

MS (m / e, M ⁺ ): 434

Example 5: 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -benzofuran-2-carboxylic acid

100 mg (0.24 mmol) of the compound obtained in Example 2 was dissolved in 10 ml of tetrahydrofuran, and 0.36 ml (0.36 mmol) of 1 N sodium hydroxide solution was added dropwise, and the reaction mixture was heated and stirred for 2 hours under a nitrogen atmosphere. After acidification with 1 N hydrochloric acid solution, the mixture was extracted with ethyl acetate and brine, and the resulting impure compound was purified by column chromatography (methanol: methylene chloride = 1:10), to obtain 56 mg (yield 57%) of the title compound.

¹ H NMR (300 MHz, CD ₃ OD): δ 3.81 (s, 2H), 7.06 (t, 1H), 7.19 (m, 6H), 7.94 (d, 1H)

Example 6: 4-Chloro-3- (3- (pyridin-2-ylsulfanyl) -propionylamino] -benzofuran-2-carboxylic acid methyl ester

125 mg (0.45 mmol) of the compound obtained in Preparation Example 7 were dissolved in 3 ml of N, N-dimethylformamide, 69 mg (0.63 mmol, 1.5eq) of 2-merctopyridine and 0.06 ml (0.45 mmol, 1.0 of triethylamine). eq) was added dropwise and the reaction mixture was stirred for one day under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was separated by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1), to obtain 36 mg (yield 21%) of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 2.77 (t, J = 7.2 Hz, 2H), 3.37 (t, J = 7.2 Hz, 2H), 3.82 (s, 3H), 7.08 (t, J = 5.7 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 8.42 (d, J = 3.6 Hz, 1H), 10.17 (brs, 1H)

Example 7: 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -furo [2,3- b ] pyridine-2-carboxylic acid methyl ester

After using 109 mg (0.41 mmol) of the compound obtained in Preparation Example 9 and reacting in the same manner as in Example 2, the solvent was distilled off under reduced pressure and the obtained crystalline compound was washed with ether, filtered and dried to give 136 mg (79.8). %) Of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 3.91 (s, 3H), 4.11 (s, 2H), 7.40-7.55 (m, 3H), 7.54 (d, J = 8.7 Hz, 2H), 8.26 (d, J = 7.5 Hz, 1H), 8.54 (d, J = 4.2 Hz, 1H), 10.45 (brs, 1H)

Example 8: 3- (3- (pyridin-2-ylsulfanyl) -propionylamino] -furo [2,3- b ] pyridine-2-carboxylic acid methyl ester

After using 154 mg (0.63 mmol) of the compound obtained in Preparation Example 10, the reaction was carried out in the same manner as in Example 6, the solvent was distilled off under reduced pressure, extracted with ethyl acetate and brine, and the organic solvent layer was dried over anhydrous sodium sulfate. After filtration and distillation under reduced pressure. The resulting impure compound was purified by column chromatography (Hex: EA = 2: 1), to obtain 91 mg (40.8%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): δ 3.00 (t, J = 6.9 Hz, 2H), 3.58 (t, J = 6.9 Hz, 2H), 4.00 (s, 3H), 7.00 (m, 1H), 7.18-7.33 (m, 2H), 7.48 (m, 1H), 8.46-8.53 (m, 2H), 8.92 (dd, J = 7.8, 1.5 Hz, 1H), 9.62 (brs, 1H)

Example 9: 3- [2- (4-Bromo-phenylsulfanyl) -2-phenyl-acetylamino] -benzofuran-2-carboxylic acid methyl ester

1.75 g (4.50 mmol) of the compound obtained in Preparation Example 11 were used, and the reaction was carried out in the same manner as in Example 2, followed by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain 1.78 g of the target compound. (Yield 79%) was obtained.

¹ H NMR (300 MHz, DMSO): δ = 3.99 (s, 3H), 5.09 (s, 1H), 7.26-7.39 (m, 1H), 7.42-7.54 (m, 11H), 8.33 (s, 1H) , 10.38 (br, NH)

Example 10: 2- (4-Bromo-phenylsulfanyl) -N- [2- (4,5-dihydro-oxazol-2-yl) -benzofuran-3-yl] -2-phenyl- Acetamide

100 mg (0.18 mmol) of the compound obtained in Preparation Example 13 was dissolved in 5 ml of tetrahydrofuran, and 0.05 ml (0.27 mmol) of DBU was added dropwise, and the reaction mixture was heated to reflux for 3 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, extracted with ethyl acetate and brine, and then the organic solvent layer was dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane: ethyl acetate = 4: 1), to obtain 50 mg (53%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): δ 4.13 (t, 2H), 4.46 (t, 2H), 5.07 (s, 1H), 7.25-7.44 (m, 10H), 7.56 (d, 2H), 8.30 (d, 1H), 10.58 (br, NH)

Example 11: 3- (2-phenylsulfanyl-acetylamino) -benzo [b] thiophene-2-carboxylic acid methyl ester

100 mg (0.31 mmol) of the compound obtained in Preparation Example 15 were used, and the reaction was carried out in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain 65 mg of the target compound. (Yield 59%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 3.89 (s, 3H), 3.91 (s, 2H), 7.21 (m, 4H), 7.44 (m, 3H), 7.74 (d, 1H), 7.84 (d , 1H), 10.31 (br, NH)

MS (m / e, M ⁺ ): 357

Example 12: 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -benzo [b] thiophene-2-carboxylic acid methyl ester

100 mg (0.31 mmol) of the compound obtained in Preparation Example 15 were used, and the reaction was carried out in the same manner as in Example 2, followed by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to give 62 mg of the target compound. (Yield 46%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 3.88 (s, 2H), 3.90 (s, 3H), 7.33 (m, 6H), 7.75 (d, 1H), 7.84 (d, 1H), 10.28 (br) , NH)

MS (m / e, M ⁺ ): 435

Example 13: 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -4-chloro-benzo [b] thiophene-2-carboxylic acid methyl ester

After using 65 mg (0.21 mmol) of the compound obtained in Preparation Example 17 and reacting in the same manner as in Example 2, the solvent was distilled off under reduced pressure, and the obtained crystalline compound was washed with ether, filtered and dried to obtain 67 mg (69.8). %) Of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 3.83 (s, 3H), 3.99 (s, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.50-7.56 (m, 4H), 8.06 (dd, J = 6.9, 2.4 Hz, 1H), 10.23 (brs, 1H)

Example 14 3- (3-phenylsulfanyl-propionylamino] -benzo [b] thiophene-2-carboxylic acid methyl ester

100 mg (0.38 mmol) of the compound obtained in Preparation Example 18 were used and reacted in the same manner as in Example 1, followed by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to give 85 mg of the target compound. (Yield 60%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.83 (t, 2H), 3.33 (t, 2H), 3.93 (s, 3H), 7.23 (m, 4H), 7.40 (m, 3H), 7.49 (d , 1H), 8.07 (d, 1H), 9.49 (br, NH)

MS (m / e, M ⁺ ): 371

Example 15: 3- [3- (4-Bromo-phenylsulfanyl) -propionylamino] -benzo [b] thiophene-2-carboxylic acid methyl ester

200 mg (0.77 mmol) of the compound obtained in Preparation Example 18 were used, and the reaction was carried out in the same manner as in Example 2, followed by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give 225 mg of the target compound. (Yield 65%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.81 (t, 2H), 3.31 (t, 2H), 3.94 (s, 3H), 7.29 (m, 3H), 7.43 (m, 3H), 7.75 (d , 1H), 8.05 (d, 1H), 9.52 (br, NH)

MS (m / e, M ⁺ ): 451

Example 16: 4-Chloro-3- (3- (pyridin-2-ylsulfanyl) -propionylamino] -benzo [ b ] thiophene-2-carboxylic acid methyl ester

206 mg (0.69 mmol) of the compound obtained in Preparation Example 20 were used, and the reaction was carried out in the same manner as in Example 6, followed by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give 60 mg of the target compound. (Yield 21%) was obtained.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 2.82 (t, J = 7.2 Hz, 2H), 3.42 (t, J = 7.2 Hz, 2H), 3.86 (s, 3H), 7.14 (t, J = 6.4 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.52-7.57 (m, 2H), 7.66 (td, J = 7.8, 1.7 Hz, 1H), 8.06 (dd, J = 6.4, 2.6 Hz, 2H), 8.48 (d, J = 4.8 Hz, 1H), 9.96 (brs, 1H)

Example 17: 3- [2- (4-Bromo-phenylsulfanyl) -2-phenyl-acetylamino] -benzo [b] thiophene-2-carboxylic acid methyl ester

150 mg (0.37 mmol) of the compound obtained in Preparation Example 21 were used, and the reaction was carried out in the same manner as in Example 2, followed by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give the title compound 60 mg (yield 21%) were obtained.

¹ H NMR (300 MHz, CDCl ₃ ): δ 3.87 (s, 3H), 5.12 (s, 1H), 7.26 (m, 9H), 7.58 (d, 2H), 7.75 (dd, 2H), 10.34 (br) , NH)

MS (m / e, M ⁺ ): 513, 511

Example 18: 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -thieno [2,3- b ] pyridine-2-carboxylic acid methyl ester

After using 143 mg (0.50 mmol) of the compound obtained in Preparation Example 23 and reacting in the same manner as in Example 2, the solvent was distilled off under reduced pressure and the obtained crystalline compound was washed with ether, filtered and dried to give 158 mg (71.8). %) Of the title compound.

¹ H NMR (300 MHz, DMSO- d ₆ ): δ 3.85 (s, 3H), 4.06 (s, 2H), 7.43 (d, J = 8.7 Hz, 2H), 7.50-7.56 (m, 3H), 8.00 (dd, J = 8.1, 1.5 Hz, 1H), 8.75 (dd, J = 4.5, 1.5 Hz, 1H), 10.57 (brs, 1H)

MS (m / e, M ⁺ ): 438

Example 19: 3- (3- (pyridin-2-ylsulfanyl) -propionylamino] -thieno [2,3- b ] pyridine-2-carboxylic acid methyl ester

108 mg (0.42 mmol) of the compound obtained in Preparation Example 24 were used and the reaction was carried out in the same manner as in Example 6, followed by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain 34 mg of the target compound. (Yield 22%) was obtained.

¹ H NMR (300 MHz, CD ₃ OD): δ 2.98 (t, J = 6.9 Hz, 2H), 3.55 (t, J = 6.9 Hz, 2H), 3.91 (s, 3H), 7.08 (t, J = 5.7 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.46 (dd, J = 8.3, 4.6 Hz, 1H), 7.61 (m, 1H), 8.27 (dd, J = 8.3, 1.5 Hz, 1H), 8.41 (d, J = 4.8 Hz, 1H), 8.67 (dd, J = 4.6, 1.5 Hz, 1H)

MS (m / e, M ⁺ ): 373

Test Example

For benzofuran and benzothiophene derivatives substituted with amides according to the present invention

The following experiments were conducted and various pharmacological effects were evaluated.

Test Example 1 Inhibitory Effect on Ischemic Cell Death

In order to measure the ischemic cell death inhibitory effect of benzofuran and benzothiophene derivatives substituted with the amide of the present invention, the following experiment was performed.

Cardiomyocyte H9c2 cells (ATCC, CRL-1446) were cultured in DMEM (Dulbecco's modified Eagle's medium) medium supplemented with 10% fetal bovine serum and 1% penicillin / streptomycin (100 × solution). Diameter such that 35 ㎜ cell number 1 × 10 ⁴ in the dish, and the cells were incubated 48 hours at 37 ℃, CO ₂ incubator. Treat only DMSO (0.1%) (control), or dispense a solution of the derivatives (10 μM) of Examples 1 to 19 in DMSO and wash once with PBS after 30 minutes, and then a chemical hypoxia solution. (106 mmol NaCl, 4.4 mmol KCl, 1 mmol mgCl ₂ , 38 mmol NaHCO ₃ , 2.5 mmol CaCl ₂ , 20 mmol 2-deoxy glucose, 1 mmol NaCN)] or 10 μM of the derivative in DMSO (control) or DMSO The solution was dissolved for 1 to 2 hours while measuring the degree of cell damage under a microscope, and when appropriate damage occurred, washed twice with 1 ml of PBS, and then treated with 1 ml of 3.7% formaldehyde to fix the cells. It was. This was again washed with 1 ml of PBS and stained with DAPI (4 ', 6-diamidino-2-phenylindole), washed three times with 1 ml of PBS, followed by fluorescence microscopy to observe cell death and percentage of observed cell death. Converted to, and the results are shown in Table 2 and FIG. In the results of Table 2 and FIG. 1 below, "control" represents a group treated with DMSO only, and "cell" represents a group not treated with DMSO.

As can be seen in Table 2 and Figure 1, benzofuran and benzothiophene derivatives substituted with amides used in the present invention showed a strong inhibitory effect on ischemic cell death.

Test Example 2 Effects of Amide-Substituted Benzofuran and Benzothiophene Derivatives on the Brain Disorder Model of Transient Cerebral Ischemia in Rats

In order to measure the brain ischemia inhibitory effects of benzofuran and benzothiophene derivatives substituted with amides, the following experiments were conducted.

200-250 g of adult male Sprague-Dawley rats were anesthetized with 75 mg / kg of ketamine and 5 mg / kg of rumpun and 4 animals were assigned to each group. It was. The midline of the neck was dissected to separate the external carotid artery (ECA) and the internal carotid artery (ICA) located outside the cranial cavity. Next, the middle cerebral artery (MCA) was ligated by pushing a 0.37 mm diameter nylon thread from the comalon carotid artery (CCA) to the inner carotid artery (ICA) by about 20 to 22 mm. An interruption of blood supply through vascular occlusion of the middle cerebral artery was maintained for 2 hours to induce stroke due to ischemia. The body temperature of the rat was kept constant at 37.8 ℃ throughout the experimental period. After 6 hours of ischemia, 30 mg / kg of the compound of Example 2 was intraperitoneally administered. After 28 days of stroke induction, images of the stroke model were obtained using a 3.0-T, 65-cm aperture superconductung MRI apparatus manufactured by the present inventors. Photographing was performed using a fast spin-echo (FSE) method. The imaging parameters were repetition time (TR) 4000 msec and echo time 96 msec, and 15 sections of 2 mm thickness were used. The field of view (FOV) was 60 mm and the resolution was 128 × 128. Three duplicates were taken, and the volume of the infarct was measured with Osiris (Osiris ver. 4.02).

On the other hand, in the comparative example, a compound represented by the following formula (7) (KR-31378, Korea Research Institute of Chemical Technology) known to have a conventional cerebral infarction inhibitory ability as a comparative substance (Lee, MH et al ., Res . Commun . Mol . Pathol . Pharmacol . 110: 361-370, 2001; Hong, KW et a l., J. Pharmacol. Exp. Ther. 301: 210-216, 2002) was treated in the same manner as the derivative and the volume (%) of cerebral infarction was measured, and the results are shown in Table 3 and FIG. 2. In the results of Table 3 and FIG. 2 below, 'control' refers to the group treated with DMSO only.

From the results of Table 3 and FIG. 2, benzofuran and benzothiophene derivatives substituted with amides used in the present invention showed a strong inhibitory effect on cerebral ischemic cell death in a brain disorder model of transient cerebral ischemia in rats.

Although a method for preparing a formulation containing benzofuran and benzothiophene derivatives substituted with amides according to the present invention as active ingredients is exemplified below, the present invention is not necessarily limited thereto.

Formulation Example 1 Tablet (Direct Pressing)

After sifting 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and prepared under pressure and purification.

Formulation Example 2: Tablet (Wet Granulation)

After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved, mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate, and prepared by pressurized purification.

Formulation Example 3: Powders and Capsules

After sieving 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was prepared using a suitable apparatus. Filled in 5 gelatin capsules.

Formulation Example 4: Injection

Injectables were prepared by containing 100 mg as the active ingredient, followed by 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

1 is a result of measuring the degree of apoptosis of the benzofuran and benzothiophene derivatives substituted with the amide of the present invention inhibit hypoxia induced ischemic cell death.

Figure 2 shows the results of measuring the inhibition of cerebral infarction induced by cerebral ischemia of the benzofuran and benzothiophene derivatives substituted with the amide of the present invention in comparison with the comparative example and the control.

Claims (8)

A compound represented by formula (1) or a pharmaceutically acceptable salt thereof: Formula 1

Where R ¹ is —CO ₂ R ² , or

R ² is, independently from each other, H, or C ₁ to C ₆ straight, branched or cyclic alkyl; Y is S; Z is H or halogen; G is CH or N, provided that when G is CH, Z is halogen; X is O or S; W is H or halogen; A is CH or N; B is H, phenyl, provided that when B is phenyl, A and X are CH and S, respectively; n is 0 or 1, provided that when n is 1, G is N. The method of claim 1, R ² is independently of each other H, methyl or ethyl, or a pharmaceutically acceptable salt thereof. The method of claim 1, A compound or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of: 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -benzofuran-2-carboxylic acid methyl ester; 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -4-chloro-benzofuran-2-carboxylic acid methyl ester; 3- [2- (4-Bromo-phenylsulfanyl) -acetylamino] -benzofuran-2-carboxylic acid; 4-chloro-3- (3- (pyridin-2-ylsulfanyl) -propionylamino] -benzofuran-2-carboxylic acid methyl ester; 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -puro [2,3- b ] pyridine-2-carboxylic acid methyl ester; 3- (3- (pyridin-2-ylsulfanyl) -propionylamino] -furo [2,3- b ] pyridine-2-carboxylic acid methyl ester; 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -benzo [b] thiophene-2-carboxylic acid methyl ester; 3- [2- (4-bromo-phenylsulfanyl) -2-phenyl-acetylamino] -benzo [b] thiophene-2-carboxylic acid methyl ester; 3- [2- (4-bromo-phenylsulfanyl) -acetylamino] -thio [2,3- b ] pyridine-2-carboxylic acid methyl ester; And 3- (3- (pyridin-2-ylsulfanyl) -propionylamino] -thieno [2,3- b ] pyridine-2-carboxylic acid methyl ester. A process for preparing a compound according to claim 1, wherein the compound of formula 2 is reacted with a compound of formula 3 to obtain a compound of formula 1 Formula 2

Formula 3

Formula 1

Wherein R ¹ , B, n, Y, z, G, X, W and A are as defined in claim 1 and L is a leaving group. A pharmaceutical composition for preventing or treating ischemic disease, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The method of claim 5, wherein Ischemic disease is mediated by ischemic cell death, cerebral ischemia, cardiac ischemia, diabetic heart disease, heart failure, myocardial hypertrophy, retinal ischemia, ischemic colitis, ischemic acute renal failure, stroke, brain trauma, Alzheimer's disease, Parkinson's disease, neonatal hypoxia, glaucoma And diabetic neuropathy. The method of claim 6, Pharmaceutical composition, characterized in that ischemic cell death is induced by hypoxic conditions. delete

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