CN107814803A - Nafoxidine and glyoxalidine ketone and cycle compound and its prepare and purposes pharmaceutically - Google Patents

Nafoxidine and glyoxalidine ketone and cycle compound and its prepare and purposes pharmaceutically Download PDF

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CN107814803A
CN107814803A CN201710809939.6A CN201710809939A CN107814803A CN 107814803 A CN107814803 A CN 107814803A CN 201710809939 A CN201710809939 A CN 201710809939A CN 107814803 A CN107814803 A CN 107814803A
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arbitrarily substituted
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CN107814803B (en
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周国春
徐斌
翁智兵
姜滨利
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Nanjing Tech University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract

The invention discloses a kind of nafoxidine and glyoxalidine ketone and cycle compound and its prepare and purposes pharmaceutically.Its compound is compound, isomers or its pharmaceutically acceptable salt shown in formula (I)；Compound, isomers or its pharmaceutically acceptable salt of this hair invention can be applicable to be had in the medicine of related disorders (such as dengue fever, dengue hemorrhagic fever, dengue shock syndrome, stockaded village's card, chikungunya, encephalitis B, yellow fever, hepatitis C, West Nile disease) caused by preparation prevention or treatment and dengue fever virus and correlated virus.

Description

Nafoxidine and glyoxalidine ketone and cycle compound and its prepare and pharmaceutically Purposes
Technical field
The invention belongs to medicinal chemistry art, and in particular to nafoxidine and glyoxalidine ketone and cycle compound, solid The application of isomers or its pharmaceutically acceptable salt pharmaceutically.
Background technology
Dengue fever disease includes dengue fever (dengue fever, DF), dengue hemorrhagic fever (dengue hemorrhagic Fever, DHF) and dengue shock syndrome (dengue shock syndrome, DSS) symptom, it is by flaviviridae (flaviviridae) caused by dengue fever virus (dengue virus, DENV) infection.Dengue pyreticosis is infected mainly in the torrid zone And subtropical zone, pass through Aedes aegypti (Aedes aegypti), aedes albopictus (Aedes albopictus) and Pohle Ni Xi What sub- yellow-fever mosquito (Aedes polynesiensis) was propagated, typically had after communicable yellow-fever mosquito (Aedes) is bitten to go out for 3-14 days Existing dengue fever disease symptoms (average 4-7 days).The earliest pandemic record of dengue fever disease be Asia before more than 200 years, Africa, North America, present dengue fever disease occurred in global more than 100 individual countries, it is estimated that at present the whole world there are about 2,500,000,000 populations by To the threat of dengue fever disease, 2.5 ten thousand people are there are about every year and die from dengue fever disease.
Under the influence of global environment deteriorates and warmed etc. factors, Epidemic Situation of Dengue Fever has the trend of expansion, but mesh in recent years Preceding generation and the prevalence for being used to prevent dengue fever disease without effective vaccine, also without the medicine of effective anti-dengue virus Available for clinical treatment dengue fever disease, present clinical treatment is mainly progressive supporting treatment (intensive Supportive therapy), wherein it is Main Means to maintain isohydria.These limited means can not tackle Dengue pyreticosis DHF and DSS caused by poison infection has the situation of the higher death rate (~5%), so to caused by dengue virus infection The drug research of dengue fever disease seems particularly important and urgent.
Dengue fever virus is single strand plus RNA virus, containing about 11000 bases, shares 4 serotypes, i.e. DENV-1, DENV-2, DENV-3 and DENV-4, wherein DENV-2 virulence are most strong.Dengue fever virus geneome RNA can be divided into two parts：5 ' ends 3 structural proteins (C-capsid, prM-precursor membrane and E-envelope) of 1/4 sequential encoding virus, 7 non-structural proteins (NS1, NS2, NS3, NS4A, NS4B and NS5) of sequential encoding at 3 ' ends 3/4.Although these albumen are for stepping on The existence of leather fever virus is all critically important, and they can serve as anti-dengue virus drug targets, but due to these protein maturations Dependent on NS3 proteinase activities, effectively suppress NS3 proteinase activities and be likely to be breached reduction or block dengue fever virus to replicate and numerous The purpose grown, thus dengue fever virus NS3 be it is most studied be also likely to be most important dengue fever virus drug targets (Aruna Sampath,R.PadmanabhanAntiviral Res.2009,81,6–15)..Research shows that NS2B is as NS3 The confactor of protease plays enzymatic activity to NS3 and plays vital effect, so inhibitor is to NS3 inhibition of enzyme activity energy The research of power use NS3-NS2B compounds (Aruna Sampath, R.PadmanabhanAntiviral Res.2009, 81,6–15)。。
Flaviviridae family (Flaviviridae family) belonging to dengue fever virus has individual virus panel more than 70, wherein The relatively more and harm of research it is larger be yellow fever (yellow fever), west nile virus (West Nile virus, WNV), hepatitis C virus (hepatitis C virus, HCV), dengue fever virus (dengue virus, DENV), stockaded village's card (Zika) Virus infection, chikungunya disease (Chikungunya) virus infection etc., because they at many aspects of life cycle are similar , functionally there is great similitude in especially NS3-NS2B's, so generally will during NS3 protease drug researches They are connected each other together, and other flavivirus that these compounds can be used for preventing and treating outside dengue fever virus draw The relevant disease risen, such as yellow fever, West Nile Virus infection, zika virus infection, chikungunya disease (Chikungunya) disease Malicious infection, hepatitis C, encephalitis B, tick-borne encephalitis and AIDS caused by HIV etc. (Aruna Sampath, R.PadmanabhanAntiviral Res.2009,81,6–15)。
The inhibitor research for yellow fever virus NS3-NS2B is always the emphasis of antiviral drugs in recent years, is also had recently Some cyclic polypeptide class inhibitor (Shaoqiong Xu, Hua Li, Xiaoxia Shao, Chongxu Fan, Bryan Ericksen,Jinsong Liu,Chengwu Chi,Chunguang Wang J.Med.Chem.2012,55,6881-7.)、 Phenyl hydrazones inhibitor (Jing Deng, Ning Li, Hongchuan Liu, Zhili Zuo, Oi Wah Liew, Weijun Xu, Gang Chen,Xiankun Tong,Wei Tang,Jin Zhu,Jianping Zuo,Hualiang Jiang,Cai-Guang Yang, Jian Li, Weiliang Zhu J.Med.Chem.2012,55,6278-6293.) report, and this patent early stage Dipeptide NS3 inhibitor patent (201310354848.X) and article report (Guo-Chun Zhou, Zhibing Weng, Xiaoxia Shao,Fang Liu,Xin Nie,Jinsong Liu,Decai Wang,Chunguang Wang,Kai Guo* “Discovery and SAR studies of methionine–proline anilides as dengue virus NS2B-NS3protease inhibitors”,Bioorg Med Chem Lett 2013,23,6549–6554.)。
The content of the invention
The purpose of the present invention is on the basis of existing technology, there is provided one kind has the nafoxidine and dihydro of corresponding activity Imidazolone and cycle compound and its derivative, stereoisomer, cis-trans-isomer or its pharmaceutically acceptable salt.
It is a further object of the present invention to provide a kind of preparation method of above-claimed cpd.
Third object of the present invention is to provide a kind of purposes of above-claimed cpd in terms of pharmacy.
The purpose of the present invention can be reached by following measures：
Compound, isomers or its pharmaceutically acceptable salt shown in a kind of formula (I),
Wherein,
X1、X2It is identical or different, X1、X2Separately selected from covalent bond, O, S, S (O), S (O2), the C that arbitrarily substitutes6-14 Aryl, N (R5) or C (R6R7)；
X1-R1、X2-R2It is identical or different；
Or X1-R1、X2-R2Concurrently or separately form ring；
R1、R2、R3、R4、R5、R6、R7、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, arbitrarily take The C in generation1-10Alkyl, the C arbitrarily substituted3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-10Alkylene, The C arbitrarily substituted3-8Cycloalkenyl group, the C arbitrarily substituted6-14Aryl, the C arbitrarily substituted3-14Heteroaryl, the C arbitrarily substituted1-10Alkane Epoxide, the C arbitrarily substituted1-10Alkylthio group, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, arbitrarily substitute C1-10Carbonyl, the C arbitrarily substituted1-10Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde Base, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxyl Base alkyl or C6-14Nitroaryl；
Or R3、R4Merge into carbonyl；
Or X1、X2、R1、R2Formed A rings and ring；
Or X2、R2With Z1Between formed A rings and ring or loop coil；
Or R3With R4The loop coil of B rings can be formed；
* R configurations or S configurations are expressed as；
The A rings be formula (I) compound in the five-membered ring containing two N, the B rings be compound of formula I in R3And R4Phase The five-membered ring containing a N of connection.
Preferably, the compound shown in formula (I), isomers or its pharmaceutically acceptable salt, wherein：
R1、R2、R5、R6、R7、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, arbitrarily substitute C1-8Alkyl, the C arbitrarily substituted3-8Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-8Alkylene, arbitrarily take The C in generation3-8Cycloalkenyl group, the C arbitrarily substituted6-10Aryl, the C arbitrarily substituted3-10Heteroaryl, the C arbitrarily substituted1-8Alkoxy, appoint Anticipate the C substituted1-8Alkylthio group, the C arbitrarily substituted1-8Ester group, the C arbitrarily substituted1-8Sulfonyl, the C arbitrarily substituted1-8Carbonyl, appoint Anticipate the C substituted1-8Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14 Nitroaryl；
R3、R4Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, the C arbitrarily substituted1-8It is alkyl, any Substituted C3-8Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-8Alkylene, the C arbitrarily substituted3-8Cycloolefin Base, the C arbitrarily substituted1-8Alkoxy, the C arbitrarily substituted1-8Alkylthio group, the C arbitrarily substituted1-8Carbonyl or the C arbitrarily substituted1-8Acyl Amido；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14Nitroaryl；Or R3、R4Merge into carbonyl.
It is further preferred that R3、R4、Z1For H, X1For covalent bond, X2Selected from covalent bond or C (R6R7), wherein R6、R7For H；
R1、R2Separately selected from H, cyano group, amino, nitro, hydroxyl, the C arbitrarily substituted1-10Alkyl, arbitrarily substitute C3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-10Alkylene, the C arbitrarily substituted3-8Cycloalkenyl group, appoint Anticipate the C substituted6-14Aryl, the C arbitrarily substituted3-14Heteroaryl, the C arbitrarily substituted1-10Alkoxy, the C arbitrarily substituted1-10Alkane sulphur Base, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, the C arbitrarily substituted1-10Carbonyl, the C arbitrarily substituted1-10Acyl Amido；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14Nitroaryl；It is more excellent Choosing, R1、R2Separately selected from H, cyano group, amino, nitro, hydroxyl, the C arbitrarily substituted1-6Alkyl, the C arbitrarily substituted3-6 Cycloalkyl, the C arbitrarily substituted6-10Aryl, the C arbitrarily substituted3-10Heteroaryl；Substituent be selected from halogen, cyano group, amino, nitro, Hydroxyl, borate, C1-4Aldehyde radical, C1~4Alkyl, C1~4Haloalkyl, C1~4Alkoxy, C1~4Alkylthio group, C2~6Alkylene, C0-4Carbonyl Base, C0-4Ester group, C1~4Hydroxy alkyl or C6-10Nitroaryl；R still more preferably1、R2Separately it is selected from H, arbitrarily takes The C in generation1-6Alkyl, the C arbitrarily substituted6-10Aryl；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, C1~4Alkyl, C1~4 Haloalkyl, C1~4Alkoxy.
Compound, isomers or its pharmaceutically acceptable salt shown in a kind of formula (II) or formula (III)：
Wherein,
X1、X2Can be with identical or different, X1、X2Separately selected from covalent bond, O, S, S (O), S (O2), arbitrarily substitute C6-14Aryl, N (R5) or C (R6R7)；
X1-R1、X2-R2It is identical or different；
Or X1-R1、X2-R2Ring can concurrently or separately be formed；
R1、R2、R5、R6、R7、Z1Separately selected from H, cyano group, amino, nitro, hydroxyl, the C arbitrarily substituted1-10Alkane Base, the C arbitrarily substituted3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-10Alkylene, arbitrarily substitute C3-8Cycloalkenyl group, the C arbitrarily substituted6-14Aryl, the C arbitrarily substituted3-14Heteroaryl, the C arbitrarily substituted1-10It is alkoxy, any Substituted C1-10Alkylthio group, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, the C arbitrarily substituted1-10Carbonyl, appoint Anticipate the C substituted1-10Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14 Nitroaryl；
Or X1、X2、R1、R2Formed A rings and ring；
Or X2、R2With Z1Between formed A rings and ring or loop coil；
* R configurations or S configurations are expressed as；
The A rings are the five-membered ring containing two N in formula (II) or formula (III) compound.
Preferably, formula (II) or compound, isomers or its pharmaceutically acceptable salt shown in formula (III), wherein：
R1、R2、R5、R6、R7、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, arbitrarily substitute C1-8Alkyl, the C arbitrarily substituted3-8Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-8Alkylene, arbitrarily take The C in generation3-8Cycloalkenyl group, the C arbitrarily substituted6-10Aryl, the C arbitrarily substituted3-10Heteroaryl, the C arbitrarily substituted1-8Alkoxy, appoint Anticipate the C substituted1-8Alkylthio group, the C arbitrarily substituted1-8Ester group, the C arbitrarily substituted1-8Sulfonyl, the C arbitrarily substituted1-8Carbonyl, appoint Anticipate the C substituted1-8Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14 Nitroaryl.
It is further preferred that Z1For H.
Compound, isomers or its pharmaceutically acceptable salt shown in a kind of formula (IV)：
Wherein,
X1、X2And X3Can be with identical or different, X1、X2And X3Separately selected from covalent bond, O, S, S (O), S (O2), appoint Anticipate the C substituted6-14Aryl, N (R5) or C (R6R7)；
X1-R1、X2-R2And X3-R9It is identical or different；
Or X1-R1、X2-R2、X3-R9Ring can concurrently or separately be formed；
R1、R2、R5、R6、R7、R8、R9、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, arbitrarily take The C in generation1-10Alkyl, the C arbitrarily substituted3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-10Alkylene, The C arbitrarily substituted3-8Cycloalkenyl group, the C arbitrarily substituted6-14Aryl, the C arbitrarily substituted3-14Heteroaryl, the C arbitrarily substituted1-10Alkane Epoxide, the C arbitrarily substituted1-10Alkylthio group, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, arbitrarily substitute C1-10Carbonyl, the C arbitrarily substituted1-10Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde Base, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxyl Base alkyl or C6-14Nitroaryl；
Or X1、X2、R1、R2Formed A rings and ring；
Or X2、R2With Z1Between formed A rings and ring or loop coil；
Or R8Separately or concurrently with R9、X3Between formed B rings loop coil；
Or R9、X3Between cyclization；
* R configurations or S configurations are expressed as；
The A rings be formula (I) compound in the five-membered ring containing two N, the B rings be compound of formula I in R8It is connected The five-membered ring containing a N connect.
Preferably, the compound shown in formula (IV), isomers or its pharmaceutically acceptable salt, wherein：
X1And X2Can be with identical or different, X1And X2Separately selected from covalent bond, O, S, S (O), S (O2), any substitution C6-14Aryl, N (R5) or C (R6R7)；X3For covalent bond；
R1、R2、R5、R6、R7、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, arbitrarily substitute C1-8Alkyl, the C arbitrarily substituted3-8Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-8Alkylene, arbitrarily take The C in generation3-8Cycloalkenyl group, the C arbitrarily substituted6-10Aryl, the C arbitrarily substituted3-10Heteroaryl, the C arbitrarily substituted1-8Alkoxy, appoint Anticipate the C substituted1-8Alkylthio group, the C arbitrarily substituted1-8Ester group, the C arbitrarily substituted1-8Sulfonyl, the C arbitrarily substituted1-8Carbonyl, appoint Anticipate the C substituted1-8Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14 Nitroaryl；
R8For H；R9The C selected from H, arbitrarily substituted1-8Alkyl, the C arbitrarily substituted3-8Cycloalkyl, the C arbitrarily substituted3-8Heterocycle Alkyl, the C arbitrarily substituted2-8Alkylene, the C arbitrarily substituted3-8Cycloalkenyl group, the C arbitrarily substituted1-8Alkoxy, arbitrarily substitute C1-8Alkylthio group, the C arbitrarily substituted1-8Carbonyl or the C arbitrarily substituted1-8Amide groups；Substituent is selected from halogen, cyano group, amino, nitre Base, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14Nitroaryl.
Compound, isomers or its pharmaceutically acceptable salt shown in a kind of formula (V)：
Wherein,
X1、X2Can be with identical or different, X1、X2Separately selected from covalent bond, O, S, S (O), S (O2), arbitrarily substitute C6-14Aryl, N (R5) or C (R6R7)；
X1-R1、X2-R2It is identical or different；
Or X1-R1、X2-R2Concurrently or separately form ring；
R1、R2、R5、R6、R7、R8、R10、R11、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, appoint Anticipate the C substituted1-10Alkyl, the C arbitrarily substituted3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-10Alkene Base, the C arbitrarily substituted3-8Cycloalkenyl group, the C arbitrarily substituted6-14Aryl, the C arbitrarily substituted3-14Heteroaryl, arbitrarily substitute C1-10Alkoxy, the C arbitrarily substituted1-10Alkylthio group, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, arbitrarily take The C in generation1-10Carbonyl, the C arbitrarily substituted1-10Amide groups；Substituent be selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14Nitroaryl；
Or R10For amino acid residue；
Or X1、X2、R1、R2Formed A rings and ring；
Or X2、R2With Z1Between formed A rings and ring or loop coil；
Or R8Separately or concurrently with R10、R11Between formed B rings loop coil；
Or R10、R11Between cyclization；
* R configurations or S configurations are expressed as；
The A rings be formula (I) compound in the five-membered ring containing two N, the B rings be compound of formula I in R8It is connected The five-membered ring containing a N connect.
Preferably, the compound shown in formula (V), isomers or its pharmaceutically acceptable salt, wherein：
R1、R2、R5、R6、R7、R8、R10、R11、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, appoint Anticipate the C substituted1-8Alkyl, the C arbitrarily substituted3-8Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-8Alkene Base, the C arbitrarily substituted3-8Cycloalkenyl group, the C arbitrarily substituted6-10Aryl, the C arbitrarily substituted3-10Heteroaryl, the C arbitrarily substituted1-8 Alkoxy, the C arbitrarily substituted1-8Alkylthio group, the C arbitrarily substituted1-8Ester group, the C arbitrarily substituted1-8Sulfonyl, arbitrarily substitute C1-8Carbonyl, the C arbitrarily substituted1-8Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde Base, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxyl Base alkyl or C6-14Nitroaryl.
Compound, isomers or its pharmaceutically acceptable salt shown in a kind of formula (VI)：
Wherein,
X1、X2、X4Can be with identical or different, X1、X2、X4Separately selected from covalent bond, O, S, S (O), S (O2), it is any Substituted C6-14Aryl, N (R5) or C (R6R7)；
X1-R1、X2-R2、X4-R13It is identical or different；
Or X1-R1、X2-R2、X4-R13Ring can concurrently or separately be formed；
R1、R2、R5、R6、R7、R8、R12、R13、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, appoint Anticipate the C substituted1-10Alkyl, the C arbitrarily substituted3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-10Alkene Base, the C arbitrarily substituted3-8Cycloalkenyl group, the C arbitrarily substituted6-14Aryl, the C arbitrarily substituted3-14Heteroaryl, arbitrarily substitute C1-10Alkoxy, the C arbitrarily substituted1-10Alkylthio group, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, arbitrarily take The C in generation1-10Carbonyl, the C arbitrarily substituted1-10Amide groups；Substituent be selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14Nitroaryl；
Or R12For amino acid residue；
Or X1、X2、R1、R2Formed A rings and ring；
Or X2、R2With Z1Between formed A rings and ring or loop coil；
Or R8Separately or concurrently with X4、R12、R13Between formed B rings loop coil；
Or R12Individually or simultaneously with X4、R13Between cyclization；
* R configurations or S configurations are expressed as；
The A rings be formula (I) compound in the five-membered ring containing two N, the B rings be compound of formula I in R8It is connected The five-membered ring containing a N connect.
Compound, isomers or its pharmaceutically acceptable salt shown in a kind of formula (VII)：
Wherein,
X1、X2、X5Can be with identical or different, X1、X2、X5Separately selected from covalent bond, O, S, S (O), S (O2), it is any Substituted C6-14Aryl, N (R5) or C (R6R7)；
X1-R1、X2-R2、X5-R14It is identical or different；
Or X1-R1、X2-R2、X5-R14Ring can concurrently or separately be formed；
R1、R2、R5、R6、R7、R8、R14、R15、R16、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl Base, the C arbitrarily substituted1-10Alkyl, the C arbitrarily substituted3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, arbitrarily substitute C2-10Alkylene, the C arbitrarily substituted3-8Cycloalkenyl group, the C arbitrarily substituted6-14Aryl, the C arbitrarily substituted3-14It is heteroaryl, any Substituted C1-10Alkoxy, the C arbitrarily substituted1-10Alkylthio group, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, The C arbitrarily substituted1-10Carbonyl, the C arbitrarily substituted1-10Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, boron Acid esters, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6 Ester group, C1~6Hydroxy alkyl or C6-14Nitroaryl；
Or X1、X2、R1、R2Formed A rings and ring；
Or X2、R2With Z1Between formed A rings and ring or loop coil；
Or R8Separately or concurrently with X5、R14、R15、R16Between formed B rings loop coil；
Or R15、R16Between form ring；
Or X5Separately or concurrently with R15、R16Between cyclization；
Or R14Separately or concurrently with R15、R16Between cyclization；
* R configurations or S configurations are expressed as；
The A rings be formula (I) compound in the five-membered ring containing two N, the B rings be compound of formula I in R8It is connected The five-membered ring containing a N connect.
Compound, isomers or its pharmaceutically acceptable salt shown in a kind of formula (VIII)：
Wherein,
X1、X2And X6Can be with identical or different, X1、X2And X6Separately selected from covalent bond, O, S, S (O), S (O2), appoint Anticipate the C substituted6-14Aryl, N (R5) or C (R6R7)；
X1-R1、X2-R2And X6-R17It is identical or different；
Or X1-R1、X2-R2、X6-R18Ring can concurrently or separately be formed；
R1、R2、R5、R6、R7、R8、R17、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, any Substituted C1-10Alkyl, the C arbitrarily substituted3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-10Alkene Base, the C arbitrarily substituted3-8Cycloalkenyl group, the C arbitrarily substituted6-14Aryl, the C arbitrarily substituted3-14Heteroaryl, arbitrarily substitute C1-10Alkoxy, the C arbitrarily substituted1-10Alkylthio group, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, arbitrarily take The C in generation1-10Carbonyl, the C arbitrarily substituted1-10Amide groups；Substituent be selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14Nitroaryl；
Or X1、X2、R1、R2Formed A rings and ring；
Or X2、R2With Z1Between formed A rings and ring or loop coil；
Or R8Separately or concurrently with R17、X6Between formed B rings loop coil；
* R configurations or S configurations are expressed as；
The A rings be formula (I) compound in the five-membered ring containing two N, the B rings be compound of formula I in R8It is connected The five-membered ring containing a N connect.
The present invention also provides the preparation method of above-claimed cpd, it is characterised in that comprises the following steps：
The present invention also provides：
Above-mentioned each compound, isomers or its pharmaceutically acceptable salt of the present invention is preparing prevention or treatment and Dengue Fever virus protease N S3 inhibitor has the purposes in the medicine of related disorders.
The purposes of above-claimed cpd, it is characterised in that described have with dengue fever virus protease N S3 inhibitor the related disorders to be Dengue fever caused by dengue fever virus and dengue hemorrhagic fever and Dengue shock syndrome.
Above-mentioned compound, isomers or its salt is preparing the application in being used to treat or prevent disease medicament, wherein institute Disease is stated as dengue fever disease, yellow fever, West Nile Virus infection, zika virus infection, chikungunya disease (Chikungunya) in the medicine of viral infection, hepatitis C, encephalitis B, tick-borne encephalitis or the AIDS as caused by HIV Purposes.
A kind of pharmaceutical composition for preventing or treating to have related disorders with dengue fever virus NS3-NS2B protease inhibitors, its Be characterised by said composition with any compound shown in formula (I)~formula (VIII), stereoisomer or its pharmaceutically may be used The salt of receiving is one of active component.
A kind of pharmaceutical composition, it is characterised in that said composition with any compound shown in formula (I)~formula (VIII), Isomers or itself or its pharmaceutically acceptable salt are main active, are aided with pharmaceutically acceptable carrier composition.
Definition
Form the present invention a part be pharmaceutically acceptable solvate, can make crystalline hydrate either and its Its solvent crystallization thing, such as ethanol.
" pharmaceutically acceptable salt " represents to retain the biological effectiveness of parent compound and those salt of property.This kind of salt Including：
If the compounds of this invention is alkaline, the part for forming the present invention is pharmaceutically acceptable salt：Including this The conventional non-toxic salts for the compounds of this invention that invention compound and inorganic acid or organic acid reaction are formed.E.g., including derive from nothing Machine acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, the sodium of hydrogen sulfate one, the sodium of phosphoric acid hydrogen one, disodium hydrogen phosphate, hydrogen sulfate one The salt of potassium, the potassium of phosphoric acid hydrogen one, dipotassium hydrogen phosphate, potassium hydrogen phosphate sodium etc., also include deriving from organic acids such as acetic acid, propionic acid, amber Acid, glycolic, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, Glutamic acid, benzoic acid, salicylic acid, p-aminobenzene sulfonic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, hydroxyl second The salt of base sulfonic acid, trifluoroacetic acid etc.,
If the compounds of this invention is acid, appropriate " pharmaceutically acceptable salt " refers to that the compounds of this invention leads to Crossing pharmaceutically acceptable nontoxic alkali includes salt prepared by inorganic base and organic base.Salt derived from inorganic base include aluminium salt, ammonium salt, Calcium salt, mantoquita, molysite, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt, cesium salt etc..Derived from pharmaceutically The salt of acceptable organic nontoxic alkali, the alkali include the salt of primary amine, secondary amine and tertiary amine, and substituted amine includes naturally occurring and closed Into substitution amine, cyclic amine and deacidite.Such as arginine, glycine betaine, caffeine, choline, diethylamine, 2- DEAE diethylaminoethanol, DMAE, ethylaminoethanol, monoethanolamine, ethylenediamine, N-ethylmorpholine, N- ethyl piperazines It is pyridine, gucosamine, Glucosamine, histidine, isopropylamine, lysine, methyl glucose osamine, morpholine, piperazine, piperidines, more Polyimide resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA), tromethamine etc..
" isomers " represents that compound of the present invention can have asymmetric center, chiral axis and chiral face, and existing Racemate, racemate mixture and single diastereomer and all possible isomer and its mixture include optically-active Isomers is included in the present invention.In addition, compound disclosed by the invention can exist with dynamic isomer, and two kinds of mutually variations Configuration formula is included within the scope of the invention, even if only describing one of which tautomeric structure.For example, any require to protect The following compounds A of shield is understood as including tautomeric structure B, and vice versa, equally including its mixture.
When the present invention has double bond cis-trans-isomer, exist with individual isomer, or cis-isomer and trans different The mixture of structure body, even if only describing one of which heterogeneous structure.
Term used herein " alkyl " represents that the aliphatic group of 1 saturation, including straight chain and branched group (carry in this specification The digital scope arrived, such as " 1-10 ", refer to the group, are now alkyl, can contain 1 carbon atom, 2 carbon atoms, 3 carbon Atom etc., until including 10 carbon atoms), alkyl can be substituted or unsubstituted.
" cycloalkyl " represents that (" fusion " ring means each ring in system with being for the ring of the monocyclic of all carbon or fusion Shared a pair of the carbon atoms adjoined of other rings in system) group, wherein one or more rings are without the pi-electron system being fully connected System, the example (being not limited to) of cycloalkyl is cyclopropane, cyclobutane, pentamethylene, cyclopentene, hexamethylene etc., and cycloalkyl can be to take It is generation and unsubstituted.
" Heterocyclylalkyl " represent 3 to 8 annular atoms saturated cyclic group, wherein one or two annular atom be selected from N, O or S (O)mThe hetero atom of (wherein m is 0 to 2 integer), remaining annular atom is C, and wherein one or two C atom can be with optional Ground is replaced by carbonyl.The ring of heterocyclic radical optionally independently can be substituted by one, two or three substituent.
" alkylene " refers to straight or branched, and main chain contains the non-aromatic of 2~10 carbon atoms and at least one carbon-to-carbon double bond Alkyl.(digital scope mentioned in this specification, such as " 2-10 ", refer to the group, are now alkylene, can contain 2 carbon Atom, 3 carbon atoms etc., until including 10 carbon atoms) alkylene can be substituted or unsubstituted.
The non-aromatic alkyl containing 3~8 carbon atoms and at least one carbon-to-carbon double bond of " cycloalkenyl group " finger ring shape, ring Alkylene can be substituted or unsubstituted.
Up to 6-14 atom in the monocyclic or each ring of any stabilization of up to 6-14 atom in " aryl " expression ring Bicyclic carbocyclic, wherein at least one ring are aromatic rings.The non-limiting examples of aryl have phenyl, naphthyl, anthryl and xenyl.Virtue Base can be substituted or unsubstituted.
" heteroaryl " represents to represent in ring up to 3-14 original in the monocyclic or each ring of the stabilization of up to 3-14 atom Sub- bicyclic carbocyclic, wherein at least one ring are aromatic rings and the hetero atoms selected from O, N and S containing 1-4.As defined in the range of this Heteroaryl includes but is not limited to acridinyl, carbazyl, cinnolines base, quinoxalinyls, pyrazolyl, indyl, BTA base, furans Base, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyls, indyl, pyrazine Base, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals.Heteroaryl can be substituted or unsubstituted.When substituted, substituent It is preferably one or more, more preferably one, two or three, and then be more highly preferred to one or two
" alkoxy " expression-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl).Representative example is included but not It is limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..
" alkylthio group " expression-S- (unsubstituted alkyl) and-S- (unsubstituted cycloalkyl).Representative example is included but not It is limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..
" ester group " expression-C (O) O-R ' groups, wherein R ' are alkyl or hydrogen, and alkyl is as defined above.
" sulfonyl " represents '-S (=O)2-, wherein R ' is alkyl or hydrogen, and alkyl is as defined above.
" acylamino- " expression-(O) NR ' ' R ' groups, wherein R ' and R ' ' are alkyl, and alkyl is as defined above.
" haloalkyl " represents the alkyl of halogen substitution, and alkyl is as defined above.
" hydroxy alkyl " represents the alkyl of hydroxyl substitution, and alkyl is as defined above.
" nitroaryl " represents the aryl of nitro substitution, and aryl is as defined above.
" halogen " represents fluorine, chlorine, preferably bromine or iodine, fluorine or chlorine.
" amino " expression-NH2Group or the-NH protected by conventional protection group2The group ,-NH such as protected by Boc2。
" nitro " expression-NO2Group.
" hydroxyl " expression-OH groups or the-OH groups protected by conventional the protection group ,-OH bases such as protected by TBS or Ms Group.
" diazo " expression-N3。
Term " any substitution " represents substitution or unsubstituted two kinds of situations, it is understood that those of ordinary skill in the art may be selected The substituent and substitution pattern of the compounds of this invention and provide chemically stable and can be by art technology and method from can The compound that can be synthesized with the raw material of acquisition.A group substitution is exceeded if instead of base itself, it should be understood that these groups Can be in identical carbon atoms or on different carbon atoms, as long as making Stability Analysis of Structures.
Term " aralkyl " includes the group that wherein above-mentioned " alkyl " is substituted by above-mentioned " aryl ".The example of aralkyl includes Benzyl, phenethyl, naphthalenyhnethylene, anthryl methylene.
Term " heteroarylalkyl " includes the group that wherein above-mentioned " alkyl " is substituted by above-mentioned " heteroaryl ".The example of heteroaryl Including fural, pyridine ethyl, pyrroles's methylene.
Term " ring-type " shows the cyclic compound containing more than 3 individual carbon or other atoms in ring.
" polycyclic " structure for including wherein forming at least two ring of term, has 1 among these rings between at least two rings The loop coil or at least two of common member common atom and (conjunction) ring or bridge (across) ring structure.Typical structure such as adamantane, The basic structure of norborneol, ENB, pinane, (different) camphane, carane etc..Can be with or without substituent on these rings Structure, these multiring structures can be with miscellaneous polycyclic.
Term " independent " refers to the variable of independent utility applied to independently changing between application.
In the present invention in female ring (such as Formulas I, II, III, IV, V, VI, VII, VIII ring) of the signified A rings for the present invention Five-membered ring containing two N.In the present invention signified B rings for the present invention female ring (such as Formulas I, II, III, IV, V, VI, VII, The rings such as VIII) in R3And R4The five-membered ring containing a N being connected.
Andrographolidume derivative of the present invention can be configured to Pharmaceutical composition, be given according to a variety of appropriately selected Mode is given to patient medication, it is for example oral or parenteral that these approach include whole body, by intravenous, muscle, transdermal or subcutaneous Deng.
The administering mode of preferable medicine of the present invention is oral, but need to according to the specific physics and chemical characteristic of compound and The difference of stability, and the difference of therapeutic purposes determine the drug formulation and administering mode used, are including but not limited to sustained Controllable application method.
The beneficial effects of the invention are as follows be found that compound shown in (I) has to suppress dengue fever virus protease N S2B-NS3 The function of enzymatic activity, they by or not by suppress NS2B-NS3 enzymatic activitys be used as treat and prevent dengue fever virus caused by The medicine of disease, while they may also turn into the medicine for treating and preventing disease caused by other flavivirus, such as yellow fever, west Nile virus infection, zika virus infection, the viral infection of chikungunya disease (Chikungunya), hepatitis C, B-mode brain Inflammation, tick-borne encephalitis and AIDS caused by HIV etc..
Embodiment
Embodiment 1
The present invention also provides the preparation method of above-claimed cpd, comprises the following steps：
Following each particular compound is prepared as stated above：
Embodiment 2
(CF40 is the NS3-NS2B fusion protein expression plasmids PET15b-CF40-Linker-NS3pro185 built 40 amino acid in NS2B hydrophilic area core sequence 1394-1440 sections, Linker are that Gly4-Ser-Gly4 can freely turn Dynamic sequence, NS3pro185 be NS3 N-terminal 1476-1660 between 185 amino acid sequences) ground by Novartis of Singapore tropical disease Institute Dr.Siew Phengsuozeg Lim offers are provided and (refer to Jun Li, Siew Pheng Lim, David Beer, Viral Patel,Daying Wen,Christine Tumanut,David C.Tully,Jennifer A.Williams,Jan Jiricek,John P.Priestle,Jennifer L.Harris,and Subhash G.Vasudevan J.Biol.Chem.2005,280(31),28766-28774.).NS3-NS2B fusion protein expression plasmids PET15b-CF40- The protease of expression product recombination expressions of the Gly-NS3pro185 in e. coli bl21 (DE3) is available to pass through histidine mark Sign (His-tag) and Ni2+Affinity column is aided with other chromatography methods and purified, and the protease of purifying has normal NS3 Enzymatic activity (refers to Jun Li, Siew Pheng Lim, David Beer, Viral Patel, Daying Wen, Christine Tumanut,David C.Tully,Jennifer A.Williams,Jan Jiricek,John P.Priestle, Jennifer L.Harris,and Subhash G.Vasudevan J.Biol.Chem.2005,280(31),28766- 28774 and Shaoqiong Xu, Hua Li, Xiaoxia Shao, Chongxu Fan, Bryan Ericksen, Jinsong Liu,Chengwu Chi,Chunguang Wang J.Med.Chem.2012,55,6881-6887。)。
Inhibitor activity method for measuring is the sensitive method that proteinase activity is efficiently determined with fluorogenic substrate, be can guarantee that Effective selection is carried out to various inhibitor by the measure of inhibitor activity.Basic zymetology computational methods are by 2 or more Change the concentration of inhibitor [I] under fixed concentration of substrate [S], utilize Dixon graphing methods (M.Dixon Biochem.J.1953,55,170-171.) equationInhibition constant is sought in mapping Ki。
Screening process (refers to Jun Li, Siew Pheng Lim, David Beer, Viral Patel, Daying as follows Wen,Christine Tumanut,David C.Tully,Jennifer A.Williams,Jan Jiricek,John P.Priestle,Jennifer L.Harris,and Subhash G.Vasudevan J.Biol.Chem.2005,280 (31), 28766-28774 and Shaoqiong Xu, Hua Li, Xiaoxia Shao, Chongxu Fan, Bryan Ericksen,Jinsong Liu,Chengwu Chi,Chunguang Wang J.Med.Chem.2012,55,6881- 6887.)：Dengue protein enzyme NS2B-NS3 be incubated in 37 DEG C buffer solution (50mM Tris-HCl, pH 9.0,10mM NaCl, 20%Glycerol, 1mM CHAPS, 0.04%NaN3) in, then add the inhibitor compound for needing to detect and be incubated with enzyme After 3 minutes, add protease N S2B-NS3 substrate B enzoyl-Nle-Lys-Arg-Arg-AMC (final concentration of 33 μM and 66 μM), then detect by the enzyme NS2B-NS3 substrates decomposed be exactly the remaining NS2B-NS3 that not suppressed agent suppresses vigor, The AMC fluorescence excitations and launch wavelength being decomposed to form are respectively 356nm and 438nm.Part of compounds is shown in NS3 activity data Table 1.
The part of compounds of table 1 suppresses NS2B-NS3 proteinase activities

Claims (17)

1. compound, isomers or its pharmaceutically acceptable salt shown in formula (I)；
Wherein,
X1、X2It is identical or different, X1、X2Separately selected from covalent bond, O, S, S (O), S (O2), the C that arbitrarily substitutes6-14Virtue Base, N (R5) or C (R6R7)；
X1-R1、X2-R2It is identical or different；
Or X1-R1、X2-R2Concurrently or separately form ring；
R1、R2、R3、R4、R5、R6、R7、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, arbitrarily substitute C1-10Alkyl, the C arbitrarily substituted3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-10It is alkylene, any Substituted C3-8Cycloalkenyl group, the C arbitrarily substituted6-14Aryl, the C arbitrarily substituted3-14Heteroaryl, the C arbitrarily substituted1-10Alcoxyl Base, the C arbitrarily substituted1-10Alkylthio group, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, the C arbitrarily substituted1-10 Carbonyl, the C arbitrarily substituted1-10Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxyl alkane Base or C6-14Nitroaryl；
Or R3、R4Merge into carbonyl；
Or X1、X2、R1、R2Formed A rings and ring；
Or X2、R2With Z1Between formed A rings and ring or loop coil；
Or R3With R4The loop coil of B rings can be formed；
* R configurations or S configurations are expressed as；
The A rings be formula (I) compound in the five-membered ring containing two N, the B rings be compound of formula I in R3And R4It is connected The five-membered ring containing N.
2. compound, isomers or its pharmaceutically acceptable salt shown in formula (I) as claimed in claim 1, its feature exist In, wherein,
R1、R2、R5、R6、R7、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, the C arbitrarily substituted1-8Alkane Base, the C arbitrarily substituted3-8Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-8Alkylene, arbitrarily substitute C3-8Cycloalkenyl group, the C arbitrarily substituted6-10Aryl, the C arbitrarily substituted3-10Heteroaryl, the C arbitrarily substituted1-8Alkoxy, arbitrarily take The C in generation1-8Alkylthio group, the C arbitrarily substituted1-8Ester group, the C arbitrarily substituted1-8Sulfonyl, the C arbitrarily substituted1-8Carbonyl, arbitrarily take The C in generation1-8Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6 Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14Nitro Aryl；
R3、R4Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, the C arbitrarily substituted1-8Alkyl, any substitution C3-8Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-8Alkylene, the C arbitrarily substituted3-8Cycloalkenyl group, The C arbitrarily substituted1-8Alkoxy, the C arbitrarily substituted1-8Alkylthio group, the C arbitrarily substituted1-8Carbonyl or the C arbitrarily substituted1-8Acid amides Base；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6 Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14Nitroaryl；Or R3、 R4Merge into carbonyl.
3. compound, isomers or its pharmaceutically acceptable salt shown in formula (II) or formula (III)：
Wherein,
X1、X2Can be with identical or different, X1、X2Separately selected from covalent bond, O, S, S (O), S (O2), the C that arbitrarily substitutes6-14 Aryl, N (R5) or C (R6R7)；
X1-R1、X2-R2It is identical or different；
Or X1-R1、X2-R2Ring can concurrently or separately be formed；
R1、R2、R5、R6、R7、Z1Separately selected from H, cyano group, amino, nitro, hydroxyl, the C arbitrarily substituted1-10It is alkyl, any Substituted C3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-10Alkylene, the C arbitrarily substituted3-8Cyclenes Alkyl, the C arbitrarily substituted6-14Aryl, the C arbitrarily substituted3-14Heteroaryl, the C arbitrarily substituted1-10Alkoxy, arbitrarily substitute C1-10Alkylthio group, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, the C arbitrarily substituted1-10Carbonyl, any substitution C1-10Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Halogen Substituted alkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14Nitro virtue Base；
Or X1、X2、R1、R2Formed A rings and ring；
Or X2、R2With Z1Between formed A rings and ring or loop coil；
* R configurations or S configurations are expressed as；
The A rings are the five-membered ring containing two N in formula (II) or formula (III) compound.
4. compound, isomers shown in formula (II) as claimed in claim 3 or formula (III) or its is pharmaceutically acceptable Salt, it is characterised in that wherein,
R1、R2、R5、R6、R7、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, the C arbitrarily substituted1-8Alkane Base, the C arbitrarily substituted3-8Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-8Alkylene, arbitrarily substitute C3-8Cycloalkenyl group, the C arbitrarily substituted6-10Aryl, the C arbitrarily substituted3-10Heteroaryl, the C arbitrarily substituted1-8Alkoxy, arbitrarily take The C in generation1-8Alkylthio group, the C arbitrarily substituted1-8Ester group, the C arbitrarily substituted1-8Sulfonyl, the C arbitrarily substituted1-8Carbonyl, arbitrarily take The C in generation1-8Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6 Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14Nitro Aryl.
5. compound, isomers or its pharmaceutically acceptable salt shown in formula (IV)：
Wherein,
X1、X2And X3Can be with identical or different, X1、X2And X3Separately selected from covalent bond, O, S, S (O), S (O2), arbitrarily take The C in generation6-14Aryl, N (R5) or C (R6R7)；
X1-R1、X2-R2And X3-R9It is identical or different；
Or X1-R1、X2-R2、X3-R9Ring can concurrently or separately be formed；
R1、R2、R5、R6、R7、R8、R9、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, arbitrarily substitute C1-10Alkyl, the C arbitrarily substituted3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-10It is alkylene, any Substituted C3-8Cycloalkenyl group, the C arbitrarily substituted6-14Aryl, the C arbitrarily substituted3-14Heteroaryl, the C arbitrarily substituted1-10Alcoxyl Base, the C arbitrarily substituted1-10Alkylthio group, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, the C arbitrarily substituted1-10 Carbonyl, the C arbitrarily substituted1-10Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxyl alkane Base or C6-14Nitroaryl；
Or X1、X2、R1、R2Formed A rings and ring；
Or X2、R2With Z1Between formed A rings and ring or loop coil；
Or R8Separately or concurrently with R9、X3Between formed B rings loop coil；
Or R9、X3Between cyclization；
* R configurations or S configurations are expressed as；
The A rings be formula (I) compound in the five-membered ring containing two N, the B rings be compound of formula I in R8What is be connected contains One N five-membered ring.
6. compound, isomers or its pharmaceutically acceptable salt shown in formula (IV) as claimed in claim 5, its feature exist In, wherein：
X1And X2Can be with identical or different, X1And X2Separately selected from covalent bond, O, S, S (O), S (O2), arbitrarily substitute C6-14Aryl, N (R5) or C (R6R7)；X3For covalent bond；
R1、R2、R5、R6、R7、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, the C arbitrarily substituted1-8Alkane Base, the C arbitrarily substituted3-8Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-8Alkylene, arbitrarily substitute C3-8Cycloalkenyl group, the C arbitrarily substituted6-10Aryl, the C arbitrarily substituted3-10Heteroaryl, the C arbitrarily substituted1-8Alkoxy, arbitrarily take The C in generation1-8Alkylthio group, the C arbitrarily substituted1-8Ester group, the C arbitrarily substituted1-8Sulfonyl, the C arbitrarily substituted1-8Carbonyl, arbitrarily take The C in generation1-8Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6 Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14Nitro Aryl；
R8For H；R9The C selected from H, arbitrarily substituted1-8Alkyl, the C arbitrarily substituted3-8Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, The C arbitrarily substituted2-8Alkylene, the C arbitrarily substituted3-8Cycloalkenyl group, the C arbitrarily substituted1-8Alkoxy, the C arbitrarily substituted1-8Alkane Sulfenyl, the C arbitrarily substituted1-8Carbonyl or the C arbitrarily substituted1-8Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl Base, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl Base, C0-6Ester group, C1~6Hydroxy alkyl or C6-14Nitroaryl.
7. compound, isomers or its pharmaceutically acceptable salt shown in formula (V)：
Wherein,
X1、X2Can be with identical or different, X1、X2Separately selected from covalent bond, O, S, S (O), S (O2), the C that arbitrarily substitutes6-14 Aryl, N (R5) or C (R6R7)；
X1-R1、X2-R2It is identical or different；
Or X1-R1、X2-R2Concurrently or separately form ring；
R1、R2、R5、R6、R7、R8、R10、R11、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, arbitrarily take The C in generation1-10Alkyl, the C arbitrarily substituted3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-10Alkylene, The C arbitrarily substituted3-8Cycloalkenyl group, the C arbitrarily substituted6-14Aryl, the C arbitrarily substituted3-14Heteroaryl, the C arbitrarily substituted1-10Alkane Epoxide, the C arbitrarily substituted1-10Alkylthio group, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, arbitrarily substitute C1-10Carbonyl, the C arbitrarily substituted1-10Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde Base, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxyl Base alkyl or C6-14Nitroaryl；
Or R10For amino acid residue；
Or X1、X2、R1、R2Formed A rings and ring；
Or X2、R2With Z1Between formed A rings and ring or loop coil；
Or R8Separately or concurrently with R10、R11Between formed B rings loop coil；
Or R10、R11Between cyclization；
* R configurations or S configurations are expressed as；
The A rings be formula (I) compound in the five-membered ring containing two N, the B rings be compound of formula I in R8What is be connected contains One N five-membered ring.
8. compound, isomers or its pharmaceutically acceptable salt shown in formula (VI)：
Wherein,
X1、X2、X4Can be with identical or different, X1、X2、X4Separately selected from covalent bond, O, S, S (O), S (O2), any substitution C6-14Aryl, N (R5) or C (R6R7)；
X1-R1、X2-R2、X4-R13It is identical or different；
Or X1-R1、X2-R2、X4-R13Ring can concurrently or separately be formed；
R1、R2、R5、R6、R7、R8、R12、R13、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, arbitrarily take The C in generation1-10Alkyl, the C arbitrarily substituted3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-10Alkylene, The C arbitrarily substituted3-8Cycloalkenyl group, the C arbitrarily substituted6-14Aryl, the C arbitrarily substituted3-14Heteroaryl, the C arbitrarily substituted1-10Alkane Epoxide, the C arbitrarily substituted1-10Alkylthio group, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, arbitrarily substitute C1-10Carbonyl, the C arbitrarily substituted1-10Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde Base, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxyl Base alkyl or C6-14Nitroaryl；
Or R12For amino acid residue；
Or X1、X2、R1、R2Formed A rings and ring；
Or X2、R2With Z1Between formed A rings and ring or loop coil；
Or R8Separately or concurrently with X4、R12、R13Between formed B rings loop coil；
Or R12Individually or simultaneously with X4、R13Between cyclization；
* R configurations or S configurations are expressed as；
The A rings be formula (I) compound in the five-membered ring containing two N, the B rings be compound of formula I in R8What is be connected contains One N five-membered ring.
9. compound, isomers or its pharmaceutically acceptable salt shown in formula (VII)：
Wherein,
X1、X2、X5Can be with identical or different, X1、X2、X5Separately selected from covalent bond, O, S, S (O), S (O2), any substitution C6-14Aryl, N (R5) or C (R6R7)；
X1-R1、X2-R2、X5-R14It is identical or different；
Or X1-R1、X2-R2、X5-R14Ring can concurrently or separately be formed；
R1、R2、R5、R6、R7、R8、R14、R15、R16、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, appoint Anticipate the C substituted1-10Alkyl, the C arbitrarily substituted3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-10Alkene Base, the C arbitrarily substituted3-8Cycloalkenyl group, the C arbitrarily substituted6-14Aryl, the C arbitrarily substituted3-14Heteroaryl, arbitrarily substitute C1-10Alkoxy, the C arbitrarily substituted1-10Alkylthio group, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, arbitrarily take The C in generation1-10Carbonyl, the C arbitrarily substituted1-10Amide groups；Substituent be selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxy alkyl or C6-14Nitroaryl；
Or X1、X2、R1、R2Formed A rings and ring；
Or X2、R2With Z1Between formed A rings and ring or loop coil；
Or R8Separately or concurrently with X5、R14、R15、R16Between formed B rings loop coil；
Or R15、R16Between form ring；
Or X5Separately or concurrently with R15、R16Between cyclization；
Or R14Separately or concurrently with R15、R16Between cyclization；
* R configurations or S configurations are expressed as；
The A rings be formula (I) compound in the five-membered ring containing two N, the B rings be compound of formula I in R8What is be connected contains One N five-membered ring.
10. compound, isomers or its pharmaceutically acceptable salt shown in formula (VIII)：
Wherein,
X1、X2And X6Can be with identical or different, X1、X2And X6Separately selected from covalent bond, O, S, S (O), S (O2), arbitrarily take The C in generation6-14Aryl, N (R5) or C (R6R7)；
X1-R1、X2-R2And X6-R17It is identical or different；
Or X1-R1、X2-R2、X6-R18Ring can concurrently or separately be formed；
R1、R2、R5、R6、R7、R8、R17、Z1Separately selected from H, cyano group, amino, nitro, diazo, hydroxyl, any substitution C1-10Alkyl, the C arbitrarily substituted3-10Cycloalkyl, the C arbitrarily substituted3-8Heterocyclylalkyl, the C arbitrarily substituted2-10Alkylene, appoint Anticipate the C substituted3-8Cycloalkenyl group, the C arbitrarily substituted6-14Aryl, the C arbitrarily substituted3-14Heteroaryl, the C arbitrarily substituted1-10Alcoxyl Base, the C arbitrarily substituted1-10Alkylthio group, the C arbitrarily substituted1-10Ester group, the C arbitrarily substituted1-10Sulfonyl, the C arbitrarily substituted1-10 Carbonyl, the C arbitrarily substituted1-10Amide groups；Substituent is selected from halogen, cyano group, amino, nitro, hydroxyl, borate, C1-6Aldehyde radical, C1~6Alkyl, C1~6Haloalkyl, C1~6Alkoxy, C1~6Alkylthio group, C2~6Alkylene, C0-6Carbonyl, C0-6Ester group, C1~6Hydroxyl alkane Base or C6-14Nitroaryl；
Or X1、X2、R1、R2Formed A rings and ring；
Or X2、R2With Z1Between formed A rings and ring or loop coil；
Or R8Separately or concurrently with R17、X6Between formed B rings loop coil；
* R configurations or S configurations are expressed as；
The A rings be formula (I) compound in the five-membered ring containing two N, the B rings be compound of formula I in R8What is be connected contains One N five-membered ring.
11. compound according to claim 1, isomers or its pharmaceutically acceptable salt, the compound are selected from：
12. the preparation method of claim 1 formula (I) compound, claim 3 formula (II) or formula (III) described compound, It is characterised in that it includes following steps：
13. compound, isomers or its pharmaceutically acceptable salt described in any one of claim 1~12 prepare prevention or Treatment has the purposes in the medicine of related disorders with dengue fever virus protease N S3 inhibitor.
14. purposes according to claim 13, it is characterised in that described relevant with dengue fever virus protease N S3 inhibitor Disease is dengue fever and dengue hemorrhagic fever caused by dengue fever virus and Dengue shock syndrome.
15. any one of claim 1~12 described compound, isomers or its salt by or not by suppressing NS2B- NS3 enzymatic activitys prepare be used for treat or prevent dengue fever disease, yellow fever, West Nile Virus infection, zika virus infection, The infection of chikungunya disease virus, hepatitis C, encephalitis B, tick-borne encephalitis or the AIDS as caused by HIV disease medicament in Purposes.
16. a kind of pharmaceutical composition for preventing or treating to have related disorders with dengue fever virus NS3-NS2B protease inhibitors, its It is characterised by said composition with the compound described in any one of claim 1~12, isomers or its is pharmaceutically acceptable Salt is one of active component.
17. a kind of pharmaceutical composition, it is characterised in that said composition is with the compound described in any one of claim 1~12, different Structure body or its pharmaceutically acceptable salt are main active, are aided with pharmaceutically acceptable carrier.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111518102A (en) * 2019-05-14 2020-08-11 南京工业大学 Cycloformyl and cyclic ketone compound, preparation method and pharmaceutical application thereof
CN113827599A (en) * 2021-09-23 2021-12-24 天津国际生物医药联合研究院 Potential application of demethylzelaronal in resisting dengue virus infection

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4616990Y1 (en) * 1968-03-23 1971-06-14
WO1994014817A1 (en) * 1992-12-21 1994-07-07 E.I. Du Pont De Nemours And Company Herbicidal imidazolones and a process for their manufacture
WO2003011824A1 (en) * 2001-07-31 2003-02-13 Bristol-Myers Squibb Company Bicyclic modulators of androgen receptor function

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4616990Y1 (en) * 1968-03-23 1971-06-14
WO1994014817A1 (en) * 1992-12-21 1994-07-07 E.I. Du Pont De Nemours And Company Herbicidal imidazolones and a process for their manufacture
WO2003011824A1 (en) * 2001-07-31 2003-02-13 Bristol-Myers Squibb Company Bicyclic modulators of androgen receptor function

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ANGEL L. FUENTES DE ARRIBA ET AL.: ""Imidazolidinone intermediates in prolinamide-catalyzed aldol reactions"", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 *
JUN-AN XIAO ET AL.: ""Highly stereoselective synthesis of novel spiroimidazolidinones directed by pyridine prolinamide"", 《TETRAHEDRON》 *
MARI GABRIELSEN ET AL.: ""Identification of Novel Serotonin Transporter Compounds by Virtual Screening"", 《JOURNAL OF CHEMICAL INFORMATION AND MODELING》 *
SERGEY TIN ET AL.: ""The Stability of Imidazolidinones is the Primary Influence on the Catalytic Activity of Proline Amides and Proline Sulfonamides in Enamine Catalysis Using Alkyl Aldehyde Substrates"", 《EUR. J. ORG. CHEM.》 *
XIANG-RONG HUANG ET AL.: ""Solvent-effects tuning the catalytic reactivity of prolinamides in asymmetric aldol reactions"", 《TETRAHEDRON: ASYMMETRY》 *
YASUHIRO UOZUMI ET AL.: ""A parallel preparation of a bicyclic N-chiral amine library and its use for chiral catalyst screening"", 《TETRAHEDRON LETTERS》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111518102A (en) * 2019-05-14 2020-08-11 南京工业大学 Cycloformyl and cyclic ketone compound, preparation method and pharmaceutical application thereof
WO2020228783A1 (en) * 2019-05-14 2020-11-19 南京工业大学 Cyclic formyl and cyclic ketone compounds, preparation method therefor, and pharmaceutical use
CN111518102B (en) * 2019-05-14 2023-09-05 南京工业大学 Cycloformyl and cyclic ketone compounds, and preparation method and pharmaceutical application thereof
CN113827599A (en) * 2021-09-23 2021-12-24 天津国际生物医药联合研究院 Potential application of demethylzelaronal in resisting dengue virus infection

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