CN107814803B - Fused ring compound of tetrahydropyrrole and dihydroimidazolone, preparation and pharmaceutical application thereof - Google Patents

Fused ring compound of tetrahydropyrrole and dihydroimidazolone, preparation and pharmaceutical application thereof Download PDF

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CN107814803B
CN107814803B CN201710809939.6A CN201710809939A CN107814803B CN 107814803 B CN107814803 B CN 107814803B CN 201710809939 A CN201710809939 A CN 201710809939A CN 107814803 B CN107814803 B CN 107814803B
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CN107814803A (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
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Abstract

The invention discloses a fused ring compound of pyrrolidine and dihydroimidazolone, and preparation and pharmaceutical application thereof. The compound is a compound shown as a formula (I), an isomer or a pharmaceutically acceptable salt thereof; the compound, isomer or pharmaceutically acceptable salt thereof can be applied to preparation of medicines for preventing or treating dengue fever virus and related virus-caused diseasesThe related diseases (such as dengue fever, dengue hemorrhagic fever, dengue shock syndrome, Zika, chikungunya, encephalitis B, yellow fever, hepatitis C, West Nile disease, etc.).

Description

Fused ring compound of tetrahydropyrrole and dihydroimidazolone, preparation and pharmaceutical application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to application of a fused ring compound, a stereoisomer or a pharmaceutically acceptable salt of pyrrolidine and dihydroimidazolone in pharmacy.
Background
Dengue diseases include Dengue (DF), Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS) symptoms caused by infection with dengue virus (DENV) of the flaviviridae family. Dengue disease transmission is primarily transmitted in tropical and subtropical regions by the Aedes aegypti (Aedes aegypti), Aedes albopictus (Aedes albopictus) and Aedes borenii (Aedes polynesiensis), and symptoms of dengue disease typically appear 3-14 days after being bitten by the Aedes infestans (Aedes) (4-7 days on average). The earliest record of a pandemic of dengue disease was in asia, africa, north america more than 200 years ago, and dengue disease has now occurred in more than 100 countries around the world, with an estimated current threat of dengue disease to approximately 25 million people around the world, with approximately 2.5 million people dying from dengue disease each year.
Under the influence of a plurality of factors such as global environment deterioration and warming, the dengue epidemic situation has a tendency to expand in recent years, but no effective vaccine is available at present for preventing the occurrence and prevalence of dengue diseases, and no effective drug against dengue viruses is available for clinical treatment of dengue diseases, and the clinical treatment is mainly progressive support therapy (intensive therapy) at present, wherein the maintenance of the fluid balance is a main means. These limited approaches cannot cope with the situation of high mortality (-5%) of DHF and DSS caused by dengue virus infection, so that the pharmaceutical research on dengue disease caused by dengue virus infection is very important and urgent.
Dengue viruses are single-stranded positive-stranded RNA viruses of about 11000 bases and share a total of 4 serotypes, DENV-1, DENV-2, DENV-3 and DENV-4, with DENV-2 being the most virulent. The dengue virus genomic RNA can be divided into two parts: the sequence of 1/4 at the 5 'end encodes 3 structural proteins of the virus (C-capsid, prM-precursor membrane and E-envelope), and the sequence of 3/4 at the 3' end encodes 7 non-structural proteins (NS1, NS2, NS3, NS4A, NS4B and NS 5). Although these proteins are important for the survival of dengue viruses and can be used as drug targets against dengue viruses, dengue virus NS3 is the most studied and probably the most important drug target of dengue viruses, since maturation of these proteins is dependent on the activity of NS3protease, and effective inhibition of NS3protease activity may serve the purpose of reducing or blocking replication and reproduction of dengue viruses (Aruna Sampath, r. padmanahanantibrival res.2009,81, 6-15). . Research shows that NS2B plays a crucial role as a cofactor of NS3protease in the enzymatic activity of NS3, so NS3-NS2B complex (Aruna Sampath, R.Padmanahanavian Experimental Res.2009,81, 6-15) is used for the research of the inhibitory ability of the inhibitor on the enzymatic activity of NS 3. .
The dengue virus belongs to the flavivirus family (Flaviviridae family) with more than 70 virus members, among which the more studied and more harmful are yellow fever (yellow fever), West Nile Virus (WNV), Hepatitis C Virus (HCV), dengue virus (DENV), Zika (Zika) virus infection, Chikungunya (Chikungunya) virus infection, etc., which are similar in many aspects of the life cycle, especially the NS3-NS2B, so they are usually linked together during the NS3protease drug research, and these compounds can also be used for preventing and treating related diseases caused by other flaviviruses than dengue virus, such as yellow fever, West Nile virus infection, Kaya virus infection, Chikungunya (Chikungunya) virus infection, hepatitis C virus infection, etc., because they are similar in many aspects of the life cycle, especially there is a great similarity in the function of NS3-NS2 NS B, Encephalitis B, forest encephalitis, and AIDS caused by HIV (Aruna Sampath, R.Padmanabhantiarviral Res.2009,81, 6-15).
In recent years, the research on inhibitors of yellow fever virus NS3-NS2B has been the focus of antiviral drugs, and recently, there are some cyclic polypeptide inhibitors (Shaoqiong Xu, Hua Li, Xiaooxina Shao, Chongxu Fan, BryanEricksen, Jindong Liu, Chengwu Chi, Chungu Wang J. Med. chem.2012,55,6881-7.), phenylhydrazone inhibitors (Jing Deng, Ning Li, Hongchou Liu, Zhulii Zuo, Oi Wah Liew, Weijun Xu, GaChen, Xiankun Tong, Wei Tang, Jin Zhu, Jian Zuo, Hualang Jian, Cai-guan Yang Yan Yang, Jian J. Ben Wang, Jiang Zhang Zuo, Jiang Ju, Cailing Ju, Caignin-Gui Tang Wang, Jian Ben Tang Wang Zhang Shu, Jian Zhang Ju Wang 3, Jian, Shang Ju Wang 3, Wei Chang 3, Jian Ben Wang 3, Wei Ben Jian Ben Wang 3, Wei Ju Chang 3, Jian Ben Chang 3, Jian Ben Shu Shi, and Shi, bioorg Med Chem Lett 2013,23, 6549-.
Disclosure of Invention
The invention aims to provide a fused ring compound of pyrrolidine and dihydroimidazolone with corresponding activity, and a derivative, a stereoisomer, a cis-trans isomer or a pharmaceutically acceptable salt thereof on the basis of the prior art.
Another object of the present invention is to provide a process for the preparation of the above compound.
The third purpose of the invention is to provide the application of the compound in pharmacy.
The object of the invention can be achieved by the following measures:
a compound, isomer or pharmaceutically acceptable salt thereof shown in formula (I),
Figure BDA0001403604930000031
wherein,
X1、X2identical or different, X1、X2Each independently selected from covalent bond, O, S, S (O), S (O)2) Optionally substituted C6-14Aryl, N (R)5) Or C (R)6R7)；
X1-R1、X2-R2The same or different;
or X1-R1、X2-R2Form a ring simultaneously or separately;
R1、R2、R3、R4、R5、R6、R7、Z1each independently selected from H, cyano, amino, nitro, diazo, hydroxy, optionally substituted C1-10Alkyl, optionally substituted C3-10Cycloalkyl, optionally substituted C3-8Heterocycloalkyl, optionally substituted C2-10Alkylene, optionally substituted C3-8Cycloalkenylhydrocarbyl, optionally substituted C6-14Aryl, optionally substituted C3-14Heteroaryl, optionally substituted C1-10Alkoxy, optionally substituted C1-10Alkylthio, optionally substituted C1-10Ester group, optionally substituted C1-10Sulfonyl, optionally substituted C1-10Carbonyl, optionally substituted C1-10An amide group; the substituent is selected from halogen, cyano, amino, nitro, hydroxyl, borate, C1-6Aldehyde group, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio radical, C2～6Alkylene radical, C0-6Carbonyl group, C0-6Ester group, C1～6Hydroxyalkyl or C6-14A nitroaryl group;
or R3、R4Merging into carbonyl;
or X1、X2、R1、R2A fused ring forming ring A;
or X2、R2And Z1A fused ring or spiro ring between which an A ring is formed;
or R3And R4Spiro ring which may form ring B;
represents represented by R configuration or S configuration;
the ring A is a five-membered ring containing two N in the compound of the formula (I), and the ring B is a five-membered ring with R in the compound of the formula (I)3And R4A five-membered ring containing one N attached.
Preferably, the compound of formula (I), isomer or a pharmaceutically acceptable salt thereof, wherein:
R1、R2、R5、R6、R7、Z1each independently selected from H, cyano, amino, nitro, diazo, hydroxy, optionally substituted C1-8Alkyl, optionally substituted C3-8Cycloalkyl, optionally substituted C3-8Heterocycloalkyl, optionally substituted C2-8Alkylene, optionally substituted C3-8Cycloalkenylhydrocarbyl, optionally substituted C6-10Aryl, optionally substituted C3-10Heteroaryl, optionally substituted C1-8Alkoxy, optionally substituted C1-8Alkylthio, optionally substituted C1-8Ester group, optionally substituted C1-8Sulfonyl, optionally substituted C1-8Carbonyl, optionally substituted C1-8An amide group; the substituent is selected from halogen, cyano, amino, nitro, hydroxyl, borate, C1-6Aldehyde group, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio radical, C2～6Alkylene radical, C0-6Carbonyl group, C0-6Ester group, C1～6Hydroxyalkyl or C6-14A nitroaryl group;
R3、R4each independently selected from H, cyano, amino, nitro, diazo, hydroxy, optionally substituted C1-8Alkyl, optionally substituted C3-8Cycloalkyl, optionally substitutedC3-8Heterocycloalkyl, optionally substituted C2-8Alkylene, optionally substituted C3-8Cycloalkenylhydrocarbyl, optionally substituted C1-8Alkoxy, optionally substituted C1-8Alkylthio, optionally substituted C1-8Carbonyl or optionally substituted C1-8An amide group; the substituent is selected from halogen, cyano, amino, nitro, hydroxyl, borate, C1-6Aldehyde group, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio radical, C2～6Alkylene radical, C0-6Carbonyl group, C0-6Ester group, C1～6Hydroxyalkyl or C6-14A nitroaryl group; or R3、R4Are combined into carbonyl.
Further preferably, R3、R4、Z1Is H, X1Is a covalent bond, X2Selected from covalent bond or C (R)6R7) Wherein R is6、R7Is H;
R1、R2each independently selected from H, cyano, amino, nitro, hydroxy, optionally substituted C1-10Alkyl, optionally substituted C3-10Cycloalkyl, optionally substituted C3-8Heterocycloalkyl, optionally substituted C2-10Alkylene, optionally substituted C3-8Cycloalkenylhydrocarbyl, optionally substituted C6-14Aryl, optionally substituted C3-14Heteroaryl, optionally substituted C1-10Alkoxy, optionally substituted C1-10Alkylthio, optionally substituted C1-10Ester group, optionally substituted C1-10Sulfonyl, optionally substituted C1-10Carbonyl, optionally substituted C1-10An amide group; the substituent is selected from halogen, cyano, amino, nitro, hydroxyl, borate, C1-6Aldehyde group, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio radical, C2～6Alkylene radical, C0-6Carbonyl group, C0-6Ester group, C1～6Hydroxyalkyl or C6-14A nitroaryl group; more preferably, R1、R2Each independently selected from H, cyano, amino, nitroRadical, hydroxy, optionally substituted C1-6Alkyl, optionally substituted C3-6Cycloalkyl, optionally substituted C6-10Aryl, optionally substituted C3-10A heteroaryl group; the substituent is selected from halogen, cyano, amino, nitro, hydroxyl, borate, C1-4Aldehyde group, C1～4Alkyl radical, C1～4Haloalkyl, C1～4Alkoxy radical, C1～4Alkylthio radical, C2～6Alkylene radical, C0-4Carbonyl group, C0-4Ester group, C1～4Hydroxyalkyl or C6-10A nitroaryl group; further preferred R1、R2Each independently selected from H, optionally substituted C1-6Alkyl, optionally substituted C6-10An aryl group; the substituent is selected from halogen, cyano, amino, nitro, hydroxyl and C1～4Alkyl radical, C1～4Haloalkyl, C1～4An alkoxy group.
A compound of formula (II) or formula (III), an isomer, or a pharmaceutically acceptable salt thereof:
Figure BDA0001403604930000041
wherein,
X1、X2which may be the same or different, X1、X2Each independently selected from covalent bond, O, S, S (O), S (O)2) Optionally substituted C6-14Aryl, N (R)5) Or C (R)6R7)；
X1-R1、X2-R2The same or different;
or X1-R1、X2-R2Can form rings simultaneously or independently;
R1、R2、R5、R6、R7、Z1each independently selected from H, cyano, amino, nitro, hydroxy, optionally substituted C1-10Alkyl, optionally substituted C3-10Cycloalkyl, optionally substituted C3-8Heterocycloalkyl, optionally substituted C2-10Alkylene radical, renSubstituted C3-8Cycloalkenylhydrocarbyl, optionally substituted C6-14Aryl, optionally substituted C3-14Heteroaryl, optionally substituted C1-10Alkoxy, optionally substituted C1-10Alkylthio, optionally substituted C1-10Ester group, optionally substituted C1-10Sulfonyl, optionally substituted C1-10Carbonyl, optionally substituted C1-10An amide group; the substituent is selected from halogen, cyano, amino, nitro, hydroxyl, borate, C1-6Aldehyde group, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio radical, C2～6Alkylene radical, C0-6Carbonyl group, C0-6Ester group, C1～6Hydroxyalkyl or C6-14A nitroaryl group;
or X1、X2、R1、R2A fused ring forming ring A;
or X2、R2And Z1A fused ring or spiro ring between which an A ring is formed;
represents represented by R configuration or S configuration;
the ring A is a five-membered ring containing two N in the compound of the formula (II) or the formula (III).
Preferably, the compound of formula (II) or formula (III), isomer or pharmaceutically acceptable salt thereof, wherein:
R1、R2、R5、R6、R7、Z1each independently selected from H, cyano, amino, nitro, diazo, hydroxy, optionally substituted C1-8Alkyl, optionally substituted C3-8Cycloalkyl, optionally substituted C3-8Heterocycloalkyl, optionally substituted C2-8Alkylene, optionally substituted C3-8Cycloalkenylhydrocarbyl, optionally substituted C6-10Aryl, optionally substituted C3-10Heteroaryl, optionally substituted C1-8Alkoxy, optionally substituted C1-8Alkylthio, optionally substituted C1-8Ester group, optionally substituted C1-8Sulfonyl, optionally substituted C1-8Carbonyl, optionally substituted C1-8An amide group; substituent groupSelected from halogen, cyano, amino, nitro, hydroxy, borate, C1-6Aldehyde group, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio radical, C2～6Alkylene radical, C0-6Carbonyl group, C0-6Ester group, C1～6Hydroxyalkyl or C6-14A nitroaryl group.
Further preferably, Z1Is H.
A compound, isomer, or pharmaceutically acceptable salt thereof of formula (IV):
Figure BDA0001403604930000051
wherein,
X1、X2and X3Which may be the same or different, X1、X2And X3Each independently selected from covalent bond, O, S, S (O), S (O)2) Optionally substituted C6-14Aryl, N (R)5) Or C (R)6R7)；
X1-R1、X2-R2And X3-R9The same or different;
or X1-R1、X2-R2、X3-R9Can form rings simultaneously or independently;
R1、R2、R5、R6、R7、R8、R9、Z1each independently selected from H, cyano, amino, nitro, diazo, hydroxy, optionally substituted C1-10Alkyl, optionally substituted C3-10Cycloalkyl, optionally substituted C3-8Heterocycloalkyl, optionally substituted C2-10Alkylene, optionally substituted C3-8Cycloalkenylhydrocarbyl, optionally substituted C6-14Aryl, optionally substituted C3-14Heteroaryl, optionally substituted C1-10Alkoxy, optionally substituted C1-10Alkylthio, optionally substituted C1-10Ester group, optionally substituted C1-10Sulfonyl radicalRadical, optionally substituted C1-10Carbonyl, optionally substituted C1-10An amide group; the substituent is selected from halogen, cyano, amino, nitro, hydroxyl, borate, C1-6Aldehyde group, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio radical, C2～6Alkylene radical, C0-6Carbonyl group, C0-6Ester group, C1～6Hydroxyalkyl or C6-14A nitroaryl group;
or X1、X2、R1、R2A fused ring forming ring A;
or X2、R2And Z1A fused ring or spiro ring between which an A ring is formed;
or R8Independently or simultaneously with R9、X3Spiro rings forming a ring B therebetween;
or R9、X3Forming a ring;
represents represented by R configuration or S configuration;
the ring A is a five-membered ring containing two N in the compound of the formula (I), and the ring B is a five-membered ring with R in the compound of the formula (I)8A five-membered ring containing one N attached.
Preferably, the compound represented by formula (IV), isomer or pharmaceutically acceptable salt thereof, wherein:
X1and X2Which may be the same or different, X1And X2Each independently selected from covalent bond, O, S, S (O), S (O)2) Optionally substituted C6-14Aryl, N (R)5) Or C (R)6R7)；X3Is a covalent bond;
R1、R2、R5、R6、R7、Z1each independently selected from H, cyano, amino, nitro, diazo, hydroxy, optionally substituted C1-8Alkyl, optionally substituted C3-8Cycloalkyl, optionally substituted C3-8Heterocycloalkyl, optionally substituted C2-8Alkylene, optionally substituted C3-8Cycloalkenylhydrocarbyl, optionally substituted C6-10Aryl, optionally substitutedSubstituted C3-10Heteroaryl, optionally substituted C1-8Alkoxy, optionally substituted C1-8Alkylthio, optionally substituted C1-8Ester group, optionally substituted C1-8Sulfonyl, optionally substituted C1-8Carbonyl, optionally substituted C1-8An amide group; the substituent is selected from halogen, cyano, amino, nitro, hydroxyl, borate, C1-6Aldehyde group, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio radical, C2～6Alkylene radical, C0-6Carbonyl group, C0-6Ester group, C1～6Hydroxyalkyl or C6-14A nitroaryl group;
R8is H; r9Selected from H, optionally substituted C1-8Alkyl, optionally substituted C3-8Cycloalkyl, optionally substituted C3-8Heterocycloalkyl, optionally substituted C2-8Alkylene, optionally substituted C3-8Cycloalkenylhydrocarbyl, optionally substituted C1-8Alkoxy, optionally substituted C1-8Alkylthio, optionally substituted C1-8Carbonyl or optionally substituted C1-8An amide group; the substituent is selected from halogen, cyano, amino, nitro, hydroxyl, borate, C1-6Aldehyde group, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio radical, C2～6Alkylene radical, C0-6Carbonyl group, C0-6Ester group, C1～6Hydroxyalkyl or C6-14A nitroaryl group.
A compound, isomer, or pharmaceutically acceptable salt thereof of formula (V):
Figure BDA0001403604930000071
wherein,
X1、X2which may be the same or different, X1、X2Each independently selected from covalent bond, O, S, S (O), S (O)2) Optionally substituted C6-14Aryl, N (R)5) Or C (R)6R7)；
X1-R1、X2-R2The same or different;
or X1-R1、X2-R2Form a ring simultaneously or separately;
R1、R2、R5、R6、R7、R8、R10、R11、Z1each independently selected from H, cyano, amino, nitro, diazo, hydroxy, optionally substituted C1-10Alkyl, optionally substituted C3-10Cycloalkyl, optionally substituted C3-8Heterocycloalkyl, optionally substituted C2-10Alkylene, optionally substituted C3-8Cycloalkenylhydrocarbyl, optionally substituted C6-14Aryl, optionally substituted C3-14Heteroaryl, optionally substituted C1-10Alkoxy, optionally substituted C1-10Alkylthio, optionally substituted C1-10Ester group, optionally substituted C1-10Sulfonyl, optionally substituted C1-10Carbonyl, optionally substituted C1-10An amide group; the substituent is selected from halogen, cyano, amino, nitro, hydroxyl, borate, C1-6Aldehyde group, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio radical, C2～6Alkylene radical, C0-6Carbonyl group, C0-6Ester group, C1～6Hydroxyalkyl or C6-14A nitroaryl group;
or R10Is an amino acid residue;
or X1、X2、R1、R2A fused ring forming ring A;
or X2、R2And Z1A fused ring or spiro ring between which an A ring is formed;
or R8Independently or simultaneously with R10、R11Spiro rings forming a ring B therebetween;
or R10、R11Forming a ring;
represents represented by R configuration or S configuration;
the A ringIs a five-membered ring containing two N in the compound of formula (I), and the B ring is the ring of formula I and R8A five-membered ring containing one N attached.
Preferably, the compound represented by formula (V), isomer or pharmaceutically acceptable salt thereof, wherein:
R1、R2、R5、R6、R7、R8、R10、R11、Z1each independently selected from H, cyano, amino, nitro, diazo, hydroxy, optionally substituted C1-8Alkyl, optionally substituted C3-8Cycloalkyl, optionally substituted C3-8Heterocycloalkyl, optionally substituted C2-8Alkylene, optionally substituted C3-8Cycloalkenylhydrocarbyl, optionally substituted C6-10Aryl, optionally substituted C3-10Heteroaryl, optionally substituted C1-8Alkoxy, optionally substituted C1-8Alkylthio, optionally substituted C1-8Ester group, optionally substituted C1-8Sulfonyl, optionally substituted C1-8Carbonyl, optionally substituted C1-8An amide group; the substituent is selected from halogen, cyano, amino, nitro, hydroxyl, borate, C1-6Aldehyde group, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio radical, C2～6Alkylene radical, C0-6Carbonyl group, C0-6Ester group, C1～6Hydroxyalkyl or C6-14A nitroaryl group.
A compound, isomer, or pharmaceutically acceptable salt thereof of formula (VI):
Figure BDA0001403604930000081
wherein,
X1、X2、X4which may be the same or different, X1、X2、X4Each independently selected from covalent bond, O, S, S (O), S (O)2) Optionally substituted C6-14Aryl, N (R)5) Or C (R)6R7)；
X1-R1、X2-R2、X4-R13The same or different;
or X1-R1、X2-R2、X4-R13Can form rings simultaneously or independently;
R1、R2、R5、R6、R7、R8、R12、R13、Z1each independently selected from H, cyano, amino, nitro, diazo, hydroxy, optionally substituted C1-10Alkyl, optionally substituted C3-10Cycloalkyl, optionally substituted C3-8Heterocycloalkyl, optionally substituted C2-10Alkylene, optionally substituted C3-8Cycloalkenylhydrocarbyl, optionally substituted C6-14Aryl, optionally substituted C3-14Heteroaryl, optionally substituted C1-10Alkoxy, optionally substituted C1-10Alkylthio, optionally substituted C1-10Ester group, optionally substituted C1-10Sulfonyl, optionally substituted C1-10Carbonyl, optionally substituted C1-10An amide group; the substituent is selected from halogen, cyano, amino, nitro, hydroxyl, borate, C1-6Aldehyde group, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio radical, C2～6Alkylene radical, C0-6Carbonyl group, C0-6Ester group, C1～6Hydroxyalkyl or C6-14A nitroaryl group;
or R12Is an amino acid residue;
or X1、X2、R1、R2A fused ring forming ring A;
or X2、R2And Z1A fused ring or spiro ring between which an A ring is formed;
or R8Separately or simultaneously with X4、R12、R13Spiro rings forming a ring B therebetween;
or R12Alone or simultaneously with X4、R13Forming a ring;
represents represented by R configuration or S configuration;
the ring A is a five-membered ring containing two N in the compound of the formula (I), and the ring B is a five-membered ring with R in the compound of the formula (I)8A five-membered ring containing one N attached.
A compound, isomer, or pharmaceutically acceptable salt thereof of formula (VII):
Figure BDA0001403604930000091
wherein,
X1、X2、X5which may be the same or different, X1、X2、X5Each independently selected from covalent bond, O, S, S (O), S (O)2) Optionally substituted C6-14Aryl, N (R)5) Or C (R)6R7)；
X1-R1、X2-R2、X5-R14The same or different;
or X1-R1、X2-R2、X5-R14Can form rings simultaneously or independently;
R1、R2、R5、R6、R7、R8、R14、R15、R16、Z1each independently selected from H, cyano, amino, nitro, diazo, hydroxy, optionally substituted C1-10Alkyl, optionally substituted C3-10Cycloalkyl, optionally substituted C3-8Heterocycloalkyl, optionally substituted C2-10Alkylene, optionally substituted C3-8Cycloalkenylhydrocarbyl, optionally substituted C6-14Aryl, optionally substituted C3-14Heteroaryl, optionally substituted C1-10Alkoxy, optionally substituted C1-10Alkylthio, optionally substituted C1-10Ester group, optionally substituted C1-10Sulfonyl, optionally substituted C1-10Carbonyl, optionally substituted C1-10An amide group; the substituent is selected from halogen, cyano, amino, nitro and hydroxylBase, borate ester, C1-6Aldehyde group, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio radical, C2～6Alkylene radical, C0-6Carbonyl group, C0-6Ester group, C1～6Hydroxyalkyl or C6-14A nitroaryl group;
or X1、X2、R1、R2A fused ring forming ring A;
or X2、R2And Z1A fused ring or spiro ring between which an A ring is formed;
or R8Separately or simultaneously with X5、R14、R15、R16Spiro rings forming a ring B therebetween;
or R15、R16Form a ring between the two;
or X5Independently or simultaneously with R15、R16Forming a ring;
or R14Independently or simultaneously with R15、R16Forming a ring;
represents represented by R configuration or S configuration;
the ring A is a five-membered ring containing two N in the compound of the formula (I), and the ring B is a five-membered ring with R in the compound of the formula (I)8A five-membered ring containing one N attached.
A compound, isomer, or pharmaceutically acceptable salt thereof of formula (VIII):
Figure BDA0001403604930000101
wherein,
X1、X2and X6Which may be the same or different, X1、X2And X6Each independently selected from covalent bond, O, S, S (O), S (O)2) Optionally substituted C6-14Aryl, N (R)5) Or C (R)6R7)；
X1-R1、X2-R2And X6-R17The same or different;
or X1-R1、X2-R2、X6-R18Can form rings simultaneously or independently;
R1、R2、R5、R6、R7、R8、R17、Z1each independently selected from H, cyano, amino, nitro, diazo, hydroxy, optionally substituted C1-10Alkyl, optionally substituted C3-10Cycloalkyl, optionally substituted C3-8Heterocycloalkyl, optionally substituted C2-10Alkylene, optionally substituted C3-8Cycloalkenylhydrocarbyl, optionally substituted C6-14Aryl, optionally substituted C3-14Heteroaryl, optionally substituted C1-10Alkoxy, optionally substituted C1-10Alkylthio, optionally substituted C1-10Ester group, optionally substituted C1-10Sulfonyl, optionally substituted C1-10Carbonyl, optionally substituted C1-10An amide group; the substituent is selected from halogen, cyano, amino, nitro, hydroxyl, borate, C1-6Aldehyde group, C1～6Alkyl radical, C1～6Haloalkyl, C1～6Alkoxy radical, C1～6Alkylthio radical, C2～6Alkylene radical, C0-6Carbonyl group, C0-6Ester group, C1～6Hydroxyalkyl or C6-14A nitroaryl group;
or X1、X2、R1、R2A fused ring forming ring A;
or X2、R2And Z1A fused ring or spiro ring between which an A ring is formed;
or R8Independently or simultaneously with R17、X6Spiro rings forming a ring B therebetween;
represents represented by R configuration or S configuration;
the ring A is a five-membered ring containing two N in the compound of the formula (I), and the ring B is a five-membered ring with R in the compound of the formula (I)8A five-membered ring containing one N attached.
The invention also provides a preparation method of the compound, which is characterized by comprising the following steps:
Figure BDA0001403604930000102
Figure BDA0001403604930000111
the present invention also provides:
the use of each of the above compounds, isomers or pharmaceutically acceptable salts thereof of the present invention in the manufacture of a medicament for the prevention or treatment of a disease associated with the dengue virus protease NS3 inhibitor.
The use of the above compound, characterized in that the disease associated with the dengue virus protease NS3 inhibitor is dengue fever caused by dengue virus and dengue hemorrhagic fever and dengue shock syndrome.
Use of the above compound, isomer or salt thereof for the manufacture of a medicament for treating or preventing a disease selected from the group consisting of dengue fever, yellow fever, west nile virus, zika virus, Chikungunya virus, hepatitis c, encephalitis b, forest encephalitis, and aids caused by HIV.
A pharmaceutical composition for preventing or treating diseases related to dengue virus NS3-NS2B protease inhibitor is characterized in that any one of compounds, stereoisomers or pharmaceutically acceptable salts thereof shown as formulas (I) to (VIII) is taken as one of active ingredients in the composition.
A pharmaceutical composition is characterized in that the composition takes any one of compounds shown in formulas (I) to (VIII), isomers or pharmaceutically acceptable salts thereof as a main active ingredient, and is assisted by a pharmaceutically acceptable carrier.
Definition of
The invention is also directed to a pharmaceutically acceptable solvate, which may be a crystalline hydrate or a crystalline form with other solvents, such as ethanol.
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
if the compounds of the invention are basic, the compounds forming part of the invention are pharmaceutically acceptable salts: including the conventional non-toxic salts of the compounds of the present invention formed by the reaction of the compounds of the present invention with an inorganic or organic acid. For example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, monosodium hydrogen sulfate, monosodium hydrogen phosphate, disodium hydrogen phosphate, monopotassium hydrogen sulfate, monopotassium hydrogen phosphate, dipotassium hydrogen phosphate, sodium potassium hydrogen phosphate and the like, and salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid and the like,
if a compound of the invention is acidic, an appropriate "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared by a pharmaceutically acceptable non-toxic base including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, cesium and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, and substituted amines including naturally occurring and synthetic substituted amines, cyclic amines and basic ion exchange resins. Such as arginine, betaine, caffeine, choline, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
"isomers" means that the compounds of the present invention may have asymmetric centers, chiral axes and chiral planes, and that the racemates, racemic mixtures and single diastereomers and all possible isomers and mixtures thereof, including optical isomers, that exist are included in the present invention. In addition, the compounds disclosed herein may exist as tautomers, and both tautomeric forms are included within the scope of the invention, even if only one of the tautomeric structures is depicted. For example, any claim below to compound a is understood to include the tautomeric structure B and vice versa, including mixtures thereof as well.
The double bond cis-trans isomers present in the present invention may be present as a single isomer, or as a mixture of cis and trans isomers, even though only one of the isomeric structures is depicted.
The term "alkyl" as used herein denotes 1 saturated aliphatic radical and includes straight and branched chain radicals (the numerical ranges mentioned in this application, e.g. "1 to 10", refer to radicals, in this case alkyl, which may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms), which may be substituted or unsubstituted.
"cycloalkyl" means a monocyclic or fused ring of all carbons (a "fused" ring meaning that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system) group in which one or more rings do not have a fully connected pi-electron system, examples of cycloalkyl (without limitation) are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, and the like, and cycloalkyl groups can be substituted and unsubstituted.
"Heterocycloalkyl" means a saturated cyclic group of 3 to 8 ring atoms in which one or two ring atoms are selected from N, O or S (O)m(wherein m is an integer from 0 to 2) and the remaining ring atoms are C, wherein one or two C atoms may optionally be replaced by a carbonyl group. The rings of the heterocyclyl may be optionally independently substituted with one, two or three substituents.
The term "alkenyl" refers to a straight or branched chain nonaromatic hydrocarbon group having a main chain containing 2 to 10 carbon atoms and at least one carbon-carbon double bond. (A numerical range such as "2 to 10" as referred to herein means that the group, in this case the alkylene group, may contain 2 carbon atoms, 3 carbon atoms, etc. up to and including 10 carbon atoms) the alkylene group may be substituted or unsubstituted.
"cycloalkenyl" refers to cyclic nonaromatic hydrocarbyl radicals containing from 3 to 8 carbon atoms and at least one carbon-carbon double bond, and cycloalkenyl radicals may be substituted or unsubstituted.
"aryl" means any stable monocyclic or bicyclic carbocyclic ring of up to 6 to 14 atoms in each ring, wherein at least one ring is aromatic. Non-limiting examples of aryl groups are phenyl, naphthyl, anthracenyl and biphenyl. The aryl group may be substituted or unsubstituted.
"heteroaryl" means a stable monocyclic or bicyclic carbon ring of up to 3-14 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl. Heteroaryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and still more preferably one or two.
"alkoxy" means-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"alkylthio" means-S- (unsubstituted alkyl) and-S- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"ester group" means a-C (O) O-R 'group, wherein R' is alkyl or hydrogen, and alkyl is as defined above.
"Sulfonyl" means' -S (═ O)2-, where R' is alkyl or hydrogen,alkyl is as defined above.
"amido" means a- (O) NR '' R 'group wherein R' and R '' are alkyl groups, the alkyl groups being as defined above.
"haloalkyl" means a halogen-substituted alkyl group, as defined above.
"hydroxyalkyl" means a hydroxy-substituted alkyl group, as defined above.
"nitroaryl" means a nitro-substituted aryl group, which is as defined above.
"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
"amino" means-NH2Radicals or-NH protected by customary protecting groups2Radicals, e.g. Boc-protected-NH2。
"nitro" means-NO2A group.
"hydroxy" means an-OH group or an-OH group protected by a conventional protecting group, such as a-OH group protected by TBS or Ms.
"diazo" means-N3。
The term "optionally substituted" refers to both substituted and unsubstituted, it being understood that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and may be synthesized by techniques and methods of the art from available starting materials. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stable.
The term "aralkyl" includes groups in which the above-mentioned "alkyl" is substituted with the above-mentioned "aryl". Examples of aralkyl groups include benzyl, phenethyl, naphthylmethylene, anthracenylmethylene.
The term "heteroaralkyl" includes groups in which the above-described "alkyl" is substituted with the above-described "heteroaryl". Examples of heteroaryl groups include furanmethylene, pyridylethyl, pyrrolymethylene.
The term "cyclic" indicates cyclic compounds containing more than 3 carbons or other atoms in the ring.
The term "polycyclic" includes structures in which at least 2 rings are formed, spiro rings in which at least two of the rings have 1 atom in common between them or fused or bridged (bridged) ring structures in which at least 2 atoms are in common between them. Typical structures are the basic structures of adamantane, norbornane, norbornene, pinane, (iso) camphane, carane, and the like. Structures which may or may not contain substituents on these rings, and these polycyclic structures may be hetero-polycyclic.
The term "individual" means that the variables that are applied independently vary independently between applications.
The ring A in the invention is a five-membered ring containing two N in a mother ring (such as rings I, II, III, IV, V, VI, VII, VIII and the like) in the invention. The B ring in the invention is the parent ring (such as the rings of formula I, II, III, IV, V, VI, VII, VIII and the like) and R3And R4A five-membered ring containing one N attached.
The andrographolide derivatives of the present invention may be formulated into pharmaceutical compositions for administration to a patient in accordance with a variety of suitably selected modes of administration, including systemically, e.g., orally or parenterally, intravenously, intramuscularly, transdermally, or subcutaneously, etc.
The preferred mode of administration of the drug of the present invention is oral, but the dosage form and mode of administration used will depend on the particular physical and chemical characteristics and stability of the compound, as well as on the difference in therapeutic objectives, including but not limited to sustained release controlled administration.
The compound shown in the formula (I) has the function of inhibiting the activity of dengue virus protease NS2B-NS3, is used as a medicine for treating and preventing diseases caused by dengue virus by inhibiting the activity of NS2B-NS3, and can also be used as a medicine for treating and preventing diseases caused by other flaviviruses, such as yellow fever, West Nile virus infection, Zika virus infection, Chikungunya virus infection, hepatitis C, encephalitis B, forest encephalitis, HIV-caused AIDS and the like.
Detailed Description
Example 1
The invention also provides a preparation method of the compound, which comprises the following steps:
Figure BDA0001403604930000151
Figure BDA0001403604930000161
the following specific compounds were prepared according to the above procedure:
Figure BDA0001403604930000162
Figure BDA0001403604930000171
Figure BDA0001403604930000181
Figure BDA0001403604930000191
Figure BDA0001403604930000201
Figure BDA0001403604930000211
Figure BDA0001403604930000221
Figure BDA0001403604930000231
Figure BDA0001403604930000241
Figure BDA0001403604930000251
Figure BDA0001403604930000261
Figure BDA0001403604930000271
Figure BDA0001403604930000281
Figure BDA0001403604930000291
Figure BDA0001403604930000301
Figure BDA0001403604930000311
Figure BDA0001403604930000321
example 2
The constructed NS3-NS2B fusion protein expression plasmid PET15b-CF40-Linker-NS3pro185(CF40 is 40 amino acids in 1394-1440 region of core sequence of hydrophilic region of NS2B, Linker is a sequence freely rotatable from Gly4-Ser-Gly4, and NS3pro185 is 185 amino acid sequences between 1476-1660 of N-terminal of NS 3) was provided by Dr.Sieve Phengsuzeg Lim (see Jun Li, Siew Pheng Lim, David Beer, ViralPatel, DayWen, Christine Tumaniut, David C.Tully, Jennifer A.Williams, JanJeriirk, John P.Priese, Jennier L.Harris, Bhav.774 J.28766.31, Van J.766, Van J.31, J.766, Van J.31, J.. Expression product recombination of NS3-NS2B fusion protein expression plasmid PET15b-CF40-Gly-NS3pro185 in Escherichia coli BL21(DE3)The expressed protease can be obtained by reacting histidine tag (His-tag) with Ni2+The affinity column was purified with the aid of other chromatographic methods, the purified protease having normal NS3 enzyme activity (see, for details, Jun Li, Siew Pheng Lim, David Beer, Viral Patel, Daying Wen, ChristineTumanut, David C.Tully, Jennifer A.Williams, Jan Jivicek, John P.Priesle, Jennifer L.Harris, and Subha G.Vasudevan J.biol.Chem.2005,280(31),28766 28774 and Shaoqong Xu, Hua Li, Xiaoxa Shao, Chongxu Fan, Bryan. Medicken 2012, Jinson Liu, Chengwu Chi, Chunguang J.Cheng J.688.688.6887, Wa1 Wa.1. Er.).
The method for measuring the activity of the inhibitor is a sensitive and efficient method for measuring the protease activity by using a fluorogenic substrate, and can ensure that various inhibitors can be effectively screened by measuring the activity of the inhibitor. The basic enzymological calculation method is by 2 or more fixed substrate concentrations [ S]Down-change inhibitors [ I]The concentration of (D) was determined by using Dixon mapping (M. Dixon biochem. J.1953,55,170-
Figure BDA0001403604930000322
Plotting inhibition constant Ki。
The screening procedure is as follows (cf. Jun Li, Siew Pheng Lim, David Beer, Viral Patel, DayingWen, Christine Tumanut, David C.Tully, Jennifer A.Williams, Jan Jircick, John P.Priestlele, Jennifer L.Harris, and Subha G.Vasudevan J.biol.Chem.2005,280(31),28766-28774 and Shaoqong Xu, Hua Li, Xiaoxa Shao, Chongxu Fan, BryanEricksen, Jinsong Liu, Jungwu Chi, Chungung Wang J.2012, 55, 6881.): dengue protease NS2B-NS3 was incubated in 37 ℃ buffer (50mM Tris-HCl, pH 9.0,10mM NaCl, 20% Glycerol,1mM CHAPS, 0.04% NaN3), followed by addition of the inhibitor compound to be detected and incubation with the enzyme for 3 minutes, followed by addition of the substrate Benzoyl-Nle-Lys-Arg-Arg-AMC of protease NS2B-NS3 (final concentration 33. mu.M and 66. mu.M), followed by detection of the activity of the remaining NS2B-NS3, which was not inhibited by the inhibitor, as substrate decomposed by enzyme NS2B-NS3, with fluorescence excitation and emission wavelengths of 356nm and 438nm, respectively. The activity data of the partial compounds on NS3 are shown in table 1.
Partial compounds of Table 1 inhibit NS2B-NS3protease activity
Figure BDA0001403604930000331
Figure BDA0001403604930000341

Claims (7)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof;
Figure FDA0002478613880000011
wherein the compound is selected from the following compounds:
Figure FDA0002478613880000012
2. a process for the preparation of a compound of formula (I) according to claim 1, comprising the steps of:
Figure FDA0002478613880000013
wherein, X1、X2Each independently selected from the group consisting of covalent bond, R1Is p-nitrophenyl, R2Selected from H, methyl, isopropyl, n-butyl, p-nitrophenyl, R3、R4Each independently selected from H, Z1Is selected from H.
3. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of a disease associated with an inhibitor of dengue virus protease NS 3.
4. Use according to claim 3, characterized in that the disease associated with the dengue virus protease NS3 inhibitor is dengue fever and dengue hemorrhagic fever and dengue shock syndrome caused by dengue virus.
5. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing dengue disease, yellow fever, west nile virus infection, zika virus infection, chikungunya virus infection, hepatitis c, encephalitis b, forest encephalitis, or HIV-induced aids.
6. A pharmaceutical composition for preventing or treating a disease associated with dengue virus NS3-NS2B protease inhibitor, wherein the composition comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof as one of active ingredients.
7. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as a main active ingredient, together with a pharmaceutically acceptable carrier.
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