CN103159665A - Isatin-5-amide inhibiting agent with inhibition effect against SARS coronavirus main protease - Google Patents
Isatin-5-amide inhibiting agent with inhibition effect against SARS coronavirus main protease Download PDFInfo
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- NTNYHMJYSGPGCQ-UHFFFAOYSA-N NC(c(cc1C2=O)ccc1N(Cc1ccc(cccc3)c3c1)C2=O)=O Chemical compound NC(c(cc1C2=O)ccc1N(Cc1ccc(cccc3)c3c1)C2=O)=O NTNYHMJYSGPGCQ-UHFFFAOYSA-N 0.000 description 1
- VCOSFOBPDCQTQJ-UHFFFAOYSA-N O=C(c(cc1C2=O)ccc1N(Cc1ccccc1)C2=O)N1CCCC1 Chemical compound O=C(c(cc1C2=O)ccc1N(Cc1ccccc1)C2=O)N1CCCC1 VCOSFOBPDCQTQJ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides an isatin-5-amide compound represented by a formula (1). The compound has an inhibition activity against SARS coronavirus main protease, and can be used as a SARS coronavirus main protease inhibiting agent, and can be applied in SARS treatment. The structural formula of the compound represented by the formula (1) is as the following.
Description
Technical field
The present invention relates to a class to the inhibited isatin of sars coronavirus main protease-5-amides inhibitor, belong to the pharmaceutical chemistry field.
Background technology
Severe acute respiratory syndrome is the strong respiratory system disease of a kind of infectivity, and the World Health Organization is referred to as severe acute respiratory syndrome (Severe Acute Respiratory Syndromes), is called for short SARS.Mainly by the closely infection such as the air spittle and close contact, clinical main manifestations is pneumonia to SARS, in family and hospital, significant clustering phenomena is arranged.2003, atypical pneumonia swept across global 32 countries, cause people's very big fear, and the perpetrator of this storm is sars coronavirus.
At present the human and animal is not also treated specific medicine through clinical proof.During SARS in 2003 breaks out, be the methods for the treatment of of use experience treatment, supportive treatment and control complication clinically.Wherein antiviral, glucocorticosteroid, microbiotic and immunomodulator etc. are widely used in clinical, though play an important role in certain stage, but itself all has the defective of self this several drugs, has brought certain interference also for every sign research of patient SARS and the observation of positive regular incidence course that should disease.In general, at present without narrow spectrum medicine for patient SARS by clinical experiment.Although SARS has worldwide obtained effective control, the mankind can't guarantee that the SARS storm can not stage a comeback, and in order to reduce the loss of life and property, are significant for the efficient anti-SARS drug of existing achievement in research development.
Rao Zi and academician laboratory have successfully parsed sars coronavirus main protease (SARS CoV M in 2003
PROBe called again SARS 3CL) at the eutectic structure of different pH values and single inhibitor (hexapeptidyl CMK), this enzyme is the broad sense serine protease take Cys-His as avtive spot, it discharges replicative enzyme PP1a and PP1ab by hydrolysis replicative enzyme polyprotein, regulate and control copying and transcribing of virus, this provides larger possibility for developing single-minded effective SARS resisting medicine.
Li Rung Chen etc. has synthesized a series of Isatine derivatives, and (Bioorg.Med.Chem.Lett.15 (2005) 3058-3062), wherein has two derivatives to the IC of SARS 3CL
50Reached respectively 0.98 μ M and 0.95 μ M, the structure of these two derivatives is as follows:
IC
50＝0.98μM
Lu Zhou etc. synthesized a series of isatin amide derivatives (J.Med.Chem.2006,49,3440-3443), the IC of active best compound wherein
50Reached 0.37 μ M, this compound structure is as follows:
Above two pieces of documents are not all put down in writing compound of the present invention, and after also being substituted without any the amino about 5 amidos, whether the compound that obtains also has the inhibiting prompting of SARS 3CL.
Summary of the invention
The present invention designs and has synthesized a series of isatin amidess that have no bibliographical information, and it has been carried out SARS CoV M
PROThe active inhibition tests, and experimental data proves that these compounds are for SARS CoV M
PROActive inhibited, can be used for the sars coronavirus main proteinase inhibitor.Nsp5 is the sars coronavirus main protease.
Isatin shown in a kind of formula (1)-5-amides, structural formula is as follows:
Wherein,
R
1Be selected from C
1-6Alkyl, aromatic ring yl-methyl, aromatic heterocyclic-methyl; Described alkyl, aromatic ring yl, aromatic heterocyclic are chosen wantonly by one or more following groups and are replaced: halogen, C
1-4Alkyl, hydroxyl, nitro;
R
2Be the heterocyclic radical that contains at least a N atom, this heterocyclic radical is connected with 5 acyl groups by the N on ring, and described heterocyclic radical is optional to be replaced by one or more following groups: halogen, C
1-4Alkyl, aromatic ring yl, hetero-aromatic ring base, heterocyclic radical, aromatic ring yl-C
1-4Alkyl; Perhaps R
2By the amino that aromatic ring yl replaces, this aromatic ring yl is optional to be replaced by one or more halogens;
Above-described aromatic ring yl be monocycle or dicyclo, 6-10 unit aromatic ring yl,
Aromatic heterocyclic is monocycle or dicyclo, 6-10 unit, contains one or more optional aromatic heterocyclics from N or O or S atom,
Heterocyclic radical is monocycle or dicyclo, 5-9 unit, contains one or more optional saturated heterocyclyls from N or O or S atom.
Preferred technical scheme of the present invention is:
Isatin shown in a kind of formula (1)-5-amides, structural formula as previously mentioned,
Wherein,
R
1Be selected from C
1-6Alkyl, phenyl-methyl, naphthyl-methyl; Described alkyl, phenyl, naphthyl are chosen wantonly by one or more following groups and are replaced: halogen, C
1-4Alkyl, hydroxyl, nitro;
R
2Be selected from pyrrolidyl, piperidyl, piperazinyl, morpholinyl, above-mentioned group is connected with 5 acyl groups by the N on ring, and optional by one or more following groups replacements: halogen, C
1-4Alkyl, pyrrolidyl, pyrryl, pyridyl, phenyl, phenyl-C
1-4Alkyl; Perhaps R
2By the amino of phenyl substituted, this phenyl is optional to be replaced by one or more halogens.
The further preferred technical scheme of the present invention is:
Isatin shown in a kind of formula (1)-5-amides, structural formula as previously mentioned,
Wherein,
R
1Be selected from:
R
2Be selected from:
The further preferred technical scheme of the present invention is:
Isatin shown in a kind of formula (1)-5-amides, structural formula as previously mentioned,
Wherein: R
1Be selected from methyl, benzyl, 2-naphthyl methyl; R
2Be selected from morpholinyl, pyrrolidyl, piperidyl, 4-methyl piperidine base.
Alkyl in the present invention is the straight or branched saturated alkyl, preferable methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, n-pentyl, isopentyl, n-hexyl; The preferred fluorine of halogen, chlorine, bromine etc.; Aromatic ring yl is the cyclic group with aromaticity of monocycle or dicyclo, 6-10 unit, preferred phenyl, naphthyl, phenanthryl etc.; Aromatic heterocyclic is monocycle or dicyclo, 6-10 unit, contains one or more optional cyclic groups with aromaticity from N or O or S atom, preferred pyrryl, pyridyl, quinolyl, isoquinolyl etc.; Heterocyclic radical is monocycle or dicyclo, 5-9 unit, contains one or more optional saturated cyclic group from N or O or S atom, preferred pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuran base etc.
The preferred compound of the present invention is:
1-methyl-5-(4-morpholine methanoyl) isatin (compound 1),
1-benzyl-5-(1-pyrrolidine formyl base) isatin (compound 2),
1-(2-menaphthyl)-5-(1-pyrrolidine formyl base) isatin (compound 3),
1-(2-menaphthyl)-5-(1-piperidine formyl base) isatin (compound 4),
1-(2-menaphthyl)-5-[(4-methyl isophthalic acid-piperidyl) formyl radical] isatin (compound 5).
Formula of the present invention (1) compound proves that through activity experiment it has sars coronavirus main protease restraining effect, therefore can be for the preparation of the pharmaceutical composition for the treatment of SARS, in particular for preparation sars coronavirus main proteinase inhibitor, described pharmaceutical composition or inhibitor comprise formula of the present invention (1) compound and the pharmaceutical excipient for the treatment of significant quantity, and reach the useful effect of SARS treatment by the activity that suppresses the sars coronavirus main protease.
Embodiment
The following examples can make the present invention of those skilled in the art's comprehend, but do not limit the present invention in any way.
The general synthetic route of formula (1) compound is as follows:
Embodiment one:
1-methyl-5-(4-morpholine methanoyl) isatin (compound 1)
Concrete steps:
1. with Chloral Hydrate 21.6g (0.13mol), anhydrous sodium sulphate 158g (1.10mol) adds in the flask that fills 440mL water, be heated to 40 ℃, stir to clarify, with what configure, urethanum aqueous hydrochloric acid 1 (is dissolved in 180mL to urethanum 19.8g (0.12mol), in 2.5% hydrochloric acid) drop in reaction solution, 10-15min adds.Continue reaction 0.5h, separate out a large amount of white flockss, add oxammonium hydrochloride 16.7g (0.24mol).Be warming up to 90 ℃.Solution becomes faint yellow, reaction 4h.Be cooled to room temperature, suction filtration obtains yellow powder product 2.
2. the 60mL vitriol oil is heated to 60 ℃, adds product 2 2.0g altogether in batches, stir and be warming up to 80 ℃.Reaction 4h.Be cooled to room temperature.Reaction solution is slowly poured in the 300mL frozen water, stirred.Ethyl acetate extraction.Merge organic phase, anhydrous sodium sulfate drying.Be spin-dried for solvent, obtain isatin-5-formic acid, red powder product 3.
3. under nitrogen protection condition, 355mg (1.86mmol) product 3 is dissolved in dry tetrahydrofuran (THF) (10mL), adds N, N '-carbonyl dimidazoles 300mg (1.86mmol), stirring at room is to emitting without bubble.Add triethylamine 0.52mL (3.72mmol), morpholine 323mg (3.72mmol).Stirring at room 10h adds water treatment, ethyl acetate extraction.Merge organic phase, anhydrous sodium sulfate drying.Desolventizing.Column chromatography purification, methylene dichloride: methyl alcohol=150: 1 obtains product 4.
4. 260mg (1mmol) product 4 is dissolved in the 5ml dry DMF, add 36mg (1.5mmol) NaH, reaction 15min, then 213mg (1.5mmol) methyl iodide is dissolved in 1ml DMF, splash in reaction solution, room temperature reaction 1h with ethyl acetate and water extraction, collects organic phase, desolventizing, cross column purification, methylene dichloride: methyl alcohol=100: 1 gets yellow solid 5.Yield 73%,
1H NMR (400MHz, DMSO-d6, δ in ppm): 3.17 (s, 3H), 3.65 (t, J=4.8Hz, 4H), 3.51 (t, J=4.8Hz, 4H), 7.21 (d, J=8.8Hz, 1H), 7.44 (s, 1H), 8.18 (d, J=8.8Hz, 1H); ESI-MS m/z 275.10 ([M+H
+]).
Adopt the method identical with synthetic compound 1, select the synthetic following compound of corresponding raw material:
1-benzyl-5-(1-pyrrolidine formyl base) isatin (compound 2)
Yellow solid, yield 81%.
1H?NMR(400MHz，DMSO-d6，δin?ppm)：1.98(t，J＝5.6Hz，2H)，3.49(t，J＝5.6Hz，2H)，4.94(s，2H)，7.03(d，J＝8.8Hz，1H)，7.27-7.45(m，6H)，8.10(d，J＝8.8Hz，1H)；ESI-MS?m/z?335.13([M+H
+])。
1-(2-menaphthyl)-5-(1-pyrrolidine formyl base) isatin (compound 3)
Orange solids, yield 78%.
1H?NMR(400MHz，DMSO-d6，δin?ppm)：1.96(t，J＝5.6Hz，2H)，3.43(t，J＝5.6Hz，2H)，5.14(s，2H)，6.91(d，J＝8.4Hz，1H)，7.27-7.45(m，8H)，8.15(d，J＝8.4Hz，1H)；ESI-MS?m/z?385.13([M+H
+])。
1-(2-menaphthyl)-5-(1-piperidine formyl base) isatin (compound 4)
Orange solids, yield 78%.
1H?NMR(400MHz，DMSO-d6，δin?ppm)：1.80(m，4H)，1.66(m，2H)，3.43(t，J＝5.6Hz，4H)，5.04(s，2H)，6.87(d，J＝8.4Hz，1H)，7.24-7.48(m，8H)，8.13(d，J＝8.4Hz，1H)；；ESI-MS?m/z?399.16([M+H
+])。
1-(2-menaphthyl)-5-[(4-methyl isophthalic acid-piperidyl) formyl radical] isatin (compound 5)
Yellow solid, yield 76%.
1H?NMR(400MHz，DMSO-d6，δin?ppm)：0.98(d，J＝7.2Hz，3H)，1.67(m，1H)，1.33-1.58(m，4H)，3.28-3.42(m，4H)5.07(s，2H)，6.91(d，J＝8.4Hz，1H)，7.31-7.65(m，8H)，8.24(d，J＝8.4Hz，1H)；ESI-MS?m/z?413.18([M+H
+])。
Pharmacologically active testing method of the present invention is as follows:
1.SARS the expression of coronavirus proteolytic and purifying
According to document (Yang H et al.Proc Natl Acad Sci.2003 Nov; 100 (23): the expression and the purifying that 13190-5) carry out the sars coronavirus main protease.Concrete grammar is as follows:
1.1SARS the structure of the expression vector of coronavirus proteolytic, concrete steps comprise:
A. utilize the cDNA library of the SARS virus strain that is numbered BJ01 that the large gene center of Beijing China provides, carry out amplification in vitro with round pcr;
Forward primer: 5 '-CGGGATCCAGTGGTTTTAGGAAAATG-3 '
Reverse primer: 5 '-CCGCTCGAGTCATTGGAAGGTAACACCAGA-3 '
B. through the gene fragment of pcr amplification after BamHI and the two enzyme enzymes of XhoI are cut, reclaiming size with agarose gel electrophoresis is fragment about 1kb;
C. will reclaim fragment and be connected with the T carrier, and then transform colibacillus Escherichia coli DH5 α competent cell with connecting product, and be coated on LB flat board (containing the 100mg/L penbritin) overnight incubation;
D. a plurality of mono-clonals of picking from the flat board are inoculated in respectively and are equipped with approximately in the test tube of the LB of 5mL (add penbritin in this LB solution, making its final concentration is 100mg/L), overnight incubation.Then use plasmid extraction kit (vast Imtech Type B plasmid is the rapid extraction test kit in a small amount) to extract plasmid, and cut with BamHI and XhoI enzyme, then reclaim with sepharose the target gene fragment that size is about the 1kb left and right;
E. destination carrier pGEX-4T-1 (available from Pharmacia company) is cut with BamHI and XhoI enzyme, then reclaim with sepharose the fragment that enzyme is cut;
F. (the target gene segment after enzyme is cut back to close and destination carrier fragment are mixed according to the mole number ratio of 3: 1～6: 1 in the fragment connection that d is connected with e, requirement according to Takara DNA Ligation was reacted 30 minutes～18 hours at 16 ℃), transform colibacillus Escherichia coli DH5 α competent cell, be coated in the upper overnight incubation of LB flat board (containing the 100mg/L penbritin).With the positive colony that screens, for the identification of and the order-checking.Sequencing result shows, the encoding gene of the main protease of sars coronavirus correctly is cloned in the pGEX-4T-1 carrier.
1.2SARS the expression and purification of coronavirus proteolytic, concrete steps comprise:
A. with the bacterial strain of the pGEX-4T-1 carrier Transformed E scherichia coli BL21 (DE3) that contains encoding SARS coronavirus proteolytic gene that obtains in above-mentioned steps 1.1, and with dull and stereotyped (the containing the 100mg/L penbritin) screening positive clone of LB;
B. at picking positive colony on the LB flat board described in a (containing the mono-clonal that grows out on the LB flat board of penbritin), then overnight incubation changes the LB substratum (containing the 100mg/L penbritin) of 1L over to, works as OD
600When reaching 0.6-0.8, add the IPTG of 1mM left and right, cultivated about 12 hours at 16 ℃;
C.5000 the centrifugal 10～15min collecting cell of～8000rpm, the then broken bacterium 20～30min of ice-bath ultrasonic; Collect supernatant liquor after the broken centrifugal 20～40min of bacterium liquid 13000rpm～15000rpm;
D. supernatant liquor is added in the GST affinity column (GE company) of PBS pre-equilibration, remove foreign protein with 20～30 column volumes of PBS drip washing.Add at last human rhinovirus's HRV 3CP of 2mL 0.1mg/mL left and right, cut 12～20 hours at 4 ℃ of enzymes, collect afterwards albumen;
E. the albumen that obtains in previous step d is used Mono Q (GE company) anion-exchange chromatography to carry out purifying again, just can be obtained the higher sars coronavirus main protease of purity.
2.SARS the screening method of coronavirus proteolytic inhibitor
The method of screening sars coronavirus main proteinase inhibitor of the present invention is Rao Zi and disclosed screening method in CN101418334A such as grade, and concrete grammar is as follows:
The determination of activity of sars coronavirus main protease is to use fluorogenic substrate MCA-AVLQSGFR-Lys (Dnp)-Lys-NH2 (purity greater than 95%, Shanghai gill biochemical company limited) to complete.The aminoacid sequence of this fluorogenic substrate derives from the N end of sars coronavirus main protease from shearing sequence.
The instrument that is used for fluorescent strength determining is Fluoraskan Ascent luminoscope (ThermoLabsystems, Helsinki, Finland), and exciting light and radiative wavelength are respectively 320nm and 405nm.
At buffered soln (50mM Tris-HCl (pH 7.3), 1mM EDTA (containing or do not contain DTT)) add sars coronavirus main protease (final concentration 0.5 μ M) in, add the DMSO solute of compound (to make its final concentration be: 500 μ g/mL, concentration of substrate is 20 μ M, 298K placed after 10 minutes, add rapidly fluorescent mark substrate (MCA-AVLQSGFRL (DNP) L-NH2, final concentration 20 μ M).Set negative control: do not add compound, all the other conditions are identical.Excitation wavelength and emission wavelength are respectively 320nm and 405nm, and temperature keeps 298K, and record the first order fluorescence reading every 10 seconds, measures altogether 10 points.Take the time as X-axis, fluorescent value is that the Y-axis mapping obtains the movable mechanics curve of enzyme.The initial velocity V that just can obtain reacting by the numerical evaluation slope of scheming upper the first two point is defined as V with the initial velocity of reaction of negative control
0, add the initial velocity of reaction of compound to be defined as V
iThereby, calculate the remaining activity (V that adds main protease after respective compound
i/ V
0), the inhibiting rate of respective compound is (1-V
i/ V
0).During less than 20% (or inhibiting rate is greater than 80%), the IC of this compound will be measured further when the remaining activity of main protease
50Value.
3. compound suppresses active IC to the sars coronavirus main protease
50The mensuration of value
Compound is dissolved into respectively the solution of 50mol/mL with 95% DMSO.The mentioned solution of getting 10 μ L carries out the gradient dilution of 2 times with 95% DMSO, be diluted to altogether the sample solution of 12 left and right.Remaining activity with main protease under the different chemical combination concentration of above-mentioned measuring method test.Divided by the molecular weight of respective compound and get the denary logarithm value as X-axis, corresponding remaining activity value is Y-axis, maps and calculates corresponding IC with GraphPad Prism 5 (GraphPad software company) with the compound concentration of dilution
50Value.
Embodiment two:
IC according to above-mentioned pharmacologically active test determines compound (1)～(5)
50Be worth as shown in table 2.
The activity data table of table 2 compound (1)～(5)
Although illustrated and described embodiments of the invention, for the ordinary skill in the art, be appreciated that without departing from the principles and spirit of the present invention and can carry out multiple variation, modification, replacement and modification to these embodiment, scope of the present invention is limited by claims and equivalent thereof.
Claims (10)
1. the isatin shown in a formula (1)-5-amides, structural formula is as follows:
Wherein,
R
1Be selected from C
1-6Alkyl, aromatic ring yl-methyl, aromatic heterocyclic-methyl; Described alkyl, aromatic ring yl, aromatic heterocyclic are optional to be selected from following group and to replace by one or more: halogen, C
1-4Alkyl;
R
2Be the heterocyclic radical that contains at least a N atom, this heterocyclic radical is connected with 5 acyl groups by the N on ring, and described heterocyclic radical is chosen wantonly by one or more and is selected from following group and replaces: halogen, C
1-4Alkyl, aromatic ring yl, aromatic heterocyclic, heterocyclic radical, aromatic ring yl-C
1-4Alkyl; Perhaps R
2By the amino that aromatic ring yl replaces, this aromatic ring yl is optional to be replaced by one or more halogen;
Above-described aromatic ring yl be monocycle or dicyclo, 6-10 unit aromatic ring yl,
Aromatic heterocyclic is monocycle or dicyclo, 6-10 unit, contains one or more optional aromatic heterocyclics from N or O or S atom,
Heterocyclic radical is monocycle or dicyclo, 5-9 unit, contains one or more optional saturated heterocyclyls from N or O or S atom.
2. according to claim 1 formula (1) compound is characterized in that:
R
1Be selected from C
1-6Alkyl, phenyl-methyl, naphthyl-methyl; Described alkyl, phenyl, naphthyl are optional to be selected from following group and to replace by one or more: halogen, C
1-4Alkyl;
R
2Be selected from pyrrolidyl, piperidyl, piperazinyl, morpholinyl, above-mentioned group is connected with 5 acyl groups by the N on ring, and optional is selected from following group replacement by one or more: halogen, C
1-4Alkyl, pyrrolidyl, pyrryl, pyridyl, phenyl, phenyl-C
1-4Alkyl; Perhaps R
2By the amino of phenyl substituted, this phenyl is optional to be replaced by one or more halogens.
3. according to claim 2 formula (1) compound is characterized in that:
R
1Be selected from:
R
2Be selected from:
4. according to claim 3 formula (1) compound, is characterized in that: R
1Be selected from methyl, benzyl, 2-naphthyl methyl.
5. according to claim 3 formula (1) compound, is characterized in that: R
2Be selected from morpholinyl, pyrrolidyl, piperidyl, 4-methyl piperidine base.
6. the formula of according to claim 1-5 any one (1) compound, described compound is:
1-methyl-5-(4-morpholine methanoyl) isatin,
1-benzyl-5-(1-pyrrolidine formyl base) isatin,
1-(2-menaphthyl)-5-(1-pyrrolidine formyl base) isatin,
1-(2-menaphthyl)-5-(1-piperidine formyl base) isatin,
1-(2-menaphthyl)-5-[(4-methyl isophthalic acid-piperidyl) formyl radical] isatin.
7. pharmaceutical composition, described composition comprises formula (1) compound of the claim 1-6 any one for the treatment of significant quantity, and pharmaceutical excipient.
8. according to claim 7 pharmaceutical composition, is characterized in that this pharmaceutical composition is the sars coronavirus main proteinase inhibitor.
The formula of claim 1-6 any one (1) compound for the preparation of the treatment SARS pharmaceutical composition in purposes
10. purposes according to claim 9, is characterized in that described pharmaceutical composition is the sars coronavirus main proteinase inhibitor.
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Cited By (4)
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| CN108017570A (en) * | 2017-12-21 | 2018-05-11 | 常州大学 | A kind of production method of isatin |
| CN113773259A (en) * | 2021-07-14 | 2021-12-10 | 上海药明康德新药开发有限公司 | Virus main protease inhibitor and preparation method and application thereof |
| CN115073431A (en) * | 2021-04-14 | 2022-09-20 | 盐野义制药株式会社 | Triazine derivatives having virus proliferation inhibitory activity and pharmaceutical composition containing the same |
| WO2023283831A1 (en) * | 2021-07-14 | 2023-01-19 | 上海药明康德新药开发有限公司 | Virus main protease inhibitor, preparation method therefor, and use |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108017570A (en) * | 2017-12-21 | 2018-05-11 | 常州大学 | A kind of production method of isatin |
| CN115073431A (en) * | 2021-04-14 | 2022-09-20 | 盐野义制药株式会社 | Triazine derivatives having virus proliferation inhibitory activity and pharmaceutical composition containing the same |
| CN115073431B (en) * | 2021-04-14 | 2023-09-05 | 盐野义制药株式会社 | Triazine derivative with virus proliferation inhibition effect and pharmaceutical composition containing triazine derivative |
| CN113773259A (en) * | 2021-07-14 | 2021-12-10 | 上海药明康德新药开发有限公司 | Virus main protease inhibitor and preparation method and application thereof |
| WO2023283831A1 (en) * | 2021-07-14 | 2023-01-19 | 上海药明康德新药开发有限公司 | Virus main protease inhibitor, preparation method therefor, and use |
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