WO2004060873A1

WO2004060873A1 - Novel 5-hydroxyindole-3-carboxylate derivatives

Info

Publication number: WO2004060873A1
Application number: PCT/CN2003/000481
Authority: WO
Inventors: Ping Gong; Dun Wang; Yangfang Zhao
Original assignee: Shenyand Pharmaceutical University
Priority date: 2003-01-04
Filing date: 2003-06-20
Publication date: 2004-07-22
Also published as: CN100361975C; CN1482118A; AU2003303648A1

Abstract

The invention relates to novel 5-hydroxyindole-3-carboxylate derivatives, especially to novel 5-hydroxyindole-3-carboxylate derivatives of the general formula (1), in which, R1, R2, Z, R3, R4 and X are as defined in the description; to the pharmacologically acceptable salts thereof and pharmaceutical compositions containing them as the active ingredients, which have prominent inhibitory effects on influenza virus and acute respiratory virus as antivirual agent, as well as to the use of them as antiinfluenza agent and their use for treatment and prophylaxis acute viral respiratory infection. The invention also relates to method for preparing them.

Description

New 5-hydroxy-3-carboxylic acid ester indole derivatives TECHNICAL FIELD

The present invention relates to a novel 5-hydroxy-3-carboxylic acid ester indole derivative and a pharmaceutically acceptable salt thereof, and also relates to a pharmaceutical composition using the compound as an active ingredient, as an antiviral agent, for influenza viruses and Respiratory viruses have significant inhibitory effects and their use as anti-influenza virus agents and in the treatment and prevention of acute viral respiratory infections. The invention also relates to a method for their preparation. Background technique

Influenza is an acute viral inspiratory infectious disease caused by the influenza virus, which mainly affects the elderly and people with compromised immune systems. Influenza virus belongs to the family Orthomyxoviridae, and is divided into three types: A, B, and C according to different antigens. Type A often appears in epidemic forms and can cause worldwide pandemics. Type B often causes local outbreaks and type C. Mainly in the form of distribution. In the flu epidemic, the main role is the type A virus, which is the main cause of the current influenza epidemic.

Due to the virus variability and multi-drug resistance of influenza virus strains, the originally effective influenza vaccines quickly failed; the current types and quantities of anti-influenza drugs are limited, and they usually have drug resistance and toxic side effects. To address these issues, many studies have been conducted to develop new anti-influenza virus chemotherapeutics with potent anti-influenza virus activity and lower toxicity.

The study of 5-hydroxy-3-carboxylic acid ester indole derivatives as novel anti-influenza virus drugs began in the early 1980s. Grinev AH, et al. Khim-Farm Zh, 1987, 21 (1), 52; Parisheva EK et al, Khim Farm Zh, 1988, 22 (5), 565; Mezentseva MV et al. Khim Farm Zh, 1990, 24 (10), 52; Otova SA, et al. Khim Farm Zh, 1992, 26 (1), 52; Zotova SA et al. Khim Farm Zh, 1995, 29 (1), 51, etc. reported some 5-hydroxy groups Studies on the synthesis of -3-carboxylic acid ester indole compounds and their pharmacological activities. Experiments have shown that some of these compounds have anti-influenza virus activity, and have pharmacological effects of inducing interferon production and enhancing human immunity.

In 1993, a derivative of this type of structure, 6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-methyl-2-[(phenyl) thio], was developed by the former Soviet Union VNIKhFI. Methyl-1H-indole-3-carboxylic acid ethyl ester hydrochloride (Arbidol, PCT Int Appl. WO 9008135 (RUSS), 1990-6-26) was marketed in Russia for the treatment and prevention of influenza A and B And acute viral respiratory infections, it also has interferon-inducing and immunoregulatory effects.

In order to develop a new and highly effective anti-influenza virus drug, the inventors indole 5-hydroxy-3-carboxylic acid esters The compounds have been extensively studied, multiple structural sites have been modified and modified, and a series of new 5-hydroxy-3-carboxylate indole derivatives have been synthesized with good antiviral effects. Summary of the invention

It is an object of the present invention to provide a compound of formula I and a pharmaceutically acceptable salt thereof.

among them,

R, for. Alkyl, C ₃ -C ₇ cyclofluorenyl;

R ₂ is C, ~ C ₄ fluorenyl;

Z is CH ₂ SR ₅ and CH ₂ NR ₆ R ₇ ;

R ₅ is phenyl optionally substituted with 1 to 3 R ₈ ;

Or R ₅ is a monocyclic or polycyclic saturated ring having 4 to 10 atoms or 1 to ₄ heteroatoms selected from nitrogen, oxygen, and sulfur, or a heteroaromatic ring containing 5 to 10 atoms, wherein the saturated The ring and heteroaryl ring may be optionally substituted with 1 to 3 R ₈ ; '' or ₁₅ is an alkyl group,. ₃ ~ cyclofluorenyl, C ₂ -C ,. Alkenyl, C ₂ -C _1Q alkynyl, which may be optionally substituted by 1 to 3;

1¾ and _{14 are} independently selected from H, amino, or a group as defined in ₅ ;

Or R ₃ , 1 ₄ and 1 ^ together form a guanidyl group, or a 4 to 10 membered monocyclic or polycyclic saturated ring or a 5 to 10 membered heteroaryl ring, wherein the saturated ring and heteroaryl ring optionally include 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, in addition to 1 ₃ and the attached nitrogen atom, the saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, the saturated ring and heteroaryl The ring may be optionally substituted by 1 to 3;

And ₁₇ are independently selected from H, an amino group, or a group R ₅ as defined above;

Or 1, ₇ and 1 ^ together form a guanidyl group, or a 4 to 10 membered monocyclic or polycyclic saturated ring or a 5 to 10 membered heteroaromatic ring, wherein the saturated ring and heteroaromatic ring optionally include 1 to 4 members Heteroatoms from nitrogen, oxygen and sulfur, except! Outside the nitrogen atom to which ₆ and ^ are connected, the saturated ring optionally includes 1 or 2 carbon-carbon double bonds or triple bonds, and the saturated ring and heteroaryl ring may be optionally substituted by 1 to 3;

X represents H, halogen; R ₈ represents C _r C ₆ fluorenyl, C ₃ ~ C ₇ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, hydroxyl, ₆ methoxy, C ₂ -alkenyloxy, ₆ alkynyloxy, mercapto, alkylthio embankment ^ _6, ₆ alkenylthio group, a phenyl group, a benzyl group, a free, salified, esterified and amidated carboxy, halogen, trifluoromethyl, embankment acyl, nitro Group, cyano, amino or amino substituted by mono or di (C, -C ₆ fluorenyl);

Provided that-when X is a bromine atom, 1 is a methyl group, R ₂ is an ethyl group, R ₃ and R ₄ are both methyl groups, and Z is CH ₂ SR ₅ , where R ₅ is not p-chlorophenyl, Ethoxyphenyl, p-ethylphenyl, p-methylphenyl, o-nitrophenyl, benzyl, 2-pyridyl, 4-hydroxy-3,5-di-t-butylphenyl, cyclohexyl, 2-thienyl, phenyl, 3-thienyl; when X is a bromine atom,! ^ Is methyl, is ethyl, NR ₃ R ₄ is 1-morpholinyl, and Z is CH ₂ NR ₆ R ₇ , where R _fi and R ₇ are either H or methyl, and the other Not p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl;

When X is a bromine atom, 1 is a methyl group, is an ethyl group, and ₁₄ are both a methyl group, and Z is CH ₂ NR ₆ R ₇ , wherein R ₆ and R ₇ are either H or methyl When the other is not phenyl, p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, and R ₆ and R ₇ cannot be benzyl at the same time;

When X is H, methyl, ethyl ₁₂ and ₁₄ are both methyl, Z is ₂ NR ₆ ₇ when CH R, wherein, R _6, R ₇ can not both be H, methyl, ethyl, NR ₆ R ₇ is not a morpholinyl group; when Z is CH ₂ SR ₅ , wherein R ₅ is not phenyl and benzyl.

According to the invention, in the definition of a substituent:

Preferred R is preferably C ^ fluorenyl, especially methyl, ethyl, propyl, isopropyl, cyclopropyl; preferred Z is CH ₂ SR _5;

Preferred R ₅ is unsubstituted phenyl or 1 to 3 selected from hydroxy, C, -C ₄ alkyl, ^-^ fluorenyloxy, halogen, trifluoromethyl, nitro, cyano or amino. Group-substituted phenyl;

Preferably R ₅ is phenyl substituted with 1 to 3 halogen atoms;

Preferred R ₅ is pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazine Groups, indolyl, benzofuranyl, benzothienyl, quinolinyl, and purine base residues;

Preferred R ₆ , R ₇ and N—are from pyrrolyl, pyrazolyl, imidazolyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, morpholinyl;

Preferably, 1 ₃ and R _{4 are} independently selected from H, methyl, ethyl, propyl, cyclopropyl, butyl, cyclopentyl, cyclohexyl, n-octyl; Preferred R ₃ and RPN are guanidyl, pyrrolyl, pyrazolyl, imidazolyl, 2-methylimidazolyl, pyrrolidin, piperidinyl, piperazinyl, 4-methylpiperazinyl, Phosphono

Preferably X represents H and a bromine atom;

According to the present invention, particularly preferred 5-hydroxy-3-carboxylic acid ester indole derivatives of the above formula I include:

6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-ethyl-2-[(4-isopropylphenyl) thio] methyl-1H-indole-3-carboxy Ethyl Ester (AD-1)

6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-ethyl-2-[(4-fluorophenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl Ester (AD-2)

6-bromo-4- (diethylamino) methyl-5-hydroxy-1-ethyl-2-[(4-isopropylphenyl) thio] methyl-1H-indole-3-carboxy Ethyl Ester (AD-5)

6-bromo-4- (morpholin-4-yl) methyl-5-hydroxy small ethyl-2-[(4-fluorophenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl Ester (AD-11)

6-bromo-4- (4-methylpiperazin-1-yl) methyl-5-hydroxy-1-methyl-2-[(2,6-dichlorophenyl) thio] methyl-1H -Indole-3-carboxylic acid ethyl ester (AD-18)

6-bromo-4- (4-methylpiperazin-1-yl) methyl-5-hydroxy small methyl-2-[(4-fluorophenyl) thio] methyl Ethyl Ester AD-19)

6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-ethyl-2-[(4-chlorophenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl Ester (AD-21)

6-bromo-4- (4-methylpiperazin-1-yl) methyl-5-hydroxy-1-ethyl-2-[(4-chlorophenyl) thio] methyl-1H-indole -3-carboxylic acid ethyl ester (AD-25)

6-Meth-4- (dimethylamino) methyl-5-hydroxy-1-methyl-2-[(2, 6-dichlorophenyl) thio] methyl-1H-indole-3- Ethyl carboxylate (AD-32)

6-bromo-4- (morpholin-4-yl) methyl-5-light small methyl-2-[(pyridin-2-yl) thio] methyl-1H-indole-3-carboxylic acid Ethyl ester (AD-39)

6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-cyclopropyl-2-[(phenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl ester ( AD-40)

6-bromo-4- (morpholin-4-yl) methyl-5-hydroxy-1-cyclopropyl-2-[(phenyl) thio] methylindole-3-carboxylic acid ethyl ester (AD -41)

6-bromo-4- (pyrrolidinyl) methyl-5-hydroxy-1-cyclopropyl-2-[(phenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl ester ( AD-42) 6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-cyclopropyl-2-[(4-fluorophenyl) thio] methyl-1H-indole-3-carboxylic acid Ethyl ester (AD-45)

6-Bromo (4-methylpiperazin-1-yl) methyl-5-hydroxy-1-cyclopropyl-2-[(4-fluorophenyl) thio] methyl-1H-indole- 3-carboxylic acid ethyl ester (AD-46)

6-bromo-4- (morpholin-4-yl) methyl-5-hydroxy-1-cyclopropyl-2-[(4-fluorophenyl) thio] methyl-1H-indole-3- Ethyl carboxylate (AD-47)

6-bromo-4- (4-methylpiperazine small group) methyl-5-hydroxy small cyclopropyl-2-[(3,4-difluorophenyl) thio] methyl-1H-indole -3-carboxylic acid ethyl ester (AD-51)

6-bromo-4- (dimethylamino) methyl-5-lightyl-1-ethyl-2-[(3-methoxyphenyl) thio] methyl-1H-indole-3- Ethyl carboxylate (AD-61)

6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-isopropyl-2-[(4-isopropylphenyl) thio] methyl-1H-indole-3- Ethyl carboxylate (SY-8)

6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-cyclopropyl-2-[(3-methoxyphenyl) thio] methyl-1H-indole-3- Ethyl carboxylate (AD-69)

6-bromo-4- (morpholin-4-yl) methyl-5-hydroxy-1-cyclopropyl-2-[(2,6-dichlorophenyl) thio] methyl-1H-indole -3-carboxylic acid ethyl ester (AD-74)

6-bromo-4- (4-methylpiperazin-1-yl) methyl-5-hydroxy-1-cyclopropyl-2-[(2-fluorophenyl) thio] methyl-1H-ind Indole-3-carboxylic acid ethyl ester (AD-91)

6-4- (pyrrolidin-1-yl) methyl-5-hydroxy small ethyl-2-[(3-methylphenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl ester (AD-92)

6-bromo-4- (pyrrolidin-1-yl) methyl-5-hydroxysmallethyl-2-[(3-chlorophenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl Ester (AD-97)

6-bromo-4- (guanidino) methyl-5-hydroxy small methyl-2-[(phenyl) thio] methyl indole-3-carboxylic acid ethyl ester (AD-100)

And pharmaceutically acceptable salts.

Moreover, according to some general methods in the field to which the present invention belongs, the 5-hydroxy-3-carboxylic acid ester indole derivative of the above formula I of the present invention may form an pharmaceutically acceptable salt thereof with an acid. Acids can include inorganic or organic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid Acid, p-toluenesulfonic acid, etc.

Another object of the present invention is to provide a compound of formula II or a pharmaceutically acceptable compound thereof. The method for preparing a salt is characterized in that: a compound of the general formula III is obtained by reacting HR ₃ R ₄ .

Wherein, X, Z, R, and are the same as defined in claim 1, R ₃ , ₁₄ and ^^ together are a guanidino group, or a heteroaryl ring containing 5 to 10 atoms, wherein the heteroaryl ring It optionally includes 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and may be optionally substituted by 1 to 3; R and R 'are independently selected from H,. Alkyl, ~. ₇ Huanyuanji.

Since the 5-hydroxy-3-carboxylic acid ester indole compound of the above formula I according to the present invention has potential anti-influenza virus and anti-respiratory virus effects, it is clinically used as an anti-influenza virus agent and for Treatment and prevention of acute viral respiratory infections, particularly caused by the following viruses such as influenza A virus, influenza B virus, respiratory syncytial virus, parainfluenza virus, rhinovirus and adenovirus.

The compound according to the present invention can be used as an active ingredient for treating or preventing influenza and acute viral respiratory infections. The present invention also provides a method for treating or preventing the above-mentioned diseases, which comprises administering a therapeutically effective amount of Compounds according to the invention.

The present invention includes a pharmaceutical composition containing the 5-hydroxy-3-carboxylic acid ester indole compound of the above formula I or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient refers to any diluent, adjuvant and / or carrier that can be used in the pharmaceutical field. The compounds of the present invention can be used in combination with other active ingredients, as long as they do not cause other adverse effects, such as allergic reactions.

When the pharmaceutical composition of the present invention is used clinically, it can be formulated into several dosage forms, which contain some excipients commonly used in the pharmaceutical field; for example, oral preparations (such as tablets, capsules, dragees, solutions or Suspensions); Injectable preparations (such as injectable solutions or suspensions, or injectable dry powders, which can be used immediately after adding water for injection); Topical preparations (such as ointments or solutions).

The carriers used in the pharmaceutical composition of the present invention are common types available in the pharmaceutical field and include: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, pigment-free for oral preparations , Flavoring agents, etc .; preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations. Pharmaceutical preparations can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally, or topically). If certain drugs are unstable under gastric conditions, they can be formulated as enteric-coated tablets.

Moreover, the clinical dosage of the 5-hydroxy-3-carboxylic acid ester indole compounds of the above formula I for patients can be based on- The therapeutic efficacy and bioavailability of active ingredients in the body, their metabolism and excretion rates, and the age, sex, and disease stage of the patient are appropriately adjusted, but the daily dose for adults should generally be 10 ~ 500mg, preferably 50 ~ 300mg . Therefore, when the pharmaceutical composition of the present invention is made into a unit dosage form, in consideration of the above effective dose, each unit preparation should contain 10 to 500 mg of the 5-hydroxy-3-carboxylate indole compound of the above formula I, preferably 5 (K300mg. According to the guidance of a doctor or pharmacist, these preparations can be administered at intervals (preferably one to six times). The following synthetic routes A to C describe the preparation of the compound of formula I of the present invention. All the raw materials are Are prepared by the methods described in these schemes, by methods well known to those skilled in the art of organic chemistry, or are commercially available. All final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, These methods are well known to those of ordinary skill in the art of organic chemistry. All variable factors applied in these diagrams are as defined below or as defined in the claims.

According to the compound of formula I according to the present invention, in Scheme A, Z is 01 ₂ 31 ₅ or 0 ^^ ₇ , and the substituents R ,, R ₂ , R ₅ , and ₁₇ are as defined above, wherein R ₃ , R ₄ is independently selected from H, amino, -C ^ embankment group, C ₃ ~ C ₇ cycloalkyl group embankment, C ₂ -C _{1 ()} alkenyl, C ₂ -C _1Q alkynyl group which may be substituted with 1 to 3 R ₈ Optionally substituted; or R ₃ , 11 ₄ and N together form a monocyclic or polycyclic saturated ring of 4 to 10 atoms, wherein the saturated ring optionally includes 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, In addition to the nitrogen atom to which ¾ is attached, the saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, which may be optionally substituted by 1 to 3 R ₈ ;

The substituted amine is added to the acetoacetate, and the reaction is heated to form the compound 3-amino-2-butenoate (A-1). The compound A-1 and p-benzoquinone are in 1,2-dichloroacetamidine. Addition under medium reflux to obtain compound 1-substituted-2-methyl-5-hydroxyindole-3-carboxylic acid ester (A-2), which is acylated with acetic anhydride or acetyl chloride to obtain 1-substituted-2-methyl -5-acetoxyindole-3-carboxylic acid ester (A-3), under the catalysis of benzoyl peroxide, A-3 and liquid bromine in carbon tetrachloride, heated to reflux to obtain 6-bromo- 5-acetoxy-1-substituted-2-bromomethyl-1H-indole-3-carboxylic acid ester (A-4), substituted with the appropriate 1¾ _{1 5} or 10¾ ₆ 1 ₇ under basic conditions Reaction to obtain compound A-5, and then Mannich reaction with formaldehyde and R ₃ R ₄ NH to form compound A-6 of formula I.

In the compound of formula I according to the present invention, in the route B, the substituent X is a hydrogen, fluorine, chlorine atom, and other substituents are defined as the substituents of the compound in the route A.

Route B

Ethyl chloroacetate is commercially available, and it can be reacted with 1¾ ^ or 1 ^ ₆ 1 ₇ (substituted thiophenol or amine) under basic conditions at room temperature to obtain compound B-1. The amine was refluxed for 12 to 24 hours in 1,2-dichloroethane to obtain compound B-2, and then was refluxed for 6 to 12 hours in reaction with p-benzoquinone in 1,2-dichloroethane. Compound Manganese Formula B-4 is obtained by Mannich reaction.

Compounds of formula I according to the invention, in scheme C, Z is as defined for compounds of formula I, and X is H or halogen Together, R ₃ , 1 ₄ and: ^ are guanidino together, or contain 5 to 10 membered heteroaromatic rings, which may be optionally substituted by 1 to 3 members. R and R 'are independently selected from H, -C ,. Alkyl,. ₃ ~ cycloalkyl.

Scheme C The compound Cl is prepared as in the above schemes A and B. The compound Cl is reacted with a compound of the formula HN ₃ R ₄ , where NR ₃ R _{4 is} as defined above. The organic solvent used in the reaction is ~ 0 »linear or branched alcohol and For a polar organic solvent such as acetonitrile, the reaction temperature is heated to reflux and the reaction time is 4 to 6 hours to obtain a compound C-2 of formula I. detailed description:

The compounds of the invention and their preparation will be better understood in connection with the following examples, which are intended to illustrate rather than limit the scope of the invention.

Example 1:

6-bromo-4- (diethylamino) methyl-5-hydroxy-1-methyl-2-[(phenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl salt Acid salt

Step A: Preparation of ethyl 3-methylamino-3-butenoate (1)

With slight stirring, 274 ml (1.4 mol) of methylamine solution was added dropwise to 300 ml of 50% sodium hydroxide solution, and the generated methylamine gas was introduced into 169 ml (1.3 mol) of ethyl acetoacetate. Heat, stir, and cool the reaction solution in a water bath. The reaction temperature is maintained at 35-40. C, until the reaction solution became cloudy, a pale green turbid liquid was obtained, the aeration was stopped, and the mixture was stirred at room temperature overnight. The next day, it was stirred and pumped for 2h, and 300 ml of ether was added to separate the layers. The organic layer was washed with water to pH 8, dried over anhydrous sodium sulfate, and the organic layer was concentrated under reduced pressure to obtain 180.6 g of a transparent liquid. Yield: 97.1%. Used directly in the next step.

Step B: Preparation of ethyl 1,2-dimethyl-5-hydroxyindole-3-carboxylic acid (2)

Dissolve 117.5 g (1.05 mol) of p-benzoquinone in 1200 ml of 1,2-dichloroacetamidine, add the compound (1) dropwise with stirring, control the reaction temperature of 40-45 V, react for 1 h, and naturally cool to room temperature. Allow to stand overnight to precipitate solid Body, suction filtration, cold acetone washing, drying, recrystallization from acetone to obtain compound (2) 165.0 g, yield: 57.8%, rap 207-208

V.

Step C: Preparation of 6-bromo-2- (bromomethyl) -5-hydroxy small methyl-1H-indole-3-carboxylic acid ethyl ester (3) Add compound (2) 65.0 g (0.28 mol) to To 400 ml of carbon tetrachloride, add 3 pieces of benzoyl peroxide, dropwise add 40.0 ml (0.70 mol) of bromine, reflux after dripping for 4 h, complete the reaction, leave to stand, cool, suction filter, and recrystallize ethyl acetate 94.9 g of compound (3) was obtained with a yield of 86.7%,

Step D: Preparation of 6-bromo-5-hydroxy-1-methyl-2-[(phenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl ester (4)

In 400 ml of methanol, add 11.5 g (0.29 mol) of sodium hydroxide and 30.4 g (0.24 mol) of thiophenol, and stir at room temperature for 2 h, then add compound (3) 94.0 g (0.24 mol) in portions, and stir at room temperature for 6 h The reaction solution was neutralized with dilute acetic acid to neutrality, and a large amount of solid was precipitated. Suction filtration, washing with water, drying, and recrystallization of ethyl acetate, 92.7 g of compound (4) was obtained, yield: 92.0%, mp _: 195 ~ 197 ° C.

Step E: 6-bromo-4- (diethylamino) methyl-5-hydroxy-1-methyl-2- (phenylthiomethyl) -1H-indole-3-carboxylic acid ethyl ester hydrochloride Preparation of salt

Add 2.6 ml (0.029 mol) of diethylamine, 3.8 ml (0.024 mol) of 37% formaldehyde solution and 10 g (0.024 mol) of compound (4) to 400 ml of ethanol, and then add an appropriate amount of glacial acetic acid to adjust the pH to 4 ~ 5. Reaction at 40-45 ° C for 6 h. Evaporate part of the ethanol under reduced pressure, pour the concentrate into 200 ml of water, add 50% sodium hydroxide solution to adjust the pH to 10-12, extract with ether, and dry the organic layer with water. Dry the magnesium sulfate, evaporate to dryness, dissolve the obtained oil in 30 ml of acetone, dropwise add ethereal hydrochloric acid solution under reflux until the reaction solution ρΗ is 2 ~ 3, continue to reflux for 0.5 h, let it cool naturally, and let it stand for crystallization. Ethanol recrystallization gave 9.9 g of a pale yellow solid with a yield of 76.1%, mp _: 168-170 ° C.

'H-NMR (CDC1 ₃ ): 1.35 (t, 3H), 1.45 (t, 6H), 3.15 (s, 4H), 3.60 (s, 3H), 4.19 (q, 2H), 4.56 (s, 2H) , 5.28 (d, 2H), 7.28 (s, 5H), 7.65 (s, 1H), 10.08 (s, 1H)

The methods for preparing the compounds of Examples 2 to 37 are the same as in Example 1.

Example 2:

6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-ethyl-2-[(4-isopropylphenyl) thio] methyl-1H-indole-3- Ethyl carboxylate phosphate

'H-NMR (DMSO): 1.25 ~ 1.38 (m, 12H), 2.49 (s, 6H), 2.95 (m, 1H), 4.18 ~ 4.34 (s, m, 6H), 4.69 (s, 2H), 7.26 (d, 2H), 7.36 (d, 2H), 7.38 (s, 1H), 7.89 (s, 1H)

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Example 15:

6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-cyclopropyl-2-[(4-fluorophenyl) thio] methyl-1H-indole-3-carboxy Ethyl acetate hydrochloride

'Η- MR (DMSO): 1.07 (m, 2H), 1.24 (m, 2H), 1.34 (t, 3H), 2.79 (s, 6H), 2.91 (m, IH), 4.20 (m, 2H), 4.67 (s, 2H), 5.15 (s, 2H), 6.92 (m, 2H), 7.23 (m, 2H), 7.89 (s, IH), 10.81 (s, IH) Example 16:

6-bromo-4- (4-methylpiperazin-1-yl) methyl-5-hydroxysmallcyclopropyl-2-[(4-fluorophenyl) thio] methyl-1H-indole- 3-carboxylic acid ethyl ester hydrochloride

Ή-NMR (DMSO): 1.04 (s, 2H), 1.23 ~ 1.28 (m, 5H), 2.77 (m, 3H), 3.09 (s, 2H), 3.10 ~ 3.41 (m, 9H), 4.18 (m, 2H), 4.70 (s, 2H), 7.18 (m, 2H), 7.39 (m, 2H), 7.86 (s, IH) Example 17:

6-bromo-4- (morpholin-4-yl) methyl-5-hydroxy-1-cyclopropyl-2-[(4-fluorophenyl) thio] methyl-1H-indole- · 3 -Ethyl carboxylate hydrochloride

'H-NMR (DMSO): 1.08 (m, 2H), 1.26 (m, 2H), 1.37 (t, 3H), 2.93 (m, IH), 3.20 (m, 2H), 3.88 (d, 2H), 4.19 ~ 4.35 (m, 4H), 4.68 (s, 2H), 5.25 (s, 2H), 6.94 (m, 2H), 7.25 (m, 2H), 7.93 (s, IH), 11.22 (s, IH)

Example 18:

6-4- (4-methylpiperazin-1-yl) methyl-5-lightylcyclocyclo-2-[(3,4-difluorophenyl) thio] methyl-1H-ind Indole-3-carboxylic acid ethyl ester hydrochloride

'H-NMR (DMSO): 1.06 (m, 2H), 1.26 ~ 1.28 (m, 5H), 2.79 (m, 3H), 3.17 (s, 2H), 3.56 ~ 3.93 (m, 9H), 4.22 (m , 2H), 4.79 (s, 2H), 7.22 (m, IH), 7.4 l (m, IH), 7.5 l (m, IH), 7.95 (s, IH), 9.87 (s, IH), 11.95 ( s, IH)

Example 19:

6-bromo-4- (dimethylamino) methyl-5-hydroxysmallethyl-2-[(3-methoxyphenyl) thio] methyl-1H-indole-3-carboxylic acid Ethyl ester hydrochloride

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6- (4- (dimethylamino) methyl) -5-hydroxycyclocyclo-2- (piperidinyl) methyl-1H-indole-3-carboxylic acid ethyl ester hydrochloride

'H- MR (DMSO): 1.05 (m, 2H), 1.41 (m, 5H), 1.66-1.91 (m, 6H), 2.72 (s, 6H), 3.20 (s, 2H), 3.47 (m, 2H ), 3.73 (m, 1H), 4.4 l (m, 2H), 7.87 (s, 2H), 4.99 (s, 2H), 1.07 (s, 8.07), 9.21 (s, 1H), 9.61 (s, 1H ), 9.93 (s, 1H)

Example 37:

6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-cyclopropyl-2- (morpholine small group) methyl-1H-indole-3-carboxylic acid ethyl ester hydrochloride Salt

'H-NMR (DMSO): 1.05 (m, 2H), 1.39 ~ 1.43 (m, 5H), 2.75 (s, 6H), 3.42 (m, 4H), 3.77 (s, 1H), 3.95 (s, 4H ), 4.4 l (m, 2H), 4.98 (m, 4H), 8.08 (s, 1H), 9.16 (s, 1H), 9.62 (s, 1H, -oh), 10.85 (s, 1H)

Example 38:

4- (dimethylamino) methyl-5-hydroxy-1-methyl-2- (phenylthio) methyl-1H-indole-3-carboxylic acid ethyl ester hydrochloride

Step A Preparation of ethyl phenylthioacetoacetate:

4.7 g (0.12 mol) of sodium hydroxide was dissolved in 80 ml of absolute ethanol, 12 g (0.1 mol) of thiophenol was added dropwise, and the mixture was stirred at room temperature for 1 h. The reaction was performed at room temperature for 6 hours. After the reaction was completed, the reaction solution was concentrated, extracted with ether, washed with a 10% sodium carbonate solution, dried, and evaporated to dryness to obtain 20 g of ethyl phenylthioacetoacetate with a yield of 67%.

Step B: Preparation of 4-phenylthio-2-methylamino-2-butenoic acid ethyl ester

Methylamine gas (about 0.14 mol) was passed into a solution of 16.7 g (0.07 mol) of ethyl phenylthioacetoacetate in 150 ml of 1,2-dichloroacetamidine, and the reaction was carried out at 50-60 ° C for 18 hours. After the reaction was completed, washing , Dried, and evaporated to dryness to obtain 15 g of 4-phenylthio-2-methylamino-2-butenoic acid ethyl ester in a yield of 86%.

Step C: Preparation of 5-hydroxy-1-methyl-2- (phenylthiomethyl) -1H-indole-3-carboxylic acid ethyl ester

A solution of 25 g (0.1 mol) of ethyl 4-phenylthio-2-methylamino-2-butenoate in 100 ml of 1,2-dichloroethane was dropped into 60 ml of 11.9 g (0.1 mol) of p-benzoquinone. In the 1,2-dichloroacetamidine solution, keep the solution slightly boiled during the dropwise addition, drop the solution, and react at reflux for 8 hours. After the reaction is complete, cool and crystallize, suction filter, and dry to obtain 5-hydroxy-1-methyl-2. -(Phenylthio) 20.1 g of methyl-1H-indole-3-carboxylic acid ethyl ester, yield 59%.

Step D: 4- (dimethylamino) methyl-5-hydroxy-1-methyl-2- (phenylthio) methyl-1H-indole-3- 81

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Example 43:

4- (methyl-n-butylamino) methyl-5-hydroxy-1-cyclopropyl-2- (phenylthio) methyl-1H-indole-3-carboxylate ethyl oxalate

'H-NMR (DMSO): 0.89 (t, 3H), 1.03 (m, 2H), 1.19 (m, 2H), 1.25 (t, 3H), 1.33 (m, 2H), 1.63 (m, 2H), 2.50 (s, 3H), 2.9 l (m, 2H), 3.06 (m, 1H), 4.20 (m, 2H), 4.56 (s, 2H), 4.82 (s, 2H), 7.00 (d, 1H), 7.29 ~ 7.42 (m, 5H), 7.60 (d, 1H), 8.35 (s, 2H)

Example 44: '

6-fluoro-4- (morpholin-1-yl) methyl-5-hydroxy-1-ethyl-2-[(3-methylphenyl) thio] methyl-1H-indole-3- Carboxylic acid ethyl ester hydrochloride

H-NMR (DMSO): 1.26-1.43 (m, 6H), 2.32 (s, 3H), 3.26 (m, 4H), 3.89 (m, 2H), 4.10 ~ 4.37 (m, 6H), 4.67 (s , 2H), 5.29 (d, 2H), 7.05 (m, 4H), 8.25 (d, 1H)

Example 45

_ A _{_6-chloro-4} - (4-methylpiperazin-1-yl) methyl-5-hydroxy-1-ethyl-2- [(4-isopropylphenyl) thio] methyl - 1H- Indole-3-carboxylic acid ethyl ester hydrochloride

'H-NMR (DMSO): 1.12 ~ 1.25 (m, 12H), 2.74 (s, 3H), 3.26 (s, 8H), 4.15 ~ 4.24 (m, 4H), 4.67 (s, 2H), 4.94 (s , 2H), 7.30 (d, 2H), 7.34 (d, 2H), 8.10 (s, 1H)

Example 46:

6-bromo-4- (imidazole small group) methyl-5-light small small methyl-2-[(4-chlorophenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl salt Acid salt

6-bromo-4- (dimethylamino) methyl-5-lightyl-1-methyl-2-[(4-chlorophenyl) thio] methyl-1H- was prepared according to the method of Example 1. Indole-3-carboxylic acid ethyl ester, 10.2 g (0.02 mol) of the compound was added to 80 mL of ethanol, stirred to dissolve, 3.4 g (0.05 mol) of imidazole was added, heated under reflux for 4 h, and concentrated under reduced pressure to obtain an oil. After reacting with ether hydrochloride, a solid was obtained, and the target compound was recrystallized to obtain 9.7 g of the target compound in a yield of 91%.

H-NMR (DMSO): 1.14 (t, 3H), 3.72 (s, 3H), 4.08 (q, 2), 4.65 (s, 2H), 5.73 (s, 2H), 7.28 ~ 7.39 (m, 5H ), 7.89 (s, 1H), 9.05 (s, 1H)

The method for preparing the compounds of Examples 47 to 55 is the same as that of Example 46.

Embodiment 47;

6-bromo-4- (guanidino) methyl-5-hydroxy-1-methyl-2-[(phenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl ester'H-NMR (CDC1 ₃ ): 1.16 (t, 3H), 2.72 (s, 2H), 3,33 (s, 3H), 4.03 (m, 2H), 4.34 (s, 2H), 4.62 (s, 2H), 6.34 (s, 2H), 7.12 ~ 7.35 (m, 7H)

Example 48:

₆ -bromo_4- (guanidino) methyl-5-hydroxy-1-methyl-2-[(3,4-difluorophenyl) thio] methyl-1H-indole-3-carboxylic acid Ethyl ester hydrochloride

• H- MRCDMSO): 1.22 (t, 3H), 3.54 (s, 3H), 4.15 (q, 2), 4.52 (s, 2H), 4.66 (s, 2H), 6.89 (m, 4H), 7, 18 (s, 1H), 7.40 (m, 1H), 7.5 l (m, 2H)

Example 49:

6-4- (2-methyl-imidazole small group) methyl-5-hydroxy-1-methyl-2-[(3,4-difluorophenyl) thio] methyl-1H-indole- 3-carboxylic acid ethyl ester hydrochloride

H-NMR (DMSO): 1.06 (t, 3H), 2.30 (s, 3H), 3.77 (s, 3H), 3.98 (q, 2), 4.66 (s, 2H), 5.48 (s, 2H), 6.24 (s, 1H), 6.51 (s, 1H), 7.11 (s, 1H), 7.36 (m, 2H), 7.89 (s, 1H)

Example 50:

6-bromo-4- (guanidino) methyl-5-hydroxy-1-methyl-2-[(4-isopropylphenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl Ester hydrochloride

'H-NMR (DMSO): 1.19 (t, 6H), 1.24 (t, 3H), 2.85 (m, 1H), 3.47 (s, 3H), 4.18 (q, 2H), 4.6 l (m, 4H) , 7.2 l (d, 2H), 7.29 (d, 2H), 7.49 (s, 1H), 7.95 (s, 1H)

Example 51:

₆ -bromo_4- (guanidino) methyl-5-hydroxy small methyl-2-[(4-chlorophenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl ester hydrochloride

'H-NMR (DMSO): 1.23 (t, 3H), 3.54 (s, 3H), 4.18 (q, 2H), 4.55 (d, 2H), 4.67 (s, 2H), 6.58 (s, 2H), 6.93 (s, 1H), 7.39 (s, 4H), 7.49 (s, 1H)

Example 52:

₆ _bromo- _4- (2-methylimidazol-1-yl) methyl-5-hydroxy small methyl-2-[(phenyl) thio] methyl-1H-indole-

3-carboxylic acid ethyl ester hydrochloride

'H- MR (DMSO): 1.07 (t, 3H), 2.33 (s, 3H), 3.70 (s, 3H), 3.99 (q, 2H), 4.65 (s, 2H), 5.52 (s, 2H), 6.27 (s, 1H), 6.52 (s, 1H), 7.29 (s, 5H), 7.88 (s, 1H)

Example 53:

4- (2-methylimidazol-1-yl) methyl-5-hydroxy-1-methyl-1H-indole-3-carboxylic acid ethyl ester hydrochloride

'H-NMR (DMSO): 1.26 (t, 3H), 2.59 (s, 3H), 3.66 (s, 3H), 4.25 (m, 2H), 5.73 (s, 2H), 6.74 (s, 1H), 6.89 (d, 2H), 7.37 (d, 1H), 7.42 (s, 1H), 9.44 (s, 1H) Example 54:

4- (2-methyl-5-nitroimidazol-1-yl) methyl-5-hydroxy small methyl-1H-indole-3-carboxylic acid ethyl ester hydrochloride'H-NMR (DMSO): 1.36 (t, 3H), 2.76 (s, 3H), 3.72 (s, 3H), 4.32 (m, 2H), 4.75 (s, 2H),

6.97 (d, 1H), 7.53 (d, 1H), 8.21 (s, 1H), 8.64 (s, 1H), 9.93 (s, 1H), 13.0 (s, 1H)

Example 55:

4- (imidazol-1-yl) methyl-5-hydroxy-1-cyclopropyl-2-methyl-1H-B indole-3-carboxylic acid ethyl ester hydrochloride

'H-NMR (DMSO): 0.94 (m, 2H), 1.23 ~ 1.27 (m, 5H), 2.67 (s, 3H), 3.23 (m, 1H), 4'26 (t, 2H), 5.74 (s , 2H), 6.93 (d, 1H), 7.09 (d, 1H), 7.66 (d, 1H), 8.20 (s, 1H), 9.63 (s, 1H)

Cell culture is one of the most common methods for screening antiviral activity in vitro. The virus replicates in the host cell, including the entire process of the reproduction cycle (adsorption, invasion, husking, and release of virions). Therefore, antiviral drugs that hinder virus replication at any stage can eventually appear to be capable of inhibiting progeny virions The cytopathic effect (CPE) method is a commonly used method for screening antiviral drugs. Any virus that can induce cytopathic diseases can be used. This method uses CPE as an indicator. The method is simple and can inhibit virus tests on most test drugs. The effect is measured, the chance of missing the screen is small, and the toxicity of the drug to the host cell can be observed at the same time. The screening process is roughly divided into two steps: the first step is to select the compound for cell toxicity test, and the second step is to perform the compound antiviral test.

Next, the antiviral activity of the 5-hydroxyindole-3-carboxylic acid ester derivatives of the above formula I according to the present invention was evaluated in vitro. In dog kidney cells (MDCK) and human cervical cancer cell (Hela) cell cultures, cytopathic methods were used to detect the inhibitory effect of compounds on influenza A-3 and RSV viruses. virus.

experimental method:

1. Toxicity of compounds to MDCK cells

MDCK cells were plated at 400,000 ΛηΓ 96-well plates, 37 ° C, 5% C0 2 culture 24h, test compounds were added, Arbidol, adamantyl amine embankment and ribavirin, were diluted with 4000 g / ml ~ 31.3 g / ml, inoculate 3 wells per concentration, 100 μl per well. At the same time, a normal cell control was set. Incubate at 37 ° C and 5% C0 _{2 for} 5-7 days. The morphological changes of cells were observed under an inverted microscope every 24 hours, and the morphological changes of cells (CPE) were recorded: the change below 25% was +, the change from 26% to 50% was ++, 51 ° /. ~ 75% is +++, and 76% ~ 100% is changed to ++++. The Reed-Muench method was used to calculate the drug's half poisoning concentration (TD ₅ ) and the maximum non-toxic concentration (TD _Q ). 2. Toxicity determination of compounds on Hela cells

Hela cells were seeded in a 96-well culture plate at a concentration of 400,000 / ml, and cultured at 37 ° C and 5% CO _{2 for} 24 hours. The test compounds, Arbidol, amantadine, and ribavirin were added and diluted to 4000 yg / ml ~ 31.3 yg / ml, inoculate 3 wells per concentration, 100 μl per well. At the same time, a normal cell control was set. Incubate at 37 ° C and 5% CO _{2 for} 5-7 days. The morphological changes of the cells were observed under an inverted microscope every 24 hours, and the morphological changes of the cells were recorded. The Reed-Muench method was used to calculate the half poisoning concentration of the drug (TD ₅ ) and the maximum non-toxic concentration (TD.). The test was repeated twice.

3. Determination of A3 virus virulence in MDCK cell culture

MDCK cells at a concentration of 400,000 per ml of culture were seeded in 96-well plates, 37 ° C5% C0 ₂ culture 24h, added A3 virus, virus 1: 10-1: 40, diluted with 4 concentrations, each concentration in 3 wells, each well 100 μ 1. A normal cell control was set and cultured at 5% C0 _{2 at} 33 ° C for 5-7 days. The morphological changes of the cells were observed under an inverted microscope every 24 hours, and the morphological changes of the cells were recorded. The Reed-Muench method was used to calculate the half infection concentration TCID _{5 of the} virus. .

4. Determination of RSV virus virulence in Hela cell culture

Hela cells were cultured at a concentration of 400,000 per ml were seeded in 96-well pull, 37Ό culture 24h, RSV virus was added, diluted 10-fold concentrations 10_i ~ 10- ^7, 3 wells per concentration per well of 100 μ 1. A normal cell control was set. Incubate at 37 ° C for 5 ~ 7 days. Cell morphology CPE was observed, and Reed-Muench method was used to calculate the virus infection concentration TCID ₅ . .

5. Inhibition of compounds against A3 and RSV viruses in MDCK and Hela cell cultures

MDCK and Hela cells were seeded in 96-well culture plates at a concentration of 400,000 / ml, 37. After C-culture for 24-48 hours, discard the culture medium and add 1:30 A3 virus solution, 100 μl / 33 for 1.5 h, and 100 TCID ₅ per well. RSV virus solution, 100 μl / well, adsorbed at 37 ° C for 1 h. Discard the virus solution. Add test compound and Arbidol solution with the maximum non-toxic concentration (TD _Q ) to the cells, dilute 8 ~ 10 concentrations, 3 wells per concentration, 100 L per well. The positive control is amantadine and ribavirin. The concentration is 500 yg / ml ~ 0.97 wg / ml, diluted twice, 3 wells per concentration, 100 L per well, virus control and normal cell control are set at 33Ό and 37, respectively. C, 5% C0 _{2 was} cultured for 5-7 days, and the virus CPE was observed under an inverted microscope every 24 hours, and the test was terminated when the virus control cytopathy (CPE) appeared "+++ ~ ++++". The test was repeated 2 times to calculate the compound effective half concentration1. ₅ . And minimum effective concentration MIC and therapeutic index TI (TI = TD. / MIC).

The measurement results of some compounds of the present invention are shown in Table 1 to Table 2: Assay results of compounds on MDCK cells and HELA cells

TD ₀ TD ₅₀ TD ₀ TD ₅₀ Example 1 125 ± 0 250 ± 0 125 ± 0 250 ± 0 Example 2 250 ± 0 500 ± 0 250 ± 0 500 ± 0 Example 3 2000 ± 0 3000 ± 0 2000 ± 0 3000 ± 0 Example 4 2000 ± 0 3000 ± 0 2000 ± 0 3000 ± 0 Example 5 2000 ± 0 2500 ± 0 1000 ± 0 1500 ± 0 Example 6 2000 ± 0 3000 ± 0 2000 ± 0 3000 ± 0 Example Ί 2000 ± 0 4000 ± 0 2000 ± 0 3000 ± 0 Example 8 1000 ± 0 1500 ± 0 1000 ± 0 1500 ± 0 Example 9 2000 ± 0 3000 ± 0 2000 ± 0 3000 ± 0 Example 10 4000 ± 0> 4000 ± 0 4000 ± 0> 4000 ± 0 Example 11 4000 ± 0> 4000 ± 0 4000 ± 0> 4000 ± 0 Example 12 2000 ± 0 3000 ± 0 2000 ± 0 3000 ± 0 Example 13 2000 ± 0 4000 ± 0 2000 ± 0 4000 ± 0 Example 14 2000 ± 0 3000 ± 0 2000 ± 0 3000 ± 0 Example 15 2000 ± 0 3000 ± 0 2000 ± 0 3000 ± 0 Example 16 2000 ± 0 3000 ± 0 2000 ± 0 3000 ± 0 Example 17 2000 ± 0 3000 ± 0 2000 ± 0 3000 ± 0 Example 18 2000 ± 0 4000 ± 0 2000 ± 0 4000 ± 0 Example 19 2000 ± 0 3000 ± 0 2000 ± 0 3000 ± 0 Example 20 1000 ± 0 2000 ± 0 1000 ± 0 2000 ± 0 Example 21 2000 ± 0 4000 ± 0 2000 ± 0 3000 ± 0 Example 22 2000 ± 0 4000 ± 0 1000 ± 0 2000 ± 0 Example 23 1000 ± 0 200 0 ± 0 1000 ± 0 2000 ± 0 Example 24 4000 ± 0> 4000 ± 0 4000 ± 0> 4000 ± 0 Example 25 2000 ± 0 3000 ± 0 2000 ± 0 3000 ± 0 Example 31 250 ± 0 5000 ± 0 250 ± 0 500 ± 0 Example 33 250 ± 0 500 ± 0 250 ± 0 500 ± 0 Example 34 1000 ± 0 2000 ± 0 1000 ± 0 2000 ± 0 Example 35 250 ± 0 500 ± 0 500 ± 0 750 ± 0 Example 47 1000 ± 0 2000 ± 0 1000 ± 0 2000 ± 0 Inhibition test of A3 and RSV viruses in MDCK and HELA cell cultures by compound MDCK HELA

IC ₅₀ MIC TI IC ₅₀ MIC TI Example 1 7.8 ± 0 15.6 ± 0 8 3.9 ± 0 15.6 ± 0 8 Example 2 <3.9 ± 0 3.9 ± 0 64 <3.9 ± 0 3.9 ± 0 64 Example 3 3.9 ± 0 7.8 ± 0 256 <3.9 ± 0 3.9 ± 0 513 Example 4 7.8 ± 0 15.6 ± 0 128 3.9 ± 0 7.8 ± 0 256 Example 5 15.6 ± 0 31.3 ± 0 64 15.6 ± 0 31.3 ± 0 64 Example 6 < 3.9 ± 0 3.9 ± 0 512 <3.9 ± 0 3.9 ± 0 512 Example 7 <3.9 ± 0 3.9 ± 0 512 3.9 ± 0 7.8 ± 0 256 Example S <3.9 ± 0 3.9 ± 0 256 3.9 ± 0 7.8 ± 0 128 Example 9 15.6 ± 0 31.3 ± 0 64 15.6 ± 0 31.3 ± 0 64 Example 10 <3.9 ± 0 3.9 ± 0 1026 <3.9 ± 0 3.9 ± 0 1026 Example 11 <3.9 ± 0 3.9 ± 0 1026 <3.9 ± 0 3.9 ± 0 1026 Example 12 3.9 ± 0 7.8 ± 0 256 3.9 ± 0 7.8 ± 0 256 Example 13 3.9 ± 0 15.6 ± 0 128 7.8 ± Q 15.6 ± 0 128 Example 14 3.9 ± 0 7.8 ± 0 256 3.9 ± 0 7.8 ± 0 256 Example 15 3.9 ± 0 7.8 ± 0 256 3.9 ± 0 7.8 ± 0 256 Example 16 3.9 ± 0 7.8 ± 0 256 7.8 ± 0 15.6 ± 0 128 Example 17 3.9 ± 0 7.8 ± 0 256 7.8 ± 0 15.6 ± 0 128 Example 18 3.9 ± 0 7.8 ± 0 256 3.9 ± 0 7.8 ± 0 256 Example 19 7.8 ± 0 15.6 ± 0 128 7.8 ± 0 15.6 ± 0 128 Example 20 7.8 ± 0 15.6 ± 0 64 7.8 ± 0 15.6 ± 0 64 Example 21 3.9 ± 0 7.8 ± 0 256 3.9 ± 0 7.8 ± 0 513 Example 22 3.9 ± 0 7.8 ± 0 256 3.9 ± 0 7.8 ± 0 128 Example 23 3.9 ± 0 7.8 ± 0 128 <3.9 ± 0 7.8 ± 0 128 Example 24 <3.9 ± 0 7.8 ± 0 513 <3.9 ± 0 7.8 ± 0 513 Example 25 <3.9 ± 0 7.8 ± 0 256 <3.9 ± 0 7.8 ± 0 256 Example 31 15.6 ± 0 31.3 ± 0 16 15.6 ± 0 31.3 ± 0 16 Example 33 3.9 ± 0 7.8 ± 0 32 <3.9 ± 0 7.8 ± 0 32 Example 34 62.5 ± 0 125 ± 0 8 125 ± 0 250 ± 0 4 Example 35 125 ± 0 250 ± 0 2 125 ± 0 62.5 ± 0 8 Example 47 3.9 ± 0 7.8 ± 0 128 3.9 ± 0 7.8 ± 0 128

Claims

Rights request

1.5-hydroxy-3-carboxylic acid ester indole derivatives of formula I or pharmaceutically acceptable salts thereof:

among them,

R, for. Alkyl, C ₃ -C ₇ cycloalkyl;

1 ₂ for. wide. ₄ alkyl;

Z is CH ₂ SR ₅ and CH ₂ NR ₆ R _V ;

R ₅ is 1 to 3 optionally substituted phenyl groups;

Or R ₅ is a 4 to 10 membered monocyclic or polycyclic saturated ring or a 5 to 10 membered heteroaromatic ring having 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the saturated ring and heteroaromatic ring Can be optionally substituted by 1 ~ 3 R _s ;

Or it is an alkyl group, C ₃ ~ C ₇ ring 垸 ¾, C ₂ -C ,. Alkenyl, C ₂ -C ,. Alkynyl, which can be optionally substituted with 1 to 3 1 ₈ ;

₁₃ and _{14 are} independently selected from H, amino, or a group as defined;

Or R ₃ , R ^^ BN—to form a guanidyl group, or a 4 to 10-membered monocyclic or polycyclic saturated ring or a 5 to 10-membered heteroaryl ring, wherein the saturated ring and heteroaryl ring optionally include 1 to 4 selected from nitrogen, oxygen and sulfur atoms, in addition to the nitrogen atom R ₃ and ₁₄ are attached, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated hetero ring The aromatic ring may be optionally substituted by 1 to 3;

And! _{7 are} independently selected from 11, amino, or a group as defined;

Or R ₆ and R fl N—to form a guanidyl group, or a 4 to 10 membered monocyclic or polycyclic saturated ring or a 5 to 10 membered heteroaromatic ring, wherein the saturated ring and the heteroaromatic ring optionally include 1 to 4 heteroatom selected from nitrogen, oxygen and sulfur, and in addition _116: outer ^ ₇ attached nitrogen atom, said saturated ring optionally includes 1 or 2 carbon-carbon double or triple bonds, and said saturated hetero ring The aromatic ring may be optionally substituted by 1 to 3;

X means H, halogen;

R ₈ represents a C′-Cd fluorenyl group, a cycloalkyl group, a C ₂ -C ₆ alkenyl group, a C ₂ -C ₆ alkynyl group, a hydroxyl group,. , ₆ alkoxy, - alkenyloxy, ₆ alkynyl group, a mercapto group, an alkylthio group _6, ₆ alkenylthio group, a phenyl group, a benzyl group, a free , Salted, esterified and amidated carboxyl, halogen, trifluoromethyl, alkanoyl, nitro, cyano, amino or amino substituted with mono or di (C, -C ₆ fluorenyl);

Provided that-when X is a bromine atom, ^ is a methyl group, is an ethyl group, RPR ₄ is a methyl group, and Z is CH ₂ SR ₅ , where R ₅ is not p-chlorophenyl, p-ethoxyphenyl, P-ethylphenyl, p-methylphenyl, o-nitrophenyl, benzyl, 2-pyridyl, 4-hydroxy-3,5-di-tert-butylphenyl, cyclohexyl, phenyl, 2-thiophene , 3-thienyl; when X is a bromine atom,! ^ Is methyl, is ethyl, NR ₃ R ₄ is 1-morpholinyl, and Z is CH ₂ NR ₆ R ₇ , where R ₆ and R ₇ are either H or methyl, and the other Not p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl;

When X is a bromine atom,! ^ Is methyl, is ethyl, and ^ ₄ are both methyl, and Z is CH ₂ NR ₆ R ₇ , where R ₆ and R ₇ are either H or methyl, and the other is not benzene. P-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, and R ₆ and R ₇ cannot be benzyl simultaneously;

When X is H,! ^ Is a methyl group, an ethyl group _12, and ₁₄ are both methyl, Z is ₂ NR ₆ ₇ when CH R, wherein, R _6, R ₇ can not both be H, methyl, ethyl; NR ₆ R ₇ is not a morpholinyl group; when Z is CH ₂ SR ₅ , wherein R ₅ is not phenyl and benzyl.

2. The compound of claim 1, wherein ^ is methyl, ethyl, propyl, isopropyl, cyclopropyl.

3. The compound of claim 1, wherein Z is CH ₂ SR ₅ .

4. The compound of claim 3, wherein ₁₅ is unsubstituted or is selected from 1 to 3 hydroxyl groups,-. ₄ alkyl, C,-. ₄ -alkoxy, halogen, trifluoromethyl, nitro, cyano or amino group substituted phenyl.

5. The compound according to claim 4, wherein R ₅ is a phenyl group substituted with 1 to 3 halogen atoms. .

6. The compound of claim 1, wherein R ₅ is pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazine , Pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl, quinolinyl, and purine base residues.

7. The compound of claim 1, wherein R ₆ , ₁₇ and ^^ together are pyrrolyl, pyrazolyl, imidazolyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, Porphyrinyl.

8. The compound of claim 1, wherein ₁₃ and _{14 are} independently selected from H, methyl, ethyl, propyl, cyclopropyl, butyl, cyclopentyl, cyclohexyl, n-octyl.

9. The compound of claim 1, wherein R _3, 11 ₄ and together guanidino, pyrrolyl, pyrazolyl, imidazolyl, 2-imidazolyl, pyrrolidinyl, piperidinyl, piperazinyl, 4 -Methylpiperazinyl, morpholinyl.

10. The compound of claim 1, wherein X is H and a bromine atom. ·

11. The compound of claim 1, comprising:

6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-ethyl-2-[(4-isopropylphenyl) thio] methylindole-3-carboxylic acid ethyl ester ;

6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-ethyl-2-[(4-fluorophenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl Ester

6-bromo-4- (diethylamino) methyl-5-hydroxy-1-ethyl-2-[(4-isopropylphenyl) thio] methyl-1H-indole-3-carboxy Ethyl acetate

6-bromo-4- (morpholin-4-yl) methyl-5-hydroxy-1-ethyl-2-[(4-fluorophenyl) thio] methyl-1H-indole-3-carboxy Ethyl acetate

₆ -bromo_4- (4-methylpiperazin-1-yl) methyl-5-hydroxy-1-methyl-2-[(2, 6-dichlorophenyl) thio] methyl-1H -Ethyl indole-3-carboxylic acid;

₆ -bromo_4- (4-methylpiperazin-1-yl) methyl-5-hydroxy-1-methyl-2-[(4-fluorophenyl) thio] methyl-1H-indole Ethyl-3-carboxylic acid;

₆ -bromo-4- (dimethylamino) methyl-5-hydroxy-1-ethyl-2-[(4-chlorophenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl ester;

₆ _bromo-4- (4-methylpiperazine small group) methyl-5-hydroxy small ethyl-2-[(4-chlorophenyl) thio] methyl-1H-indole-3-carboxy Ethyl acetate

₆ -bromo_4- (dimethylamino) methyl-5-hydroxy small methyl-2-[(2,6-dichlorophenyl) thio] methyl-1H-indole-3-carboxylic acid Ethyl ester

6-bromo-4- (morpholin-4-yl) methyl-5-hydroxy-1-methyl-2-[(pyridin-2-yl) thio] methyl-1H-indole-3-carboxy Ethyl acetate

₆ -bromo- _4— (dimethylamino) methyl-5-hydroxy-1-cyclopropyl-2-[(phenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl ester;

6-bromo-4- (morpholin-4-yl) methyl-5-hydroxy-1-cyclopropyl-2-[(phenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl Ester

6-bromo-4- (pyrrolidin-1-yl) methyl-5-hydroxy-1-cyclopropyl-2-[(phenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl Ester

6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-cyclopropyl-2-[(4-fluorophenyl) thio] methyl-1H-indole-3-carboxylic acid Ethyl ester 6-bromo_4- (4-methylpiperazine small group) methyl-5-hydroxy small cyclopropyl-2-[(4-fluorophenyl) thio] methyl-1H-indole-3- Ethyl carboxylate

6-bromo_4- (morpholin-4-yl) methyl-5-lightyl-1-cyclopropyl-2-[(4-fluorophenyl) thio] methyl-1H-indole-3 -Ethyl carboxylate;

6-bromo-4- (4-methylpiperazine small group) methyl-5-hydroxy small cyclopropyl-2-[(3,4-difluorophenyl) thio] methyl-1H-indole Ethyl-3-carboxylic acid;

6-4- (Dimethylamino) methyl-5-hydroxy-1-ethyl-2-[(3-methoxyphenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl Ester

6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-isopropyl-2-[(4-isopropylphenyl) thio] methyl-1H-indole-3- Ethyl carboxylate

6-bromo-4- (dimethylamino) methyl-5-hydroxy-1-cyclopropyl-2-[(3-methoxyphenyl) thio] methyl-1H-indole-3- Ethyl carboxylate

6-bromo-4- (morpholin-4-yl) methyl-5-hydroxy-1-cyclopropyl-2-[(2,6-dichlorophenyl) thio] methyl-1H-indole Ethyl-3-carboxylic acid;

₆ _bromo_4- (4-methylpiperazin-1-yl) methyl-5-hydroxysmallcyclopropyl-2-[(2-fluorophenyl) thio] methyl-1H-indole- 3-carboxylic acid ethyl ester;

6-bromo-4- (pyrrolidin-1-yl) methyl-5-hydroxy-1-ethyl-2-[(3-methylphenyl) thio] methyl-1H-indole-3- Ethyl carboxylate

6-bromo-4- (pyrrolidin-1-yl) methyl-5-hydroxy-1-ethyl-2-[(3-chlorophenyl) thio] methyl-1H-indole-3-carboxylic acid Ethyl acetate

_6- bromo-4- (guanidino) methyl-5-hydroxy-1-methyl-2-[(phenyl) thio] methyl-1H-indole-3-carboxylic acid ethyl ester.

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 and a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient.

13. Use of a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable salt thereof in the preparation of an antiviral medicament.

14. The use of claim 13, wherein said viruses represent influenza viruses and respiratory viruses.

15. The use according to claim 14, wherein said virus represents influenza A virus, influenza B virus, respiratory syncytial virus, parainfluenza virus, rhinovirus and adenovirus.

16. Use of a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of influenza and acute viral respiratory infections.

17. A method for preparing a compound of formula II or a pharmaceutically acceptable salt thereof, characterized in that: a compound of formula III is reacted with HNR ₃ R ₄ to obtain ...

Wherein, X, Z,! ^ And 11 ₂ are respectively the same as defined in claim 1, R ₃ ,. R ₄ and N—are guanidino, or a 5- to 10-membered heteroaryl ring, wherein the heteroaryl ring is 1 ~ 4 hetero atoms selected from the group comprising selected from nitrogen, oxygen and sulfur, which may be substituted with 1 to 3 ₁₈ optionally, R and R 'are independently selected from H, C _r C, ₀ alkyl, C ₃ ~ C ₇ cycloalkyl.