WO2015192672A1 - Benzofuran derivative, preparation method therefor, and application thereof - Google Patents

Abstract

Disclosed are a benzofuran derivative having a structure represented by general formula I or a pharmaceutically acceptable salt thereof, a preparation method therefor, and an application thereof in preparation of antiarrhythmic drugs. The definitions of the groups are as described in the specification.

Description

Benzofuran derivative, preparation method and application thereof Technical field

The present invention relates to the field of medicine, and in particular, the present invention relates to a benzofuran derivative or a pharmaceutically acceptable salt thereof, a process for producing the derivative, a pharmaceutical composition comprising the derivative, and the derivative and Use of a pharmaceutical composition for the preparation of an antiarrhythmic drug and a treatment related disorder.

Background technique

Amiodarone is a benzofuran derivative and is used for the prevention and treatment of ventricular arrhythmia and atrial fibrillation. It has been used as an antiarrhythmic drug for more than 40 years. Since the molecular structure of amiodarone contains 2 iodine atoms, accounting for 37.2% of its relative molecular mass, about 5% to 28% of patients have thyroid dysfunction after 2 to 3 months of treatment. The long-term use of amiodarone increases the risk of adverse reactions, among which lung toxicity is the most common, the incidence rate is 1% to 17%, and interstitial pneumonia or allergic pneumonia occurs after 3 to 12 months of continuous medication.

Dronedarone (SR33589) is a Class III antiarrhythmic drug developed by Sanofi-Aventis, France. It was approved for marketing in the United States on July 1, 2009 and approved by the European Union EMEA on December 16, 2009. It is suitable for heart rhythm control, maintenance of sinus rhythm and slowing ventricular rhythm in patients with atrial fibrillation (AF) and atrial flutter (AFL). It is mainly used for the treatment of arrhythmia. Dronedarone is a derivative of benzofuran similar in structure to Amiodarone and has an electrophysiological effect similar to that of amiodarone.

Clinical studies have shown that dronedarone has certain effects of class I, class II and class IV antiarrhythmic drugs, inhibiting sodium, potassium and calcium influx, and also antagonizing alpha and beta adrenergic receptors. Unlike amiodarone, dronedarone rarely affects thyroid receptors, treats atrial fibrillation and atrial flutter, maintains sinus rhythm, and is well tolerated. This has been a large-scale clinical practice. Test confirmed.

Dronedarone hydrochloride is almost insoluble in water, and its bioavailability is relatively poor, only 15% to 20%. This is due to the obvious first-pass effect of the liver, which can increase the blood concentration by 2 to 3 times with food. Druidron hydrochloride is widely metabolized in the human body after oral administration, mainly by CYP3A4 metabolism. Debutyl butyl dronedarone (SR35021) is the main metabolite, which is equivalent to the blood concentration of dronedarone. SR35021 has antiarrhythmic, electrophysiological and hemodynamic activities similar to that of dronedarone, but its activity is 3 to 10 times weaker than that of dronedarone. Recent studies have shown heart failure with severe heart failure or new hospitalization The risk of death from dronedarone hydrochloride was at least doubled in patients; in addition, dronedarone hydrochloride may cause severe liver damage.

The structure of amiodarone, dronedarone and debutylcyclodine is shown in the figure below:

In order to overcome the disadvantages of poor water solubility of dronedarone hydrochloride, prone to liver first pass effect in vivo and low oral bioavailability, the present invention has modified the structure of dronedarone hydrochloride by using a five- or six-membered ring. The amine replaces the dibutylamine group of dronedarone hydrochloride. The results show that the compounds of the present invention have better water solubility than dronedarone hydrochloride, and most of the compounds have better in vitro stability and antiarrhythmic effects than dronedarone hydrochloride. Therefore, the present invention is expected to develop a more effective antiarrhythmic drug.

Summary of the invention

A first object of the present invention is to provide a benzofuran derivative represented by the formula I or a pharmaceutically acceptable salt thereof:

among them:

R ₁ , R ₂ and R ₃ are a hydrogen atom, a halogen, a cyano group or a trifluoromethyl group;

n is 2 or 3;

A is -(CH ₂ ) _m - or -(CH ₂ ) _m -O-, wherein m is 1 or 2;

R ₄ is a hydrogen atom, a hydroxyl group, a C _1-4 alkyl group or a halogen-substituted C _1-4 alkyl group.

Preferably,

The R ₁ , R ₂ and R ₃ groups are a hydrogen atom, a fluorine atom, a cyano group or a trifluoromethyl group;

The R ₄ group is a hydrogen atom, a hydroxyl group or a methyl group.

The group A is -CH ₂ -, -CH ₂ CH ₂ - or -CH ₂ -O-;

Preferably, the compounds of the invention are:

2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[4-[3-(morpholinyl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[4-[3-(pyrrolidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

(R)-2-butyl-3-[4-[3-(3-hydroxypyrrolidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[4-[3-(2,6-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[4-[3-(3,5-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[4-[2-(piperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[4-[2-(2,6-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[4-[2-(3,5-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[3-fluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[3-fluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[3-fluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[3,5-difluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[3,5-difluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[3,5-difluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

2-butyl-3-[3,5-difluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylamino-6-trifluoromethyl Benzofuran;

2-butyl-3-[3-trifluoromethyl-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylamino-6-fluorobenzofuran ;with

2-Butyl-3-[3,5-dicyano-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran.

The salt of the benzofuran derivative of the present invention is a salt of a benzofuran derivative of the above formula I and an organic acid or an inorganic acid.

The compound represented by the formula I may form a pharmaceutically acceptable salt with a mineral acid, such as a sulfate, a phosphate, a hydrochloride or a hydrobromide salt; or may form a pharmaceutically acceptable salt with an organic acid, such as an acetate or an oxalate. Citrate, succinate, gluconate, tartrate, p-toluenesulfonate, besylate, methanesulfonate, benzoate, lactate, maleate, and the like. Preferred is the hydrochloride salt.

A second object of the present invention is to provide a process for producing a benzofuran derivative represented by the formula I or a pharmaceutically acceptable salt thereof.

The benzofuran derivative of the present invention or a pharmaceutically acceptable salt thereof: the preparation method comprises the following steps:

(1) reacting a compound of formula II with thionyl chloride to form a compound of formula III:

(2) The compound of the formula IV is reacted with a compound of the formula IV under the action of anhydrous aluminum trichloride to form a compound of the formula V:

(3) reacting a compound of the formula V with 1-chloro-3-bromopropane or 1,2-dibromoethane to form a compound of the formula VI (X represents a chlorine atom or a bromine atom):

(4) reacting a compound of formula VI with the corresponding amine to form a compound of formula VII:

(5) Reduction of the nitro group of the compound of the formula VII to give a compound of the formula VIII:

(6) reacting a compound of formula VIII with methanesulfonyl chloride to form a compound of formula I:

among them:

R ₁ , R ₂ and R ₃ are a hydrogen atom, a halogen, a cyano group or a trifluoromethyl group;

n is 2 or 3;

A is -(CH ₂ ) _m - or -(CH ₂ ) _m -O-, wherein m is 1 or 2;

R ₄ is a hydrogen atom, a hydroxyl group, a C _1-4 alkyl group or a halogen-substituted C _1-4 alkyl group.

A third object of the present invention is to provide a pharmaceutical composition comprising at least one benzofuran derivative represented by the formula I or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition of the present invention may also be added with one or more pharmaceutically acceptable carriers or excipients as needed.

The pharmaceutical composition of the present invention, the benzofuran derivative represented by the formula I or a pharmaceutically acceptable salt thereof may be in an amount of from 0.1 to 99.9% by weight, the balance being a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention can be prepared into any pharmaceutically acceptable dosage form, including: tablets, sugar-coated tablets, film-coated tablets, enteric coated tablets, capsules, hard capsules, soft capsules, orally. Liquid, buccal, granules, granules, pills, powders, ointments, dans, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches . The preparation of the present invention is preferably an oral dosage form such as a capsule, a tablet, an oral solution, a granule, a pill, a powder, an agent, a paste or the like.

The route of administration of the present invention may be oral, parenteral or topical, preferably oral and injectable. The pharmaceutically acceptable oral administration preparation may be in the form of a tablet, a capsule, a granule or other pharmaceutically acceptable liquid form preparation such as a solution, an emulsion, a suspension or the like. Preferred oral formulations are tablets, and the tablets may be in the form of a coating, enteric, sustained release or quantitative release.

The pharmaceutical composition of the present invention, which is orally administered, may contain conventional excipients such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent, and a moisturizing agent. The tablets can be coated if necessary.

Suitable fillers include cellulose, mannitol, lactose and other similar fillers. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

Solid oral compositions can be prepared by conventional methods such as mixing, filling, tableting, and the like. Repeated mixing allows the active material to be distributed throughout those compositions that use large amounts of filler.

The oral liquid preparation may be in the form of, for example, an aqueous or oily suspension, solution, emulsion, syrup or elixir, or may be a dry product which may be formulated with water or other suitable carrier before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats. Emulsifiers such as lecithin, sorbitan monooleate or gum arabic; non-aqueous carriers (they may include edible Oil), for example, almond oil, fractionated coconut oil, an oily ester of an ester such as glycerol, propylene glycol or ethanol; a preservative such as p-hydroxybenzyl or propylparaben or sorbic acid, and if desired, may be conventional Aroma or colorant.

For injection, the liquid unit dosage form prepared contains the active substance of the invention and a sterile vehicle. This compound can be suspended or dissolved depending on the carrier and concentration. The solution is usually prepared by dissolving the active substance in a carrier, sterilizing it by filtration before filling it into a suitable vial or ampoule, and then sealing. Excipients such as a local anesthetic, preservative and buffer may also be dissolved in such a carrier. To increase its stability, the composition can be frozen after filling the vial and the water removed under vacuum.

The pharmaceutical composition of the present invention may optionally be added to a suitable pharmaceutically acceptable carrier when prepared as a medicament, the pharmaceutically acceptable carrier being selected from the group consisting of: mannitol, sorbitol, sodium metabisulfite, sodium hydrogen sulfite, sulfur Sodium sulfate, cysteine hydrochloride, thioglycolic acid, methionine, vitamin C, disodium EDTA, calcium EDTA, monovalent alkali metal carbonate, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid , phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and their derivatives , alginate, gelatin, polyvinylpyrrolidone, glycerin, earth temperature 80, agar, calcium carbonate, calcium hydrogencarbonate, surfactant, polyethylene glycol, cyclodextrin, β-cyclodextrin, phospholipids, Kaolin, talc, calcium stearate, magnesium stearate, and the like.

The compound of the present invention or a pharmaceutically acceptable salt thereof can be administered alone or in the form of a pharmaceutical composition. The pharmaceutical composition of the present invention can be formulated into various suitable dosage forms depending on the route of administration. The use of one or more physiologically acceptable carriers, including excipients and auxiliaries, facilitates processing of the active compounds into preparations which may be employed in pharmaceutical compositions. The appropriate form of formulation will depend on the route of administration chosen and may be prepared according to common general knowledge in the art.

A fourth object of the present invention is to provide a use of a benzofuran derivative or a pharmaceutically acceptable salt thereof for the preparation of an antiarrhythmic drug.

A fifth object of the present invention is to provide a pharmaceutical composition using a benzofuran derivative or a pharmaceutically acceptable salt thereof as an active ingredient for the preparation of an antiarrhythmic drug.

The benzofuran derivative or the pharmaceutically acceptable salt thereof of the invention has better water solubility than dronedarone hydrochloride, and has better in vitro stability and antiarrhythmic effect than dronedarone hydrochloride.

detailed description

The technical solutions of the present invention are further illustrated by the following specific embodiments, and the exemplary embodiments are illustrative of the present invention and are not intended to limit the scope of the invention.

Preparation Example 1 2-Butyl-3-[4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran

2-Butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (33.94 g, 100 mmol) was added to 300 ml of a 95% aqueous acetonitrile solution and potassium carbonate (27.64 g, 200 mmol) and tetrabutyl Ammonium bromide (1.61 g, 5 mmol), heated under reflux for 20 min, added 1-bromo-3-chloropropane (17.32 g, 110 mmol), and refluxed for 17 h. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with a small amount of acetonitrile. The filtrate was concentrated, and the residue was purified (jjjjjjjjjjjjjjj

Preparation Example 2 2-Butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran

2-Butyl-3-[4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran (8.32 g, 20 mmol) was dissolved in 60 ml of acetonitrile and piperidine (2.56 g, 30 mmol), potassium carbonate (8.29 g, 60 mmol) and potassium iodide (0.33 g, 2 mmol), and refluxed for 24 h, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with a small amount of acetonitrile, and the filtrate was concentrated. The residue was dissolved in EtOAc (EtOAc) (EtOAcjjjjjj 87%.

PREPARATIVE EXAMPLE 3 2-Butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran

2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran (4.65 g, 10 mmol) was dissolved in 45 mL absolute ethanol Among them, 0.93 g of palladium carbon was added, and the reaction system was charged and discharged three times with hydrogen, and reacted at 50 ° C for 16 hours under hydrogen gas. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with a small portion of anhydrous ethanol, and the filtrate was concentrated to give 4.15 g of a yellow oil.

PREPARATIVE EXAMPLE 4 2-Butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran

2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran (2.26 g, 5 mmol) was dissolved in 23 mL of dichloromethane Add sodium hydrogencarbonate (1.26 g, 15 mmol), and slowly add methanesulfonyl chloride (0.86 g, 7.5 mmol) under stirring, and react at room temperature for 6 h. The reaction solution was washed with water (30 ml×2), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The yield was 71%, LC-MS: m/z 513.3 [M+H] ⁺ .

Example 1 2-Butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran hydrochloride (I1)

2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran (2.05 g, 4 mmol) was dissolved in 10 mL of acetic acid To the ethyl ester, 1.1 g of a 20% aqueous solution of isopropyl alcohol was added dropwise, and the mixture was stirred at room temperature for 2 hr.

^{1 H NMR (400MHz, DMSO-} d 6): δ = 0.80 (t, J = 7.2Hz, 3H), 1.21-1.26 (m, 2H), 1.37-1.40 (m, 1H), 1.61-1.72 (m, 3H), 1.79-1.91 (m, 4H), 2.27 (d, J = 6.0 Hz, 2H), 2.29-2.89 (m, 7H), 3.17-3.18 (m, 2H), 3.43-3.46 (m, 3H) , 4.18 (t, J = 5.6 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.21-7.27 (m, 2H), 7.61 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 9.64 (s, 1H), 9.64 (s, 1H), 10.73 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 13.87, 21.87, 22.07, 22.76, 23.60, 27.64, 29.89, 39.08, 52.43, 53.67, 65.99, 112.09, 113.70, 114.96, 116.85, 119.33, 127.69, 131.61, 131.85, 134.75, 150.79, 162.69, 165.16, 189.68.

Preparation Example 5 2-Butyl-3-[4-[3-(morpholino)propoxy]benzoyl]-5-nitrobenzofuran

According to the procedure described in Preparation Example 2, only piperidine was changed to morpholine in a yield of 82%.

PREPARATIVE EXAMPLE 6 2-Butyl-3-[4-[3-(morpholino)propoxy]benzoyl]-5-aminobenzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. It was 2-butyl-3-[4-[3-(morpholinyl)propoxy]benzoyl]-5-nitrobenzofuran in a yield of 91%.

PREPARATIVE EXAMPLE 7 2-Butyl-3-[4-[3-(morpholino)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[4-[3-(morpholino)propoxy]benzoyl]-5-aminobenzofuran, yield 68%, LC-MS: m/z 515.3 [M +H] ⁺ .

Example 2 2-Butyl-3-[4-[3-(morpholinyl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran hydrochloride (I2)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl ]]-5-Methanesulfonylaminobenzofuran was changed to 2-butyl-3-[4-[3-(morpholinyl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran The yield is 90%.

^{1 H NMR (400MHz, DMSO-} d 6): δ = 0.81 (t, J = 7.2Hz, 3H), 1.21-1.28 (m, 2H), 1.62-1.69 (m, 2H), 2.24-2.31 (m, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.89 (s, 3H), 3.05-3.12 (m, 2H), 3.26-3.28 (m, 2H), 3.37-3.47 (m, 2H), 3.85 -3.97 (m, 4H), 4.20 (t, J = 5.6 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 7.21-7.27 (m, 1H), 7.28 (s, 1H), 7.61 ( d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 9.62 (s, 1H), 11.01 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 13.87, 22.07, 23.31, 27.64, 29.89, 39.08, 51.48, 53.76, 63.61, 65.91, 112.09, 113.71, 114.97, 116.85, 119.33, 127.69, 131.63, 131.86, 134.74, 150.79, 162.68, 165.18, 189.69.

PREPARATIVE EXAMPLE 8 2-Butyl-3-[4-[3-(pyrrolidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran

According to the procedure described in Preparation Example 2, the piperidine was changed to pyrrolidine in a yield of 84%.

PREPARATIVE EXAMPLE 9 2-Butyl-3-[4-[3-(pyrrolidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. It was 2-butyl-3-[4-[3-(pyrrolidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran in a yield of 87%.

PREPARATIVE EXAMPLE 10 2-Butyl-3-[4-[3-(pyrrolidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[4-[3-(pyrrolidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran, yield 63%, LC-MS: m/z 499.2 [M+H] ⁺ .

Example 3 2-Butyl-3-[4-[3-(pyrrolidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran hydrochloride (I3)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran Change to 2-butyl-3-[4-[3-(pyrrolidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran in a yield of 88%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 0.79 (t, J = 7.2 Hz, 3H), 1.20 - 1.25 (m, 2H), 1.64 (t, J = 7.2 Hz, 2H), 1.88-1.91 (m, 2H), 1.98-2.21 (m, 2H), 2.23 - 2.24 (m, 2H), 2.78-2.82 (m, 2H), 2.89 (s, 3H), 3.00-3.02 (m, 2H), 3.28 -3.30 (m, 2H), 3.53-3.54 (m, 2H), 4.18-4.21 (m, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.22 - 7.28 (m, 2H), 7.61 (d) , J = 8.8 Hz, 1H), 7.78 (d, J = 8.8 Hz, 2H), 9.66 (s, 1H), 11.25 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 13.86, 22.07, 23.22, 25.54, 27.64, 29.88, 39.07, 51.23, 53.27, 65.83, 112.08, 113.72, 114.96, 116.84, 119.84, 127.69, 131.58, 131.85, 134.75, 150.79, 162.70, 165.15, 189.68.

PREPARATIVE EXAMPLE 11 2-Butyl-3-[4-(3-chloropropoxy)benzoyl]-5-aminobenzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. It was 2-butyl-3-[4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran in a yield of 90%.

PREPARATIVE EXAMPLE 12 2-Butyl-3-[4-(3-chloropropoxy)benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[4-(3-chloropropoxy)benzoyl]-5-aminobenzofuran in a yield of 72%.

PREPARATIVE EXAMPLE 13 (R)-2-Butyl-3-[4-[3-(3-hydroxypyrrolidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran

According to the procedure described in Preparation Example 2, except that the piperidine was changed to (R)-3-(+)-hydroxypyrrolidine in a yield of 78%, LC-MS: m/z 515.3 [M+H] ⁺ .

Example 4 (R)-2-Butyl-3-[4-[3-(3-hydroxypyrrolidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran salt Acid salt (I4)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran Changed to (R)-2-butyl-3-[4-[3-(3-hydroxypyrrolidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran The rate is 93%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 0.79 (t, J = 7.2 Hz, 3H), 1.18-1.27 (m, 2H), 1.60-1.68 (m, 2H), 1.85-2.00 (m, 1H), 2.21-2.23 (m, 2H), 2.80 (t, J = 7.2 Hz, 2H), 2.97 (s, 3H), 3.15-3.16 (m, 1H), 3.17-3.22 (m, 2H), 3.24 -3.44(m,3H),3.63-3.66(m,2H),4.16-4.21(m,2H),4.41-4.45(m,1H),7.09(d,J=7.2Hz,2H),7.22-7.28 (m, 2H), 7.61 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 9.66 (s, 1H), 11.45 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 13.86, 22.07, 25.44, 27.64, 29.88, 39.08, 52.30, 53.28, 60.60, 61.13, 65.78, 68.81, 112.07, 113.74, 114.96, 116.85, 119.36, 127.69, 131.59, 131.84, 134.75, 150.79, 162.70, 165.13, 189.68.

PREPARATIVE EXAMPLE 14 2-Butyl-3-[4-[3-(2,6-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran

According to the procedure described in Preparation Example 2, the piperidine was changed to 2,6-dimethylpiperidine in a yield of 80%.

PREPARATIVE EXAMPLE 15 2-Butyl-3-[4-[3-(2,6-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. Is 2-butyl-3-[4-[3-(2,6-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran in a yield of 89 %.

PREPARATIVE EXAMPLE 16 2-Butyl-3-[4-[3-(2,6-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[4-[3-(2,6-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran, yield 65%, LC-MS: m/z 541.3 [M+H] ⁺ .

Example 5 2-Butyl-3-[4-[3-(2,6-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran salt Acid salt (I5)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran Changed to 2-butyl-3-[4-[3-(2,6-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran The rate is 90%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 0.79 (t, J = 7.2 Hz, 3H), 1.18-1.27 (m, 2H), 1.30-1.32 (m, 1H), 1.35-1.36 (m, 5H), 1.50-1.63 (m, 2H), 1.64-1.70 (m, 3H), 1.81 (s, 3H), 2.10 (s, 2H), 2.80 (t, J = 7.2 Hz, 2H), 2.89 (s , 3H), 3.28-3.29 (m, 4H), 4.24 - 4.25 (m, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 4.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 9.66 (s, 1H), 10.85 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 13.86, 17.18, 17.97, 20.92, 22.08, 22.61, 25.34, 27.66, 29.88, 31.79, 39.08, 44.13, 58.02, 60.37, 65.49, 112.07, 113.73, 114.92, 116.84, 119.33, 127.69, 131.65, 131.89, 134.77, 150.80, 162.63, 165.16, 189.68.

PREPARATIVE EXAMPLE 17 2-Butyl-3-[4-[3-(3,5-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran

According to the procedure described in Preparation Example 2, only piperidine was changed to 3,5-dimethylpiperidine in a yield of 83%.

PREPARATIVE EXAMPLE 18 2-Butyl-3-[4-[3-(3,5-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. Is 2-butyl-3-[4-[3-(3,5-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran in a yield of 93 %.

PREPARATIVE EXAMPLE 19 2-Butyl-3-[4-[3-(3,5-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[4-[3-(3,5-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran, yield 62%, LC-MS: m/z 541.3 [M+H] ⁺ .

Example 6 2-Butyl-3-[4-[3-(3,5-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran salt Acid salt (I6)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran Changed to 2-butyl-3-[4-[3-(3,5-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran The rate is 92%.

^{1 H NMR (400MHz, DMSO-} d 6): δ = 0.80 (t, J = 7.2Hz, 3H), 0.88-0.93 (m, 6H), 1.20-1.26 (m, 2H), 1.61-1.69 (m, 2H), 1.72-1.75 (m, 1H), 2.09-2.10 (m, 2H), 2.28-2.32 (m, 2H), 2.41-2.47 (m, 2H), 2.81 (t, J = 7.2 Hz, 2H) , 2.89 (s, 3H), 3.15-3.20 (m, 2H), 3.36-3.39 (m, 3H), 4.19 (t, J = 6.0 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.23 (dd, J = 2.0, 8.8 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 9.66 (s, 1H), 11.10 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 13.87, 18.78, 22.07, 23.58, 27.65, 28.61, 29.89, 39.08, 39.34, 53.91, 57.39, 66.02, 112.08, 113.72, 114.96, 116.85, 119.35, 127.69, 131.60, 131.85, 134.76, 150.79, 162.70, 165.14, 189.67.

Preparation Example 20 2-Butyl-3-[4-(2-bromoethoxy)benzoyl]-5-nitrobenzofuran

2-Butyl-3-[4-hydroxybenzoyl]-5-nitrobenzofuran (20.36 g, 60 mmol) was added to 200 ml of a 95% aqueous acetonitrile solution and potassium carbonate (16.59 g, 120 mmol) and tetrabutyl Ammonium bromide (0.97 g, 3 mmol), heated under reflux for 20 min, then added 1,2-dibromoethane (22.54 g, 120 mmol), refluxed for 10 h, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with a small amount of acetonitrile. The filtrate was concentrated, and the residue was purified (jjjjjjjjjjjj

PREPARATIVE EXAMPLE 21 2-Butyl-3-[4-[2-(piperidin-1-yl)ethoxy]benzoyl]-5-nitrobenzofuran

2-Butyl-3-[4-(2-bromoethoxy)benzoyl]-5-nitrobenzofuran (13.39 g, 30 mmol) was dissolved in 60 ml of acetonitrile and piperidine (3.83 g, 45 mmol), potassium carbonate (12.44 g, 90 mmol) and potassium iodide (0.50 g, 3 mmol), and refluxed for 4 h, the reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with a small amount of acetonitrile, and the filtrate was concentrated. The residue was dissolved in EtOAc (EtOAc) (EtOAcjjjjjj 59%.

Preparation Example 22 2-Butyl-3-[4-[2-(piperidin-1-yl)ethoxy]benzoyl]-5-aminobenzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. It was 2-butyl-3-[4-[2-(piperidin-1-yl)ethoxy]benzoyl]-5-aminobenzofuran in a yield of 86%.

Preparation Example 23 2-Butyl-3-[4-[2-(piperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[4-[2-(piperidin-1-yl)ethoxy]benzoyl]-5-aminobenzofuran, yield 67%, LC-MS: m/z 499.2 [M+H] ⁺ .

Example 7 2-Butyl-3-[4-[2-(piperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran hydrochloride (I7)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl ]]-5-Methanesulfonylaminobenzofuran was changed to 2-butyl-3-[4-[2-(piperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylamino Benzofuran in a yield of 95%.

^{1 H NMR (400MHz, DMSO-} d 6): δ = 0.80 (t, J = 7.2Hz, 3H), 1.19-1.28 (m, 2H), 1.37-1.43 (m, 1H), 1.62-1.71 (m, 3H), 1.77-1.91 (m, 4H), 2.81 (t, J = 7.6 Hz, 2H), 2.89 (s, 3H), 2.96-3.05 (m, 2H), 3.49-3.51 (m, 4H), 4.56 (t, J = 4.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 7.22 (dd, J = 1.6, 8.8 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 9.66 (s, 1H), 11.00 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 13.87, 21.66, 22.06, 22.74, 27.66, 29.87, 39.10, 53.04, 54.93, 63.14, 112.10, 113.64, 115.16, 116.83, 119.32, 127.66, 131.82, 132.11, 134.78, 150.78, 161.84, 165.28, 189.76.

PREPARATIVE EXAMPLE 24 2-Butyl-3-[4-[2-(2,6-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-nitrobenzofuran

The procedure described in Preparation Example 21 was carried out except that piperidine was changed to 2,6-dimethylpiperidine in a yield of 63%.

PREPARATIVE EXAMPLE 25 2-Butyl-3-[4-[2-(2,6-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-aminobenzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. Is 2-butyl-3-[4-[2-(2,6-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-nitrobenzofuran in a yield of 89 %.

PREPARATIVE EXAMPLE 26 2-Butyl-3-[4-[2-(2,6-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[4-[2-(2,6-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-aminobenzofuran, yield 61%, LC-MS: m/z 527.2 [M+H] ⁺ .

Example 8 2-Butyl-3-[4-[2-(2,6-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran salt Acid salt (I8)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran Changed to 2-butyl-3-[4-[2-(2,6-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran The rate is 90%.

^{1 H NMR (400MHz, DMSO-} d 6): δ = 0.80 (t, J = 7.2Hz, 3H), 1.17-1.28 (m, 2H), 1.35 (d, J = 6.8Hz, 2H), 1.42 (d , J=6.0 Hz, 4H), 1.49-1.58 (m, 2H), 1.62-1.67 (m, 3H), 1.71-1.91 (m, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.89 ( s, 3H), 3.43-3.47 (m, 4H), 3.65 (s, 1H), 4.34 (t, J = 4.8 Hz, 1H), 4.49 (t, J = 4.8 Hz, 1H), 7.10-7.15 (m , 2H), 7.22 (dd, J = 2.0, 8.8 Hz, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.81 - 7.83 (m, 2H) , 9.68 (s, 1H), 10.80 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 13.87, 17.54, 18.51, 22.06, 22.55, 25.42, 27.69, 29.86, 32.02, 39.09, 46.63, 59.47, 60.93, 62.36, 112.10, 113.76, 115.09, 116.85, 119.41, 127.69, 131.81, 132.05, 134.77, 150.82, 162.00, 165.19, 189.77.

PREPARATIVE EXAMPLE 27 2-Butyl-3-[4-[2-(3,5-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-nitrobenzofuran

The procedure described in Preparation Example 21 was carried out except that piperidine was changed to 3,5-dimethylpiperidine in a yield of 66%.

PREPARATIVE EXAMPLE 28 2-Butyl-3-[4-[2-(3,5-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-aminobenzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. Is 2-butyl-3-[4-[2-(3,5-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-nitrobenzofuran in a yield of 93 %.

PREPARATIVE EXAMPLE 29 2-Butyl-3-[4-[2-(3,5-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[4-[2-(3,5-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-aminobenzofuran, yield 57% LC-MS: m/z 527.2 [M+H] ⁺ .

Example 9 2-Butyl-3-[4-[2-(3,5-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran salt Acid salt (I9)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran Changed to 2-butyl-3-[4-[2-(3,5-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran The rate is 92%.

^{1 H NMR (400MHz, DMSO-} d 6): δ = 0.80 (t, J = 7.2Hz, 3H), 0.88-0.90 (m, 6H), 1.21-1.26 (m, 2H), 1.61-1.67 (m, 2H), 1.69-1.75 (m, 1H), 2.11 (s, 2H), 2.54-2.63 (m, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.89 (s, 3H), 3.42-3.50 (m, 5H), 4.59 (s, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.8 Hz, 1H), 7.28 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 9.67 (s, 1H), 11.35 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 13.87, 18.81, 22.07, 27.66, 28.61, 29.88, 39.08, 55.14, 57.92, 62.98, 112.09, 113.65, 115.16, 116.83, 119.33, 127.66, 131.83, 132.10, 134.79, 150.78, 161.85, 165.28, 189.75.

Preparation Example 30 2-Butyl-3-[4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-nitrobenzofuran

The procedure described in Preparation Example 21 was carried out except that piperidine was changed to pyrrolidine in a yield of 69%.

Preparation Example 31 2-Butyl-3-[4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-aminobenzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. It was 2-butyl-3-[4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-nitrobenzofuran in a yield of 91%.

Preparation Example 32 2-Butyl-3-[4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-aminobenzofuran, yield 60%, LC-MS: m/z 485.2 [M+H] ⁺ .

Example 10 2-Butyl-3-[4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran hydrochloride (I10)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran Change to 2-butyl-3-[4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran in a yield of 96%.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 0.79 (t, J = 7.2 Hz, 3H), 1.20-1.27 (m, 2H), 1.61-1.68 (m, 2H), 1.90-1.95 (m, 2H), 2.01 (s, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.90 (s, 3H), 3.10-3.14 (m, 2H), 3.59-3.62 (m, 4H), 4.51 (t , J = 4.4 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 7.24 (dd, J = 2.0, 8.8 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.61 (d , J = 8.8 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 9.70 (s, 1H), 11.43 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 13.86, 22.06, 23.11, 27.66, 29.88, 39.09, 52.78, 54.00, 64.06, 112.07, 113.67, 115.16, 116.82, 119.35, 127.65, 131.82, 132.09, 134.80, 150.78, 161.90, 165.27, 189.75.

Preparation Example 33 3-Fluoro-4-methoxybenzoyl chloride

3-Fluoro-4-methoxybenzoic acid (8.51 g, 50 mmol) and 40 ml of dichloromethane were placed in a 100 ml round bottom flask, and thionyl chloride (8.93 g, 75 mmol) and 3 to 5 drops of N, N were added. - dimethylformamide, refluxing for 2 h, the reaction mixture was taken to room temperature, and concentrated to dryness under vacuo to give 9.25 g of pale white solid.

Preparation Example 34 2-Butyl-3-(3-fluoro-4-hydroxybenzoyl)-5-nitrobenzofuran

2-butyl-5-nitrobenzofuran (8.77 g, 40 mmol) was dissolved in 50 ml of dichloromethane, 3-fluoro-4-methoxybenzoyl chloride (7.55 g, 40 mmol) and anhydrous Aluminum chloride (8.00 g, 40 mmol) was reacted at room temperature for 12 h, and anhydrous aluminum trichloride (8.00 g, 40 mmol) was added to the reaction mixture, and the mixture was heated to reflux. The reaction mixture was poured into water (100 ml), evaporated, evaporated, evaporated.

Preparation Example 35 2-butyl-3-[3-fluoro-4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran;

According to the method described in Preparation Example 1, except that 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran was changed to 2-butyl-3-(3-fluoro4- Hydroxybenzoyl)-5-nitrobenzofuran in a yield of 65%.

PREPARATIVE EXAMPLE 36 2-Butyl-3-[3-fluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran

According to the procedure described in Preparation Example 2, except that 2-butyl-3-[4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran was changed to 2-butyl-3. -[3-Fluoro-4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran in a yield of 80%.

PREPARATIVE EXAMPLE 37 2-Butyl-3-[3-fluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. It was 2-butyl-3-[3-fluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran in a yield of 89%.

PREPARATIVE EXAMPLE 38 2-Butyl-3-[3-fluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[3-fluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran, yield 55%, LC-MS :m/z 531.3[M+H] ⁺ .

Example 11 2-Butyl-3-[3-fluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran hydrochloride ( I11)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran Changed to 2-butyl-3-[3-fluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran in a yield of 93 %.

^{1 H NMR (400MHz, DMSO-} d 6): δ = 0.80 (t, J = 7.2Hz, 3H), 1.21-1.27 (m, 2H), 1.37-1.40 (m, 1H), 1.61-1.91 (m, 8H), 2.29-2.32 (m, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.90 (s, 3H), 3.15-3.20 (m, 2H), 3.43-3.46 (m, 3H), 4.28 (t, J = 6.0 Hz, 2H), 7.24 (dd, J = 2.0, 8.8 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.60 -7.64 (m, 3H), 9.69 (s, 1H), 10.80 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 13.85, 21.85, 22.09, 22.75, 23.53, 27.70, 29.87, 39.02, 52.43, 53.60, 67.14, 112.11, 113.63, 114.82, 116.49, 116.64 (d, J = 20 Hz), 119.37, 127.43 (d, J = 7 Hz), 131.85 (d, J = 5 Hz), 134.86, 150.56 (d, J = 28 Hz), 150.79, 152.87, 165.83, 172.40, 188.88.

Preparation Example 392-Butyl-3-[3-fluoro-4-(2-bromoethoxy)benzoyl]-5-nitrobenzofuran

According to the procedure described in Preparation Example 20, except that 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran was changed to 2-butyl-3-(3-fluoro-4) -Hydroxybenzoyl)-5-nitrobenzofuran in a yield of 63%.

Preparation Example 40 2-Butyl-3-[3-fluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-nitrobenzofuran

According to the procedure described in Preparation Example 21, except that 2-butyl-3-[4-(2-bromoethoxy)benzoyl]-5-nitrobenzofuran was changed to 2-butyl-3. -[3-Fluoro-4-(2-bromoethoxy)benzoyl]-5-nitrobenzofuran, piperidine was changed to pyrrolidine in a yield of 57%.

PREPARATIVE EXAMPLE 41 2-Butyl-3-[3-fluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-aminobenzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. Is 2-butyl-3-[3-fluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl The base]-5-nitrobenzofuran has a yield of 92%.

PREPARATIVE EXAMPLE 42 2-Butyl-3-[3-fluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[3-fluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-aminobenzofuran, yield 53%, LC-MS :m/z 503.2[M+H] ⁺ .

Example 12 2-Butyl-3-[3-fluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran hydrochloride ( I12)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran Changed to 2-butyl-3-[3-fluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran in a yield of 91 %.

^{1 H NMR (400MHz, DMSO-} d 6): δ = 0.81 (t, J = 7.2Hz, 3H), 1.22-1.30 (m, 2H), 1.63-1.70 (m, 2H), 1.89-1.96 (m, 2H), 1.98-2.03 (m, 2H), 2.82 (t, J = 7.6 Hz, 2H), 2.89 (s, 3H), 3.13 - 3.14 (m, 2H), 3.60-3.67 (m, 4H), 4.61 (t, J = 4.8 Hz, 2H), 7.22 (dd, J = 2.0, 8.8 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.61 - 7.69 (m, 3H), 9.67 (s, 1H), 11.40 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 13.87, 22.09, 23.09, 27.73, 29.86, 39.06, 52.68, 54.16, 65.29, 112.15, 113.50, 115.05, 116.48, 116.82 (d, J = 19 Hz), 119.31 , 127.40 (d, J = 12 Hz), 132.51, 134.88, 149.95 (d, J = 11 Hz), 150.47, 150.77, 152.92, 165.96, 188.93.

Preparation Example 43 2-Butyl-3-[3-fluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-nitrobenzofuran

2-Butyl-3-(3-fluoro-4-hydroxybenzoyl)-5-nitrobenzofuran (7.15 g, 20 mmol) was dissolved in 40 ml of acetonitrile and potassium carbonate (5.53 g, 40 mmol) Potassium iodide (0.33 g, 2 mmol), stirred at room temperature for 10 min, added 2-diethylaminochloroethane hydrochloride (3.44 g, 20 mmol), refluxed for 14 h, the reaction mixture was cooled to room temperature, filtered, filter cake with a small amount of acetonitrile After washing, the filtrate was concentrated, and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 4.93 g of solid was obtained in a yield of 54%.

PREPARATIVE EXAMPLE 44 2-Butyl-3-[3-fluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-amino Benzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. It was 2-butyl-3-[3-fluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-nitrobenzofuran in a yield of 88%.

PREPARATIVE EXAMPLE 45 2-Butyl-3-[3-fluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[3-fluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-aminobenzofuran, yield 58%, LC-MS: m /z 505.3[M+H] ⁺ .

Example 13 2-Butyl-3-[3-fluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran hydrochloride (I13)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran Change to 2-butyl-3-[3-fluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran in a yield of 90%.

^{1 H NMR (400MHz, DMSO-} d 6): δ = 0.81 (t, J = 7.2Hz, 3H), 1.20-1.31 (m, 8H), 1.62-1.69 (m, 2H), 2.82 (t, J = 7.2 Hz, 2H), 2.89 (s, 3H), 3.24 (s, 4H), 3.58 (d, J = 4.4 Hz, 2H), 4.64 (t, J = 4.4 Hz, 2H), 7.22 - 7.29 (m, 2H), 7.36-7.41 (m, 1H), 7.61-7.68 (m, 3H), 9.68 (s, 1H), 11.20 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ=8.92, 13.86, 22.09, 27.73, 29.86, 39.05, 47.60, 49.77, 64.41, 112.13, 113.57, 114.96, 116.48, 116.74 (d, J=19 Hz), 119.36 , 127.40 (d, J = 13 Hz), 132.45 (d, J = 5 Hz), 134.89, 149.97 (d, J = 10 Hz), 150.44, 150.78, 152.89, 165.92, 188.95.

Preparation Example 46 3,5-Difluoro-4-methoxybenzoyl chloride

The procedure described in Preparation Example 33 was carried out except that 3-fluoro-4-methoxybenzoic acid was changed to 3,5-difluoro-4-methoxybenzoic acid in a yield of 96%.

Preparation Example 47 2-Butyl-3-(3,5-difluoro-4-hydroxybenzoyl)-5-nitrobenzofuran

The procedure described in Preparation Example 34 was carried out except that 3-fluoro-4-methoxybenzoyl chloride was changed to 3,5-difluoro-4-methoxybenzoyl chloride in a yield of 47%.

Preparation Example 48 2-Butyl-3-[3,5-difluoro-4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran Mutter

According to the method described in Preparation Example 1, except that 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran was changed to 2-butyl-3-(3,5-di Fluorine 4-hydroxybenzoyl)-5-nitrobenzofuran in a yield of 69%.

PREPARATIVE EXAMPLE 49 2-Butyl-3-[3,5-difluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran

According to the procedure described in Preparation Example 2, except that 2-butyl-3-[4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran was changed to 2-butyl-3. -[3,5-Difluoro-4-(3-chloropropoxy)benzoyl]-5-nitrobenzofuran in a yield of 82%.

PREPARATIVE EXAMPLE 50 2-Butyl-3-[3,5-difluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. Is 2-butyl-3-[3,5-difluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran in a yield of 93 %.

Preparation Example 51 2-Butyl-3-[3,5-difluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[3,5-difluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran, yield 57%, LC-MS: m/z 549.3 [M+H] ⁺ .

Example 14 2-Butyl-3-[3,5-difluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran salt Acid salt (I14)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran Changed to 2-butyl-3-[3,5-difluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran The rate is 93%.

^{1 H NMR (400MHz, DMSO-} d 6): δ = 0.81 (t, J = 7.2Hz, 3H), 1.24-1.31 (m, 2H), 1.37-1.41 (m, 1H), 1.63-1.92 (m, 7H), 2.23-2.30 (m, 2H), 2.82-2.93 (m, 7H), 3.16-3.22 (m, 2H), 3.41-3.44 (m, 2H), 4.36 (t, J = 6.0 Hz, 2H) , 7.24 (dd, J = 2.0, 8.8 Hz, 1H), 7.29 (d, J = 2.0, Hz, 1H), 7.55 (d, J = 8.4, Hz, 2H), 7.62 (d, J = 8.8, Hz , 1H), 9.74 (s, 1H), 10.95 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 13.85, 21.83, 22.14, 22.73, 24.45, 25.90, 27.82, 29.84, 38.92, 52.43, 53.42, 62.45, 72.40, 112.15, 113.50-113.85 (m), 116.00 , 119.35, 127.10, 133.94 (t, J = 7 Hz), 135.05, 138.80 (t, J = 14 Hz), 150.77, 153.89 (d, J = 6 Hz), 156.36 (d, J = 5 Hz), 167.16, 188.19.

PREPARATIVE EXAMPLE 52 2-Butyl-3-[3,5-difluoro-4-(2-bromoethoxy)benzoyl]-5-nitrobenzofuran

According to the method described in Preparation Example 20, except that 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran was changed to 2-butyl-3-(3,5-di Fluoro-4-hydroxybenzoyl)-5-nitrobenzofuran in a yield of 71%.

Preparation Example 53 2-Butyl-3-[3,5-fluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-nitrobenzofuran

According to the procedure described in Preparation Example 21, except that 2-butyl-3-[4-(2-bromoethoxy)benzoyl]-5-nitrobenzofuran was changed to 2-butyl-3. -[3,5-Difluoro-4-(2-bromoethoxy)benzoyl]-5-nitrobenzofuran, piperidine was changed to pyrrolidine in a yield of 57%.

Preparation Example 54 2-Butyl-3-[3,5-difluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-aminobenzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. Is 2-butyl-3-[3,5-difluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-nitrobenzofuran in a yield of 90 %.

PREPARATIVE EXAMPLE 55 2-Butyl-3-[3,5-difluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[3,5-difluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-aminobenzofuran, yield 56%, LC-MS: m/z 521.2 [M+H] ⁺ .

Example 15 2-Butyl-3-[3,5-difluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran salt Acid salt (I15)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran Changed to 2-butyl-3-[3,5-difluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran The rate is 91%.

^{1 H NMR (400MHz, DMSO-} d 6): δ = 0.83 (t, J = 7.2Hz, 3H), 1.20-1.30 (m, 2H), 1.64-1.69 (m, 2H), 1.91-1.96 (m, 2H), 1.98-2.04 (m, 2H), 2.84 (t, J = 7.6 Hz, 2H), 2.89 (s, 3H), 3.12-3.16 (m, 2H), 3.60-3.65 (m, 4H), 4.68 (t, J = 4.8 Hz, 3H), 7.22 (dd, J = 2.0, 8.8 Hz, 1H), 7.28 (d, J = 2.0, Hz, 1H), 7.59 - 7.64 (m, 4H), 9.71 (s , 1H), 11.35 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 13.8, 22.14, 23.12, 27.86, 29.84, 38.97, 53.46, 53.95, 70.14, 112.20, 113.40-113.94 (m), 116.00, 119.29, 127.12, 134.324 (t , J = 7 Hz), 135.04, 138.18 (t, J = 14 Hz), 150.77, 153.57, 156.09, 167.25, 188.21.

PREPARATIVE EXAMPLE 56 2-Butyl-3-[3,5-difluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-nitrobenzofuran

Following the procedure described in Preparation Example 43, except that 2-butyl-3-(3-fluoro-4-hydroxybenzoyl)-5-nitrobenzofuran was changed to 2-butyl-3-(3) , 5-difluoro 4-hydroxybenzoyl)-5-nitrobenzofuran, yield 58%.

Preparation Example 57 2-Butyl-3-[3,5-difluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-aminobenzofuran

According to the method described in Preparation Example 3, except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-nitrobenzofuran was changed. It was 2-butyl-3-[3,5-difluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-nitrobenzofuran in a yield of 93%.

PREPARATIVE EXAMPLE 58 2-Butyl-3-[3,5-difluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran

Follow the procedure described in Preparation Example 4 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-aminobenzofuran was changed to 2-butyl-3-[3,5-difluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-aminobenzofuran, yield 53%, LC- MS: m/z 523.3 [M + H] ⁺ .

Example 16 2-Butyl-3-[3,5-difluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran hydrochloride (I16)

Follow the procedure described in Example 1 except that 2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran Changed to 2-butyl-3-[3,5-difluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran in the yield 90%.

^{1 H NMR (400MHz, DMSO-} d 6): δ = 0.82 (t, J = 7.2Hz, 3H), 1.15-1.32 (m, 8H), 1.62-1.70 (m, 2H), 2.84 (t, J = 7.2 Hz, 2H), 2.90 (s, 3H), 3.26-3.27 (m, 4H), 3.56-3.57 (m, 2H), 4.76 (t, J = 4.4 Hz, 2H), 7.24 - 7.29 (m, 2H) ), 7.55-7.63 (m, 3H), 9.77 (s, 1H), 11.26 (s, 1H).

¹³ C NMR (100 MHz, DMSO-d ₆ ): δ = 8.94, 13.85, 22.14, 27.83, 19.84, 38.92, 47.49, 50.67, 69.33, 112.14, 113.51-113.88 (m), 115.98, 119.37, 127.08, 134.15 (t , J = 7 Hz), 135.07, 138.25 (t, J = 14 Hz), 150.77, 153.51 (d, J = 6 Hz), 156.48 (d, J = 5 Hz), 167.20, 188.17.

Example 17 2-Butyl-3-[3,5-difluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylamino-6-III Fluoromethylbenzofuran hydrochloride (I17)

2-butyl-5-nitro-6-trifluoromethylbenzofuran was used as a starting material, and the synthesis method was the same as the preparation method of the compound described in Example 14, LC-MS: m/z 617.2 [M+H] ⁺ .

Example 18 2-Butyl-3-[3-trifluoromethyl-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylamino-6-fluoro Benzofuran hydrochloride (I18)

Using 2-butyl-5-nitro-6-fluorobenzofuran and 3-trifluoromethyl-4-methoxybenzoic acid as starting materials, the synthesis method is the same as the preparation method of the compound described in Example 11, LC- MS: m/z 599.2 [M+H] ⁺ .

Example 19 2-Butyl-3-[3,5-dicyano-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran Hydrochloride (I19)

The method for synthesizing the same as the compound described in Example 14 using 2-butyl-5-nitrobenzofuran and 3,5-dicyano-4-methoxybenzoic acid as the starting material, LC-MS: m /z 563.2[M+H] ⁺ .

Example 20 The solubility of the compound described in Examples 1 to 19 and dronedarone hydrochloride in water

According to the "Chinese Pharmacopoeia" 2010 edition of the second part of the test, weighed the ground fine powder test sample, as for 25 ° C ± 2 ° C a certain volume of water, shaking vigorously every 5 minutes for 30s, observe the dissolution within 30min, such as When there are no visible solute particles or droplets, it is considered to be completely dissolved. The specific results are shown in the following table:

Compound	Dissolution	Compound	Dissolution
				I1	Dissolve	I11	Slightly soluble
I2	Dissolve	I12	Dissolve
				I3	Dissolve	I13	Dissolve
I4	Dissolve	I14	Dissolve
				I5	Dissolve	I15	Dissolve
I6	Dissolve	I16	Dissolve
				I7	Dissolve	I17	Dissolve
I8	Slightly soluble	I18	Dissolve
				I9	Slightly soluble	I19	Dissolve

I10

Slightly soluble

Dronedarone hydrochloride

Almost insoluble

As can be seen from the results of the above table, the solubility of the compound of the present invention in water is significantly better than that of the marketed drug dronedarone hydrochloride.

Example 20 in vitro stability test

Test method: Phosphate buffer (0.05 M, Ph=7.4) containing human liver microsomes at a concentration of 1.27 mg/mL was added to a 1.1 mL tube, 2.5 μL of the test compound was added, and pre-incubated for 5 min at 37 °C. 50 μL of NADPH solution was added, and the final concentration of the test compound was 1 μM (1% DMSO), and the total volume of the incubation solution was 250 μL. 15 μL aliquots were taken from the reaction system at 0, 15, 30, 45 and 60 minutes, and 200 μL of methanol/acetonitrile (1:1) was added to terminate the reaction. The resulting mixture was centrifuged at 3400 rpm for 15 min, and the supernatant was used for LC-MS/MS analysis.

The instruments and conditions used for LC analysis are:

Column: Kinetex 2.6u C18100A column (3.0mm × 30mm)

Mobile phase: 0.1% aqueous formic acid (A) and 0.1% formic acid-acetonitrile (B); elution procedure is 0-0.5 min, maintaining mobile phase B is 5%; 0.5-1.0 min, mobile phase B is 5% to 95 %; 1.0 ~ 1.5min, maintain mobile phase B is 95%; 1.5 ~ 2.0min, equilibrated to mobile phase B is 5%. The running time was 2 min, the flow rate was 1 mL/min, and the loading volume was 5 μL.

The instruments and conditions used for MS analysis are:

API 4000QTrap

Ionization mode: ESI

Scan type: MRM

Test results:

The in vitro stability results of the compounds described in Examples 1 to 19 and dronedarone hydrochloride in the human liver microsome system in which NADPH is present are shown in the following table:

Compound	T 1/2 of HLM(min)	Compound	T 1/2 of HLM(min)
				I1	154	I11	96
I2	40.5	I12	106
				I3	231	I13	125
I4	113	I14	187
				I5	26.7	I15	175
I6	16.5	I16	158
				I7	40.8	I17	119
I8	8.3	I18	143

I9	8.6	I19	136
				I10	173	Dronedarone hydrochloride	31.4

As can be seen from the above table data, in addition to the compounds I5, I6, I8 and I9, the stability of the compounds of the present invention in human liver microsomes is superior to that of the marketed drug dronedarone hydrochloride.

Example 21 The inhibitory effects of the compounds described in Examples 1 to 19 and dronedarone hydrochloride on the potassium channel of hERG

Experimental steps:

(1) The collected cells (recombinant HEK293 cell line express human hERG (ether-a-go-go related gene) potassium channel) suspension is placed in the cell pool, and the cells are sucked once every 30s to avoid cell sedimentation or agglomeration . The robotic arm automatically injects intracellular fluid, extracellular fluid and injects the cell suspension into the sealing chip. The cells were randomly attached to the well under the suction of negative pressure, and then the membrane attached to the well was ruptured by suction to form a whole cell recording mode.

(2) Whole-cell patch clamp recording was performed according to standard procedures established by patchmaster. The administration was started when the whole cell recording was stable (the experimental group was the compound described in Examples 1 to 19; the control group was Cisapride and dronedarone hydrochloride), and the concentration of each drug was stabilized to detect the next concentration. Three cells were independently and repeatedly detected during the recording period.

(3) Whole-cell patch clamp recording of whole-cell hERG potassium current recording method is as follows: the clamping voltage is maintained from -80 mV to +40 mV for 500 msec, then rapidly maintained at -40 mV for 500 msec, the tail current is recorded, and every 10 seconds Repeat the data collection. Data was collected by the HEKA EPC-10 Quatro amplifier and stored in the PatchMaster software.

All electrophysiological experiments were performed at room temperature (25 ° C).

QC:

(1) During the whole process of the experiment, all data meet the following criteria to be adopted:

(2) In the whole experiment, the pre-breaking sealing resistance Rseal>1GΩ.

(3) Current decay is less than 1%/min in the negative control group

(4) The leakage current is less than 100pA.

(5) The series resistance Rs < 20 MΩ throughout the experiment.

(6) The current before administration is greater than 400 pA.

data analysis:

(1) All data are expressed as mean ± standard deviation of n cells.

(2) The normalized current amplitude was fitted by the following equation: 1 (1-(c(IC ₅₀ )-1)h)-1. In the equation, c is the drug concentration, the IC ₅₀ is the drug concentration at which the maximum effect is 50%, and h is the Hill coefficient. The fitting was done through a data analysis software package integrated by Nanion Technologies.

Experimental results:

The table below summarizes the inhibition of hERG potassium channel compound, wherein A represents an IC ₅₀ value in the range 1nM to 1μM; B Representative IC ₅₀ values in the range of 1μM to 5μM.

Compound	IC 50 )	Compound	IC 50
				I1	A	I12	B
I2	A	I13	A
				I3	B	I14	A
I4	A	I15	A
				I5	B	I16	A
I6	A	I17	A
				I7	B	I18	A
I8	B	I19	A
				I9	B	Dronedarone hydrochloride	A
I10	A	Cisapride	A
				I11	A

Claims (10)

1. A benzofuran derivative having the structure of formula I or a pharmaceutically acceptable salt thereof:

   

   among them:

   R ₁ , R ₂ and R ₃ are a hydrogen atom, a halogen, a cyano group or a trifluoromethyl group;

   n is 2 or 3;

   A is -(CH ₂ ) _m - or -(CH ₂ ) _m -O-, wherein m is 1 or 2;

   R ₄ is a hydrogen atom, a hydroxyl group, a C _1-4 alkyl group or a halogen-substituted C _1-4 alkyl group.
2. The benzofuran derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the group A is -CH ₂ -, -CH ₂ CH ₂ - or -CH ₂ -O-.
3. The benzofuran derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the halogen is preferably a fluorine atom.
4. The benzofuran derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the R ₄ group is a hydrogen atom, a hydroxyl group or a methyl group.
5. The benzofuran derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

   2-butyl-3-[4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[4-[3-(morpholinyl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[4-[3-(pyrrolidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   (R)-2-butyl-3-[4-[3-(3-hydroxypyrrolidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[4-[3-(2,6-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[4-[3-(3,5-dimethylpiperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[4-[2-(piperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[4-[2-(2,6-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[4-[2-(3,5-dimethylpiperidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[3-fluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[3-fluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[3-fluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[3,5-difluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[3,5-difluoro-4-[2-(pyrrolidin-1-yl)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[3,5-difluoro-4-[2-(diethylamino)ethoxy]benzoyl]-5-methanesulfonylaminobenzofuran;

   2-butyl-3-[3,5-difluoro-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylamino-6-trifluoromethyl Benzofuran;

   2-butyl-3-[3-trifluoromethyl-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylamino-6-fluorobenzofuran ;with

   2-Butyl-3-[3,5-dicyano-4-[3-(piperidin-1-yl)propoxy]benzoyl]-5-methanesulfonylaminobenzofuran.
6. The benzofuran derivative according to any one of claims 1 to 5, wherein the salt is a benzofuran derivative of the formula I and an organic or inorganic acid Into the salt.
7. The benzofuran derivative according to claim 6 or a pharmaceutically acceptable salt thereof, wherein the salt is selected from the group consisting of sulfates, phosphates, hydrochlorides, hydrobromides, acetates, Oxalate, citrate, succinate, gluconate, tartrate, p-toluenesulfonate, besylate, methanesulfonate, benzoate, lactate, maleate.
8. A pharmaceutical composition comprising the benzofuran derivative according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.
9. Use of the benzofuran derivative according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, for the preparation of an antiarrhythmic drug.
10. A method for producing a benzofuran derivative according to claim 1 or a pharmaceutically acceptable salt thereof, comprising the steps of:

    (1) reacting a compound of formula II with thionyl chloride to form a compound of formula III:

    

    (2) The compound of the formula IV is reacted with a compound of the formula IV under the action of anhydrous aluminum trichloride to form a compound of the formula V:

    

    (3) reacting a compound of the formula V with 1-chloro-3-bromopropane or 1,2-dibromoethane to form a compound of the formula VI (X represents a chlorine atom or a bromine atom):

    

    (4) reacting a compound of formula VI with the corresponding amine to form a compound of formula VII:

    

    (5) Reduction of the nitro group of the compound of the formula VII to give a compound of the formula VIII:

    

    (6) reacting a compound of formula VIII with methanesulfonyl chloride to form a compound of formula I:

    

    among them:

    R ₁ , R ₂ and R ₃ are a hydrogen atom, a halogen, a cyano group or a trifluoromethyl group;

    n is 2 or 3;

    A is -(CH ₂ ) _m - or -(CH ₂ ) _m -O-, wherein m is 1 or 2;

    R ₄ is a hydrogen atom, a hydroxyl group, a C _1-4 alkyl group or a halogen-substituted C _1-4 alkyl group.