CN113912590B - (+/-) -Marinopyrole A derivative and preparation method and application thereof - Google Patents

(+/-) -Marinopyrole A derivative and preparation method and application thereof Download PDF

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CN113912590B
CN113912590B CN202111088596.1A CN202111088596A CN113912590B CN 113912590 B CN113912590 B CN 113912590B CN 202111088596 A CN202111088596 A CN 202111088596A CN 113912590 B CN113912590 B CN 113912590B
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pharmaceutically acceptable
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racemate
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pyridyl
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CN113912590A (en
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秦勇
钟武
宋颢
肖雅心
吴平舟
曹瑞源
李月香
李薇
李松
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Sichuan University
Academy of Military Medical Sciences AMMS of PLA
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Abstract

The invention relates to (+/-) -Marinopyrole A derivatives shown as a formula 1, optical isomers, racemes or pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compounds, a method for preparing the compounds and application of the compounds in resisting viruses.

Description

(+/-) -Marinopyrole A derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a (+/-) -Marinopyrole A derivative, a medicinal composition containing the compound, a method for preparing the compound, and application of the compound in resisting viruses.
Background
The natural product (+/-) -marinopyrole A is extracted from a marine streptomyces strain, is a high-halogenated dipyrrole compound, has strong Methicillin-resistant staphylococcus aureus (MRSA) activity in vitro, can be used as a specific inhibitor of an anti-apoptotic protein family member Mcl-1 (mycloid cell leukemia-1), and can be used for synergistically inducing ABT-737 drug-resistant cancer cell apoptosis by ABT-737 (J.biol.chem.2012, 287, 10224). In silico target prediction and biochemical analysis showed that (+ -) -marinopyrole A can inhibit trypsin activity in a concentration-dependent manner and can act as an antagonist of glucocorticoid receptor, cholecystokinin receptor and orexin receptor (chem. Commun.2017,53, 2272).
Although (+/-) -marinopyrole A shows good in vitro antibacterial and cancer cell apoptosis activity, the compound is easy to combine with the serum of mammals in vivo, so that the activity in vivo is reduced and the toxicity is increased, and the further clinical application of the compound is limited. Therefore, the search for the (+/-) -marinopyrole A derivative with higher activity becomes a new hotspot for the research of the natural products. Further studies found that compound 2, having trifluoromethyl substitution at the 4,4' -position on the phenyl ring, exhibited superior anti-MRSA activity over the natural products (+ -) -marinopyrole a and vancomycin (mar. Drugs.2013,11,2927; 2014,12, 2458).
Figure BDA0003266451510000021
Disclosure of Invention
The inventors of the present invention have unexpectedly found that the (±) -marinopyrole a derivative represented by formula 1 has an antiviral activity, and particularly has an inhibitory activity against flaviviruses such as ZIKV, dengue virus (DENV), encephalitis b virus (JEV), and Yellow Fever Virus (YFV), and enteroviruses such as coxsackie virus (CA 6, CA 16), and enterovirus 71.
Accordingly, the present invention provides, in a first aspect, a compound represented by formula 1, an optical isomer, a racemate, or a pharmaceutically acceptable salt thereof,
Figure BDA0003266451510000022
wherein: n is an integer of 0 to 5,
r is hydroxy, C 1 -C 6 Alkoxycarbonyl group, C 1 -C 6 Alkyl, azido, 5-10 membered aryl, 5-10 membered cycloalkyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, substituted with one or more R 1 Substituted 5-10 membered aryl, substituted by one or more R 1 Substituted 5-10 membered cycloalkyl, substituted by one or more R 1 Substituted 5-10 membered heteroaryl or substituted with one or more R 1 Substituted 5-10 membered heterocyclyl, each R 1 Each independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, hydroxy-substituted C 1 -C 6 Alkyl, methylamino substituted C 1 -C 6 Alkyl, dimethylamino substituted C 1 -C 6 Alkyl, 5-6 membered aryl, 5-6 membered cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl.
In a second aspect, the present invention provides a pharmaceutical composition comprising at least one compound represented by formula 1, an optical isomer, a racemate or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention, and one or more pharmaceutically acceptable carriers and/or excipients. In certain embodiments, the compound of formula 1, an optical isomer, racemate or pharmaceutically acceptable salt thereof is present in an amount effective to treat a viral infection or a disease caused by a viral infection.
A third aspect of the present invention provides a method for preparing a compound represented by formula 1, an optical isomer, a racemate or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention, comprising:
Figure BDA0003266451510000031
1) Providing a compound shown as a formula 2 and a compound shown as a formula 3;
2) Subjecting a compound represented by formula 2 to nucleophilic substitution reaction with a compound represented by formula 3 in a solvent and in the presence of a base;
wherein n and R are as defined herein.
The fourth aspect of the present invention provides the use of a compound represented by formula 1, an optical isomer, a racemate or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention for the preparation of a medicament for antiviral treatment; or in the manufacture of a medicament for the treatment of a viral infection or a disease caused by a viral infection; or in the manufacture of a medicament for inhibiting replication or proliferation of a virus in a cell.
A fifth aspect of the present invention provides a compound represented by formula 1, an optical isomer, a racemate, or a pharmaceutically acceptable salt thereof, according to the first aspect of the present invention, for use in antiviral therapy; or for treating viral infections or diseases caused by viral infections; or for inhibiting replication or proliferation of the virus in the cell.
A sixth aspect of the present invention provides a method for treating a viral infection or a disease caused by a viral infection, comprising administering to a subject in need thereof an effective amount of a compound represented by formula 1, an optical isomer, a racemate or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention, or a pharmaceutical composition thereof.
A seventh aspect of the invention provides a method of inhibiting replication or proliferation of a virus in a cell (e.g. in vitro or in vivo), comprising:
1) Providing a compound represented by formula 1, an optical isomer, a racemate or a pharmaceutically acceptable salt thereof according to the first aspect of the invention;
2) Contacting the compound represented by formula 1, an optical isomer, a racemate, or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention with the cell.
In certain embodiments, n in formula 1 is 0, 1,2, 3,4, or 5.
In certain embodiments, n in formula 1 is 0, 1,2, 3, or 4.
In certain embodiments, n in formula 1 is 0, 1,2, or 3.
In certain embodiments, n in formula 1 is 1,2, 3,4, or 5.
In certain embodiments, n in formula 1 is 1,2, 3, or 4.
In certain embodiments, n in formula 1 is 1,2, or 3.
In certain embodiments, n in formula 1 is 1,2, 3,4, or 5, and R is hydroxy, C 1 -C 6 Alkoxycarbonyl group, C 1 -C 6 An alkyl group or an azido group.
In certain embodiments, n in formula 1 is 0, 1,2, 3,4, or 5, and R is 5-10 membered aryl, 5-10 membered cycloalkyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, substituted with one or more R 1 Substituted 5-10 membered aryl, substituted by one or more R 1 Substituted 5-10 membered cycloalkyl, substituted by one or more R 1 Substituted 5-10 membered heteroaryl or substituted with one or more R 1 Substituted 5-10 membered heterocyclyl, each R 1 Each independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, hydroxy-substituted C 1 -C 6 Alkyl, methylamino substituted C 1 -C 6 Alkyl, dimethylamino substituted C 1 -C 6 Alkyl, 5-6 membered aryl, 5-6 membered cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl.
In certain embodiments, R in formula 1 is hydroxy, C 1 -C 4 Alkoxycarbonyl group, C 1 -C 4 An alkyl group or an azido group.
In certain embodiments, R in formula 1 is 5-6 membered aryl, 5-6 membered cycloalkyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, substituted with one or more R 1 Substituted 5-6 membered aryl, substituted with one or more R 1 Substituted 5-6 membered cycloalkyl, substituted by one or more R 1 Substituted 5-10 membered heteroaryl or substituted with one or more R 1 Substituted 5-10 membered heterocyclyl, wherein R 1 Is defined as described in the present invention.
In certain embodiments, R in formula 1 is 5-6 membered aryl, 5-6 membered cycloalkyl, 5-10 membered nitrogen containing heteroaryl, 5-10 membered nitrogen containing heterocyclyl, substituted with one or more R 1 Substituted 5-6 membered aryl, substituted by one or more R 1 Substituted 5-6 membered cycloalkyl, substituted by one or more R 1 Substituted 5-10 membered heteroaryl or substituted with one or more R 1 Substituted 5-10 membered heterocyclyl, wherein R 1 Is defined in the present invention.
In certain embodiments, R in formula 1 is hydroxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, methyl, ethyl, n-propyl, n-butyl, or azido.
In certain embodiments, R in formula 1 is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazinyl, benzothiazolyl, pyrimidinyl, pyridinyl, benzoxazolyl, 1,3, 4-thiadiazolyl, 1H-tetrazolyl, imidazolyl, benzimidazolyl, 1-oxy-pyridinyl (1-oxy-pyridinyl), 1H-imidazo [4,5-b]Pyridyl, thiazolyl, 1,2, 4-triazolyl, said phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazinyl, benzothiazolyl, pyrimidinyl, pyridyl, benzoxazolyl, 1,3, 4-thiadiazolyl, 1H-Tetrazolyl, imidazolyl, benzimidazolyl, 1-oxo-pyridyl, 1H-imidazo [4,5-b ]]Pyridyl, thiazolyl or 1,2, 4-triazolyl optionally substituted with one or more R 1 Is substituted in which R 1 Is defined in the present invention.
In certain embodiments, R in formula 1 is hydroxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, or azido.
In certain embodiments, R in formula 1 is pyrazinyl, benzothiazolyl, pyrimidinyl, pyridyl, benzoxazolyl, pyridyl, 1,3, 4-thiadiazolyl, 1H-tetrazolyl, imidazolyl, benzimidazolyl, 1-oxy-pyridyl, 1H-imidazo [4,5-b ] in]Pyridyl, thiazolyl, 1,2, 4-triazolyl, pyrazinyl, benzothiazolyl, pyrimidinyl, pyridyl, benzoxazolyl, pyridyl, 1,3, 4-thiadiazolyl, 1H-tetrazolyl, imidazolyl, benzimidazolyl, 1-oxy-pyridyl, 1H-imidazo [4,5-b ]]Pyridyl, thiazolyl or 1,2, 4-triazolyl optionally substituted with one or more R 1 Substituted in which R 1 Is defined as described in the present invention.
In certain embodiments, R in formula 1 is hydroxy, ethoxycarbonyl, or azido.
In certain embodiments, R in formula 1 is pyrazin-2-yl, benzothiazol-2-yl, pyrimidin-2-yl, pyridin-2-yl, benzoxazol-2-yl, pyridin-3-yl, 5-methyl-1, 3, 4-thiadiazol-2-yl, 1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, imidazol-2-yl, benzimidazol-2-yl, 1-oxy-pyridin-2-yl, 1H-imidazo [4,5-b ] pyridin-2-yl, 4- (4-pyridinyl) thiazol-2-yl, 1-hydroxyethyl-1H-tetrazol-5-yl, 1,2, 4-triazol-3-yl.
In certain embodiments, each R in formula 1 1 Each independently is C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy, hydroxy-substituted C 1 -C 4 Alkyl, methylamino substituted C 1 -C 4 Alkyl, dimethylamino substituted C 1 -C 4 Alkyl, 5-6 membered aryl, 5-6 membered cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl.
In certain embodiments, each R in formula 1 1 Each independently is methyl, ethyl, n-propyl, n-butyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl or pyridinyl.
In certain embodiments, each R in formula 1 1 Each independently being methyl, ethyl, n-propyl or n-butyl.
In certain embodiments, each R in formula 1 1 Each independently is dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, or dimethylaminobutyl.
In certain embodiments, each R in formula 1 1 Each independently is hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxybutyl.
In certain embodiments, each R in formula 1 1 Each independently is phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In certain embodiments, each R in formula 1 1 Each independently is piperidinyl or pyridinyl.
In certain embodiments, each R in formula 1 1 Each independently being methyl, dimethylaminoethyl, hydroxyethyl or pyridin-4-yl.
In certain embodiments, the compound of formula 1 is selected from:
Figure BDA0003266451510000061
Figure BDA0003266451510000071
Figure BDA0003266451510000081
in certain embodiments, a method of preparing a compound represented by formula 1, an optical isomer, a racemate, or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention may be performed by a method according to the second aspect of the present invention, the method comprising:
Figure BDA0003266451510000091
1) Providing a compound shown as a formula 2 and a compound shown as a formula 3;
2) Subjecting a compound represented by formula 2 to nucleophilic substitution reaction with a compound represented by formula 3 in a solvent and in the presence of a base;
wherein n and R are as defined herein.
In certain embodiments, the nucleophilic substitution reaction is performed in an inert gas atmosphere (e.g., an argon atmosphere).
In certain embodiments, the nucleophilic substitution reaction is carried out at a temperature of from 25 ℃ to 100 ℃ (e.g., 70-80 ℃).
In certain embodiments, the solvent is selected from dimethylsulfoxide, N-methylpyrrolidone, N '-dimethylformamide, acetonitrile, toluene, or any combination thereof, preferably N, N' -dimethylformamide.
In certain embodiments, the base is selected from potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, 2, 4-lutidine, N' -diisopropylethylamine, or any combination thereof, preferably potassium carbonate.
In certain embodiments, the antiviral agent of the present invention is an anti-flavivirus virus (e.g., zika virus (ZIKV), dengue virus (DENV), japanese Encephalitis Virus (JEV), yellow Fever Virus (YFV), etc.) or an enterovirus (e.g., coxsackie virus (CA 6 type, CA16 type) and Enterovirus 71).
In certain embodiments, the viral infection of the present invention is an infection caused by a virus of the flavivirus genus (e.g., ZIKV, dengue virus (DENV), japanese Encephalitis Virus (JEV), yellow Fever Virus (YFV), etc.) or a virus of the enterovirus genus (e.g., coxsackie virus (CA 6, CA 16), and enterovirus 71).
In certain embodiments, the virus of the invention is a virus of the genus flavivirus (e.g., zika virus (ZIKV), dengue virus (DENV), japanese Encephalitis Virus (JEV), yellow Fever Virus (YFV), etc.) or a virus of the genus enterovirus (e.g., coxsackie virus (CA 6 type, CA16 type) and Enterovirus 71).
In certain embodiments, the subjects of the invention are mammalian subjects and human subjects, including male and female subjects and including neonatal, infant, juvenile, adolescent, adult and geriatric subjects.
In certain embodiments, the cells of the invention are mammalian cells, e.g., bovine, equine, ovine, porcine, canine, feline, rodent, primate, including dog, cat, horse, cow, pig, sheep, goat, mouse, monkey, human, and the like, with preferred mammals being humans.
The compounds of the present invention may be used either as such or in the form of their pharmaceutically acceptable salts. The pharmaceutically acceptable salt of the compound shown in the formula 1 comprises a salt formed by pharmaceutically acceptable inorganic acid or organic acid, or pharmaceutically acceptable inorganic base or organic base. Examples of suitable acid addition salts include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, pamoic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, tannic acid, and the like. Examples of suitable base addition salts include salts with sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, procaine, and the like. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art. Reference herein to the compounds of the invention includes reference to the compounds of formula 1 and pharmaceutically acceptable salts thereof.
The pharmaceutical composition comprises the compound shown in the formula 1, optical isomer, racemate or pharmaceutically acceptable salt thereof and a conventional pharmaceutical carrier and/or excipient. The pharmaceutical composition of the present invention can be prepared into various dosage forms including, but not limited to, tablets, capsules, solutions, suspensions, granules or injections according to conventional methods in the art, and administered by routes such as oral or parenteral routes.
It should be further noted that the dosage and method of administration of the compound of formula 1, optical isomer, racemate or pharmaceutically acceptable salt thereof according to the present invention depend on a variety of factors, including the age, body weight, sex, physical health, nutritional status, activity intensity of the compound, administration time, metabolic rate, severity of the disease, and subjective judgment of the treating physician. The preferred dosage is between 0.001-1000mg/kg body weight/day.
Definition of
In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Meanwhile, in order to better understand the present invention, the definitions and explanations of related terms are provided below.
The term "optionally" as used herein means that the event or circumstance described therein occurs or does not occur, and if a substituent is described as "optionally substituted with" … the substituent may or may not be substituted.
The term "one or more" as used herein means 1 or more than 1, such as 2, 3,4, 5, 6, 7, 8, 9 or 10, under reasonable conditions.
Unless indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.
The term "hydroxy" as used herein refers to-OH.
The term "amino" as used herein means-NH 2 。
The term "C" as used in the present invention 1 -C 6 Alkyl "refers to a saturated straight or branched chain monovalent hydrocarbon radical having 1 to 6 carbon atoms, including C 1-5 Alkyl radical, C 1-4 Alkyl radical, C 1-3 Alkyl radical, C 1-2 Alkyl radical, C 2-5 Alkyl radical, C 2-4 Alkyl groups, and the like. ' C 1 -C 6 Typical examples of alkyl groups "include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, hexyl and the like.
The term "azido" as used herein refers to-N 3 。
The term "C" as used herein 1 -C 6 Alkoxycarbonyl "refers to the group-OC (O) R 2 Wherein R is 2 Is C as defined in the present invention 1 -C 6 Alkyl radicals including C 1-5 Alkoxycarbonyl group, C 1-4 Alkoxycarbonyl group, C 1-3 Alkoxycarbonyl group, C 1-2 Alkoxycarbonyl group, C 2-5 Alkoxycarbonyl group, C 2-4 Alkoxycarbonyl groups, and the like. "C 1 -C 6 Typical examples of alkoxycarbonyl "include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and the like.
The term "C" as used in the present invention 1 -C 6 Alkoxy "means a group-OR 3 Wherein R is 3 Is C as defined in the present invention 1 -C 6 Alkyl radicals including C 1-5 Alkoxy radical, C 1-4 Alkoxy radical, C 1-3 Alkoxy radical, C 1-2 Alkoxy radical, C 2-5 Alkoxy radical, C 2-4 Alkoxy, and the like. "C 1 -C 6 Typical examples of the alkoxy group "include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1, 2-dimethylbutoxy, and the like.
The term "methylamino" as used herein refers to an amino group substituted with one methyl group.
The term "dimethylamino" as used herein refers to an amino group substituted with two methyl groups.
The term "5-10 membered aryl" as used herein refers to an unsaturated aromatic carbocyclic group of 5-10 carbon atoms having a single ring or two or more fused rings, e.g. having 5-8 or 5-6 carbon atoms. The "5-to 10-membered aryl" includes 5-to 8-membered or 5-to 6-membered aryl. Typical examples of "5-to 10-membered aryl" include, but are not limited to, phenyl, naphthyl and the like.
The term "5-10 membered cycloalkyl" as used herein refers to a saturated cyclic hydrocarbon group having 5-10 carbon atoms and having a single ring or two or more fused rings (including fused and bridged ring systems), for example having 3-8,5-8,3-6 or 5-6 carbon atoms. The "5-to 10-membered cycloalkyl group" includes 3-to 8, 5-to 8, 3-to 6-or 5-to 6-membered cycloalkyl groups. Typical examples of "5-to 10-membered cycloalkyl" include, but are not limited to, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like; bicyclic structures, such as bicyclo [2.2.1] heptyl, and polycyclic structures, such as adamantyl, and the like.
The term "5-10 membered heteroaryl" as used herein refers to a heteroaromatic ring group having 5-10 ring members, including monocyclic heteroaromatic rings and polycyclic aromatic rings in which a monocyclic aromatic ring is fused to one or more other aromatic rings. The "5-to 10-membered heteroaryl" group has one or two or more heteroatoms selected from O, S or N, preferably at least one nitrogen atom. Also included within the scope of the term "heteroaryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings (carbocyclic or heterocyclic), wherein the linking group or point is on the aromatic or non-aromatic ring. The "5-10 membered heteroaryl" may be oxo. For example, a "5-to 10-membered heteroaryl" as described herein contains 1 to 2 heteroatoms, preferably at least one nitrogen atom, for example 1 nitrogen, oxygen or sulfur atom, or 1 nitrogen and 1 oxygen atom. The "5-to 10-membered heteroaryl" includes "5-to 8-membered heteroaryl", "5-to 7-membered heteroaryl", "5-to 6-membered heteroaryl", "5-to 10-membered nitrogen-containing heteroaryl", "5-to 7-membered nitrogen-containing heteroaryl", "5-to 8-membered nitrogen-containing heteroaryl", "5-to 6-membered nitrogen-containing heteroaryl", and the like, wherein nitrogen atoms in some of the nitrogen-containing heteroaryl groups can be oxidized to form an N-oxide. Those skilled in the art will recognize these nitrogen-containing heteroaromatic ring groups that are capable of forming N-oxides. The "5-to 10-membered heteroaryl" has, for example, 5 to 6 ring members. Typical examples of "5-to 10-membered heteroaryl" include, but are not limited to, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzothiazolyl, pyrimidinyl, benzoxazolyl, thiadiazolyl, benzimidazolyl, imidazopyridinyl, thiazolyl, 1-oxo-pyridyl (1-oxy-pyridinyl), and the like.
The term "5-to 10-membered heterocyclic group" as used herein means a saturated or partially saturated monocyclic or bicyclic or multiple condensed cyclic group having at least one heteroatom (e.g., 1,2, 3,4 or 5) which is a nitrogen atom, an oxygen atom and/or a sulfur atom, and having 5 to 10 ring atoms and no aromaticity. The "5-10 membered heterocyclyl" may be oxo. For example, a "5-to 10-membered heterocyclyl" as described herein contains 1-2 heteroatoms, preferably at least one nitrogen atom, for example 1 nitrogen, oxygen or sulfur atom, or 1 nitrogen and 1 oxygen atom. The "5-to 10-membered heterocyclic group" includes "5-to 8-membered heterocyclic group", "5-to 7-membered heterocyclic group", "5-to 6-membered heterocyclic group", "5-to 10-membered nitrogen-containing heterocyclic group", "5-to 7-membered nitrogen-containing heterocyclic group", "5-to 8-membered nitrogen-containing heterocyclic group", "5-to 6-membered nitrogen-containing heterocyclic group" and the like, wherein nitrogen atoms in some of the nitrogen-containing heterocyclic groups can be oxidized to form an N-oxide. Those skilled in the art will recognize these nitrogen-containing heterocyclic groups which are capable of forming N-oxides. Specific examples of "5-10 membered heterocyclyl" include, but are not limited to: tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperazinyl, thiazinyl, piperidinyl, morpholinyl and the like.
The term "pharmaceutically acceptable" as used herein means that the substance described therein is not only physiologically acceptable to the subject, but also pharmaceutically valuable. For example, when "pharmaceutically acceptable salt" is described, it is meant that the salt is not only physiologically acceptable to the subject, but may also refer to a synthetic substance of pharmaceutical value.
The term "pharmaceutically acceptable carrier and/or excipient" as used herein refers to carriers and/or excipients that are pharmacologically and/or physiologically compatible with the subject and active ingredient, which are well known in the art (see, e.g., remington's Pharmaceutical sciences. Edded by Gennaro AR, 19th. Pennsylvania. Typical pharmaceutically acceptable carriers and/or excipients include, for example, microcrystalline cellulose, starch, crospovidone, povidone, polyvinylpyrrolidone, maltitol, citric acid, sodium lauryl sulfate, or magnesium stearate, and the like.
The term "effective amount" as used herein refers to an amount effective to achieve the intended purpose. For example, an amount effective to treat a disease (e.g., a viral infection or a disease caused by a viral infection) refers to an amount that reduces or eliminates a disease state or condition. It is within the ability of those skilled in the art to determine such an effective amount.
The term "about" as used herein means within an acceptable standard error of the stated value, e.g., within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the stated value, as recognized by one of ordinary skill in the art.
For the same compound, if the name is inconsistent with the structural formula, the structural formula of the compound is taken as the standard.
The invention has the beneficial technical effects
Through a large number of studies, it has been surprisingly found that the compound represented by formula 1 of the present invention has antiviral activity, and particularly has inhibitory activity against viruses belonging to the flaviviruses such as ZIKV, dengue virus (DENV), japanese Encephalitis Virus (JEV), yellow Fever Virus (YFV), and enteroviruses such as coxsackie virus (CA 6, CA 16), enterovirus 71, and the like.
In addition, the preparation method of the compound shown in the formula 1 is simple and universal, and is convenient for large-scale preparation.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are conventional products which are commercially available, and are not indicated by manufacturers.
The starting compound 2 used in the examples of the present invention can be referred to as mar. Drugs 2013,11, 2927-2948; doi:10.3390/md 11082927.
The compound shown in the formula 1 can be prepared by adopting a general synthesis method in the embodiment of the invention.
Figure BDA0003266451510000141
The general synthesis method comprises the following steps: under the protection of argon, compound 2 (1.0 eq), K 2 CO 3 (2-10.0 eq) and the mercapto compound represented by formula 3 (2-10.0 eq) were dissolved in 20mL of N, N' -dimethylformamide, the reaction mixture was stirred at 70-80 ℃ overnight, after completion of the reaction, 50mL of saturated NH was added 4 The mixture was quenched with aqueous Cl, extracted three times with ethyl acetate (3X 50 mL), and the combined organic layers were washed once with 50mL of saturated aqueous saline. Anhydrous Na for organic phase 2 SO 4 Dried and concentrated in vacuo. The crude product is purified by silica gel column chromatography.
EXAMPLE 1 preparation of Compound 1-1
Figure BDA0003266451510000151
Compound 2 (50.0 mg, 77.8. Mu. Mol), K were used 2 CO 3 (108mg, 0.778mmol), 2-mercaptopyrazine 3-1 (87.3mg, 0.778mmol), according to the general synthesis steps to obtain crude products. The crude product was purified by silica gel column chromatography (petroleum ether: acetone (v/v) = 3) to obtain compound 1-1 (40.3 mg, 72%) as a yellow powder. IR (neat) v max ＝2922,1597,1403,1330,1259.,1173,1129,1014,795 cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ10.91(s,1H),8.34–8.31(m,2H), 8.18–8.15(m,2H),7.66(d,J＝8.0Hz,1H),7.37(d,J＝8.0Hz,1H),7.35(s, 1H),,7.19(s,2H),7.01(d,J＝8.0Hz,1H).； 13 C NMR(150MHz,Acetone-d 6 ) δ187.0,184.4,161.7,159.3,155.0,145.2,143.0,142.7,136.5(q,J＝33Hz), 135.4,(q,J＝33Hz),134.2,134.1,132.0,126.2,125.8,125.7,125.1,124.5, 124.4(q,J＝271.5Hz),124.3(q,J＝271.5Hz).124.01,121.6,120.6,116.6(q,J ＝3Hz),116.2(q,J＝3Hz),115.5,114.7,111.0.；HRMS(m/z):[M-H]-calcd. for C 28 H 12 C l3 F 6 N 4 O 4 S - ,718.9554；found,718.9552.
EXAMPLE 2 preparation of Compounds 1-2
Figure BDA0003266451510000152
Compound 2 (50.0 mg, 77.8. Mu. Mol), K was used 2 CO 3 (108mg, 0.778mmol), 2-mercaptobenzothiazole 3-2 (130mg, 0.778mmol), according to the general synthesis steps to obtain crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =10: 1-3) to obtain a pale yellow solid compound 1-2 (41.6mg, 69%). IR (neat): v max ＝2923,2855,1638,1604,1414, 1333,1173,1135,1068,945,928,867cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ 10.88(s,1H),8.19(d,J＝8.0Hz,1H),7.83(d,J＝8.0Hz,1H),7.76(d,J＝ 8.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.45–7.40(m,2H),7.36–7.31(m,2 H),7.25(s,1H),7.15(s,1H),6.93(d,J＝8.0Hz,1H).； 13 C NMR(100MHz, Acetone-d 6 )δ187.2,184.2,165.1,161.7,159.2,154.5,136.6(q,J＝33Hz), 136.5,135.4(q,J＝32Hz),135.0,134.1,131.8,127.3,125.9,125.7,125.6, 124.8,124.7,124.4,124.3(q,J＝270Hz),124.2(q,J＝270Hz),122.9,122.9, 122.2,121.1,120.5,116.6(q,J＝4Hz),116.3(q,J＝3Hz),115.6(q,J＝4Hz), 114.6(q,J＝3Hz),111.2.；HRMS(m/z):[M-H] - calcd.for C 31 H 13 Cl 3 F 6 N 3 O 4 S 2 - , 773.9323；found,773.9315.
EXAMPLE 3 preparation of Compounds 1-3
Figure BDA0003266451510000161
Compound 2 (30.0 mg, 46.4. Mu. Mol), K were used 2 CO 3 (52.0 mg, 464. Mu. Mol), 2-mercaptopyrimidine 3-3 (52.1mg, 464. Mu. Mol), and crude products were obtained according to the general synthetic procedures. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 6. IR (neat) v max ＝2937,1638,1602,1565,1505, 1400,1334,1168,1125,1066,947,868,785cm –1 ； 1 H NMR(600MHz, Acetone-d 6 )δ12.43(s,1H),10.99(s,1H),10.28(s,1H),8.47(d,J＝4.8Hz,2 H),8.14(d,J＝8.4Hz,1H),7.69(d,J＝8.4Hz,1H),7.39(d,J＝7.8Hz,1H), 7.35(s,1H),7.19(s,1H),7.18(t,J＝4.8Hz,1H),7.15(s,1H),6.99(d,J＝8.4 Hz,1H).； 13 C NMR(150MHz,Acetone-d 6 )δ187.2,184.7,169.7,161.9,159.7, 159.0,159.0,159.0,136.5(q,J＝32.7Hz),135.5(q,J＝32.3Hz),134.1,133.7, 132.3,127.2,125.4,125.2,124,4(q,J＝271.1Hz),124.3(q,J＝271.1Hz), 124.4,124.0,121.5,120.5,119.5,116.5(q,J＝3Hz),116.1(q,J＝3Hz),115.7 (q,J＝3Hz),114.7,111.1.；HRMS(m/z):[M-H] - calcd.for C 28 H 12 Cl 3 F 6 N 4 O 4 S - , 718.9555；found,718.9555.
EXAMPLE 4 preparation of Compounds 1-4
Figure BDA0003266451510000171
Compound 2 (30.0 mg, 46.4. Mu. Mol), K were used 2 CO 3 (52.0 mg, 464. Mu. Mol), 2-mercaptopyridine 3-4 (51.6 mg, 464. Mu. Mol), crude product was obtained according to the general synthetic procedure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 8. IR (neat) v max ＝2926,2852,1606,1505,1401,1332, 1168,1124,1066,946,866,786cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ10.96 (s,1H),8.28(d,J＝4Hz,1H),8.14(d,J＝8Hz,1H),7.67(d,J＝8Hz,1H), 7.59(td,J＝7.6,1.6Hz,1H),7.37(d,J＝8.4Hz,1H),7.35(s,1H),7.18(s,1 H),7.17(s,1H),7.10(dd,J＝6.8,5.2Hz,1H),6.99(d,J＝8Hz,1H),6.89(d, J＝8Hz,1H).； 13 C NMR(100MHz,Acetone-d 6 )δ187.0,184.6,161.8,159.5, 157.6,150.6,150.6,138.2,136.5(q,J＝32Hz),135.4(q,J＝32Hz),134.1, 133.7,132.1,128.1,125.5,125.3,124.4,124.4(q,J＝270Hz),124.3(q,J＝271 Hz),123.7,122.1,121.7,121.7,120.5,116.5(q,J＝4Hz),116.1(q,J＝4Hz), 115.5(q,J＝4Hz),114.7(q,J＝4Hz),110.9.；HRMS(m/z):[M-H] - calcd.for C 29 H 13 Cl 3 F 6 N 3 O 4 S - ,717.9602；found,717.9590.
EXAMPLE 5 preparation of Compounds 1-5a
Figure BDA0003266451510000172
Compound 2 (30.0 mg, 46.4. Mu. Mol), K was used 2 CO 3 (52.1mg, 464. Mu. Mol), 3-mercapto-1-propanol 3-5 (40.1. Mu.L, 464. Mu. Mol), and the crude product was prepared according to the general synthetic procedure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 5. IR (neat): v max ＝3132,2942,2885,1702,1636,1597, 1505,1405,1332,1127,1066,944,866,738cm –1 ； 1 H NMR(400MHz, Acetone-d 6 )δ12.59(s,1H),10.98(s,1H),10.15(s,1H),8.08(d,J＝8.4Hz,1 H),7.65(d,J＝8.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.33(s,1H),7.16(s,1 H),7.05(s,1H),6.93(d,J＝8.4Hz,1H),3.59(t,J＝5.2Hz,1H),3.50–3.39 (m,2H),2.78–2.71(m,1H),2.61–2.54(m,1H),1.61–1.41(m,2H).； 13 C NMR(150MHz,Acetone-d 6 )δ186.7,184.7,161.7,159.5,136.3(q,J＝32.2 Hz),135.3(q,J＝32.2Hz),134.0,132.5,132.3,131.9,125.9,125.8,125.4, 124.4(q,J＝270Hz),124.4,123.4(q,J＝270Hz),122.4,122.1,120.8,116.5(q, J＝3Hz),116.0(q,J＝4.5Hz),115.4(q,J＝3Hz),114.5(q,J＝3Hz),110.7, 60.1,33.3,33.0.；HRMS(m/z):[M-H] - calcd.for C 27 H 16 Cl 3 F 6 N 2 O 5 S - ,698.9755； found,698.9742.
EXAMPLE 6 preparation of Compounds 1-5c
Figure BDA0003266451510000181
Compound 1-5a (50.0 mg, 74.9. Mu. Mol) was dissolved in 5mL of dry dichloromethane, to which PPh was added successively 3 (56.2mg, 0.225mmol), TBAI (79.2mg, 0.225mmol), DDQ (39.6mg, 0.150mmol), reaction at room temperature for 12h, TLC (petroleum ether: ethyl acetate (v/v) = 3). The reaction was quenched with water, extracted with ethyl acetate (3 × 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 5). Compound 1-5b (50.0 mg, 64.4. Mu. Mol) was dissolved in 10mL of DMF, sodium azide (25.1mg, 0.386mmol) was added thereto, reaction was carried out at 25 ℃ for 1h, and completion of the raw material reaction was checked by TLC (petroleum ether: ethyl acetate (v/v) = 3). The reaction was quenched with water, extracted with ethyl acetate (3 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 5). IR (neat) v max ＝3237,2941,2099,1638,1595, 1505,1406,1333,1169,1128,1065,945,865,735,701,496cm –1 ； 1 H NMR(400 MHz,Acetone-d 6 )δ12.61(s,1H),10.96(s,1H),10.16(s,1H),8.08(d,J＝ 8.0Hz,1H),7.65(d,J＝8.0Hz,1H),7.35–7.33(m,2H),7.16(s,1H),7.07 (s,1H),6.94(d,J＝8.0Hz,1H),3.31(t,J＝4.0Hz,2H),2.75–2.55(m,2H), 1.66–1.55(m,2H).； 13 C NMR(150MHz,Acetone-d 6 )δ186.7,184.7,161.7, 159.4,136.4(q,J＝31.5Hz).135.4(q,J＝31.5Hz),134.0,132.5,131.9,131.7, 125.9,125.7,125.4,124.4,124.4(q,J＝271.5Hz),124.3(q,J＝270Hz),122.5, 122.0,120.8,116.5(q,J＝3Hz),116.0(q,J＝4.5Hz),115.5(q,J＝3Hz), 114.6(q,J＝3Hz),110.7,50.1,33.3,29.5.；HRMS(m/z):[M-H] - calcd.for C 27 H 15 Cl 3 F 6 N 5 O 4 S - ,723.9820；found,723.9812.
EXAMPLE 7 preparation of Compounds 1-6
Figure BDA0003266451510000191
Compound 2 (50.0 mg, 77.8. Mu. Mol), K was used 2 CO 3 (53.8mg, 0.389mmol), 2-mercaptobenzoxazole 3-6 (235mg, 1.556mmol), crude product was obtained by the general synthetic procedure. The crude product was purified by silica gel column chromatography (petroleum ether: acetone (v/v) = 7. IR (neat) v max ＝2922,2852,1637,1602,1504,1411, 1333,1173.,1134,1068,948,867,746cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ 12.52(s,1H),10.87(s,1H),10.24(s,1H),8.13(d,J＝8.0Hz,1H),7.60(d,J＝ 8.0Hz,1H),7.46–7.44(m,2H),7.39(d,J＝8.0Hz,1H),7.35(s,1H),7.32– 7.26(m,2H),7.20(s,1H),7.15(s,1H),6.98(d,J＝8.0Hz,1H).； 13 C NMR (100MHz,Acetone-d 6 )δ187.1,184.3,161.7,159.3,152.7,142.5,136.6(q,J＝ 30Hz),135.5(q,J＝30Hz),134.9,134.1,132.1,125.9,125.8,125.7,125.7, 125.7,124.9,124.5,124.4,124.4(q,J＝270Hz),124.4(q,J＝270Hz),122.9, 121.2,120.5,119.9,116.6(q,J＝4Hz),116.4(q,J＝3Hz),115.6(q,J＝4Hz), 114.7(q,J＝4Hz),111.5,111.1；HRMS(m/z):[M-H] - calcd.for C 31 H 13 Cl 3 F 6 N 3 O 5 S - ,757.9551；found,757.9539.
EXAMPLE 8 preparation of Compounds 1-7
Figure BDA0003266451510000201
Compound 2 (30.0 mg, 46.4. Mu. Mol), K 2 CO 3 (52.0 mg, 464. Mu. Mol), ethyl thioglycolate 3-7 (50.9. Mu.L, 464. Mu. Mol), and the crude product was prepared according to the general synthetic procedure. Crude product is passed through silica gel columnPurification by chromatography (petroleum ether: ethyl acetate (v/v) = 8. IR (neat) v max ＝3210,2981,1732,1710,1637,1598,1505, 1407,1333,1170,1127,1066,945,866,789cm –1 ； 1 H NMR(400MHz, Acetone-d 6 )δ10.96(s,1H),8.05(d,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H), 7.35(d,J＝8.8Hz,1H),7.33(s,1H),7.16(s,1H),7.05(s,1H),6.96(d,J＝ 8.4Hz,1H),4.02(q,J＝6.8Hz,2H),3.33(q,J＝16.0Hz,2H),1.16(t,J＝ 7.2Hz,3H).； 13 C NMR(100MHz,Acetone-d 6 )δ186.8,184.5,168.6,161.8, 159.3,136.4(q,J＝48.5Hz),135.3(q,J＝48.5Hz),134.0,132.8,131.9,130.7, 125.8,125.6,122.5,124.4(q,J＝270.6Hz),124.3(q,J＝270.5Hz),124.3, 122.8,121.7,120.8,116.5(q,J＝4Hz),116.1(q,J＝4Hz),115.5(q,J＝4Hz), 114.5(q,J＝4Hz),110.9,62.1,37.3,14.3.；HRMS(m/z):[M-H] - calcd.for C 28 H 16 Cl 3 F 6 N 2 O 6 S - ,726.9704；found,726.9692.
EXAMPLE 9 preparation of Compounds 1-8
Figure BDA0003266451510000202
Compound 2 (50.0 mg, 77.8. Mu. Mol), K was used 2 CO 3 (108mg, 0.778mmol), 2-hydroxyethylthiol 3-8 (55.2. Mu.L, 0.778 mmol), and the crude product was obtained by the general synthetic procedure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =4: 1-3) to obtain compound 1-8 (40.3mg, 72%) as a yellow powder. IR (neat) v max ＝2923,1636,1597,1505,1406,1333, 1170,1129.31,944,865cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ12.6(s,1H), 10.96(s,1H),10.14(s,1H),8.06(d,J＝8.0Hz,1H),7.63(d,J＝8.0Hz,1H), 7.35–7.32(m,2H),7.15(s,1H),7.04(s,1H),6.94(dd,J＝0.8,8.0Hz,1H), 3.87(t,J＝5.2Hz,1H),3.49–3.43(m,2H),2.80–2.74(m,1H),2.68–2.62 (m,1H).； 13 C NMR(150MHz,Acetone-d 6 )δ186.6,184.5,161.7,159.3,136.3 (q,J＝33Hz),135.2(q,J＝33Hz),134.0,132.6,132.3,131.8,126.0,125.8, 125.6,124.5,124.4(q,J＝270Hz),124.3(q,J＝271.5Hz),122.0,122.0,120.7, 116.4(q,J＝3Hz),116.0(q,J＝3Hz),115.4(q,J＝3Hz),114.5(q,J＝3Hz), 110.8,61.7,38.7.；HRMS(m/z):[M-H] - calcd.for C 26 H 14 Cl 3 F 6 N 2 O 5 S - , 684.9599；found,684.9593.
EXAMPLE 10 preparation of Compounds 1-9
Figure BDA0003266451510000211
The compound 2 (100mg, 155. Mu. Mol) and K were used 2 CO 3 (107mg, 775. Mu. Mol), 3-pyridylmethanethiol 3-9 (167. Mu.L, 1.55 mmol), according to the general synthetic procedure to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 5. IR (neat) v max ＝2922,1638,1600,1506,1407,1336, 1168,1129,1066,945,865,782cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ8.45 (d,J＝4.8Hz,1H),8.28(s,1H),8.05(d,J＝8.4Hz,1H),7.61(d,J＝8.4Hz,1 H),7.48(d,J＝8Hz,1H),7.34(d,J＝8.4Hz,1H),7.32(s,1H),7.27–7.23 (m,1H),7.15(s,1H),7.00(s,1H),6.92(d,J＝8.4Hz,1H),3.89–3.73(m,2 H).； 13 C NMR(100MHz,Acetone-d 6 )δ186.9,184.7,161.7,159.4,150.3,149.3, 137.2,136.4(q,J＝32Hz),135.3(q,J＝32Hz),134.0,134.0,132.8,132.0, 130.8,125.7,125.7,125.4,124.4(q,J＝271Hz),124.4,124.4(q,J＝271 Hz),123.4,121.6,121.6,120.8,116.5(q,J＝2Hz),116.0(q,J＝2Hz),115.5(q, J＝2Hz),114.7(q,J＝2Hz),110.6,37.6.；HRMS(m/z):[M-H] - calcd.for C 30 H 15 Cl 3 F 6 N 3 O 4 S - ,731.9759；found,731.9757.
EXAMPLE 11 preparation of Compounds 1-10
Figure BDA0003266451510000221
The compound 2 (100mg, 155. Mu. Mol) and K were used 2 CO 3 (200mg, 311. Mu. Mol), pyridine-2-methanethiol 3-10 (182. Mu.L, 1.55 mmol), and the crude product was obtained according to the general synthetic procedure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 4. IR (neat): v max ＝2924,1637,1596,1406,1334,1232, 1168,1128,1066,943,866,785cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ8.41 (d,J＝4.4Hz,1H),8.02(d,J＝8Hz,1H),7.67(td,J＝1.6,7.6Hz,1H),7.61 (d,J＝8.4Hz,1H),7.34–7.31(m,2H),7.24–7.21(m,1),7.15–7.13(m,2 H),7.00(s,1H),6.92(d,J＝8Hz,1H),3.99–3.81(m,2H).； 13 C NMR(150 MHz,Acetone-d 6 )δ186.8,184.6,161.9,159.4,157.4,150.0,137.7,136.4(q,J ＝32Hz),135.3(q,J＝32Hz),134.0,132.5,132.0,131.8,126.8,125.7,125.5, 124.4(q,J＝271Hz),124.4(q,J＝271Hz),124.2,123.9,123.3,123.2,121.7, 120.7,116.4(q,J＝3Hz),116.0(q,J＝4.5Hz),115.5(q,J＝4.5Hz),114.6(q, J＝4.5Hz),110.8,42.1.；HRMS(m/z):[M-H] - calcd.for C 30 H 15 Cl 3 F 6 N 3 O 4 S - , 731.9759；found,731.9761.
EXAMPLE 12 preparation of Compounds 1-11
Figure BDA0003266451510000231
Compounds 2 (100mg, 155. Mu. Mol) and K were used 2 CO 3 (214mg, 1.55mol), pyrimidine-2-methanethiol 3-11 (199mg, 1.55mol), and a crude product was obtained according to the general synthetic procedure. The crude product was purified by silica gel column chromatography (petroleum ether: acetone (v/v) = 8. IR (neat): v max ＝2962,1599,1408,1117,1334,946,866cm –1 ； 1 H NMR(400MHz,Acetone-d6)δ12.52(s,1H),11.00(s,1H),10.28(s,1H), 8.63(d,J＝8.0Hz,2H),8.05(d,J＝8.0Hz,1H),7.63(d,J＝8.0Hz,1H), 7.35(d,J＝8.0Hz,1H),7.32–7.29(m,2H),7.16(s,1H),7.00(s,1H),6.92 (dd,J＝8.0Hz,4.0Hz,1H),4.01–3.88(m,2H).； 13 C NMR(150MHz, Acetone-d 6 )δ186.8,184.6,167.1,161.9,159.6,158.3,158.3,136.4(q,J＝30 Hz),135.4(q,J＝30Hz),134.0,132.5,132.0,131.7,125.7,125.5,125.4,124.4 (q,J＝270Hz),124.3(q,J＝270Hz),124.3,123.1,121.8,120.6,120.5,116.4 (q,J＝3Hz),116.0(q,J＝3Hz),115.5(q,J＝3Hz),114.6(q,J＝3Hz),110.6, 43.1.；HRMS(m/z):[M-H] - calcd.for C 29 H 14 Cl 3 F 6 N 4 O 4 S - ,732.9711；found, 732.9707.
EXAMPLE 13 preparation of Compounds 1-12
Figure BDA0003266451510000232
Compounds 2 (100mg, 115. Mu. Mol) and K were used 2 CO 3 (214mg, 1.55mol), 2-mercapto-5-methyl-1, 3, 4-thiadiazole 3-12 (205mg, 1.55mol), according to the general synthetic procedures. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) =4: 1-3) to obtain compound 1-12 (68.3mg, 60%) as a yellow powder. IR (neat) v max ＝1602,1504,1406,1331,1173, 1065,748cm –1 ； 1 H NMR(600MHz,Acetone-d 6 )δ12.57(s,1H),10.83(s,1 H),10.08(s,1H),8.07(d,J＝6.0Hz,1H),7.60(d,J＝6.0Hz,1H),7.37– 7.34(m,2H),7.20(s,1H),7.16(s,1H),7.05(d,J＝6.0Hz,1H),2.61(s,3 H).； 13 C NMR(100MHz,Acetone-d 6 )δ187.0,183.8,168.0,163.5,161.5,158.7, 136.5(q,J＝33Hz),135.2(q,J＝32Hz),134.5,134.0,131.7,126.5,126.3, 126.0,124.8,124.5,124.4(q,J＝271Hz),124.4(q,J＝271Hz),123.8,121.3, 120.7,116.6(q,J＝4Hz),116.5(q,J＝5Hz),115.5(q,J＝4Hz),114.5(q,J＝ 3Hz),111.2,15.6.；HRMS(m/z):[M-H] - calcd.for C 27 H 12 Cl 3 F 6 N 4 O 4 S - ,738.9275；found,738.9270.
EXAMPLE 14 preparation of Compounds 1-13
Figure BDA0003266451510000241
Compounds 2 (200mg, 311. Mu. Mol), K were used 2 CO 3 (128mg, 933. Mu. Mol) and 1- (2-dimethylaminoethyl) -1H-5-mercapto-tetrazole 3-13 (805mg, 4.67mmol) according to the general synthetic steps to prepare a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 4). IR (neat) v max ＝2956,2925, 1638,1602,1505,1410,1331,1168,1126,1066,945,927,867cm –1 ； 1 H NMR (600MHz,Acetone-d 6 )δ8.02(d,J＝8.4Hz,1H),7.94(d,J＝8.4Hz,1H), 7.28(d,J＝8.4Hz,1H),7.26(s,1H),7.13(s,1H),7.06(s,1H),7.02–7.00 (m,1H),4.66–4.50(m,2H),3.37(t,J＝5.6Hz,2H),2.80(s,6H).； 13 C NMR(100MHz,Acetone-d 6 )δ187.4,183.4,161.6,159.6,151.5,136.4(q,J＝ 32Hz),135.0(q,J＝32Hz),134.8,134.3,134.3,133.4,128.6,127.7,124.8, 124.7(q,J＝270Hz),124.4(q,J＝272Hz),124.3,123.8,122.6,120.0,116.3(q, J＝4Hz),116.1(q,J＝4Hz),115.4(q,J＝4Hz),115.2(q,J＝4Hz),110.2, 57.6,45.1,45.1,44.8.；HRMS(m/z):[M-H] - calcd.for C 29 H 19 Cl 3 F 6 N 7 O 4 S - , 780.0194；found,780.0191.
EXAMPLE 15 preparation of Compounds 1-14
Figure BDA0003266451510000251
Compounds 2 (100mg, 155. Mu. Mol) and K were used 2 CO 3 (214mg, 1.55mol) and 1-methyl-5-mercapto-1H-tetrazole 3-14 (180mg, 1.55mol), and preparing a crude product according to the general synthetic steps. The crude product was purified by silica gel column chromatography (petroleum ether: acetone (v/v) = 8. IR (neat): v max ＝2972,1636,1594,1481,1333,1131, 946,803cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ8.07–8.01(m,1H),7.94(d, J＝8.0Hz,1H),7.30–7.26(m,2H),7.14(s,1H),7.05–7.01(m,2H),3.90(s, 3H).； 13 C NMR(100MHz,Acetone-d 6 )δ187.3,183.2,161.7,159.4,150.5, 136.4(q,J＝33Hz),134.6(q,J＝32Hz),134.3,134.2,133.2,128.2,127.8, 124.7(q,J＝270Hz)，124.6,124.4(q,J＝270Hz),124.2,123.7,122.5,122.0, 120.2,116.3(q,J＝4Hz),115.9(q,J＝3Hz),115.4(q,J＝4Hz),115.2(q,J＝ 3Hz),110.2,34.5.；HRMS(m/z):[M-H] - calcd.for C 26 H 12 Cl 3 F 6 N 6 O 4 - , 722.9621；found,722.9590.
EXAMPLE 16 preparation of Compounds 1-15
Figure BDA0003266451510000252
Compound 2 (80.0 mg, 124. Mu. Mol), K was used 2 CO 3 (139mg, 1.24mmol), 2-mercaptoimidazole 3-15 (124mg, 1.24mmol), and the crude product was obtained according to the general synthetic procedure. The crude product was purified by silica gel column chromatography (petroleum ether: acetone (v/v) = 5) to obtain light yellow powdery compounds 1 to 15 (26.3 mg,30%, purity = 92.1539%). IR (neat) v max ＝3357,2923,2853,1637,1603, 1508,1455,1379,1331,1258,1170,1095,1068,1015,945,867,796cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ10.79(s,1H),7.46(d,J＝8.0Hz,1H),7.38(s, 2H),7.34(d,J＝8.0Hz,1H),7.22(s,1H),7.18(d,J＝8.4Hz,1H),7.02(s,1 H),6.97(d,J＝8.0Hz,1H),6.80(s,1H),1.29(s,1H).； 13 C NMR(150MHz, Acetone-d 6 )δ185.5,182.3,161.4,158.0,136.0(q,J＝31.2Hz),135.9,134.1(q, J＝32Hz),133.6,133.6,132.3,131.5,131.5,130.0,127.1,124.7(q,J＝270.6Hz), 124.5,124.4(q,J＝270.8Hz),124.2,122.4,122.4,120.4,119.8,116.3(q,J＝3 Hz),115.8(q,J＝3Hz),115.3,114.1(q,J＝3Hz),111.4.；HRMS(m/z):[M-H] - calcd.for C 27 H 13]2 Cl 3 F 6 N 4 O 4 S - ,706.9555；found,706.9553.
EXAMPLE 17 preparation of Compounds 1-16
Figure BDA0003266451510000261
Compound 2 (50.0 mg, 77.8. Mu. Mol), K were used 2 CO 3 (108mg, 0.778mmol), 2-mercaptobenzimidazole 3-16 (117mg, 0.778mmol), according to the general synthetic procedures to obtain crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 8. IR (neat): v max ＝2929,1604,1411,1333,1264, 1134,735,704cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ10.84(s,1H),7.74(d, J＝8.0Hz,1H),7.54-7.52(m,2H),7.47(d,J＝8.0Hz,1H),7.31–7.21(m,4 H),7.17(s,1H),7.00(d,J＝4.0Hz,2H).； 13 C NMR(100MHz,Acetone-d 6 )δ 186.2,183.5,161.5,158.6,145.6,136.2(q,J＝32Hz),134.8(q,J＝32Hz), 133.8,133.8,133.5,131.9,131.9,127.8,127.3,127.0,126.2,125.7,124.7,124.5 (q,J＝270Hz),124.4(q,J＝270Hz),124.3,124.0,124.0,122.5,121.9,120.0, 116.6(q,J＝4Hz),116.1(q,J＝4Hz),115.4(q,J＝4Hz),114.2(q,J＝4Hz), 111.4.；HRMS(m/z):[M-H] - calcd.for C 31 H 14 Cl 3 F 6 N 4 O 4 S - ,756.9711；found, 756.9703.
EXAMPLE 18 preparation of Compounds 1-17
Figure BDA0003266451510000271
Compound 2 (30.0 mg, 46.4. Mu. Mol), K were used 2 CO 3 (52.0 mg, 464. Mu. Mol), 2-mercaptopyridine-N-oxide 3-17 (122mg, 928. Mu. Mol), and the crude product was prepared according to the general synthetic procedure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 2. IR (neat) v max 2920,2851,1639,1604, 1418,1331,1214,1167,1130,1068,945,867,835cm –1 ； 1 H NMR(600MHz, Acetone-d 6 )δ12.93(s,1H),10.89(s,1H),10.27(s,1H),8.21–8.18(m,2H), 7.60(d,J＝7.8Hz,1H),7.37(d,J＝8.4Hz,1H),7.35(s,1H),7.28(t,J＝7.8 Hz,1H),7.26(s,1H),7.21(t,J＝6.4Hz,1H),7.18(s,1H),6.98(d,J＝8.4 Hz,1H),6.67(d,J＝7.8Hz,1H).； 13 C NMR(150MHz,Acetone-d 6 )δ186.9, 184.3,161.6,159.1,149.3,139.5,136.5(q,J＝32Hz),135.3(q,J＝32Hz), 135.0,134.1,131.8,127.3,126.1,126.0,125.6,124.9,124.6,124.4(q,J＝270.5 Hz),124.4,124.4(q,J＝270.9Hz),123.5,123.0,121.7,120.5,116.5(q,J＝3 Hz),116.3(q,J＝3Hz),115.5(q,J＝3Hz),114.6,111.0.；HRMS(m/z):[M+H] - calcd.for C 29 H 15 Cl 3 F 6 N 3 O 5 S + ,735.9697；found,735.9699.
EXAMPLE 19 preparation of Compounds 1-18
Figure BDA0003266451510000272
Compound 2 (50.0 mg, 77.8. Mu. Mol), K were used 2 CO 3 (108mg, 0.778mmol), 1H-imidazo [4,5-B]Pyridine-2-thiol 3-18 (235mg, 1.56mmol), was prepared as crude following the general synthetic procedure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v/v) = 5. IR (neat): v max ＝2923,1606,1399, 1332,1260,1068,799,750cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ10.86(s,1 H),8.29(d,J＝4.0Hz,1H),7.90(d,J＝8.0Hz,1H),7.81(d,J＝8.0Hz,1H), 7.53(d,J＝8.0Hz,1H),7.32–7.30(m,2H),7.19(t,J＝12Hz,2H),7.08(s, 1H),6.98(d,J＝8.0Hz,1H).； 13 C NMR(150MHz,Acetone-d 6 )δ186.7, 184.0,161.6,159.1,144.8,136.4(q,J＝33Hz),135.1(q,J＝33Hz),134.1, 134.0,134.0,132.1,132.1,126.7,126.0,125.6,124.9,124.4(q,J＝270Hz), 124.4(q,J＝271.5Hz),124.3,123.4,121.7,121.7,120.3,119.3,119.3,116.5(q, J＝3Hz),116.3(q,J＝3Hz),115.5,114.5,111.4.；HRMS(m/z):[M-H] - calcd. for C 30 H 13 Cl 3 F 6 N 5 O 4 S - ,757.9663；found,757.9655.
EXAMPLE 20 preparation of Compounds 1-19
Figure BDA0003266451510000281
The compound 2 (100mg, 155. Mu. Mol) and K were used 2 CO 3 (214mg, 1.55mol), 2-mercapto-4- (4-pyridyl) thiazole 3-19 (302mg, 1.55mmol), according to the general synthetic procedure. The crude product was purified by silica gel column chromatography (petroleum ether: acetone (v/v) = 3. IR (neat) v max ＝2925,1725,1605,1408,1333, 1132,950cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ8.55(dd,J＝8.0,4.0Hz,2 H),8.22–8.16(m,2H),8.03(s,1H),7.75–7.74(d,J＝4.0Hz,2H),7.28(d, J＝8.0Hz,1H),7.22(s,1H),7.09(s,1H),7.03(s,1H),6.92(d,J＝8.0Hz,1 H).； 13 C NMR(150MHz,Acetone-d 6 )δ187.9,182.4,166.5,161.7,160.1,154.1, 153.2,151.1,151.1,141.5,135.4,135.4,134.7,134.4,130.8,130.3,129.7,125.7, 125.5,124.6,124.4,123.1,122.3,121.0,121.0,119.8,119.3,118.7,117.4(q,J＝ 3Hz),116.0(q,J＝4.5Hz),115.3(q,J＝4.5Hz),113.7(q,J＝4.5Hz).；HRMS (m/z):[M-H] - calcd.for C 32 H 14 Cl 3 F 6 N 4 O 4 S 2 - ,800.9432；found,800.9431.
EXAMPLE 21 preparation of Compounds 1-20
Figure BDA0003266451510000291
Compounds 2 (200mg, 311. Mu. Mol), K were used 2 CO 3 (430mg, 3.11mmol) and 1-ethoxyl-5-mercapto-1H-tetrazole 3-20 (138mg, 3.11mmol) according to the general synthesis steps to prepare a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: acetone (v/v) = 4). IR (neat): v max ＝2927,2859,1703,1637,1601, 1505,1407,1331,1169,1126,1066,945,867,782cm –1 ； 1 H NMR(400MHz, Acetone-d 6 )δ10.82(s,1H)7.96(d,J＝7.6Hz,1H),7.68(d,J＝8Hz,1H), 7.32(d,J＝8.4Hz,1H),7.31(s,1H),7.19(s,1H),7.07–7.05(m,2H),4.57– 4.51(m,1H),4.46–4.39(m,2H),3.97–3.86(m,2H).； 13 C NMR(100MHz, Acetone-d 6 )δ186.0,183.5,160.3,157.9,151.6,135.8(q,J＝32Hz),134.7(q,J ＝32Hz),134.1,133.3,131.4,128.5,127.2,125.6,125.1,124.8,124.7(q,J＝ 270Hz),124.4(q,J＝270Hz),123.3,121.3,120.6,116.4(q,J＝4Hz),116.4(q, J＝4Hz),115.0(q,J＝4Hz),114.1(q,J＝4Hz),111.1,60.6,50.9.；HRMS (m/z):[M-H] - calcd.for C 27 H 14 Cl 3 F 6 N 6 O 5 S - ,752.9722；found,752.9727.
EXAMPLE 22 preparation of Compounds 1-21
Figure BDA0003266451510000292
Compound 2 (50.0 mg, 77.8. Mu. Mol), K were used 2 CO 3 (108mg, 0.778mmol), 3-mercapto-1, 2, 4-triazole 3-21 (78.7mg, 0.778mmol), according to the general synthesis steps to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: acetone (v/v) = 3). IR (neat) v max ＝2924,2855,1637,1601,1585,1408, 1332,1227,1171,1131,1067,945,868,786,105.cm –1 ； 1 H NMR(400MHz, Acetone-d 6 )δ13.39(s,1H),12.53(s,1H),10.92(s,1H),8.48(s,1H),7.89–7.85(m,1H),7.61(d,J＝8.0Hz,1H),7.31–7.29(m,2H),7.16(s,1H),7.01 –6.99(m,2H)； 13 C NMR(100MHz,Acetone-d 6 )δ186.6,184.1,161.7,159.1, 143.0,136.4(q,J＝32Hz),135.1(q,J＝32Hz),133.9,133.0,132.0,131.9, 126.2,125.7,125.2,124.4(q,J＝271Hz),124.4(q,J＝271Hz),124.2,122.7, 121.9,121.8,120.4,116.4(q,J＝4Hz),116.3(q,J＝4Hz),115.5(q,J＝4Hz), 114.5(q,J＝4Hz),111.3.；HRMS(m/z):[M-H] - calcd.for C 26 H 11 Cl 3 F 6 N 5 O 4 S - , 707.9507；found,707.9504.
EXAMPLE 23 preparation of Compounds 1-22
Figure BDA0003266451510000301
Compound 2 (50.0 mg, 77.4. Mu. Mol), K were used 2 CO 3 (107mg, 774. Mu. Mol), 2-pyridylethylthiol 3-22 (103. Mu.L, 774. Mu. Mol), according to the general synthetic procedure, a crude product was obtained. The crude product was purified by silica gel column chromatography using petroleum ether: acetone (v/v) = 15. IR (neat) v max ＝3064,1935,1637,1597,1505,1405,1331,1170,1127,1066,944, 865,798cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ8.47(d,J＝5.2Hz,1H), 8.08(d,J＝8.4Hz,1H),7.67(td,J＝7.6,2.0Hz,1H),7.62(d,J＝8.4Hz,1 H),7.34(d,J＝8.4Hz 1H),7.32(s,1H),7.20(dd,J＝7.2,4.8Hz,1H),7.15– 7.12(m,2H),7.06(s,1H),6.94(dd,J＝8.4,1.2Hz 1H),3.10-3.03(m,1H), 2.98–2.75(m,3H)； 13 C NMR(150MHz,Acetone-d 6 )δ186.7,184.5,161.7, 159.6,159.4,149.9,137.4,136.3(q,J＝31.5Hz),135.2(q,J＝31.5Hz),134.0, 132.5,131.9,125.9,125.8,125.7,124.4,124.4(q,J＝271.5Hz),124.3(q,J＝ 271.5Hz),123.9,122.6,122.4,122.2,122.1,120.7,116.4(q,J＝3Hz),116.0(q, J＝4.5Hz),115.4(q,J＝3Hz),114.6(q,J＝3Hz),110.8,38.3,35.3；HRMS (m/z):[M-H] - calcd.for C 31 H 17 Cl 3 F 6 N 3 O 4 S - ,745.9915；found,745.9910.
Example 24: experiment on reducing CPE of cells infected with flavivirus and enterovirus by the compound represented by formula 1 experimental materials and experimental methods used in the present invention are as follows:
(1) Cell culture and cell lines, viral strains
The Vero, BHK and RD are preserved in the laboratory, and the source and passage times are clear. Cell culture at 37 deg.C, 5% 2 The humidity of (2) saturates the cell culture chamber. Passages were generally carried out as 1. Cell growthThe complete medium used was a DMEM high-sugar medium (from Gibco, cat # 11995-065) supplemented with 10% of FBS (from Gbico, cat # 16000-044) and the dual penicillin antibiotic (from Gbico, cat # 15140-122), and the maintenance medium was a DMEM high-sugar medium supplemented with 2% of FBS and the dual penicillin antibiotic.
The virus strains used during the experiments and their corresponding cell lines are shown in the following table:
Figure BDA0003266451510000311
(2) Cell viability assay
When the anti-ZIKV activity of the Vero cell-based compound is evaluated, the treatment time after adding the reagent is 6 days; when the anti-ZIKV, DENV, YFV and JEV activity evaluation of the compound based on the BHK cells is carried out, the treatment time after adding the medicine is 7 days; the post-dosing treatment time was 3 days when the RD cell based compounds were evaluated for their anti-enterovirus activity. Cell viability of treated cells CellTiter
Figure BDA0003266451510000312
Luminescent Cell Viability Assay (available from Promega under the accession number G7572).
The experiment scheme is illustrated by taking a ZIKV infection cell CPE inhibition experiment based on Vero cells as an example, namely: the bottle-bottom confluent Vero cells were resuspended in complete medium after 0.25% EDTA trypsinization to prepare single cell suspension, which was then counted and inoculated into 96 well plates at a density of 10000 cells per well, and saturated in humidity at 37 ℃ 5% CO 2 Incubated under conditions for 24 hours. Diluting the ZIKV virus stock solution by using a maintenance medium, and adding the diluted ZIKV virus stock solution into a 96-well plate to ensure that the final concentration of the diluted ZIKV virus stock solution is 100TCID50; meanwhile, the compound represented by formula 1 was diluted in a 96-well plate with NITD008 (purchased from MCE under the accession number HY-12957) in a maintenance medium at a double ratio to give final concentrations of 200. Mu.M, 66.67. Mu.M, 22.22. Mu.M, 7.41. Mu.M, 2.47. Mu.M, 0.82. Mu.M, 0.27. Mu.M and 0.09. Mu.M, respectively, of the compound represented by formula 1 and 10. Mu.M, 3.33. Mu.M, 1.11. Mu.M, 0.37. Mu.M, 0.12. Mu.M, 0.04. Mu.M, 0.01. Mu.M and 0.003. Mu.M, respectively, of the NITD 008. A cell control group and a virus control group were set. Treatment 6After a day, the supernatant was discarded, and CellTiter diluted 2-fold with PBS buffer (from Gibco, cat. C10010500 BT) was added to each well
Figure BDA0003266451510000323
The luminecent Cell Viability detection solution is subjected to shake lysis for 5min in the dark, is kept stand for 3min, and finally the fluorescence signal intensity is measured by Molecular Devices M5. The CPE calculation formula is as follows:
Figure BDA0003266451510000321
the results are shown in Table 1. The results show that the compound synthesized in the examples of the present invention has strong antiviral activity against flavivirus and enterovirus.
Table 1: in vitro antiviral Activity of Compounds of the examples of the invention
Figure BDA0003266451510000322
Figure BDA0003266451510000331
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention and not to limit it; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art will understand that: modifications to the specific embodiments of the invention or equivalent substitutions for parts of the technical features may be made; without departing from the spirit of the present invention, it is intended to cover all aspects of the invention as defined by the appended claims.

Claims (31)

1. A compound represented by formula 1, its racemate or a pharmaceutically acceptable salt,
Figure FDA0003877727830000011
wherein: n is an integer of 0 to 5,
r is hydroxyl, C 1 -C 6 Alkoxycarbonyl group, C 1 -C 6 Alkyl, azido, pyrazinyl, benzothiazolyl, pyrimidinyl, pyridyl, benzoxazolyl, 1,3, 4-thiadiazolyl, 1H-tetrazolyl, imidazolyl, benzimidazolyl, 1-oxy-pyridyl, 1H-imidazo [4,5-b ]]Pyridyl, thiazolyl, 1,2, 4-triazolyl, pyrazinyl, benzothiazolyl, pyrimidinyl, pyridyl, benzoxazolyl, 1,3, 4-thiadiazolyl, 1H-tetrazolyl, imidazolyl, benzimidazolyl, 1-oxy-pyridyl, 1H-imidazo [4,5-b ]]Pyridyl, thiazolyl or 1,2, 4-triazolyl optionally substituted with one or more R 1 Substituted, each R 1 Each independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, hydroxy-substituted C 1 -C 6 Alkyl, methylamino substituted C 1 -C 6 Alkyl, dimethylamino substituted C 1 -C 6 Alkyl or pyridyl.
2. A compound according to claim 1, racemate or a pharmaceutically acceptable salt thereof wherein: n is 0, 1,2, 3,4 or 5.
3. A compound according to claim 2, racemate or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1,2, 3 or 4.
4. A compound according to claim 3, racemate or pharmaceutically acceptable salt thereof, wherein: n is 0, 1,2 or 3.
5. The compound of claim 1, racemate or pharmaceutically acceptable salt thereof, wherein: n is 1,2, 3,4 or 5.
6. A compound, racemate or pharmaceutically acceptable salt according to claim 5, wherein: n is 1,2, 3 or 4.
7. A compound, racemate or pharmaceutically acceptable salt according to claim 6, wherein: n is 1,2 or 3.
8. The compound of claim 1, racemate or pharmaceutically acceptable salt thereof, wherein: n is 1,2, 3,4 or 5, and R is hydroxy, C 1 -C 6 An alkoxycarbonyl or azido group; or
n is 0, 1,2, 3,4 or 5 and R is pyrazinyl, benzothiazolyl, pyrimidinyl, pyridyl, benzoxazolyl, 1,3, 4-thiadiazolyl, 1H-tetrazoxazolyl, imidazolyl, benzimidazolyl, 1-oxy-pyridyl, 1H-imidazo [4,5-b]Pyridyl, thiazolyl, 1,2, 4-triazolyl, pyrazinyl, benzothiazolyl, pyrimidinyl, pyridyl, benzoxazolyl, 1,3, 4-thiadiazolyl, 1H-tetrazolyl, imidazolyl, benzimidazolyl, 1-oxy-pyridyl, 1H-imidazo [4,5-b ] azo]Pyridyl, thiazolyl or 1,2, 4-triazolyl optionally substituted with one or more R 1 Substituted, each R 1 Each independently is C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy, hydroxy-substituted C 1 -C 6 Alkyl, methylamino substituted C 1 -C 6 Alkyl, dimethylamino substituted C 1 -C 6 Alkyl or pyridyl.
9. A compound according to claim 1, racemate or a pharmaceutically acceptable salt thereof wherein: r is hydroxy, C 1 -C 4 Alkoxycarbonyl group, C 1 -C 4 An alkyl group or an azido group.
10. The compound of claim 9, racemate or a pharmaceutically acceptable salt thereof, wherein: r is hydroxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, methyl, ethyl, n-propyl, n-butyl or azido.
11. The compound of claim 10, racemate or pharmaceutically acceptable salt thereof, wherein: r is hydroxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or azido.
12. A compound according to claim 11, racemate or a pharmaceutically acceptable salt thereof wherein: r is hydroxyl, ethoxycarbonyl or azido.
13. A compound according to claim 1, racemate or a pharmaceutically acceptable salt thereof wherein: r is pyrazin-2-yl, benzothiazol-2-yl, pyrimidin-2-yl, pyridin-2-yl, benzoxazol-2-yl, pyridin-3-yl, 5-methyl-1, 3, 4-thiadiazol-2-yl, 1- (2-dimethylaminoethyl) -1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, imidazol-2-yl, benzimidazol-2-yl, 1-oxy-pyridin-2-yl, 1H-imidazo [4,5-b ] pyridin-2-yl, 4- (4-pyridyl) thiazol-2-yl, 1-hydroxyethyl-1H-tetrazol-5-yl, 1,2, 4-triazol-3-yl.
14. A compound as claimed in any one of claims 1 to 8, racemate or a pharmaceutically acceptable salt thereof, wherein: each R 1 Each independently is C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy, hydroxy-substituted C 1 -C 4 Alkyl, methylamino substituted C 1 -C 4 Alkyl, dimethylamino substituted C 1 -C 4 Alkyl or pyridyl.
15. The compound of claim 14, racemate or pharmaceutically acceptable salt thereof, wherein: each R 1 Each independently is methyl, ethyl, n-propyl, n-butyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or pyridyl.
16. The compound of claim 15, racemate or pharmaceutically acceptable salt thereof, wherein: each R 1 Each independently of the other being methyl, dimethylaminoethylA hydroxy ethyl group or a pyridin-4-yl group.
17. A compound according to any one of claims 1 to 13, racemates or pharmaceutically acceptable salts thereof, wherein the compound is selected from:
Figure FDA0003877727830000031
Figure FDA0003877727830000041
Figure FDA0003877727830000051
18. a pharmaceutical composition comprising at least one compound of formula 1, racemate or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, and one or more pharmaceutically acceptable carriers or excipients.
19. A process for the preparation of a compound as claimed in any one of claims 1 to 17, racemate or a pharmaceutically acceptable salt thereof, comprising:
Figure FDA0003877727830000061
1) Providing a compound shown as a formula 2 and a compound shown as a formula 3;
2) Subjecting a compound represented by formula 2 to a nucleophilic substitution reaction with a compound represented by formula 3 in a solvent and in the presence of a base;
wherein n and R are as defined in any one of claims 1 to 17.
20. The method of claim 19, wherein the nucleophilic substitution reaction is performed in an inert gas atmosphere.
21. The method of claim 20, wherein the inert gas atmosphere is an argon atmosphere.
22. The method of claim 20 or 21, wherein the nucleophilic substitution reaction is performed at a temperature of 25 ℃ to 100 ℃.
23. The method of claim 19, wherein the solvent is selected from the group consisting of dimethyl sulfoxide, N-methylpyrrolidone, N' -dimethylformamide, acetonitrile, toluene, or any combination thereof.
24. The process of claim 23, wherein the solvent is N, N' -dimethylformamide.
25. The process of claim 19, wherein the base is selected from potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, 2, 4-lutidine, N' -diisopropylethylamine, or any combination thereof.
26. The process of claim 25, wherein the base is potassium carbonate.
27. Use of a compound according to any one of claims 1 to 17, its racemate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for combating viruses,
wherein: the antiviral agent is against a virus of the genus flavivirus or against a virus of the genus enterovirus.
28. Use of a compound according to any one of claims 1 to 17, racemate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of viral infections or diseases caused by viral infections,
wherein: the viral infection is an infection caused by a virus of the flavivirus genus or a virus of the enterovirus genus.
29. Use of a compound according to any one of claims 1 to 17, racemate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting replication or proliferation of a virus in a cell,
wherein: the virus is a virus of the genus flavivirus or a virus of the genus enterovirus.
30. The use of any one of claims 27-29, wherein: the viruses of the flavivirus genus are Zika virus, dengue virus, japanese encephalitis virus and yellow fever virus; the virus of the enterovirus genus is Coxsackie virus or enterovirus 71.
31. The use of claim 30, wherein the coxsackievirus is of CA6 or CA16 type.
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