CN113754594A

CN113754594A - Quinazolinone compound or pharmaceutically acceptable salt and isomer thereof, preparation method, pharmaceutical composition and application thereof

Info

Publication number: CN113754594A
Application number: CN202111091566.6A
Authority: CN
Inventors: 蒋晟; 肖易倍; 张阔军; 谢幼华; 武倩倩; 唐鹤; 朱琳瑜; 倪勇; 杨佳媚
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2021-09-16
Filing date: 2021-09-16
Publication date: 2021-12-07

Abstract

The invention discloses quinazolinone compounds with a structure shown in a general formula I or pharmaceutically acceptable salts and isomers thereof, a preparation method thereof, a pharmaceutical composition and application thereof, overcomes the defects of single structure, lack of non-covalent efficient micromolecule inhibitors and the like of the existing broad-spectrum antiviral drugs, has good inhibitory activity on 3C-like cysteine protease, has good treatment effect on virus infectious diseases, and has small toxic and side effects.

Description

Quinazolinone compound or pharmaceutically acceptable salt and isomer thereof, preparation method, pharmaceutical composition and application thereof

Technical Field

The invention relates to an innovative medicine, a preparation method and application thereof, in particular to a quinazolinone compound or pharmaceutically acceptable salt and isomer thereof, a preparation method thereof, a pharmaceutical composition and application thereof.

Background

Coronavirus (CoV) is a family of enveloped positive-strand RNA pathogenic viruses that can cause acute and chronic diseases including central nervous system disease, common cold, lower respiratory tract infections, and diarrhea. HCoV-229E and HCoV-OC43 are zoonotic strains that were first discovered since 1995. In 2003, the severe acute respiratory syndrome coronavirus, now designated SARS-CoV-1, caused the first global pandemic of human coronavirus, resulting in 8000-person progressive respiratory failure and 916-person death (10-15% mortality). In the following 8 years, human and animal comorbid coronaviruses HCoV-NL64 and HCoV-HKU1 with significantly reduced lethality were found. In 2012, SARs-like middle east respiratory syndrome coronavirus (MERS-CoV) was discovered, which has a low transmission rate but a high mortality rate, from 2012 appearing to 2021, 2 months and 2 days, there were 2567 diagnosed infected patients and 882 deaths (34%) globally. In 2020, the new type of coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is spreading worldwide, has become a world epidemic disease, and brings serious challenges to global public health defense and medical systems and uncertain factors to world economy. SARS-CoV-2 is a highly pathogenic, large-scale epidemic of zoonosis virus, which is of the family Coronaviridae with both SARS-CoV-1 and MERS-CoV. These three viruses, unlike several other coronaviruses, HCoV-NL63, HCoV-229E, HCoV-OC43 and HCoVHKU1, can cause severe respiratory diseases. Symptoms of SARS-CoV-2 infection range from asymptomatic disease to moderate and severe pneumonia, as well as life-threatening complications including hypoxic respiratory failure, acute respiratory distress syndrome, multiple system organ failure, and ultimately death. Furthermore, the virus is not only highly infectious, but can be transmitted by asymptomatic infected persons and those in the symptomatic and presymptomatic stages. Since the emergence of SARS-CoV in 2003, researchers have been working on the research and development of anti-coronavirus drugs, but unfortunately no effective targeted therapeutic drug or vaccine is currently available. This is also the main reason why we are stranded when faced with a fulminant SARS-CoV-infection. Although Reidesciclovir has recently been approved by the FDA for marketing, its clinical efficacy is not significant and is not effective in severe patients. Therefore, the search for new effective anti-SARS-CoV-2 infection strategies is urgent.

The mutation rate and RNA recombination rate of CoVs are high. Then, is the vaccine or drug currently being developed effective against future "packaged" coronaviruses? This is a concern. Therefore, compared with the drug research aiming at specific coronavirus, the development of broad-spectrum antiviral drugs is a more reasonable and effective strategy for resisting coronavirus infection. The key factors controlling host spectrum and virus pathogenicity are highly different in CoVs, such as different dependent receptors of virus infected hosts, poor structural protein (antigen) conservation and the like, and high mutation and recombination rate of CoVs genome, and the factors make the research and development of broad-spectrum anti-coronavirus drugs have great challenges. However, it is feared that, as the gene replication and pathogenic mechanism of coronaviruses are being continuously analyzed, some key proteins existing in pathogenic CoVs are found to be crucial to the life cycle of CoVs and highly conserved in structure and function, and the key proteins can be used as potential effective targets for developing broad-spectrum antiviral drugs.

Upon entry into the host cell, the coronavirus is broken down to release the nucleocapsid and viral genome. The host cell ribosome translates the Open Reading Frame (ORF)1a and ORF1b of the viral genome into polyproteins pp1a and pp1b, respectively, for encoding 16 non-structural proteins (nsps), while the remaining ORFs encode structural and accessory proteins. 3C-like cysteine proteases (3CLpro) and papain (PLpro) catalyze the cleavage of PP to nsp2-16, which in turn forms the replication-transcription complex (RTC). The loss of activity of these proteases leads to the cessation of the viral life cycle. Also, the structure and function of 3CLpro is highly conserved among coronaviruses. Therefore, 3CLpro becomes a potential effective target for developing anti-broad-spectrum coronavirus medicines. The 3CLpro inhibitors reported so far include covalent peptidomimetic inhibitors and non-covalent small molecule inhibitors. Although the peptidomimetic covalent inhibitor has remarkable inhibitory activity on 3CLpro, the target selectivity of the covalent inhibitor is poor, and unpredictable toxic and side effects exist. The non-covalent small molecule inhibitor is very deficient, and has the problems of single structure, weak enzyme inhibition activity, poor drug forming property and the like. Only three 3CLpro covalent inhibitors, GC-376, PF-00835231 and PF-07304814, are currently in the early clinical study stage, and no drugs are on the market. Therefore, the search for the 3CLpro small-molecule inhibitor which is non-covalent, non-peptidomimetics, remarkable in activity and excellent in drug-forming property has important significance for developing broad-spectrum anti-coronavirus drugs.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to provide quinazolinone compounds or pharmaceutically acceptable salts and isomers thereof. The invention also aims to provide a preparation method, a medicinal composition and application of the quinazolinone compound or pharmaceutically acceptable salts and isomers thereof.

The technical scheme is as follows: the invention provides a quinazolinone compound with a structure shown in a general formula I or pharmaceutically acceptable salts and isomers thereof, wherein the structure is as follows:

wherein R is¹Is hydrogen, hydroxy, amino, mercapto, OR^1-1、-NHR^1-2；

R^1-1Is unsubstituted or R^1-1-1Substituted C_1-6Alkyl, unsubstituted or R^1-1-2Substituted C_3-10Cycloalkyl, 5-to 10-membered heteroaryl with 1 to 3 heteroatoms selected from N, O and S, and heterocycloalkyl- (C)_1-4Alkyl) -,

the 4-10 membered heterocycloalkyl group is a 4-10 membered heterocycloalkyl group with 1-3 heteroatoms selected from one or more of N, O and S;

R^1-2is a 5-10 membered heteroaryl group with 1-3 heteroatoms selected from one or more of N, O and S;

R^1-1-1is hydroxyl, sulfydryl, carboxyl, amino,

C_1-4Alkoxy or C_1-4A haloalkoxy group;

R^1-1-2is hydroxyl, sulfhydryl, carboxyl or amino;

m is 1, 2 or 3; n is 0, 1, 2, 3 or 4;

R²is hydrogen, hydroxy, amino, mercapto, OR^2-1、-O(C＝O)R^2-2、

R^2-1Is unsubstituted or R^2-1-1Substituted C_1-6Alkyl, or,

R^2-1-1Is hydroxy, mercapto, carboxyl, amino

C_1-4Alkoxy or C_1-4A haloalkoxy group;

R^2-2～R^2-5independently selected from C_1-6An alkyl group;

R^2-6～R^2-9independently selected from hydrogen or C_1-6An alkyl group;

q is 1, 2 or 3; r is 0, 1, 2, 3 or 4;

R³is hydrogen, hydroxy, mercapto, OR^3-1、-O(C＝O)R^3-2、

R^3-1Is unsubstituted or R^3-1-1Substituted C_1-6An alkyl group;

R^3-1-1is hydroxy, mercapto or C_1-4Alkoxy radical, C_1-4Halogenated alkoxy, one or more of N, O and S as heteroatoms, and 1-3 of 4-to 10-membered heterocycloalkyl as the heteroatoms;

R^3-2～R^3-5independently selected from C_1-6An alkyl group;

R^3-6～R^3-9independently selected from hydrogen or C_1-6An alkyl group;

R¹、R²and R³Not hydrogen at the same time;

a is unsubstituted or R⁴Substituted C_6-10Aryl radical, C_3-10Cycloalkyl, unsubstituted or R⁵The substituted heteroatom is selected from one or more of N, O and S, 5-10-membered heteroaryl with 1-3 heteroatoms, and C_3-10Cycloalkenyl radical, C_6-10Aryl radical- (C)_2-4Alkynyl) -, C_6-10Aryl radical- (C)_2-4Alkenyl) -;

R⁴and R⁵Independently selected from deuterium, halogen, hydroxy, cyano, nitro, unsubstituted or R^4-1Substituted C_1-6Alkyl, unsubstituted or R^4-2Substituted C_1-6Alkoxy radical, C_6-10Aryl radical, C_3-10Cycloalkyl, one or more of N, O heteroatom (S), 4-10 membered heterocycloalkyl with 1-3 heteroatom (S), one or more of N, O heteroatom (S), 1-3 heteroatom (S), 5-10 membered heteroaryl, -NR^4-3R^4-4、-(C＝O)R^4-5、-(C＝O)OR^4-6、-O(C＝O)R^4-7、-(C＝O)NR^4-8R^4-9、-S(＝O)₂NR^4-10R^4-11；

R^4-1Is halogen, hydroxy, or-NR^4-1-1R^4-1-2；

R^4-2Is halogen;

R^4-3～R^4-11independently selected from hydrogen or C_1-4An alkyl group;

R^4-1-1and R^4-1-2Independently selected from hydrogen or C_1-4An alkyl group;

x is hydrogen or C_1-6Alkyl, unsubstituted or R⁶Substituted C_6-10Aryl radical, C_6-10Aryl radical- (C)_1-4Alkyl), one or more heteroatoms selected from N, O and S, 4-10 membered heterocycloalkyl with 1-3 heteroatoms, one or more heteroatoms selected from N, O and S, and 5-10 membered heteroaryl with 1-3 heteroatoms;

R⁶is halogen;

R⁷is hydrogen, C_1-6Alkyl radical, C_6-10Aryl radical, C_6-10Aryl radical- (C)_1-4Alkyl) -.

In some embodiments, when R^1-1Is unsubstituted or R^1-1-1Substituted C_1-6When it is alkyl, said R^1-1-1Is one or more, when there are more than one R^1-1-1When R is said^1-1-1May be the same or different.

In some embodiments, when R^1-1Is unsubstituted or R^1-1-1Substituted C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group.

In some embodiments, when R^1-1Is unsubstituted or R^1-1-2Substituted C_3-10When the cycloalkyl group is, said R^1-1-2Is one or more, when there are more than one R^1-1-2When R is said^1-1-2May be the same or different.

In some embodiments, when R^1-1Is unsubstituted or R^1-1-2Substituted C_3-10When there is a cycloalkyl group, said C_6-10Cycloalkyl being C_3-6A cycloalkyl group.

In some embodiments, when R^1-1When the aryl group is a 4-to 10-membered heteroaryl group having 1 to 3 heteroatoms selected from N, O and S, the 4-to 10-membered heterocycloalkyl group is a 4-to 6-membered heterocycloalkyl group.

In some implementationsIn the scheme, when R^1-1Is 'one or more of N, O and S as hetero atom, 1-3 hetero atoms' 4-10 membered heterocycloalkyl- (C)_1-4Alkyl), the 4 to 10-membered heterocycloalkyl group- (C)_1-4Alkyl) is 4-6 heterocycloalkyl- (C_1-3Alkyl groups).

And/or when R^1-1When the heteroaryl group is a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group.

In some embodiments, m is 1 or 2.

In some embodiments, n is 0, 1, or 2.

In some embodiments, when R^1-2When the heteroaryl group is a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group.

In some embodiments, when R^2-1Is unsubstituted or R^2-1-1Substituted C_1-6When it is alkyl, said R^2-1-1Is one or more, when there are more than one R^2-1-1When R is said^2-1-1May be the same or different.

In some embodiments, when R^2-1Is unsubstituted or R^2-1-1Substituted C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group.

In some embodiments, when R^2-2～R^2-5Independently selected from C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group.

In some embodiments, when R^2-6～R^2-9Independently selected from C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group.

In some embodiments, q is 1 or 2.

In some embodiments, r is 0, 1, or 2.

In some embodiments, when R^3-1Is unsubstituted or R^3-1-1Substituted C_1-6When it is alkyl, said R^3-1-1Is one or more, when there are more than one R^3-1-1When R is said^3-1-1May be the same or different.

In some embodiments, when R^3-1Is unsubstituted or R^3-1-1Substituted C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group.

In some embodiments, when R^3-1-1Is C_1-4At alkoxy, said C_1-4Alkoxy is C_1-3An alkoxy group.

In some embodiments, when R^3-1-1Is C_1-4When halogenated alkoxy, said C_1-4Haloalkoxy is C_1-3A haloalkoxy group.

In some embodiments, when R^3-1-1When the heterocyclic group is a 4-to 10-membered heterocycloalkyl group in which the number of heteroatoms is 1 to 3, the heteroatom is one or more selected from N, O and S, the 4-to 10-membered heterocycloalkyl group is a 4-to 6-membered heterocycloalkyl group.

In some embodiments, when R^3-2～R^3-5Independently selected from C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group.

In some embodiments, when R^3-6～R^3-9Independently selected from C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group.

In some embodiments, when A is unsubstituted or R⁴Substituted C_6-10When aryl is said to R⁴Is one or more, when there are more than one R⁴When R is said⁴May be the same or different.

In some embodiments, when A is unsubstituted or R⁴Substituted C_6-10When aryl, said C_6-10Aryl is phenyl or naphthyl.

In some embodiments, when A is C_3-10When there is a cycloalkyl group, said C_3-10Cycloalkyl being C_3-6A cycloalkyl group.

In some embodimentsIn the formula, when A is unsubstituted or R⁵When the substituted heteroatom is one or more selected from N, O and S, and the number of the heteroatoms is 1-3, and the heteroatom is 5-10-membered heteroaryl, R is⁵Is one or more, when there are more than one R⁵When R is said⁵May be the same or different.

In some embodiments, when A is unsubstituted or R⁵The substituted heteroatom is one or more selected from N, O and S, and when the heteroatom is 1-3 and the heteroatom is 5-10 membered heteroaryl, the 5-10 membered heteroaryl is 5-6 membered heteroaryl.

In some embodiments, when A is C_3-10Cycloalkenyl group, said C_3-10Cycloalkenyl being C_3-6A cycloalkenyl group.

In some embodiments, when A is C_6-10Aryl radical- (C)_2-4Alkynyl) -, said C_6-10Aryl radical- (C)_2-4Alkynyl) -is phenylethynyl.

In some embodiments, when A is C_6-10Aryl radical- (C)_2-4Alkenyl) -, said C_6-10Aryl radical- (C)_2-4Alkenyl) -is styryl.

In some embodiments, when R⁴And R⁵Independently selected from unsubstituted or R^4-1Substituted C_1-6When it is alkyl, said R^4-1Is one or more, when there are more than one R^4-1When R is said^4-1May be the same or different.

In some embodiments, when R⁴And R⁵Independently selected from unsubstituted or R^4-1Substituted C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group.

In some embodiments, when R⁴Is unsubstituted or R^4-2Substituted C_1-6At alkoxy, said R^4-2Is one or more, when there are more than one R^4-2When R is said^4-2May be the same or different.

In some embodiments, when R⁴Is unsubstituted or R^4-2Substituted C_1-6At alkoxy, said C_1-6Alkoxy is C_1-4An alkoxy group.

In some embodiments, when R⁴Is C_6-10When aryl, said C_6-10Aryl is phenyl.

In some embodiments, when R⁴Is C_3-10When there is a cycloalkyl group, said C_3-10Cycloalkyl being C_3-6A cycloalkyl group.

In some embodiments, when R⁴When the heterocyclic group is a 4-to 10-membered heterocycloalkyl group in which the number of heteroatoms is 1 to 3, the heteroatom is one or more selected from N, O and S, the 4-to 10-membered heterocycloalkyl group is a 4-to 6-membered heterocycloalkyl group.

In some embodiments, when R^4-1When halogen is used, the halogen is fluorine.

In some embodiments, when R^4-2When halogen is used, the halogen is fluorine.

In some embodiments, when R^4-3～R^4-7Independently selected from C_1-4When alkyl, said C_1-4Alkyl is methyl, ethyl or n-propyl.

In some embodiments, when R^4-1-1And R^4-1-2Independently is C_1-4When alkyl, said C_1-4Alkyl is methyl, ethyl or n-propyl.

In some embodiments, when X is C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group.

In some embodiments, when X is unsubstituted or R⁶Substituted C_6-10When aryl is said to R⁶Is one or more, when there are more than one R⁶When R is said⁶May be the same or different.

In some embodiments, when X is unsubstituted or R⁶Substituted C_6-10When aryl, said C_6-10Aryl is phenyl.

In some embodiments, when X is C_6-10Aryl radical- (C)_1-4Alkyl) -said C_6-10Aryl radicals-(C_1-4Alkyl) -is phenyl- (C)_1-3Alkyl) -.

In some embodiments, when R⁶When the halogen is fluorine, chlorine, bromine or iodine.

In some embodiments, when X is a "4-to 10-membered heterocycloalkyl group having 1 to 3 heteroatoms selected from one or more of N, O and S, the 4-to 10-membered heterocycloalkyl group is a 4-to 6-membered heterocycloalkyl group.

In some embodiments, when X is a "5-to 10-membered heteroaryl group having 1 to 3 heteroatoms" and "heteroatoms selected from one or more of N, O and S, the 5-to 10-membered heteroaryl group is a 5-to 6-membered heteroaryl group.

In some embodiments, when R⁷Is C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group.

In some embodiments, when R^1-1Is unsubstituted or R^1-1-1Substituted C_1-6When it is alkyl, said R^1-1-1The number of (a) is 1, 2 or 3.

In some embodiments, when R^1-1Is unsubstituted or R^1-1-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl or n-butyl.

In some embodiments, when R^1-1Is unsubstituted or R^1-1-2Substituted C_3-10When the cycloalkyl group is, said R^1-1-2The number of (2) or (3).

In some embodiments, when R^1-1Is unsubstituted or R^1-1-2Substituted C_3-10When there is a cycloalkyl group, said C_3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, when R^1-1When the aryl group is a 4-10 membered heteroaryl group with 1-3 heteroatoms selected from N, O and S, the 4-10 membered heterocycloalkyl group is a pyrrolidinyl group, an azetidine group or a piperidine ring.

In some embodimentsIn when R is^1-1Is 'one or more of N, O and S as hetero atom, 1-3 hetero atoms' 4-10 membered heterocycloalkyl- (C)_1-4Alkyl), the 4 to 10-membered heterocycloalkyl group- (C)_1-4Alkyl) is pyrrolidinylmethyl, azetidinylmethyl or piperidinylmethyl.

In some embodiments, when R^1-1When the heteroaryl group is a 5-10 membered heteroaryl group with 1-3 heteroatoms selected from N, O and S, the 5-10 membered heteroaryl group is imidazolyl or pyrazolyl.

In some embodiments, when R^1-2When the heteroaryl group is a 5-10 membered heteroaryl group with 1-3 heteroatoms selected from N, O and S, the 5-10 membered heteroaryl group is imidazolyl or pyrazolyl.

In some embodiments, when R^2-1Is unsubstituted or R^2-1-1Substituted C_1-6When it is alkyl, said R^2-1-1The number of (2) or (3).

In some embodiments, when R^2-1Is unsubstituted or R^2-1-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl or n-butyl.

In some embodiments, when R^2-2～R^2-5Independently selected from C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In some embodiments, when R^2-6～R^2-9Independently selected from C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In some embodiments, when R^3-1Is unsubstituted or R^3-1-1Substituted C_1-6When it is alkyl, said R^3-1-1The number of (2) or (3).

In some embodiments, when R^3-1Is unsubstituted or R^3-1-1Substituted C_1-6When there is alkyl, theC_1-6Alkyl is methyl, ethyl, n-propyl or n-butyl.

In some embodiments, when R^3-1-1Is C_1-4At alkoxy, said C_1-4Alkoxy is methoxy, ethoxy or n-propoxy.

In some embodiments, when R^3-1-1Is C_1-4When halogenated alkoxy, said C_1-4Haloalkoxy is trifluoromethoxy or difluoromethoxy.

In some embodiments, when R^3-1-1When the heterocyclic group is a 4-10 membered heterocycloalkyl group having 1 to 3 heteroatoms selected from N, O and S, the 4-10 membered heterocycloalkyl group is a morpholinyl group, a piperidinyl group, a piperazinyl group, a pyrrolidinyl group or an azetidine group.

In some embodiments, when R^3-2～R^3-5Independently selected from C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In some embodiments, when R^3-6～R^3-9Independently selected from C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

In some embodiments, when A is unsubstituted or R⁴Substituted C_6-10When aryl is said to R⁴The number of (a) is 1, 2 or 3.

In some embodiments, when A is C_3-10When there is a cycloalkyl group, said C_3-6Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, when A is C_3-10Cycloalkenyl group, said C_3-10The cycloalkenyl is cyclobutenyl, cyclopentenyl or cyclobutenyl.

In some embodiments, when A is unsubstituted or R⁵When the substituted heteroatom is one or more selected from N, O and S, and the number of the heteroatoms is 1-3, and the heteroatom is 5-10-membered heteroaryl, R is⁵Is given by1, 2 or 3.

In some embodiments, when A is unsubstituted or R⁵And when the substituted heteroatom is one or more of N, O and S, and the number of the heteroatoms is 1-3, and the 5-10 membered heteroaryl is pyridyl, pyrimidyl, thienyl, thiazolyl, furyl, pyrazolyl, pyrrolyl, pyridazinyl, pyrazinyl, oxazolyl or imidazolyl.

In some embodiments, when R⁴And R⁵Independently selected from unsubstituted or R^4-1Substituted C_1-6When it is alkyl, said R^4-1The number of (a) is 1, 2 or 3.

In some embodiments, when R⁴And R⁵Independently selected from unsubstituted or R^4-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

In some embodiments, when R⁴Is unsubstituted or R^4-2Substituted C_1-6At alkoxy, said R^4-2The number of (a) is 1, 2 or 3.

In some embodiments, when R⁴Is unsubstituted or R^4-2Substituted C_1-6At alkoxy, said C_1-6Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

In some embodiments, when R⁴Is C_3-10When there is a cycloalkyl group, said C_3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In some embodiments, when R⁴When the heterocyclic group is a 4-10 membered heterocycloalkyl group having 1 to 3 heteroatoms selected from N, O and S, the 4-10 membered heterocycloalkyl group is a morpholinyl group, a piperidinyl group, a piperazinyl group, an azetidine group or a pyrrolidinyl group.

In some embodiments, when R⁴is-NR^4-3R^4-4When said is-NR^4-3R^4-4is-NH₂Or (b) or (c),

In some embodiments, when R⁴Is- (C ═ O) R^4-5When said- (C ═ O) R^4-5Is composed of

In some embodiments, when R⁴Is- (C ═ O) OR^4-6When said- (C ═ O) OR^4-6is-COOH or

In some embodiments, when R⁴is-O (C ═ O) R^4-7When said group is represented by-O (C ═ O) R^4-7Is composed of

In some embodiments, when R⁴Is- (C ═ O) NR^4-8R^4-9When said- (C ═ O) NR^4-8R^4-9Is composed of

In some embodiments, when R^4-1And R^4-2Independently selected from-NR^4-1-1R^4-1-2When said is-NR^4-1-1R^4-1-2is-NH₂Or (b) or (c),

In some embodiments, when X is C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

In some embodiments, when X is unsubstituted or R⁶Substituted C_6-10In the case of an aryl group,said R⁶The number of (a) is 1, 2 or 3.

In some embodiments, when X is C_6-10Aryl radical- (C)_1-4Alkyl) -said C_6-10Aryl radical- (C)_1-4Alkyl) -is benzyl.

In some embodiments, when X is a "4-10 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S, the 4-10 membered heterocycloalkyl is morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, or azetidine.

In some embodiments, when X is a "5-10 membered heteroaryl group having 1 to 3 heteroatoms" and "heteroatoms selected from one or more of N, O and S, the 5-10 membered heteroaryl group is a pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, oxazolyl, or isoxazolyl.

In some embodiments, when R⁷Is C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

In some embodiments, when R^1-1Is R^1-1-1Substituted C_1-6When it is alkyl, said R^1-1-1Substituted C_1-6Alkyl is

In some embodiments, when R^1-1Is R^1-1-2Substituted C_3-10When the cycloalkyl group is, said R^1-1-2Substituted C_3-10Cycloalkyl is

In some embodiments, when R^1-1When the aryl group is a 4-10 membered heteroaryl group in which the heteroatom is one or more selected from N, O and S and the number of the heteroatoms is 1-3, the 4-10 membered heterocycloalkyl group is a 4-10 membered heterocycloalkyl group

In some embodiments, when R^1-1Is 'one or more of N, O and S as hetero atom, 1-3 hetero atoms' 4-10 membered heterocycloalkyl- (C)_1-4Alkyl), the 4 to 10-membered heterocycloalkyl group- (C)_1-4Alkyl) is

In some embodiments, when R^1-1When the heteroaryl group is a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, the 5-10 membered heteroaryl group is

In some embodiments, when R^1-2When the heteroaryl group is a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, the 5-10 membered heteroaryl group is

In some embodiments, when R^2-1Is R^2-1-1Substituted C_1-6When it is alkyl, said R^2-1-1Substituted C_1-6Alkyl is

In some embodiments, when R^3-1Is R^3-1-1Substituted C_1-6When it is alkyl, said R^3-1-1Substituted C_1-6Alkyl is

In some embodiments, when A is C_3-10Cycloalkenyl group, said C_3-10Cycloalkenyl radical is

In some embodiments, when R⁴Is R^4-1Substituted C_1-6When it is alkyl, said R^4-1Substituted C_1-6The alkyl is trifluoromethyl, difluoromethyl,

In some embodiments, when R⁴Is R^4-2Substituted C_1-6At alkoxy, said R^4-2Substituted C_1-6Alkoxy is trifluoromethoxy.

In some embodiments, when R⁵Is R^4-1Substituted C_1-6When it is alkyl, said R^4-1Substituted C_1-6The alkyl group is trifluoromethyl.

In some embodiments, when X is unsubstituted or R⁶Substituted C_6-10When aryl, said is unsubstituted or R⁶Substituted C_6-10Aryl is

In some embodiments, when X is a "4-to 10-membered heterocycloalkyl group having 1 to 3 heteroatoms" and "one or more heteroatoms selected from N, O and S, the 4-to 10-membered heterocycloalkyl group is

In some embodiments, when X is a "5-to 10-membered heteroaryl group having 1 to 3 heteroatoms" and "one or more heteroatoms selected from N, O and S, the 5-to 10-membered heteroaryl group is

In some embodiments, when A is unsubstituted or R⁴Substituted C_6-10When aryl, said C unsubstituted or substituted by R4_6-10Aryl is

In some embodiments, when A is unsubstituted or R⁵The substituted heteroatom is selected from one or more of N, O and S, and when the heteroatom is 1-3 and the heteroatom is 5-10 membered heteroaryl, the substituent is unsubstituted or R⁵Substituted heteroaryl is

In some embodiments, R¹Is hydroxy, OR^1-1、-NHR^1-2。

In some embodiments, R²Is hydrogen, hydroxy, OR^2-1、-O(C＝O)R^2-2、

In some embodiments, R^2-6～R^2-9Is hydrogen.

In some embodiments, R^1-1-1Is hydroxyl, carboxyl, or,

In some embodiments, R^1-1-2Is a hydroxyl group.

In some embodiments, R^2-1-1Is a hydroxyl group, or,

In some embodiments, m is 1.

In some embodiments, n is 0 or 1.

In some embodiments, q is 1.

In some embodiments, r is 0 or 1.

In some embodiments, R³Is hydrogen, hydroxy, OR^3-1、-O(C＝O)R^3-2、

In some embodiments, R^3-6～R^3-9Is hydrogen.

In some embodiments, R^3-1-1Is hydroxy, C_1-4Alkoxy radical, C_1-4Halogenated alkoxy, one or more of N, O heteroatoms selected from S, and 4-10 membered heterocycloalkyl with 1-3 heteroatoms.

In some embodiments, R⁴Is halogen, hydroxy, cyano, nitro, unsubstituted or R^4-1Substituted C_1-6Alkyl, unsubstituted or R^4-2Substituted C_1-6Alkoxy radical, C_6-10Aryl radical, C_3-10Cycloalkyl, one or more of N, O heteroatoms selected from N, O and S, 4-to 10-membered heterocycloalkyl with 1-3 heteroatoms, and-NR^4-3R^4-4、-(C＝O)R^4-5、-(C＝O)OR^4-6、-O(C＝O)R⁴ ^-7、-(C＝O)NR^4-8R^4-9。

In some embodiments, R⁵Is halogen, unsubstituted or R^5-1Substituted C_1-6An alkyl group.

In some embodiments, R^4-1Is halogen or hydroxyl.

In some embodiments, R^4-7Is C_1-4An alkyl group.

In some embodimentsIn the scheme, R^4-8Is hydrogen.

In some embodiments, R^4-9Is hydrogen.

In some embodiments, R¹Is hydroxy, OR^1-1、-NHR^1-2；

R^1-1Is unsubstituted or R^1-1-1Substituted C_1-6Alkyl, unsubstituted or R^1-1-2Substituted C_3-10Cycloalkyl, 5-to 10-membered heteroaryl with 1 to 3 heteroatoms selected from N, O and S, and heterocycloalkyl- (C)_1-4Alkyl) -, or,

R^1-1-1is a hydroxyl group, a carboxyl group,

R^1-1-2Is a hydroxyl group;

m is 1;

n is 0 or 1;

R²is hydrogen, hydroxy, OR^2-1、-O(C＝O)R^2-2、

R^2-1Is unsubstituted or R^2-1-1Substituted C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,

R^2-1-1Is a hydroxyl group,

q is 1;

r is 0 or 1;

R^2-2～R^2-5independently selected from C_1-6An alkyl group;

R^2-6～R^2-9independently selected from hydrogen;

R³is hydrogen, hydroxy, OR^3-1、-O(C＝O)R^3-2、

R^3-1Is unsubstituted or R^3-1-1Substituted C_1-6An alkyl group;

R^3-1-1is hydroxy, C_1-4Alkoxy radical, C_1-4Halogenated alkoxy, one or more of N, O and S as heteroatoms, and 1-3 of 4-to 10-membered heterocycloalkyl as the heteroatoms;

R^3-2～R^3-5independently selected from C_1-6An alkyl group;

R^3-6～R^3-9independently selected from hydrogen;

R⁴is halogen, hydroxy, cyano, nitro, unsubstituted or R^4-1Substituted C_1-6Alkyl, unsubstituted or R^4-2Substituted C_1-6Alkoxy radical, C_6-10Aryl radical, C_3-10Cycloalkyl, a "heteroatom selected from N, O and SOne or more of 4-to 10-membered heterocycloalkyl group having 1 to 3 hetero atoms and-NR^4-3R^4-4、-(C＝O)R^4-5、-(C＝O)OR^4-6、-O(C＝O)R^4-7Or, - (C ═ O) NR^4-8R^4-9；

R⁵Is halogen, unsubstituted or R^4-1Substituted C_1-6An alkyl group;

R^4-1is halogen or hydroxy;

R^4-2is halogen;

R^4-3～R^4-6independently selected from hydrogen or C_1-4An alkyl group;

R^4-7is C_1-4An alkyl group;

R^4-8is hydrogen;

R^4-9is hydrogen;

R⁶is halogen;

R⁷is hydrogen or C_1-6An alkyl group.

In some embodiments, R¹Is hydroxy, OR^1-1、-NHR^1-2；

R^1-1-1is a hydroxyl group, a carboxyl group,

R^1-1-2Is a hydroxyl group;

m is 1;

n is 0 or 1;

R²is hydroxy, OR^2-1、-O(C＝O)R^2-2、

R^2-1-1Is a hydroxyl group,

q is 1;

r is 0 or 1;

R^2-2～R^2-5independently selected from C_1-6An alkyl group;

R^2-6～R^2-9independently selected from hydrogen;

R³is hydroxy, OR^3-1、-O(C＝O)R^3-2、

R^3-1Is unsubstituted or R^3-1-1Substituted C_1-6An alkyl group;

R^3-1-1a hydroxyl group, a 4-to 10-membered heterocycloalkyl group in which the number of heteroatoms is 1 to 3, and one or more heteroatoms selected from N, O and S;

R^3-2～R^3-5independently selected from C_1-6An alkyl group;

R^3-6～R^3-9independently selected from hydrogen;

R⁴is halogen, nitro, hydroxy, unsubstituted or R^4-1Substituted C_1-6Alkyl, unsubstituted or R^4-2Substituted C_1-6Alkoxy, - (C ═ O) OR^4-6、-O(C＝O)R^4-7；

R⁵Is halogen, unsubstituted or R^4-1Substituted C_1-6An alkyl group;

R^4-1is hydroxy or halogen;

R^4-2is halogen;

R^4-6is hydrogen or C_1-4An alkyl group;

R^4-7is C_1-4An alkyl group;

x is hydrogen or C_1-6An alkyl group, one or more of N, O and S as a heteroatom, 1-3 of 4-to 10-membered heterocycloalkyl as a heteroatom, one or more of N, O and S as a heteroatom, and 1-3 of 5-to 10-membered heteroaryl as a heteroatom;

R⁷is hydrogen.

In some embodiments, the quinazolinone compound with the structure shown in the general formula I or the pharmaceutically acceptable salt and isomer thereof is any one of the following compounds,

the preparation method of the quinazolinone compound with the structure shown in the general formula I or the pharmaceutically acceptable salt and the isomer thereof,

the method comprises the following steps: in a solvent, the compound II and the compound III generate a compound I-1 under the action of a catalyst,

the second method comprises the following steps: in a solvent, reacting a compound IV with a compound V and a compound VI to generate a compound I-2;

wherein R is¹、R²、R³、R⁷X and A are as defined above.

A pharmaceutical composition contains a therapeutically effective amount of one or more quinazolinone compounds with the structure shown in the general formula I or pharmaceutically acceptable salts and isomers thereof, and pharmaceutically acceptable carriers or auxiliary materials.

The quinazolinone compound with the structure shown in the general formula I or pharmaceutically acceptable salt and isomer thereof can be used for preparing 3C-like cysteine protease inhibitors or medicines for treating and/or preventing virus infectious diseases. The virus includes, but is not limited to, middle east respiratory syndrome associated coronavirus (MERS-CoV), severe acute respiratory syndrome associated coronavirus-1 (SARS-CoV-1), influenza A virus, influenza B virus, severe acute respiratory syndrome associated coronavirus-2 (SARS-CoV-2), Spanish influenza virus, arenavirus, bunyavirus, rabies virus, avian influenza virus, poliovirus, rhinovirus, adenovirus, Ebola virus, enterovirus, hepatitis A virus, hepatitis C virus, hepatitis E virus, enterovirus, HIV virus, echovirus, filovirus, measles virus, yellow fever virus, Japanese encephalitis virus, West Nile virus, Newcastle disease virus, RS virus, vesicular stomatitis virus, mumps virus, dengue virus, Coxsackie virus, rotavirus or tobacco mosaic virus.

The application of the pharmaceutical composition in preparing 3C-like cysteine protease inhibitors or preparing medicaments for treating and/or preventing virus infectious diseases. The virus includes, but is not limited to, middle east respiratory syndrome associated coronavirus (MERS-CoV), severe acute respiratory syndrome associated coronavirus-1 (SARS-CoV-1), influenza A virus, influenza B virus, severe acute respiratory syndrome associated coronavirus-2 (SARS-CoV-2), Spanish influenza virus, arenavirus, bunyavirus, rabies virus, avian influenza virus, poliovirus, rhinovirus, adenovirus, Ebola virus, enterovirus, hepatitis A virus, hepatitis C virus, hepatitis E virus, enterovirus, HIV virus, echovirus, filovirus, measles virus, yellow fever virus, Japanese encephalitis virus, West Nile virus, Newcastle disease virus, RS virus, vesicular stomatitis virus, mumps virus, dengue virus, Coxsackie virus, rotavirus or tobacco mosaic virus.

The pharmaceutical excipients can be those widely used in the field of pharmaceutical production. The excipients are used primarily to provide a safe, stable and functional pharmaceutical composition and may also provide methods for dissolving the active ingredient at a desired rate or for promoting the effective absorption of the active ingredient after administration of the composition by a subject. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, antiadherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

The pharmaceutical compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.

The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting free forms of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting free forms of such compounds with a sufficient amount of an acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfuric acid (forming sulfates or bicarbonates), hydroiodic acid, phosphorous acid, and the like, as well as salts of organic acids including similar acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, salts of organic acids also including salts of amino acids such as arginine, and the like, and salts of organic acids such as glucuronic acid, certain specific compounds of the invention contain basic and acidic functional groups and thus can be converted to any base or acid addition salt. The free form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The free form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

The term "isomers" refers to compounds having the same chemical formula but different arrangements of atoms.

The term "metabolite" refers to a pharmaceutically active product produced by the in vivo metabolism of a compound of formula I or a salt thereof. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by a method comprising contacting a compound of the invention with a mammal for a period of time sufficient to obtain a metabolite thereof.

Identification of metabolites is typically accomplished by preparing a radiolabeled isotope of a compound of the invention, parenterally administering it at a detectable dose (e.g., greater than about 0.5mg/kg) to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from urine, blood or other biological samples. These products are easy to isolate because they are labelled (others are isolated by using antibodies capable of binding to epitopes present in the metabolite). Metabolite structure is determined in a conventional manner, e.g., by MS, LC/MS or NMR analysis. Typically, analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolite products are useful in assays for the administration of therapeutic doses of the compounds of the invention, provided that they are not otherwise detectable in vivo. The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C) and C)³H) Iodine-125 (¹²⁵I) Or C-14(¹⁴C) In that respect All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the present invention. For example, compounds containing a carboxyl group may form physiologically hydrolyzable esters that act as prodrugs by hydrolyzing in vivo to give the compounds of formula I themselves. The prodrugs are preferably administered orally, since hydrolysis in many cases takes place mainly under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.

It will be understood by those skilled in the art that, in accordance with the convention used in the art, the structural formulae used in the radicals described herein

Means that the corresponding group is connected with other fragments and groups in the compound shown in the formula I through the site.

The "substitution" in the present invention may be one or more, and when there are a plurality of "substitutions", the "substitutions" may be the same or different.

The term "plurality" may list, for example, 2, 3, or 4. The term "halogen" includes fluorine, chlorine, bromine or iodine. The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, and the like. The term "alkoxy" refers to the group-O-R^YWherein R is^YIs an alkyl group as defined above. The term "cycloalkyl" refers to a saturated monocyclic or polycyclic alkyl group. The monocyclic cycloalkyl group is preferably a monovalent saturated cyclic alkyl group having 3 to 7 ring carbon atoms, more preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Each ring of the polycyclic cycloalkyl is saturated and can be a bicyclic or tricyclic cycloalkyl having 4 to 10 carbon atoms. The term "heterocycloalkyl" refers to a saturated monocyclic or polycyclic group having a heteroatom. The monocyclic ring preferably contains 1, 2 or 3 4-to 6-membered saturated monocyclic heterocycloalkyl independently selected from N, O and S, examples of which include but are not limited to: pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidineAlkyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, dioxolanyl, dioxanyl, and the like. Said polycyclic ring preferably contains 1, 2 or 3 saturated polycyclic heterocycloalkyl ring of 8-to 10-membered ring on at least one ring independently selected from N, O and S, which may be bicyclic or tricyclic, examples include but are not limited to octahydropyrrolo [1, 2-a ] pyrrole]Pyrazinyl, (1R, 5S) -3, 8-diazabicyclo [3.2.1]And (4) octyl. The term "aryl" refers to an aromatic group having the indicated number of carbon atoms, preferably a monocyclic, bicyclic or tricyclic aromatic group, each of which, when bicyclic or tricyclic, satisfies the huckel rule. C of the invention_6-10The aryl group of (b) means an aromatic group having 6 to 10 carbon atoms, such as phenyl or naphthyl. The term "heteroaryl" refers to an aromatic group containing a heteroatom, preferably an aromatic 5-6 membered monocyclic or 9-10 membered bicyclic ring containing 1, 2 or 3 members independently selected from nitrogen, oxygen and sulfur. The 5-to 6-membered monocyclic ring includes, but is not limited to, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, furazanyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazole, 1, 2, 5-oxadiazole, 1, 3, 4-oxadiazole, thiadiazolyl, dithiazolyl, tetrazolyl, pyridyl, pyranyl, thiopyranyl, diazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, 1, 2, 3-triazinyl, 1, 2, 4-triazinyl, 1, 3, 5-triazinyl, or tetrazinyl. The 9-to 10-membered bicyclic ring includes but is not limited to benzimidazolyl, indolyl, indazolyl, benzofuranyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolyl and isoquinolyl. The term "cycloalkenyl" refers to a monocyclic or polycyclic alkyl group containing at least one double bond. The monocyclic cycloalkenyl group is preferably an incompletely saturated cyclic alkyl group having 4 to 7 ring carbon atoms, more preferably 4 to 6 carbon atoms, and having a double bond, such as cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl. At least one ring of the polycyclic cycloalkyl contains double bonds and can be bicyclic or with 4-10 carbon atomsTricyclic cycloalkenyl radicals.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

Has the advantages that: compared with the prior art, the invention has the following advantages:

1. the quinazolinones of the present invention have excellent inhibitory activity against 3C-like cysteine proteases. 2. The compound has good therapeutic action on virus infectious diseases. 3. The compound has small toxic and side effects.

Detailed Description

EXAMPLE 1 Synthesis of Compound S1

The method comprises the following steps: synthesis of Compound 2

Compound 1(25g) was dissolved in glacial acetic acid (110ml), and a mixed solution of glacial acetic acid and fuming nitric acid (110ml +220ml) was slowly added dropwise to the above solution at 0 ℃ and reacted at 0 ℃ for 2 hours after completion of the addition. And pouring the reaction into ice water, and performing suction filtration to obtain a light yellow solid 2, wherein the light yellow solid is directly put into the next reaction without purification.¹H NMR(300MHz，CDCl₃)δ10.22(s，1H)，7.28(s，1H)，3.97(s，9H)。

Step two: synthesis of Compound 3

Compound 2(15g, 62mmol) was dissolved in ethanol/water (132ml/47ml) and FeSO was added to the above solution₄·7H₂O (3.8g), iron powder (38g) was added with vigorous mechanical stirring. The reaction was heated to reflux for 4 h. After the reaction was completed, suction filtration was performed, the solvent was evaporated to dryness, and column chromatography separation and purification was performed to obtain 3(11g, 85%) as a pale yellow solid.¹H NMR(300MHz，CDCl₃)δ10.12(s，1H)，6.33(br，2H)，5.82(s，1H)，3.98(s，3H)，3.84(s，3H)，3.76(s，3H)。

Step three: synthesis of Compound 4

Compound 3(5.32g, 25.2mmol) was dissolved in 20% HCl (50ml) at 0-5 deg.C, and 16ml of sodium nitrite (1.9g) was addedThe aqueous solution was added to the above solution and mechanically stirred for 15 min. Then, 50ml of an aqueous solution of potassium iodide (20g) was slowly added dropwise to the above solution, and reacted overnight. After the reaction was completed, Na was added₂S₂O₃The reaction was quenched, extracted 3 times with chloroform (50 ml. times.3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 4(6.79g, 84%) as a pale yellow solid.¹H NMR(300MHz，CDCl₃)δ＝10.05(s，1H)，7.29(s，1H)，3.96(s，3H)，3.93(s，3H)，3.87(s，3H)。

Step four: synthesis of Compound 5

Compound 4(5g, 15.58mmol) and sulfamic acid (1.8g, 18.70mmol) were suspended in a mixed solvent of water/acetonitrile, and sodium chlorite (3.5g, 38.95mmol) was added portionwise at 0 ℃. And transferring to room temperature for reaction for 2 h. After the reaction was completed, saturated Na was added₂S₂O₃The reaction was quenched, extracted 3 times with EA (50ml × 3), the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 5(4.2g, 80%) as a white solid.¹H NMR(300MHz，CDCl₃)δ8.91(s，1H)，7.11(s，1H)，3.90(s，3H)，3.85(s，6H)。

Step five: synthesis of Compound 7

Compound 5(200mg, 0.59mmol), Compound 6(184mg, 1.18mmol), cuprous iodide (11mg, 0.059mmol) and cesium carbonate (383mg, 1.48mmol) were suspended in anhydrous DMF (4ml) and reacted overnight at room temperature under nitrogen. Saturated ammonium chloride solution (30ml) was added, stirred for 30min and filtered with suction to give 7 as a white solid (147mg, 80%).¹H NMR(300MHz，DMSO-d6)δ12.08(s，1H)，8.17-8.10(m，2H)，7.58-7.51(m，2H)，7.54-7.44(m，1H)，7.01(s，1H)，3.91(s，3H)，3.87(s，3H)，3.78(s，3H)。

Step six: synthesis of Compound S1

Compound 7(100mg, 0.32mmol) was suspended in anhydrous DCM (2ml) and a solution of BBr3 in dichloromethane (1M, 3ml) was added slowly dropwise at-10 ℃ and reacted overnight at room temperature. After the reaction is finished, slowly dropwise adding ice methanol to quench the reaction, evaporating the methanol,DCM was added, the mixture was stirred at room temperature for 30min, and the title compound S1(77mg, 90%) was obtained by suction filtration.¹H NMR(300MHz，DMSO-d₆)δ12.52(s，1H)，11.69(s，1H)，10.36(s，1H)，8.96(s，1H)，8.17-8.10(m，2H)，7.58-7.51(m，2H)，7.54-7.44(m，1H)，6.62(s，1H)。

The following syntheses of the compounds S2 to S68 in examples S2 and S68 refer to the synthesis of example 1, with only the corresponding starting materials being replaced.

Example 2: synthesis of Compound S2

¹H NMR(300MHz，DMSO-d₆)δ12.48(s，1H)，11.59(s，1H)，10.26(s，1H)，8.87(s，1H)，8.20-8.13(m，2H)，7.41-7.33(m，2H)，6.64(s，1H)。

Example 3: synthesis of Compound S3

¹H NMR(300MHz，DMSO-d₆)δ12.44(s，1H)，11.75(s，1H)，10.36(s，1H)，8.92(s，1H)，8.00-7.90(m，2H)，7.62-7.55(m，1H)，7.44-7.38(m，1H)，6.67(s，1H)。

Example 4: synthesis of Compound S4

¹H NMR(300MHz，DMSO-d₆)δ12.48(s，1H)，11.71(s，1H)，10.33(s，1H)，8.93(s，1H)，7.72(td，J＝7.6，1.7Hz，1H)，7.66-7.53(m，1H)，7.46-7.27(m，2H)，6.63(s，1H)。

Example 5: synthesis of Compound S5

¹H NMR(300MHz，DMSO-d₆)δ12.44(s，1H)，11.75(s，1H)，10.36(s，1H)，8.92(s，1H)，7.96-7.90(m，1H)，7.60-7.59(m，1H)，7.54-7.45(m，2H)，6.68(s，1H)。

Example 6: synthesis of Compound S6

¹H NMR(300MHz，DMSO-d₆)δ12.51(s，1H)，11.72(s，1H)，10.36(s，1H)，8.94(s，1H)，8.12(d，J＝8.6Hz，2H)，7.60(d，J＝8.7Hz，2H)，6.64(s，1H)。

Example 7: synthesis of Compound S7

¹H NMR(300MHz，DMSO-d₆)δ12.48(s，1H)，11.72(s，1H)，10.36(s，1H)，8.94(s，1H)，7.84-7.80(m，1H)，7.51-7.46(m，2H)，7.45-7.41(m，1H)，6.64(s，1H)。

Example 8: synthesis of Compound S8

¹H NMR(300MHz，DMSO-d₆)δ12.50(s，1H)，11.77(s，1H)，10.26(s，1H)，8.95(s，1H)，7.86-7.80(m，1H)，7.52-7.44(m，2H)，7.47-7.43(m，1H)，6.62(s，1H)。

Example 9: synthesis of Compound S9

¹H NMR(300MHz，DMSO-d₆)δ12.38(s，1H)，11.83(s，1H)，10.31(s，1H)，8.87(s，1H)，8.01(d，J＝8.3Hz，2H)，7.33(d，J＝8.0Hz，2H)，6.62(s，1H)，2.38(s，3H)。

Example 10: synthesis of Compound S10

¹H NMR(300MHz，DMSO-d₆)δ12.44(s，1H)，11.75(s，1H)，10.36(s，1H)，8.92(s，1H)，7.88-7.82(m，1H)，7.47-7.35(m，1H)，7.30-7.25(m，2H)，6.62(s，1H)。

Example 11: synthesis of Compound S11

¹H NMR(300MHz，DMSO-d₆)δ12.37(s，1H)，11.78(s，1H)，10.28(s，1H)，8.87(s，1H)，7.48-7.37(m，2H)，7.35-7.26(m，2H)，6.58(s，1H)，2.35(s，3H)。

Example 12: synthesis of Compound S12

¹H NMR(300MHz，DMSO-d₆)δ12.47(s，1H)，11.79(s，1H)，10.38(s，1H)，8.90(s，1H)，7.55-7.47(m，2H)，7.45-7.36(m，2H)，6.62(s，1H)。

Example 13: synthesis of Compound S13

¹H NMR(300MHz，DMSO-d₆)δ12.47(s，1H)，11.59(s，1H)，10.24(s，1H)，9.31(s，1H)，8.85(s，1H)，7.67(ddd，J＝7.9，2.2，1.3Hz，1H)，7.23(t，J＝7.8Hz，1H)，7.00(ddd，J＝7.9，2.2，1.1Hz，1H)，6.91(t，J＝2.3Hz，1H)，6.51(s，1H)。

Example 14: synthesis of Compound S14

¹H NMR(300MHz，DMSO-d6)δ12.49(s，1H)，11.57(s，1H)，10.24(s，1H)，9.29(s，1H)，8.85(s，1H)，7.77-7.74(m，2H)，6.96-6.92(m，2H)，6.54(s，1H)。

Example 15: synthesis of Compound S15

¹H NMR(300MHz，DMSO-d6)δ12.46(s，1H)，11.54(s，1H)，10.21(s，1H)，8.87(s，1H)，7.79-7.72(m，2H)，7.07-7.00(m，2H)，6.54(s，1H)，3.81(s，3H)。

Example 16: synthesis of Compound S16

¹H NMR(300MHz，DMSO-d6)δ12.47(s，1H)，11.55(s，1H)，10.23(s，1H)，8.86(s，1H)，7.84(dd，J＝7.9，1.6Hz，1H)，7.56(td，J＝8.1，1.6Hz，1H)，7.26(dd，J＝8.4，1.3Hz，1H)，7.15(td，J＝7.9，1.3Hz，1H)，6.48(s，1H)，3.98(s，3H)。

Example 17: synthesis of Compound S17

¹H NMR(300MHz，DMSO-d6)δ12.49(s，1H)，11.57(s，1H)，10.25(s，1H)，8.87(s，1H)，7.97(dd，J＝7.8，1.6Hz，1H)，7.78(dd，J＝7.8，1.1Hz，1H)，7.57(td，J＝7.7，1.7Hz，1H)，7.49(td，J＝7.5，1.1Hz，1H)，6.59(s，1H)。

Example 18: synthesis of Compound S18

¹H NMR(300MHz，DMSO-d6)δ12.49(s，1H)，11.57(s，1H)，10.25(s，1H)，8.87(s，1H)，8.08-8.01(m，2H)，7.78-7.72(m，1H)，7.50-7.43(m，1H)，6.55(s，1H)。

Example 19: synthesis of Compound S19

¹H NMR(300MHz，DMSO-d6)δ12.47(s，1H)，11.56(s，1H)，10.26(s，1H)，8.87(s，1H)，7.74(d，J＝0.9Hz，4H)，6.54(s，1H)。

Example 20: synthesis of Compound S20

¹H NMR(300MHz，DMSO-d6)δ12.45(s，1H)，11.54(s，1H)，10.23(s，1H)，8.87(s，1H)，8.12(dd，J＝7.9，1.7Hz，1H)，8.04(dd，J＝7.7，1.4Hz，1H)，7.76(td，1H)，7.69(td，J＝7.5，1.6Hz，1H)，6.51(s，1H)。

Example 21: synthesis of Compound S21

¹H NMR(300MHz，DMSO-d6)δ12.48(s，1H)，11.57(s，1H)，10.27(s，1H)，8.86(s，1H)，δ8.64(t，J＝2.3Hz，1H)，8.31(ddd，J＝7.7，2.2，1.1Hz，1H)，8.24(ddd，J＝7.9，2.2，1.1Hz，1H)，7.68(t，J＝7.8Hz，1H)，6.56(s，1H)。

Example 22: synthesis of Compound S22

¹H NMR(300MHz，DMSO-d6)δ12.49(s，1H)，11.53(s，1H)，10.26(s，1H)，8.82(s，1H)，δ8.40-8.32(m，2H)，8.17-8.10(m，2H)，6.55(s，1H)。

Example 23: synthesis of Compound S23

¹H NMR(300MHz，DMSO-d6)δ12.44(s，1H)，11.49(s，1H)，10.22(s，1H)，8.81(s，1H)，8.15-8.09(m，2H)，7.88-7.82(m，2H)，6.55(s，1H)。

Example 24: synthesis of Compound S24

¹H NMR(300MHz，DMSO-d6)δ12.51(s，1H)，11.52(s，1H)，10.28(s，1H)，8.87(s，1H)，7.89(dd，J＝7.5，1.9Hz，1H)，7.65(ddd，J＝7.6，1.8，1.1Hz，1H)，7.51-7.39(m，3H)，6.54(s，1H)。

Example 25: synthesis of Compound S25

¹H NMR(300MHz，DMSO-d6)δ13.22(s，1H)，12.48(s，1H)，11.52(s，1H)，10.25(s，1H)，8.86(s，1H)，δ7.74(ddd，J＝7.9，1.6，0.9Hz，1H)，7.35(t，J＝7.8Hz，1H)，7.26(ddd，J＝7.9，2.2，1.0Hz，1H)，7.20(t，J＝1.9Hz，1H)，6.52(s，1H)。

Example 26: synthesis of Compound S26

¹H NMR(300MHz，DMSO-d6)δ12.46(s，1H)，11.50(s，1H)，10.22(s，1H)，8.84(s，1H)，8.38(dd，J＝7.9，1.7Hz，1H)，7.45-7.34(m，2H)，7.15(td，J＝7.9，1.4Hz，1H)，6.53(s，1H)。

Example 27: synthesis of Compound S27

¹H NMR(300MHz，DMSO-d6)δ12.52(s，1H)，11.59(s，1H)，10.28(s，1H)，8.89(s，1H)，8.50(t，J＝2.3Hz，1H)，8.23(ddd，J＝7.9，2.2，1.1Hz，1H)，8.04(ddd，J＝7.9，2.2，1.1Hz，1H)，7.49(t，J＝7.9Hz，1H)，6.55(s，1H)，2.60(s，3H)。

Example 28: synthesis of Compound S28

¹H NMR(300MHz，DMSO-d6)δ12.50(s，1H)，11.55(s，1H)，10.28(s，1H)，8.89(s，1H)，8.55(t，J＝2.3Hz，1H)，8.21(ddd，J＝7.9，2.3，1.2Hz，1H)，8.07(ddd，J＝7.9，2.2，1.1Hz，1H)，7.49(t，J＝7.8Hz，1H)，6.56(s，1H)，3.89(s，3H)。

Example 29: synthesis of Compound S29

¹H NMR(300MHz，DMSO-d6)δ12.47(s，1H)，11.53(s，1H)，10.23(s，1H)，8.86(s，1H)，7.86-7.80(m，1H)，7.49-7.37(m，3H)，6.51(s，1H)，4.90-4.85(m，2H)，4.76(dd，J＝7.3，6.4Hz，1H)。

Example 30: synthesis of Compound S30

¹H NMR(300MHz，DMSO-d6)δ12.43(s，1H)，11.49(s，1H)，10.23(s，1H)，8.85(s，1H)，7.84-7.77(m，2H)，6.85-6.79(m，2H)，6.53(s，1H)，3.01(s，6H)。

Example 31: synthesis of Compound S31

¹H NMR(300MHz，DMSO-d6)δ12.45(s，1H)，11.47(s，1H)，10.21(s，1H)，8.86(s，1H)，7.93-7.83(m，2H)，7.36(t，J＝7.9Hz，1H)，7.22(ddd，J＝7.7，2.1，0.9Hz，1H)，6.52(s，1H)，2.30(s，3H)。

Example 32: synthesis of Compound S32

¹H NMR(300MHz，DMSO-d6)δ12.45(s，1H)，11.47(s，1H)，10.21(s，1H)，8.86(s，1H)，8.08-8.02(m，2H)，7.84-7.75(m，2H)，6.94(s，2H)，6.55(s，1H)。

Example 33: synthesis of Compound S33

¹H NMR(300MHz，DMSO-d6)δ12.48(s，1H)，11.48(s，1H)，10.28(s，1H)，8.86(s，1H)，7.82-7.72(m，1H)，7.43(ddt，J＝6.6，4.5，1.0Hz，1H)，7.36-7.28(m，2H)，6.54(s，1H)，2.81(qd，J＝7.2，1.0Hz，2H)，1.21(t，J＝7.2Hz，3H)。

Example 34: synthesis of Compound S34

¹H NMR(300MHz，DMSO-d6)δ12.43(s，1H)，11.44(s，1H)，10.24(s，1H)，8.84(s，1H)，7.77(dd，J＝7.7，1.7Hz，1H)，7.43-7.25(m，3H)，6.56(s，1H)，1.31(s，9H)。

Example 35: synthesis of Compound S35

¹H NMR(300MHz，DMSO-d6)δ12.47(s，1H)，11.48(s，1H)，10.29(s，1H)，8.89(s，1H)，7.92-7.86(m，1H)，7.41-7.29(m，3H)，6.52(s，1H)，2.73(pd，J＝5.7，0.8Hz，1H)，1.42(td，J＝10.2，5.8Hz，2H)，1.09-1.00(m，2H)。

Example 36: synthesis of Compound S36

¹H NMR(300MHz，DMSO-d6)δ12.45(s，1H)，11.48(s，1H)，10.30(s，1H)，8.82(s，1H)，8.12-8.06(m，2H)，7.73-7.69(m，2H)，7.62-7.55(m，2H)，7.49-7.34(m，3H)，6.56(s，1H)。

Example 37: synthesis of Compound S37

¹H NMR(300MHz，DMSO-d6)δ12.46(s，1H)，11.48(s，1H)，10.27(s，1H)，8.81(s，1H)，7.85-7.79(m，2H)，6.93-6.86(m，2H)，6.53(s，1H)，3.82-3.73(m，2H)，3.27-3.14(m，2H)。

Example 38: synthesis of Compound S38

¹H NMR(300MHz，DMSO-d6)δ12.43(s，1H)，11.43(s，1H)，10.24(s，1H)，8.81(s，1H)，7.84(ddd，J＝7.8，5.0，1.2Hz，1H)，7.41-7.24(m，2H)，6.47(s，1H)。

Example 39: synthesis of Compound S39

¹H NMR(300MHz，DMSO-d6)δ12.43(s，1H)，11.43(s，1H)，10.24(s，1H)，8.81(s，1H)，8.02(dt，J＝8.4，5.0Hz，1H)，7.17-7.06(m，2H)，6.49(s，1H)。

Example 40: synthesis of Compound S40

¹H NMR(300MHz，DMSO-d6)δ12.46(s，1H)，11.43(s，1H)，10.27(s，1H)，8.79(s，1H)，7.91(ddd，J＝8.5，4.9，2.2Hz，1H)，7.74(ddd，J＝8.1，5.0，2.3Hz，1H)，7.32(td，J＝8.2，5.0Hz，1H)，6.50(s，1H)。

Example 41: synthesis of Compound S41

¹H NMR(300MHz，DMSO-d6)δ12.44(s，1H)，11.47(s，1H)，10.27(s，1H)，8.83(s，1H)，7.63(dd，J＝8.4，2.0Hz，1H)，7.47(d，J＝2.1Hz，1H)，7.00(d，J＝8.5Hz，1H)，6.50(s，1H)，6.02(s，2H)。

Example 42: synthesis of Compound S42

¹H NMR(300MHz，DMSO-d6)δ12.49(s，1H)，11.50s，1H)，10.33(s，1H)，8.89(s，1H)，7.65(d，J＝8.4Hz，1H)，7.18-7.10(m，2H)，6.51(s，1H)，2.40(s，3H)，2.29(s，3H)。

Example 43: synthesis of Compound S43

¹H NMR(300MHz，DMSO-d6)δ12.49(s，1H)，11.50(s，1H)，10.33(s，1H)，8.89(s，1H)，7.74-7.64(m，1H)，7.18-7.10(m，2H)，6.51(s，1H)，2.38(s，3H)，2.24(s，3H)。

Example 44: synthesis of Compound S44

¹H NMR(300MHz，DMSO-d6)δ12.42(s，1H)，11.50(s，1H)，10.31(s，1H)，8.83(s，1H)，7.87(d，J＝8.4Hz，1H)，7.27-7.23(m，1H)，7.19-7.12(m，1H)，6.52(s，1H)，2.34(d，J＝0.7Hz，3H)。

Example 45: synthesis of Compound S45

¹H NMR(300MHz，DMSO-d6)δ12.48(s，1H)，11.57(s，1H)，10.31(s，1H)，8.83(s，1H)，7.93(dd，J＝8.4，5.0Hz，1H)，7.30-7.24(m，1H)，7.12-7.05(m，1H)，6.48(s，1H)，2.36-2.32(m，3H)。

Example 46: synthesis of Compound S46

¹H NMR(300MHz，DMSO-d6)δ12.48(s，1H)，11.57(s，1H)，10.31(s，1H)，8.83(s，1H)，7.63(ddd，J＝12.9，8.2，2.3Hz，2H)，7.39(ddq，J＝8.2，5.0，1.1Hz，1H)，6.50(s，1H)，2.27(d，J＝1.1Hz，3H)。

Example 47: synthesis of Compound S47

¹H NMR(300MHz，DMSO-d6)δ12.45(s，1H)，11.52(s，1H)，10.29(s，1H)，8.80(s，1H)，7.74(dd，J＝7.9，1.3Hz，1H)，7.37-7.31(m，1H)，7.21(t，J＝7.9Hz，1H)，6.51(s，1H)，2.35(d，J＝0.7Hz，3H)。

Example 48: synthesis of Compound S48

¹H NMR(300MHz，DMSO-d6)δ12.49(s，1H)，11.55(s，1H)，10.33(s，1H)，8.83(s，1H)，7.79-7.75(m，2H)，6.82-6.76(m，2H)，6.53(s，1H)，4.50(d，J＝6.2Hz，1H)，4.37(d，J＝6.2Hz，1H)。

Example 49: synthesis of Compound S49

¹H NMR(300MHz，DMSO-d6)δ12.51(s，1H)，11.58(s，1H)，10.37(s，1H)，8.83(s，1H)，8.99(d，J＝3.6Hz，2H)，7.49(t，J＝3.6Hz，1H)，6.62(s，1H)。

Example 50: synthesis of Compound S50

¹H NMR(300MHz，DMSO-d6)δ12.49(s，1H)，11.58(s，1H)，10.36(s，1H)，8.80(s，1H)，7.95-7.88(m，1H)，7.71(dd，J＝5.8，1.5Hz，1H)，7.19(dd，J＝7.9，5.7Hz，1H)，6.46(s，1H)。

Example 51: synthesis of Compound S51

¹H NMR(300MHz，DMSO-d6)δ12.41(s，1H)，11.51(s，1H)，10.30(s，1H)，8.87(s，1H)，8.69(dd，J＝3.5，1.5Hz，1H)，8.29(dd，J＝7.8，1.5Hz，1H)，7.69(td，J＝7.7，1.6Hz，1H)，7.38(ddd，J＝7.5，3.5，1.5Hz，1H)，6.56(s，1H)。

Example 52: synthesis of Compound S52

¹H NMR(300MHz，DMSO-d6)δ12.48(s，1H)，11.57(s，1H)，10.39(s，1H)，8.89(s，1H)，7.36(s，1H)，7.32(s，1H)，6.42(s，1H)，3.82(s，3H)。

Example 53: synthesis of Compound S53

¹H NMR(300MHz，DMSO-d6)δ12.48(s，1H)，11.57(s，1H)，10.39(s，1H)，8.89(s，1H)，7.56(d，J＝5.7Hz，1H)，7.04(d，J＝5.5Hz，1H)，6.41(s，1H)，4.15(s，3H)。

Example 54: synthesis of Compound S54

¹H NMR(300MHz，DMSO-d6)δ12.44(s，1H)，11.52(s，1H)，10.32(s，1H)，8.81(s，1H)，8.25(d，J＝1.6Hz，1H)，7.92(d，J＝1.8Hz，1H)，6.47(s，1H)。

Example 55: synthesis of Compound S55

¹H NMR(300MHz，DMSO-d6)δ12.44(s，1H)，11.52(s，1H)，10.32(s，1H)，8.81(s，1H)，8.13(d，J＝2.5Hz，1H)，7.46(d，J＝2.6Hz，1H)，6.52(s，1H)。

Example 56: synthesis of Compound S56

¹H NMR(300MHz，DMSO-d6)δ12.49(s，1H)，11.55(s，1H)，10.37(s，1H)，8.89(s，1H)，8.68(dd，J＝3.5，1.8Hz，1H)，7.79(ddq，J＝7.9，1.6，0.8Hz，1H)，7.65(dd，J＝7.7，3.5Hz，1H)，6.52(s，1H)，2.55(d，J＝0.7Hz，3H)。

Example 57: synthesis of Compound S57

¹H NMR(300MHz，DMSO-d6)δ12.50(s，1H)，11.59(s，1H)，10.40(s，1H)，8.89(s，1H)，8.51(dd，J＝3.5，1.8Hz，1H)，7.65-7.52(m，2H)，6.56(s，1H)。

Example 58: synthesis of Compound S58

¹H NMR(300MHz，DMSO-d6)δ12.47(s，1H)，11.58(s，1H)，10.38(s，1H)，8.89(s，1H)，8.83(dd，J＝3.5，1.8Hz，1H)，8.09(dd，J＝7.9，1.8Hz，1H)，7.80(dd，J＝7.9，3.5Hz，1H)，6.65(s，1H)。

Example 59: synthesis of Compound S59

¹H NMR(300MHz，DMSO-d6)δ12.41(s，1H)，11.52(s，1H)，10.33(s，1H)，8.81(s，1H)，6.48(s，1H)，2.41(p，J＝6.4Hz，1H)，1.03(tdd，J＝10.1，6.6，1.2Hz，2H)，0.85(tdd，J＝10.1，6.4，1.2Hz，2H)。

Example 60: synthesis of Compound S60

¹H NMR(300MHz，DMSO-d6)δ12.41(s，1H)，11.52(s，1H)，10.35(s，1H)，8.81(s，1H)，6.48(s，1H)，3.09-3.00(m，1H)，1.98-1.86(m，2H)，1.72-1.60(m，4H)，1.61-1.49(m，1H)，1.45-1.34(m，3H)。

Example 61: synthesis of Compound S61

¹H NMR(300MHz，DMSO-d6)δ12.46(s，1H)，11.52(s，1H)，10.34(s，1H)，8.81(s，1H)，6.48(s，1H)，4.17(p，J＝7.5Hz，1H)，2.88(p，J＝4.1Hz，1H)，2.66(td，J＝5.1，4.1Hz，4H)，2.17(dd，J＝11.3，7.4Hz，2H)，2.02(dd，J＝11.3，7.4Hz，2H)，1.72-1.56(m，4H)。

Example 62: synthesis of Compound S62

¹H NMR(300MHz，DMSO-d6)δ12.39(s，1H)，11.49(s，1H)，10.30(s，1H)，8.79(s，1H)，6.51(s，1H)，6.19(t，J＝5.1Hz，1H)，2.60-2.53(m，2H)，2.18-2.10(m，2H)，1.69-1.54(m，4H)。

Example 63: synthesis of Compound S63

¹H NMR(300MHz，DMSO-d6)δ12.51(s，1H)，11.49(s，1H)，10.39(s，1H)，8.83(s，1H)，7.49(d，J＝4.4Hz，4H)，7.33(ddd，J＝8.8，4.9，4.1Hz，1H)，6.63(s，1H)。

Example 64: synthesis of Compound S64

¹H NMR(300MHz，DMSO-d6)δ12.49(s，1H)，11.46(s，1H)，10.31(s，1H)，8.87(s，1H)，7.63(dd，J＝7.0，2.3Hz，2H)，7.40-7.32(m，2H)，7.23(ddt，J＝7.5，6.5，2.4Hz，1H)，6.90(d，J＝11.7Hz，1H)，6.68(d，J＝11.9Hz，1H)，6.55(s，1H)。

Example 65: synthesis of Compound S65

¹H NMR(300MHz，DMSO-d6)δ12.54(s，1H)，11.46(s，1H)，10.31(s，1H)，8.87(s，1H)，7.67(dd，J＝7.7，1.8Hz，1H)，7.37-7.25(m，2H)，7.22(ddd，J＝7.7，1.5，0.8Hz，1H)，4.96(dq，J＝1.9，1.0Hz，1H)，4.89(dq，J＝2.0，1.0Hz，1H)，2.44(d，J＝0.7Hz，3H)，2.15(t，J＝1.0Hz，3H)。

Example 66: synthesis of Compound S66

¹H NMR(300MHz，DMSO-d6)δ12.52(s，1H)，11.46(s，1H)，10.36(s，1H)，8.85(s，1H)，7.69(d，J＝7.2Hz，1H)，7.37-7.25(m，2H)，7.22(ddd，J＝7.8，1.5，0.8Hz，1H)，3.22(p，J＝6.5Hz，1H)，2.42(d，J＝0.7Hz，3H)，1.38(d，J＝6.4Hz，6H)。

Example 67: synthesis of Compound S67

¹H NMR(300MHz，DMSO-d6)δ12.48(s，1H)，11.46(s，1H)，10.40(s，1H)，8.87(s，1H)，7.66(dd，J＝7.7，1.8Hz，1H)，7.31(dtd，J＝22.2，7.4，1.6Hz，2H)，7.22(dq，J＝7.5，0.8Hz，1H)，2.43(d，J＝1.2Hz，6H)。

Example 68: synthesis of Compound S68

¹H NMR(300MHz，DMSO-d6)δ12.50(s，1H)，11.48(s，1H)，8.89(s，1H)，7.85-7.79(m，1H)，7.54-7.45(m，2H)，7.41(ddd，J＝7.7，6.0，2.8Hz，1H)，7.29(d，J＝8.4Hz，1H)，7.07(d，J＝8.4Hz，1H)。

Example 69: synthesis of Compound S69

The method comprises the following steps: synthesis of Compound 9

Adding the compound 8(10g, 47.2mmol) into 90ml of concentrated nitric acid (68% -70%) in batches at 0 ℃, stirring and reacting for 30min at 0 ℃, adding 500ml of ice water into the solution, stirring for 1h at 0 ℃, and performing suction filtration to obtain a light yellow solid 9(8.4g, 69%) which is directly put into the next reaction without purification. 1H NMR (CDCl)₃，300MHz)δ9.52(s，1H)，7.55(s，1H)，4.15-3.98(s，9H).

Step two: synthesis of Compound 10

Compound 9(8g, 31.1mmol) was dissolved in ethanol/water (66ml/25ml), and FeSO was added to the above solution₄·7H₂O (2.0g), iron powder (19g) was added with vigorous mechanical stirring. The reaction was heated to reflux for 4 h. After the reaction was completed, the reaction mixture was filtered with suction, the solvent was evaporated to dryness, and the resulting product was purified by column chromatography to obtain a pale yellow solid 10(6.3g, 89%).¹H NMR(300MHz，CDCl₃)δ7.53(s，1H)，3.89-3.83(s，6H)，3.63(s，3H).

Step three: synthesis of Compound 11

Compound 10(2.7g, 11.7mmol) and benzoic acid (1.42g, 11.7mmol) were dissolved in pyridine (20mL), TPP (7.64mL, 29.1mmol) was added to the above solution, and the temperature was raised to 70 ℃ for 2h under nitrogen. Aniline (1.3ml, 14mmol) was added dropwise to the above reaction solution, and reacted at 70 ℃ overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, the solvent was evaporated to dryness, the residue was dissolved in ethyl acetate, washed with 3N hydrochloric acid solution (1X 50ml), washed with brine (2X 50ml), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 11(2.3g, 50%).¹H NMR(300MHz，DMSO-d6)δ7.79-7.70(m，2H)，7.56-7.42(m，6H)，7.43-7.36(m，2H)，6.96(s，1H)，3.93(s，3H)，3.89-3.86(s，6H).

Step three: synthesis of Compound S69

Compound 11(200mg, 0.52mmol) was suspended in anhydrous DCM (2ml) and BBr3/DCM solution (4.7ml, 4.7mmol) was slowly added dropwise to the suspension at-10 deg.C. The reaction was carried out overnight at-10 ℃ until completion, and after quenching with ice-methanol, the reaction mixture was concentrated, DCM was added, and the reaction mixture was stirred at room temperature for 30min and filtered under suction to obtain the objective compound S69(162mg, 90%).¹H NMR(300MHz，DMSO-d6)δ12.45(s，1H)，11.85(s，1H)，10.26(s，1H)，8.95(s，1H)，7.79-7.70(m，2H)，7.56-7.42(m，6H)，7.43-7.36(m，2H)，6.96(s，1H)，3.93(s，3H)，3.89-3.86(s，6H).

The following syntheses of the compounds S70 to S80 in examples S70 and S80 refer to the synthesis of example 69, with only the corresponding starting materials being replaced.

Example 70: synthesis of Compound S71

¹H NMR(300MHz，DMSO-d6)δ11.51(s，1H)，10.32(s，1H)，8.87(s，1H)，7.78-7.72(m，1H)，7.71-7.65(m，1H)，7.53-7.43(m，3H)，6.52(s，1H)，3.53(s，3H)。

Example 71: synthesis of Compound S71

¹H NMR(300MHz，DMSO-d6)δ11.53(s，1H)，10.32(s，1H)，9.00(t，J＝1.7Hz，1H)，8.82(s，1H)，8.38(dt，J＝3.7，1.9Hz，1H)，7.78-7.69(m，2H)，7.54-7.42(m，4H)，7.27(dd，J＝7.8，3.5Hz，1H)，6.53(s，1H)。

Example 72: synthesis of Compound S72

¹H NMR(300MHz，DMSO-d6)δ11.50(s，1H)，10.31(s，1H)，8.88(s，1H)，7.68-7.59(m，2H)，7.57(d，J＝8.8Hz，1H)，7.52-7.42(m，3H)，6.52(s，1H)，4.68(s，2H)，3.86(dhept，J＝8.8，6.5Hz，1H)，1.17(d，J＝6.4Hz，6H)。

Example 73: synthesis of Compound S73

¹H NMR(300MHz，DMSO-d6)δ11.57(s，1H)，10.34(s，1H)，8.81(s，1H)，7.76-7.68(m，2H)，7.52-7.46(m，2H)，7.49-7.40(m，3H)，7.22(tdd，J＝7.9，2.2，1.4Hz，1H)，7.02(dt，J＝8.1，2.2Hz，1H)，6.55(s，1H)。

Example 74: synthesis of Compound S74

¹H NMR(300MHz，DMSO-d6)δ11.56(s，1H)，10.33(s，1H)，8.82(s，1H)，7.76-7.68(m，2H)，7.52-7.42(m，3H)，7.05-6.98(m，2H)，6.94(tt，J＝8.1，2.2Hz，1H)，6.56(s，1H)。

Example 75: synthesis of Compound S75

¹H NMR(300MHz，DMSO-d6)δ11.55(s，1H)，10.34(s，1H)，8.83(s，1H)，7.76-7.68(m，2H)，7.53-7.44(m，3H)，6.53(s，1H)，3.82-3.68(m，4H)，2.91(ddd，J＝6.4，5.7，0.8Hz，4H)。

Example 76: synthesis of Compound S76

¹H NMR(300MHz，DMSO-d6)δ12..51(s，1H)，11.58(s，1H)，10.31(s，1H)，8.84(s，1H)，7.76-7.68(m，2H)，7.52-7.42(m，4H)，6.54(s，1H)，6.39(d，J＝4.4Hz，1H)。

Example 77: synthesis of Compound S77

¹H NMR(300MHz，DMSO-d6)δ11.52(s，1H)，10.25(s，1H)，8.80(s，1H)，8.85(d，J＝1.8Hz，1H)，7.75-7.67(m，2H)，7.52-7.42(m，3H)，6.60(d，J＝2.0Hz，1H)，6.56(s，1H)。

Example 78: synthesis of Compound S78

¹H NMR(300MHz，DMSO-d6)δ12.51(s，1H)，11.50(s，1H)，10.27(s，1H)，8.80(s，1H)，7.75-7.68(m，2H)，7.52-7.42(m，4H)，6.54(s，1H)，6.39(d，J＝4.4Hz，1H)。

Example 79: synthesis of Compound S79

¹H NMR(300MHz，DMSO-d6)δ11.54(s，1H)，10.23(s，1H)，8.79(s，1H)，7.64-7.56(m，2H)，7.52-7.43(m，3H)，7.30(s，2H)，7.35-7.23(m，3H)，6.53(s，1H)，5.07(d，J＝0.7Hz，2H)。

Example 80: synthesis of Compound S80

¹H NMR(300MHz，DMSO-d6)δ11.51(s，1H)，10.27(s，1H)，8.78(s，1H)，8.00(s，1H)，7.88(s，1H)，7.69-7.61(m，2H)，7.52-7.43(m，3H)，6.50(s，1H)，4.08(t，J＝7.2Hz，1H)，1.79-1.64(m，2H)，0.94(d，J＝6.8Hz，6H)。

Example 81: synthesis of Compound 12

The method comprises the following steps: synthesis of Compound 12

Dichlorodiphenylmethane (18g, 52.5mmol) was added to a solution of compound S1(9.45g, 35mmol) in diphenyl ether (200ml), the temperature was raised to 175 ℃ until the reaction was complete, the reaction was stopped, and the mixture was cooled to room temperature. Petroleum ether (1000ml) was added, and the mixture was filtered under suction to give a cake, which was further purified by column chromatography to give Compound 12(12.9g, 85%).¹H NMR(300MHz，Chloroform-d)δ12.99(s，1H)，8.16-8.10(m，2H)，7.64-7.58(m，4H)，7.57-7.50(m，2H)，7.54-7.44(m，1H)，7.42-7.34(m，4H)，7.38-7.28(m，2H)，6.92(s，1H).

Step two: synthesis of Compound 13

Compound 12(500mg, 1.15mmol) was dissolved in acetone (10ml), and methyl bromoacetate (0.13ml, 1.38mmol) and potassium carbonate (476mg, 3.45mmol) were added in this order, followed by heating under reflux overnight. After completion of the reaction, the reaction was stopped, cooled to room temperature, the solvent was distilled off, 5ml of water was added to the reaction residue, DCM (3 × 10ml) was extracted, the organic phases were combined, washed with saturated brine (1 × 10ml), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 13(518mg, 89%).¹H NMR(300MHz，Chloroform-d)δ12.99(s，1H)，8.15-8.09(m，3H)，7.67-7.60(m，2H)，7.58-7.44(m，4H)，7.42-7.28(m，6H)，7.00(s，1H)，4.79(s，2H)，3.74(s，3H).

Step three: synthesis of Compound 14

Compound 13(506mg, 1mmol) was dissolved in methanol (5ml), and an aqueous solution of sodium hydroxide (1M, 2.0ml) was added thereto, followed by stirring at room temperature for 2 hours. After the reaction is completed, adjusting the pH to 2-3 with dilute hydrochloric acid at 0 ℃, and performing suction filtration to obtain a compound 14, wherein the compound is directly put into the next reaction without purification.

Step four: synthesis of Compound S81

Compound 14(400mg, 0.81mmol) was dissolved in ethanol (30ml), Pd/C (40mg, 10%) was added, and the reaction was carried out under hydrogen for 12 h. After the reaction is completed, carrying out suction filtration, concentrating the filtrate, and carrying out column chromatography purification to obtain a compound S81.¹H NMR(300MHz，DMSO-d6)δ13.02(s，1H)，11.69(s，1H)，10.36(s，1H)，8.96(s，1H)，8.17-8.10(m，2H)，7.58-7.51(m，2H)，7.54-7.44(m，1H)，6.62(s，1H)，4.33(s，2H).

The following syntheses of the compounds S82 to S88 in examples S82 and S88 refer to the synthesis of example 81, with only the corresponding starting materials being replaced.

Example 82: synthesis of Compound S82

¹H NMR(300MHz，DMSO-d6)δ12.47(s，1H)，10.31(s，1H)，8.87(s，1H)，7.67(dd，J＝7.6，1.7Hz，1H)，7.31(dtd，J＝21.4，7.4，1.6Hz，2H)，7.17(ddd，J＝7.5，1.5，0.7Hz，1H)，6.61(s，1H)，4.21(t，J＝6.5Hz，2H)，3.91(dt，J＝7.5，6.5Hz，2H)，3.54(t，J＝7.3Hz，1H)，2.45(d，J＝0.7Hz，3H)。

Example 83: synthesis of Compound S83

¹H NMR(300MHz，DMSO-d6)δ12.44(s，1H)，10.27(s，1H)，8.77(s，1H)，7.72(dd，J＝7.7，1.7Hz，1H)，7.31(dtd，J＝23.3，7.4，1.5Hz，2H)，7.20-7.14(m，1H)，6.75(s，2H)，6.63(s，1H)，4.77(s，2H)，2.43(d，J＝0.7Hz，3H)。

Example 84: synthesis of Compound S84

¹H NMR(300MHz，DMSO-d6)δ12.48(s，1H)，10.26(s，1H)，8.17-8.10(m，2H)，7.58-7.51(m，2H)，7.54-7.44(m，1H)，6.69(d，J＝2.2Hz，1H)，6.59(d，J＝2.2Hz，1H)，4.31(d，J＝6.7Hz，1H)，4.21-4.09(m，2H)，4.10-3.96(m，2H)，3.62(ddd，J＝11.8，7.1，6.2Hz，1H)，3.46(ddd，J＝11.8，7.0，6.2Hz，1H)。

Example 85: synthesis of Compound S85

¹H NMR(300MHz，DMSO-d6)δ12.49(s，1H)，10.31(s，1H)，8.79(s，1H)，8.16-8.10(m，2H)，7.58-7.51(m，2H)，7.54-7.44(m，1H)，6.70(t，J＝4.4Hz，1H)，6.62(s，1H)，4.65(t，J＝5.8Hz，1H)，3.36(dtd，J＝14.5，4.5，3.8Hz，1H)，3.25(dtd，J＝14.5，4.5，3.7Hz，1H)，2.13(dddd，J＝14.1，5.7，4.6，3.7Hz，1H)，2.05(dddd，J＝14.0，5.7，4.6，3.7Hz，1H)。

Example 86: synthesis of Compound S86

¹H NMR(300MHz，DMSO-d6)δ12.47(s，1H)，10.30(s，1H)，8.79(s，1H)，8.16-8.10(m，2H)，7.58-7.51(m，2H)，7.54-7.44(m，1H)，6.66-6.58(m，2H)，4.37(dd，J＝10.6，6.4Hz，1H)，4.23(dd，J＝10.5，6.5Hz，1H)，3.30(dtd，J＝14.5，4.5，3.7Hz，1H)，3.17(dtd，J＝14.3，4.5，3.7Hz，1H)，2.76(p，J＝6.4Hz，1H)，1.88(dddd，J＝13.2，6.4，4.7，3.7Hz，1H)，1.72(dddd，J＝13.2，6.4，4.8，3.7Hz，1H)。

Example 87: synthesis of Compound S87

¹H NMR(300MHz，DMSO-d6)δ12.45(s，1H)，10.32(s，1H)，8.16-8.10(m，2H)，7.58-7.50(m，2H)，7.52-7.44(m，1H)，6.90(t，J＝4.3Hz，1H)，6.72(d，J＝2.2Hz，1H)，6.66(d，J＝2.2Hz，1H)，4.90(t，J＝5.8Hz，1H)，3.34(dtd，J＝14.3，4.5，3.7Hz，1H)，3.19(dtd，J＝14.3，4.5，3.7Hz，1H)，2.19(dddd，J＝14.2，5.9，4.8，3.7Hz，1H)，2.08(dddd，J＝14.0，5.7，4.6，3.7Hz，1H)。

Example 88: synthesis of Compound S88

¹H NMR(300MHz，DMSO-d6)δ12.40(s，1H)，10.28(s，1H)，8.16-8.10(m，2H)，77.58-7.50(m，2H)，7.52-7.44(m，1H)，6.71(d，J＝2.0Hz，1H)，6.63(d，J＝2.2Hz，1H)，6.54(t，J＝4.4Hz，1H)，4.36(dd，J＝10.6，6.6Hz，1H)，4.27(dd，J＝10.6，6.4Hz，1H)，3.29(dtd，J＝14.5，4.6，3.9Hz，1H)，3.16(dtd，J＝14.3，4.5，3.7Hz，1H)，2.77(p，J＝6.4Hz，1H)，1.86(dddd，J＝13.2，6.4，4.6，3.7Hz，1H)，1.73(dddd，J＝13.2，6.4，4.7，3.7Hz，1H)。

Example 89: synthesis of Compound S89

¹H NMR(300MHz，DMSO-d6)δ12.40(s，1H)，10.28(s，1H)，9.87(s，1H)，8.04(s，1H)，7.58-7.50(m，2H)，7.51-7.44(m，2H)，6.82(s，1H)，4.33(s，1H)，4.63(p，J＝4.7Hz，1H)，3.56(dt，J＝11.9，4.9Hz，2H)，3.43(dt，J＝11.7，4.8Hz，2H)，1.85(p，J＝4.9Hz，1H).

Example 90: synthesis of Compound S90

¹H NMR(300MHz，DMSO-d6)δ12.40(s，1H)，10.28(s，1H)，9.87(s，1H)，8.04(s，1H)，7.58-7.51(m，2H)，7.54-7.44(m，2H)，6.62(s，1H)，4.65(p，J＝6.4Hz，1H)，3.74(s，1H)，3.84(p，J＝6.8Hz，1H)，3.09(d，J＝6.8Hz，1H)，2.23(dt，J＝13.2，6.7Hz，2H)，2.14(dt，J＝13.2，6.7Hz，1H).

Example 91: synthesis of Compound S91

¹H NMR(300MHz，DMSO-d6)δ12.40(s，1H)，10.28(s，1H)，9.87(s，1H)，8.43(s，1H)，7.58-7.50(m，2H)，7.52-7.44(m，2H)，6.63(s，1H)，4.64(tt，J＝5.5，4.6Hz，1H)，3.25(dt，J＝12.8，4.8Hz，1H)，3.16-2.99(m，3H)，2.18-2.01(m，2H)，1.98(tt，J＝4.9，4.0Hz，1H).

Example 92: synthesis of Compound S92

¹H NMR(300MHz，DMSO-d6)δ12.40(s，1H)，10.28(s，1H)，9.87(s，1H)，8.40(s，1H)，7.58-7.51(m，2H)，7.54-7.44(m，2H)，6.64(s，1H)，4.08(d，J＝6.2Hz，2H)，3.27(dt，J＝11.0，5.2Hz，2H)，3.17(dt，J＝11.0，5.2Hz，2H)，2.37(tt，J＝6.3，5.4Hz，1H)，1.83(p，J＝4.9Hz，1H).

Example 93: synthesis of Compound S93

The method comprises the following steps: synthesis of Compound 15

Compound S1(9.45g, 35mmol) was dissolved in DMF (80ml), benzyl bromide (5.4ml, 45.5mmol) and potassium carbonate (7.24mg, 52.5mmol) were added and the reaction was allowed to proceed overnight at room temperature. After completion of the reaction, the reaction was stopped, and ethyl acetate (300ml), water (3X 100ml), saturated brine and water (1X 100ml) were added to wash the mixture, and the mixture was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to obtain Compound 15(10.1g, 80%).¹H NMR(300MHz，DMSO-d6)δ12.82(s，1H)，10.11(s，1H)，8.96(s，1H)，8.17-8.10(m，2H)，7.58-7.51(m，2H)，7.54-7.40(m，6H)，6.82(s，1H)，5.23(s，2H)，3.65(t，J＝7.7，6.9Hz，1H)

Step two: synthesis of Compound 16

Compound 15(500mg, 1.39mmol) was dissolved in DMF (5ml), and 2-iodoethanol (287mg, 1.67mmol) and potassium carbonate (288mg, 2.1mmol) were sequentially added to react at room temperature overnight. After completion of the reaction, the reaction was quenched with water (10ml), extracted with ethyl acetate (3X 10ml), washed with saturated brine (1X 10ml), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 16(421mg, 75%).¹H NMR(300MHz，DMSO-d6)δ12.82(s，1H)，11.55(s，1H)，10.71(s，1H)，8.17-8.10(m，2H)，7.58-7.51(m，2H)，7.54-7.40(m，6H)，6.82(s，1H)，5.13(s，2H)，4.25(t，J＝6.5Hz，2H)，3.83-3.75(m，2H)，3.64(dd，J＝7.7，6.9Hz，1H).

Step three: synthesis of Compound S93

Compound 16(400mg, 1mmol) was dissolved in ethanol (10ml), Pd/C (40mg, 10%) was added, and the reaction was carried out under hydrogen for 8 h. After completion of the reaction, suction filtration, concentration of the filtrate, and purification by column chromatography gave compound S89(279mg, 89%).¹H NMR(300MHz，DMSO-d6)δ12.92(s，1H)，12.55(s，1H)，10.78(s，1H)，8.17-8.10(m，2H)，7.58-7.51(m，2H)，7.54-7.40(m，1H)，6.92(s，1H)，4.45(t，J＝6.5Hz，2H)，3.83-3.75(m，2H)，3.64(dd，J＝7.7，6.9Hz，1H).

The following syntheses of the compounds S94 through S104 in examples S94 and S104 were carried out by replacing the corresponding starting materials with those of example 93.

Example 94: synthesis of Compound S94

¹H NMR(300MHz，DMSO-d6)δ12.41(s，1H)，11.50(s，1H)，7.81(dd，J＝7.7，1.3Hz，1H)，7.55-7.46(m，2H)，7.40(ddd，J＝7.9，6.8，2.0Hz，1H)，6.80(s，1H)，3.94(s，3H)，3.85(s，3H)。

Example 95: synthesis of Compound S95

¹H NMR(300MHz，DMSO-d6)δ12.44(s，1H)，11.49(s，1H)，10.28(s，1H)，8.16-8.10(m，2H)，7.58-7.51(m，2H)，7.54-7.44(m，1H)，6.79(d，J＝7.7Hz，1H)，6.72(d，J＝7.7Hz，1H)，6.62(s，1H)，4.74(s，2H)。

Example 96: synthesis of Compound S96

¹H NMR(300MHz，DMSO-d6)δ12.49(s，1H)，11.51(s，1H)，10.29(s，1H)，8.16-8.10(m，2H)，7.58-7.50(m，2H)，7.52-7.44(m，1H)，6.71-6.62(m，2H)，4.94(t，J＝5.8Hz，1H)，3.34(dtd，J＝14.5，4.6，3.8Hz，1H)，3.20(dtd，J＝14.3，4.6，3.7Hz，1H)，2.17(dddd，J＝14.1，5.7，4.8，3.8Hz，1H)，2.00(dddd，J＝14.2，5.9，4.8，3.7Hz，1H)。

Example 97: synthesis of Compound S97

¹H NMR(300MHz，DMSO-d6)δ12.46(s，1H)，11.47(s，1H)，10.28(s，1H)，8.16-8.10(m，2H)，7.58-7.51(m，2H)，7.54-7.44(m，1H)，6.62(s，1H)，6.56(t，J＝4.4Hz，1H)，4.30(dd，J＝10.5，6.5Hz，1H)，4.22(dd，J＝10.5，6.5Hz，1H)，3.29(dtd，J＝14.3，4.5，3.7Hz，1H)，3.18(dtd，J＝14.5，4.6，3.9Hz，1H)，2.74(p，J＝6.4Hz，1H)，1.81(dddd，J＝13.4，6.6，4.8，3.8Hz，1H)，1.63(dddd，J＝13.2，6.4，4.7，3.8Hz，1H)。

Example 98: synthesis of Compound S98

¹H NMR(300MHz，DMSO-d6)δ12.42(s，1H)，11.43(s，1H)，10.28(s，1H)，7.71(dd，J＝7.7，1.8Hz，1H)，7.31(dtd，J＝20.7，7.4，1.6Hz，2H)，7.17(ddq，J＝7.6，1.4，0.7Hz，1H)，6.63(s，1H)，2.43(d，J＝0.7Hz，3H)，2.32(s，3H)。

Example 99: synthesis of Compound S99

¹H NMR(300MHz，DMSO-d6)δ12.45(s，1H)，11.44(s，1H)，10.27(s，1H)，8.16-8.10(m，2H)，7.58-7.51(m，2H)，7.55-7.44(m，1H)，6.57(s，1H)，6.14(s，2H)，2.11(s，3H)。

Example 100: synthesis of Compound S100

¹H NMR(300MHz，DMSO-d6)δ12.42(s，1H)，11.43(s，1H)，7.67(dd，J＝7.7，1.6Hz，1H)，7.31(dtd，J＝24.0，7.4，1.6Hz，2H)，7.17(dq，J＝7.7，0.8Hz，1H)，6.76(s，1H)，4.34-4.21(m，4H)，2.44(d，J＝0.7Hz，3H)。

Example 101: synthesis of Compound S101

¹H NMR(300MHz，DMSO-d6)δ12.40(s，1H)，11.42(s，1H)，10.28(s，1H)，8.16-8.10(m，2H)，7.58-7.51(m，2H)，7.55-7.44(m，1H)，6.57(s，1H)，6.21(s，2H)，5.38(s，1H)，3.33(s，3H)。

Example 102: synthesis of Compound S102

¹H NMR(300MHz，DMSO-d6)δ12.47(s，1H)，11.45(s，1H)，10.31(s，1H)，8.16-8.10(m，2H)，7.58-7.51(m，2H)，7.55-7.44(m，1H)，6.56(s，1H)，6.24(s，2H)，3.81(s，3H)。

Example 103: synthesis of Compound S103

¹H NMR(300MHz，DMSO-d6)δ12.41(s，1H)，11.53(s，1H)，10.38(s，1H)，8.16-8.10(m，2H)，7.58-7.44(m，3H)，6.59(s，1H)，6.14(d，J＝8.6Hz，2H)，4.20(s，2H)。

Example 104: synthesis of Compound S104

¹H NMR(300MHz，DMSO-d6)δ12.43(s，1H)，11.57(s，1H)，10.38(s，1H)，8.16-8.10(m，2H)，7.58-7.44(m，3H)，6.66(s，1H)，4.20(s，2H)。

Example 105: synthesis of Compound S105

The method comprises the following steps: synthesis of Compound 17

Starting material S1(2.7g, 10mmol) was dissolved in anhydrous pyridine (25ml), acetic anhydride (25ml) and DMAP (122mg, 0.1mmol) were added at 0 ℃ and the mixture was transferred to room temperature. After the reaction is completed, the reaction is stopped, ice water is added to quench the reaction, a filter cake is obtained by suction filtration and is dried to obtain the compound 17(3.76g, 95 percent), and the compound is directly put into the next reaction without purification.

Step two: synthesis of Compound 18

Compound 17(3g, 7.58mmol) was dissolved in anhydrous acetone (30ml), and potassium carbonate (7.3g, 53mmol) and bromobenzyl (1.6g, 9.1mmol) were added to the solution, followed by reflux reaction for 6 h. After the reaction was complete, the reaction was stopped, cooled to room temperature, the solvent was evaporated to dryness, water (50ml) was added, ethyl acetate was extracted (3 × 50ml), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 18(2.4g, 70%).¹H NMR(300MHz，DMSO-d6)δ12.96(s，1H)，7.58-7.50(m，2H)，7.54-7.39(m，2H)，7.43-7.34(m，1H)，7.01(s，1H)，5.11(t，J＝1.0Hz，2H)，2.39(s，3H)，2.29(s，3H).

Step three: synthesis of Compound 19

Compound 19(2.4g, 5.41mmol) was dissolved in ethanol (50ml), Pd/C (24mg, 10%) was added, and the reaction was carried out under hydrogen for 8 h. After completion of the reaction, suction filtration, concentration of the filtrate, and purification by column chromatography gave compound 19(1.5mg, 80%).¹H NMR(300MHz，DMSO-d6)δ12.88(s，1H)，8.99(s，1H)，6.81(s，1H)，2.39(s，3H)，2.29(s，3H).

Step four: synthesis of Compound 20

Compound 19(1.5g, 4.33mmol) was dissolved in DMF (10ml) and potassium carbonate (1.2g, 8.66mmol), 2- (4-morpholine) ethyl bromide (1g, 5.2mmol) and potassium iodide (17mg, 0.1mmol) were added. Heating to 60 deg.C for reactionThereafter, the reaction was stopped, cooled to room temperature, quenched with water (30ml), extracted with ethyl acetate (3 × 30ml), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 20(2.0g, 65%).¹H NMR(300MHz，DMSO-d6)δ12.98(s，1H)，6.81(s，1H)，4.25(t，J＝6.5Hz，2H)，3.70-3.58(m，4H)，2.72(t，J＝6.5Hz，4H)，2.59-2.48(m，2H)，2.39(s，3H)，2.29(s，3H).

Step five: synthesis of Compound S105

Compound 20(200mg, 0.43mmol) was dissolved in methanol (2ml), and potassium carbonate (, 88.7mg, 0.64mmol) was added to react at room temperature. And after the reaction is completed, adding dilute hydrochloric acid to adjust the pH value to 2-3, filtering, washing a filter cake with water, and drying the filter cake to obtain a compound S101(165mg, 90%).¹H NMR(300MHz，DMSO-d6)δ12.98(s，1H)，11.22(s，1H)，10.22(s，1H)，8.96(s，1H)6.81(s，1H)，4.25(t，J＝6.5Hz，2H)，3.70-3.58(m，4H)，2.72(t，J＝6.5Hz，4H)，2.59-2.48(m，2H)，2.39(s，3H)，2.29(s，3H).

The following syntheses of compounds S106 to S1110 in examples S106 to S110 were carried out by replacing the corresponding starting materials with those in example 105.

Example 106: synthesis of Compound S106

¹H NMR(300MHz，DMSO-d6)δ12.49(s，1H)，11.54(s，1H)，8.81(s，1H)，8.16-8.10(m，2H)，7.58-7.52(m，2H)，7.55-7.44(m，1H)，6.80(s，1H)，6.10(s，2H)，2.11(s，3H)。

Example 107: synthesis of Compound S107

¹H NMR(300MHz，DMSO-d6)δ12.53(s，1H)，11.58(s，1H)，8.90(s，1H)，8.16-8.10(m，2H)，7.58-7.50(m，2H)，7.52-7.44(m，1H)，6.80(s，1H)，6.16(s，2H)，5.58(q，J＝5.3Hz，1H)，2.67(d，J＝5.3Hz，3H)。

Example 108: synthesis of Compound S108

¹H NMR(300MHz，DMSO-d6)δ12.57(s，1H)，11.57(s，1H)，8.87(s，1H)，8.16-8.10(m，2H)，7.58-7.44(m，3H)，6.80(s，1H)，6.23(s，2H)，3.81(s，3H)。

Example 109: synthesis of Compound S109

¹H NMR(300MHz，DMSO-d6)δ12.54(s，1H)，11.52(s，1H)，8.87(s，1H)，8.17-8.10(m，2H)，7.58-7.51(m，2H)，7.54-7.44(m，1H)，6.77(s，1H)，4.24(t，J＝6.6Hz，2H)，3.74(dt，J＝7.5，6.5Hz，2H)，3.45(t，J＝7.3Hz，1H)。

Example 110: synthesis of Compound S110

¹H NMR(300MHz，DMSO-d6)δ12.48(s，1H)，11.53(s，1H)，8.79(s，1H)，8.16-8.10(m，2H)，7.58-7.44(m，3H)，6.81(s，1H)，4.32(t，J＝6.2Hz，2H)，3.74(t，J＝6.1Hz，2H)，3.40(s，3H)。

Example 111: synthesis of Compound S111

¹H NMR(300MHz，DMSO-d6)δ12.47(s，1H)，11.53(s，1H)，8.88(s，1H)，8.16-8.10(m，2H)，7.58-7.51(m，2H)，7.54-7.44(m，1H)，6.82(s，1H)，5.69(d，J＝8.4Hz，2H)，4.21(s，2H)。

Example 112: synthesis of Compound S112

¹H NMR(300MHz，DMSO-d6)δ12.43(s，1H)，11.51(s，1H)，8.88(s，1H)，8.16-8.10(m，2H)，7.56-7.52(m，2H)，7.52-7.44(m，1H)，7.05(s，1H)，4.21(s，2H)。

Example 113: synthesis of Compound S113

¹H NMR(300MHz，DMSO-d6)δ12.44(s，1H)，11.53(s，1H)，8.88(s，1H)，8.16-8.10(m，2H)，7.58-7.51(m，2H)，7.55-7.44(m，1H)，6.73(s，1H)，4.39(t，J＝6.1Hz，2H)，3.88(t，J＝6.2Hz，2H)。

Example 114: synthesis of Compound 114

The method comprises the following steps: synthesis of Compound 21

Compound 12(4.34g, 10mmol) was dissolved in anhydrous DCM (30ml) and trifluoromethanesulfonic anhydride (2.5ml, 11mmol) and TEA (2.1ml, 15mmol) were slowly added dropwise at 0 deg.C and stirred for 1 h. After the reaction was completed, DCM (30ml), water (3 × 30ml), saturated brine (1 × 30ml), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography were added to obtain compound 21, which was directly used in the next reaction without purification.

Step two: synthesis of Compound 22

Compounds 21(5.7g, 10mmol), 23(2.0g, 10 m)mol), cesium carbonate (3.9g, 12mmol) Pd₂(dba)₃(144mg, 0.25mmol), xanthphos (289mg, 0.5mmol) was dissolved in dry toluene (30ml) and reacted under nitrogen at reflux overnight. After completion of the reaction, the reaction was stopped, the solvent was distilled off, water (50ml) was added, ethyl acetate was extracted (3 × 30ml), and the organic phases were combined, washed with saturated brine ((1 × 30ml)), dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography for separation and purification to obtain compound 22(4.0g, 65%).¹H NMR(300MHz，DMSO-d6)δ12.88(s，1H)，8.14-8.07(m，2H)，7.64-7.57(m，5H)，7.57-7.49(m，2H)，7.52-7.44(m，1H)，7.41-7.34(m，4H)，7.36-7.26(m，4H)，6.98(s，1H)，6.91-6.85(m，2H)，5.99(d，J＝4.2Hz，1H)，5.55(t，J＝1.0Hz，2H)，3.78(s，3H).

Step three: synthesis of Compound S114

Compound 22(619mg, 1mmol) was dissolved in ethanol (5ml)/DCM (5ml) and Pd/C (62mg, 10%) was added and reacted under hydrogen for 8 h. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and purification was carried out by column chromatography to obtain compound S110(453mg, 80%).¹H NMR(300MHz，DMSO-d6)δ12.99(s，1H)，11.22(s，1H)，8.97(s，1H)，8.17-8.10(m，3H)，7.61(d，J＝4.3Hz，1H)，7.58-7.51(m，2H)，7.55-7.44(m，2H)，6.61(s，1H).

The following syntheses of compounds S115 to S121 in examples S115 to S121 refer to the synthesis method in example 114, and only the corresponding raw materials need to be replaced.

Example 115: synthesis of Compound S115

¹H NMR(300MHz，DMSO-d6)δ12.99(s，1H)，11.22(s，1H)，8.97(s，1H)，8.49(s，1H)，7.73-7.67(m，1H)，7.35-7.27(m，3H)，7.26(dd，J＝21.6，1.8Hz，1H)，7.17(ddt，J＝6.9，1.6，0.8Hz，1H)，6.55(s，1H)，2.45(d，J＝0.7Hz，4H).

Example 116: synthesis of Compound S116

¹H NMR(300MHz，DMSO-d6)δ12.99(s，1H)，11.22(s，1H)，8.97(s，1H)，8.17(s，1H)，7.81(t，J＝2.2Hz，1H)，7.75-7.69(m，1H)，7.34-7.25(m，2H)，7.21-7.15(m，1H)，6.98(t，J＝2.0Hz，1H)，6.59(s，1H)，2.45(d，J＝0.7Hz，3H).

Example 117: synthesis of Compound S117

¹H NMR(300MHz，DMSO-d6)δ12.99(s，1H)，11.22(s，1H)，8.97(s，1H)，8.16-8.10(m，2H)，7.89(s，1H)，7.58-7.51(m，1H)，7.55-7.44(m，2H)，7.28(q，J＝1.5Hz，2H)，6.57(s，1H).

Example 118: synthesis of Compound S118

¹H NMR(300MHz，DMSO-d6)δ12.99(s，1H)，11.22(s，1H)，8.97(s，1H)，7.68(dd，J＝7.6，1.8Hz，1H)，7.31(dtd，J＝19.4，7.4，1.6Hz，2H)，7.26-7.21(m，1H)，7.17(ddd，J＝7.5，1.5，0.7Hz，1H)，6.56(s，1H)，6.17(d，J＝4.4Hz，1H)，6.22(s，1H)，2.45(d，J＝0.7Hz，3H).

Example 119: synthesis of Compound S119

¹H NMR(300MHz，DMSO-d6)δ12.99(s，1H)，11.22(s，1H)，8.97(s，1H)，8.22(s，1H)，7.73-7.65(m，2H)，7.31(dtd，J＝19.4，7.4，1.6Hz，2H)，7.20-7.14(m，1H)，6.81(t，J＝2.0Hz，1H)，6.56(s，1H)，2.45(d，J＝0.7Hz，3H).

Example 120: synthesis of Compound S120

¹H NMR(300MHz，DMSO-d6)δ12.99(s，1H)，11.22(s，1H)，8.97(s，1H)，8.22(s，1H)，8.15(d，J＝5.7Hz，1H)，7.75-7.69(m，1H)，7.34-7.25(m，2H)，7.21-7.15(m，1H)，6.62(s，1H)，6.41(d，J＝5.7Hz，1H)，2.45(d，J＝0.7Hz，3H).

Example 121: synthesis of Compound S121

¹H NMR(300MHz，DMSO-d6)δ12.99(s，1H)，11.22(s，1H)，8.97(s，1H)，8.58(s，1H)，7.68(dd，J＝7.4，2.0Hz，1H)，7.50(d，J＝1.8Hz，1H)，7.30(pd，J＝7.3，1.7Hz，2H)，7.17(ddd，J＝7.7，1.8，0.9Hz，1H)，6.62(s，1H)，6.54(s，1H)，2.47(d，J＝0.7Hz，3H).

Example 122: SARS-CoV-2 virus 3C-like cysteine protease (3CLpro) enzyme inhibitory Activity test experiment

1.3 CLpro protein expression and purification

The gene sequence of the full-length 3CLpro protein was constructed in the expression vector pET28a (+) vector and transformed into E.coli BL21(DE3) competent cells, and purified using Ni-NTA column after 12 hours of induction at 25 ℃ with a final concentration of 0.5mM IPTG. And detecting the purified protein by SDS, purifying the part with the purity of more than 90 percent by Superdex 20010/300 GL of AKTA Pure of a GE protein chromatography purification system to obtain the protein with the purity of more than 95 percent, determining the protein concentration by using Nano Drop, subpackaging, quick-freezing by liquid nitrogen, and storing at-80 ℃.

Establishment of SARS-CoV-23 CLpro enzyme activity screening system and calculation of inhibitor inhibition rate and medicine IC50

The activity of SARS-CoV-23 CLpro and the inhibitory activity of the compound to SARS-CoV-23 CLpro are determined by Fluorescence Resonance Energy Transfer (FRET) technique. Fluorescent substrate (Dabcyl-KTSAVLQ ↓. SGFRKM-E (Edans) -NH) with SARS-CoV-23 CLpro cleavage site (indicated by arrow) was used in the assay₂) And Tris-HCl buffer (20mM Tris-HCl, 150mM NaCl, 10mM EDTA, pH 7.5). Compounds were dissolved by 100% DMSO. Mu.l of the compound was incubated with 40. mu.l of SARS-CoV-23 CLpro (final concentration 0.5. mu.M, diluted in Tris-HCl buffer) at 25 ℃ for 10min and the reaction was initiated by addition of 50. mu.l of fluorogenic substrate (final concentration 20. mu.M). The Dabcyl fluorescence signal generated due to 3 CLpro-catalyzed cleavage of the substrate was detected using a radio resonance energy transfer fluorescence spectrophotometer at an excitation wavelength of 340nm and an absorption wavelength of 490 nm. The kinetic constants (Vmax and Km) for SARS-CoV-23 CLpro were obtained by fitting the data to the Michaelis Menten equation, V-Vmax X [ S ]]/(Km+[S]). Then according to the formula kcat ═ Vmax/[ E ]]Kcat is calculated. Compounds were diluted in gradient by fold dilution using Tris-HCl buffer and assayed using the same final concentration of SARS-CoV-23 CLpro and fluorogenic substrate system described above. The values of the intrinsic (V0i) and apparent (Vappi, kappa) catalytic parameters for the hydrolysis of a polypeptide substrate catalyzed by 3CLpro were determined in the presence and absence, respectively, of the target compound. Apparent inhibition constant (kappa) of binding of target compound to Mpro from Vappi to fixed substrate concentration ([ S ] S)]) Lower inhibitor concentration ([ I ]]) Is dependent on the equation Vappi-Vapp x [ I ]]/(Kappi+[I]) And (6) obtaining. The value of the intrinsic inhibition constant (Ki) of binding of a target compound to 3CLpro is according to the equation kappa ═ Ki x (1+ [ S ])]/Km) was calculated. Inhibition curves for compounds were plotted by GraphPad Prism 8.0 software and IC calculated₅₀The value is obtained. The results are shown in the following table 1, and the compound of the embodiment has better inhibitory activity to SARS-CoV-2 virus 3CLpro, and the activity is better than that of positive baicalein or equivalent to that of the baicalein. A: IC (integrated circuit)₅₀＜0.001μM；B：IC₅₀＝0.001μM-0.01μM；

TABLE 1 SARS-CoV-2 Virus 3CLpro enzyme inhibitory Activity

Example 123: cytotoxicity and test of drug effect against SARS-CoV-2 virus infection

Vero E6 cytotoxicity test: the CCK8 method is adopted to detect the cytotoxicity of the test compound on mammalian Vero E6 cells. Vero E6 cells were added to 96-well plates and cultured overnight. The cells were then incubated with different concentrations of test compound for 48 h. The medium in the well plate was removed, replaced with fresh serum-free medium, 10% CCK8 reagent was added, incubated at 37 ℃ for 1h, and absorbance at 450nm was measured using a microplate reader.

Screening compounds without cytotoxicity or with low cytotoxicity for testing antiviral infection, and the specific operation comprises the following steps: inoculating cells: taking Vero-E6 cells in logarithmic growth phase, sucking out the culture solution, digesting the cells with pancreatin, and counting the cells as follows: 1X 106/ml; 4ml of the above cells were taken and 6ml of the medium was added to prepare a cell suspension having a cell density of 4X 105 cells/ml, which was then inoculated into a 96-well plate at 100. mu.l per well and at 4X 104 cells per well. ② pretreating cells with drugs: the cell culture medium was replaced with DMEM medium containing 2% FBS, and 100. mu.l of the drug and DMSO were added at the corresponding concentrations, followed by pretreatment in an incubator at 37 ℃ for 1 hour. ③ infection with viruses: taking 0.3ml of virus, adding 45ml of culture medium, uniformly mixing, and diluting the virus to 100TCID50/0.05 ml; discarding the drug culture medium in the cell plate, vertically hanging and dropping the virus diluent into a 96-well plate, adding 50 mu l/hole of the sample volume, simultaneously adding the corresponding drug culture medium (containing the drug with the corresponding concentration) and 50 mu l/hole of the sample volume, and uniformly mixing; fourthly, incubation: and (3) uniformly mixing the well-added cell culture plate on a shaker, placing the cell culture plate in an incubator at 37 ℃, and incubating for 1 h. After the incubation is finished, the cells are aspiratedThe virus-serum mixture inoculated with the cells was added with the drug and DMSO of the control at the corresponding concentrations in a volume of 100. mu.l/well (100TCID 50/well) and placed at 37 ℃ in CO₂Culturing for 48h in an incubator; collecting supernatant to detect virus RNA, fixing and dyeing with 4% paraformaldehyde for immunofluorescence dyeing analysis.

Specific experimental results are shown in Table 2, and the compound of the embodiment has low cytotoxicity, good inhibitory activity on SARS-CoV-2 virus infection and good selection index; a: IC (integrated circuit)₅₀＜0.1μM；B：IC₅₀＝0.1μM-1.0μM。

TABLE 2 cytotoxicity and anti-SARS-CoV-2 Virus infection Activity of test Compounds

Claims

1. A quinazolinone compound with a structure shown in a general formula I or pharmaceutically acceptable salt and isomer thereof has the following structure:

wherein R is¹Is hydrogen, hydroxy, amino, mercapto, OR^1-1、-NHR^1-2；

R^1-1-1is hydroxyl, sulfydryl, carboxyl, amino,

C_1-4Alkoxy or C_1-4A haloalkoxy group;

R^1-1-2is hydroxyl, sulfhydryl, carboxyl or amino;

m is 1, 2 or 3; n is 0, 1, 2, 3 or 4;

R²is hydrogen, hydroxy, amino, mercapto, OR^2-1、-O(C＝O)R^2-2、

R^2-1Is unsubstituted or R^2-1-1Substituted C_1-6Alkyl, or

R^2-1-1Is hydroxy, mercapto, carboxyl, amino

C_1-4Alkoxy or C_1-4A haloalkoxy group;

R^2-2～R^2-5independently selected from C_1-6An alkyl group;

R^2-6～R^2-9independently selected from hydrogen or C_1-6An alkyl group;

q is 1, 2 or 3; r is 0, 1, 2, 3 or 4;

R³is hydrogen, hydroxy, mercapto, OR^3-1、-O(C＝O)R^3-2、

R^3-1Is unsubstituted or R^3-1-1Substituted C_1-6An alkyl group;

R^3-2～R^3-5independently selected from C_1-6An alkyl group;

R^3-6～R^3-9independently selected from hydrogen or C_1-6An alkyl group;

R¹、R²and R³Not hydrogen at the same time;

R⁴and R⁵Independently selected from deuterium, halogen, hydroxy, cyano, nitro, unsubstituted or R^4-1Substituted C_1-6Alkyl, unsubstituted or R⁴ ^-2Substituted C_1-6Alkoxy radical, C_6-10Aryl radical, C_3-10Cycloalkyl, one or more of N, O heteroatom (S), 4-10 membered heterocycloalkyl with 1-3 heteroatom (S), one or more of N, O heteroatom (S), 1-3 heteroatom (S), 5-10 membered heteroaryl, -NR^4-3R^4-4、-(C＝O)R^4-5、-(C＝O)OR^4-6、-O(C＝O)R^4-7、-(C＝O)NR^4-8R^4-9、-S(＝O)₂NR^4-10R^4-11；

R^4-1Is halogen, hydroxy, or-NR^4-1-1R^4-1-2；

R^4-2Is halogen;

R^4-3～R^4-11independently selected from hydrogen or C_1-4An alkyl group;

R^4-1-1and R^4-1-2Independently selected from hydrogen or C_1-4An alkyl group;

R⁶is halogen;

2. The quinazolinone compound or pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein said quinazolinone compound has the structure shown in formula I:

when R is^1-1Is unsubstituted or R^1-1-1Substituted C_1-6When it is alkyl, said R^1-1-1Is one or more, when there are more than one R^1-1-1When R is said^1-1-1May be the same or different;

and/or when R^1-1Is unsubstituted or R^1-1-1Substituted C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or when R^1-1Is unsubstituted or R^1-1-2Substituted C_3-10When the cycloalkyl group is, said R^1-1-2Is one or more, when there are more than one R^1-1-2When R is said^1-1-2May be the same or different;

and/or when R^1-1Is unsubstituted or R^1-1-2Substituted C_3-10When there is a cycloalkyl group, said C_6-10Cycloalkyl being C_3-6A cycloalkyl group;

and/or when R^1-1When the aryl group is a 4-10 membered heteroaryl group with 1-3 heteroatoms selected from N, O and S, the 4-10 membered heterocycloalkyl group is a 4-6 membered heterocycloalkyl group;

and/or when R^1-1Is 'one or more of N, O and S as hetero atom, 1-3 hetero atoms' 4-10 membered heterocycloalkyl- (C)_1-4Alkyl), the 4 to 10-membered heterocycloalkyl group- (C)_1-4Alkyl) is 4-6 heterocycloalkyl- (C_1-3Alkyl groups);

and/or when R^1-1When the aryl group is a 5-10 membered heteroaryl group with 1-3 heteroatoms selected from N, O and S, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group;

and/or, m is 1 or 2;

and/or n is 0, 1 or 2;

and/or when R^1-2When the aryl group is a 5-10 membered heteroaryl group with 1-3 heteroatoms selected from N, O and S, the 5-10 membered heteroaryl group is a 5-6 membered heteroaryl group;

and/or when R^2-1Is unsubstituted or R^2-1-1Substituted C_1-6When it is alkyl, said R^2-1-1Is one or more, when there are more than one R^2-1-1When R is said^2-1-1May be the same or different;

and/or when R^2-1Is unsubstituted or R^2-1-1Substituted C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or when R^2-2～R^2-5Independently selected from C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or when R^2-6～R^2-9Independently selected from C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or q is 1 or 2;

and/or r is 0, 1 or 2;

and/or when R^3-1Is unsubstituted or R^3-1-1Substituted C_1-6When it is alkyl, said R^3-1-1Is one or more, when there are more than one R^3-1-1When R is said^3-1-1May be the same or different;

and/or when R^3-1Is unsubstituted or R^3-1-1Substituted C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or when R^3-1-1Is C_1-4At alkoxy, said C_1-4Alkoxy is C_1-3An alkoxy group;

and/or when R^3-1-1Is C_1-4When halogenated alkoxy, said C_1-4Haloalkoxy is C_1-3A haloalkoxy group;

and/or when R^3-1-1When the heterocyclic group is a 4-to 10-membered heterocycloalkyl group in which the number of heteroatoms is 1 to 3, the heteroatom is one or more selected from N, O and S, the 4-to 10-membered heterocycloalkyl group is a 4-to 6-membered heterocycloalkyl group;

and/or when R^3-2～R^3-5Independently selected from C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or when R^3-6～R^3-9Independently selected from C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or, when A is unsubstituted or R⁴Substituted C_6-10When aryl is said to R⁴Is one or more, when there are more than one R⁴When R is said⁴May be the same or different;

and/or, when A is unsubstituted or R⁴Substituted C_6-10When aryl, said C_6-10Aryl is phenyl or naphthyl;

and/or, when A is C_3-10When there is a cycloalkyl group, said C_3-10Cycloalkyl being C_3-6A cycloalkyl group;

and/or, when A is unsubstituted or R⁵When the substituted heteroatom is one or more selected from N, O and S, and the number of the heteroatoms is 1-3, and the heteroatom is 5-10-membered heteroaryl, R is⁵Is one or more, when there are more than one R⁵When R is said⁵May be the same or different;

and/or, when A is unsubstituted or R⁵The substituted heteroatom is selected from one or more of N, O and S, and when the heteroatom is 1-3 and the heteroatom is 5-10 membered heteroaryl, the 5-10 membered heteroaryl is 5-6 membered heteroaryl;

and/or, when A is C_3-10Cycloalkenyl group, said C_3-10Cycloalkenyl being C_3-6A cycloalkenyl group;

and/or, when A is C_6-10Aryl radical- (C)_2-4Alkynyl) -, said C_6-10Aryl radical- (C)_2-4Alkynyl) -is phenylethynyl;

and/or, when A is C_6-10Aryl radical- (C)_2-4Alkenyl) -, said C_6-10Aryl radical- (C)_2-4Alkenyl) -is styryl;

and/or when R⁴And R⁵Independently selected from unsubstituted or R^4-1Substituted C_1-6When it is alkyl, said R^4-1Is one or more, when there are more than one R^4-1When R is said^4-1May be the same or different;

and/or the presence of a gas in the gas,when R is⁴And R⁵Independently selected from unsubstituted or R^4-1Substituted C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or when R⁴Is unsubstituted or R^4-2Substituted C_1-6At alkoxy, said R^4-2Is one or more, when there are more than one R^4-2When R is said^4-2May be the same or different;

and/or when R⁴Is unsubstituted or R^4-2Substituted C_1-6At alkoxy, said C_1-6Alkoxy is C_1-4An alkoxy group;

and/or when R⁴Is C_6-10When aryl, said C_6-10Aryl is phenyl;

and/or when R⁴Is C_3-10When there is a cycloalkyl group, said C_3-10Cycloalkyl being C_3-6A cycloalkyl group;

and/or when R⁴When the heterocyclic group is a 4-to 10-membered heterocycloalkyl group in which the number of heteroatoms is 1 to 3, the heteroatom is one or more selected from N, O and S, the 4-to 10-membered heterocycloalkyl group is a 4-to 6-membered heterocycloalkyl group;

and/or when R^4-1When halogen, the halogen is fluorine;

and/or when R^4-2When halogen, the halogen is fluorine;

and/or when R^4-3～R^4-7Independently selected from C_1-4When alkyl, said C_1-4Alkyl is methyl, ethyl or n-propyl;

and/or when R^4-1-1And R^4-1-2Independently is C_1-4When alkyl, said C_1-4Alkyl is methyl, ethyl or n-propyl;

and/or, when X is C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group;

and/or, when X is unsubstituted or R⁶Substituted C_6-10When aryl is said to R⁶Is one or more, when there are more than one R⁶When, atR is as described⁶May be the same or different;

and/or, when X is unsubstituted or R⁶Substituted C_6-10When aryl, said C_6-10Aryl is phenyl;

and/or, when X is C_6-10Aryl radical- (C)_1-4Alkyl) -said C_6-10Aryl radical- (C)_1-4Alkyl) -is phenyl- (C)_1-3Alkyl) -;

and/or when R⁶When the halogen is fluorine, chlorine, bromine or iodine;

and/or, when X is' 4-10 membered heterocycloalkyl with 1-3 heteroatoms selected from one or more of N, O and S, the 4-10 membered heterocycloalkyl is 4-6 membered heterocycloalkyl;

and/or, when X is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S, the 5-10 membered heteroaryl is a 5-6 membered heteroaryl;

and/or when R⁷Is C_1-6When alkyl, said C_1-6Alkyl is C_1-4An alkyl group.

3. The quinazolinone compound or pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein said quinazolinone compound has the structure shown in formula I:

when R is^1-1Is unsubstituted or R^1-1-1Substituted C_1-6When it is alkyl, said R^1-1-1The number of (a) is 1, 2 or 3;

and/or when R^1-1Is unsubstituted or R^1-1-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl or n-butyl;

and/or when R^1-1Is unsubstituted or R^1-1-2Substituted C_3-10When the cycloalkyl group is, said R^1-1-21, 2 or 3;

and/or when R^1-1Is unsubstituted or R^1-1-2Substituted C_3-10When there is a cycloalkyl group, said C_3-10The cycloalkyl is cyclopropyl,Cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R^1-1When the aryl group is a 4-10 membered heteroaryl group with 1-3 heteroatoms selected from N, O and S, the 4-10 membered heterocycloalkyl group is a pyrrolidinyl group, an azetidine group or a piperidine ring;

and/or when R^1-1Is 'one or more of N, O and S as hetero atom, 1-3 hetero atoms' 4-10 membered heterocycloalkyl- (C)_1-4Alkyl), the 4 to 10-membered heterocycloalkyl group- (C)_1-4Alkyl) is pyrrolidinylmethyl, azetidinylmethyl, or piperidinylmethyl;

and/or when R^1-1When the aryl is a 5-10 membered heteroaryl group with 1-3 heteroatoms selected from N, O and S, the 5-10 membered heteroaryl group is imidazolyl or pyrazolyl;

and/or when R^1-2When the aryl is a 5-10 membered heteroaryl group with 1-3 heteroatoms selected from N, O and S, the 5-10 membered heteroaryl group is imidazolyl or pyrazolyl;

and/or when R^2-1Is unsubstituted or R^2-1-1Substituted C_1-6When it is alkyl, said R^2-1-11, 2 or 3;

and/or when R^2-1Is unsubstituted or R^2-1-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl or n-butyl;

and/or when R^2-2～R^2-5Independently selected from C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;

and/or when R^2-6～R^2-9Independently selected from C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;

and/or when R^3-1Is unsubstituted or R^3-1-1Substituted C_1-6When it is alkyl, said R^3-1-11, 2 or 3;

and/or when R^3-1Is unsubstituted or R^3-1-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl or n-butyl;

and/or when R^3-1-1Is C_1-4At alkoxy, said C_1-4Alkoxy is methoxy, ethoxy or n-propoxy;

and/or when R^3-1-1Is C_1-4When halogenated alkoxy, said C_1-4Haloalkoxy is trifluoromethoxy or difluoromethoxy;

and/or when R^3-1-1When the heterocyclic group is '4-10 membered heterocycloalkyl in which the heteroatom is selected from N, O and S, the number of heteroatoms is 1-3', the 4-10 membered heterocycloalkyl is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl or azetidine;

and/or when R^3-2～R^3-5Independently selected from C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;

and/or when R^3-6～R^3-9Independently selected from C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;

and/or, when A is unsubstituted or R⁴Substituted C_6-10When aryl is said to R⁴The number of (a) is 1, 2 or 3;

and/or, when A is C_3-10When there is a cycloalkyl group, said C_3-6Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or, when A is C_3-10Cycloalkenyl group, said C_3-10The cycloalkenyl is cyclobutenyl, cyclopentenyl or cyclobutenyl;

and/or, when A is unsubstituted or R⁵The substituted heteroatom is selected from N, O and S, and when the heteroatom is 1-3, the substituted heteroatom is 5-10 membered heteroaryl,said R⁵The number of (a) is 1, 2 or 3;

and/or, when A is unsubstituted or R⁵When the substituted heteroatom is one or more of N, O and S, and the number of the heteroatoms is 1-3, and the 5-10 membered heteroaryl is pyridyl, pyrimidyl, thienyl, thiazolyl, furyl, pyrazolyl, pyrrolyl, pyridazinyl, pyrazinyl, oxazolyl or imidazolyl;

and/or when R⁴And R⁵Independently selected from unsubstituted or R^4-1Substituted C_1-6When it is alkyl, said R^4-1The number of (a) is 1, 2 or 3;

and/or when R⁴And R⁵Independently selected from unsubstituted or R^4-1Substituted C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

and/or when R⁴Is unsubstituted or R^4-2Substituted C_1-6At alkoxy, said R^4-2The number of (a) is 1, 2 or 3;

and/or when R⁴Is unsubstituted or R^4-2Substituted C_1-6At alkoxy, said C_1-6Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;

and/or when R⁴Is C_3-10When there is a cycloalkyl group, said C_3-10Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

and/or when R⁴When the heterocyclic group is a 4-10 membered heterocycloalkyl group in which the heteroatom is selected from N, O and S, the number of heteroatoms is 1-3, the 4-10 membered heterocycloalkyl group is a morpholinyl group, a piperidinyl group, a piperazinyl group, an azetidine group or a pyrrolidinyl group;

and/or when R⁴is-NR^4-3R^4-4When said is-NR^4-3R^4-4is-NH₂Or is

And/or when R⁴Is- (C ═ O) R^4-5When said- (C ═ O) R^4-5Is composed of

And/or when R⁴Is- (C ═ O) OR^4-6When said- (C ═ O) OR^4-6is-COOH or

And/or when R⁴is-O (C ═ O) R^4-7When said group is represented by-O (C ═ O) R^4-7Is composed of

And/or when R⁴Is- (C ═ O) NR^4-8R^4-9When said- (C ═ O) NR^4-8R^4-9Is composed of

And/or when R^4-1And R^4-2Independently selected from-NR^4-1-1R^4-1-2When said is-NR^4-1-1R^4-1-2is-NH₂Or is

And/or, when X is C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;

and/or, when X is unsubstituted or R⁶Substituted C_6-10When aryl is said to R⁶The number of (a) is 1, 2 or 3;

and/or, when X is C_6-10Aryl radical- (C)_1-4Alkyl) -said C_6-10Aryl radical- (C)_1-4Alkyl) -is benzyl;

and/or, when X is 'one or more of N, O and S as a heteroatom, and the number of heteroatoms is 1-3,' 4-10 membered heterocycloalkyl, the 4-10 membered heterocycloalkyl is morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl or azetidine;

and/or, when X is a 5-10 membered heteroaryl with 1-3 heteroatoms selected from one or more of N, O and S, the 5-10 membered heteroaryl is pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, furyl, pyrrolyl, oxazolyl or isoxazolyl;

and/or when R⁷Is C_1-6When alkyl, said C_1-6Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

4. The quinazolinone compound or pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein said quinazolinone compound has the structure shown in formula I:

when R is^1-1Is R^1-1-1Substituted C_1-6When it is alkyl, said R^1-1-1Substituted C_1-6Alkyl is

And/or when R^1-1Is R^1-1-2Substituted C_3-10When the cycloalkyl group is, said R^1-1-2Substituted C_3-10Cycloalkyl is

And/or when R^1-1When the aryl group is a 4-10 membered heteroaryl group in which the heteroatom is one or more selected from N, O and S and the number of the heteroatoms is 1-3, the 4-10 membered heterocycloalkyl group is a 4-10 membered heterocycloalkyl group

And/or when R^1-1Is 'one or more of N, O and S as hetero atom, 1-3 hetero atoms' 4-10 membered heterocycloalkyl- (C)_1-4Alkyl), the 4 to 10-membered heterocycloalkyl group- (C)_1-4Alkyl) is

And/or when R^1-1When the heteroaryl group is a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, the 5-10 membered heteroaryl group is

And/or when R^1-2When the heteroaryl group is a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O and S, the 5-10 membered heteroaryl group is

And/or when R^2-1Is R^2-1-1Substituted C_1-6When it is alkyl, said R^2-1-1Substituted C_1-6Alkyl is

And/or when R^3-1Is R^3-1-1Substituted C_1-6When it is alkyl, said R^3-1-1Substituted C_1-6Alkyl is

And/or, when A is C_3-10Cycloalkenyl group, said C_3-10Cycloalkenyl radical is

And/or when R⁴Is R^4-1Substituted C_1-6When it is alkyl, said R^4-1Substituted C_1-6The alkyl is trifluoromethyl, difluoromethyl,

And/or when R⁴Is R^4-2Substituted C_1-6At alkoxy, said R^4-2Substituted C_1-6Alkoxy is trifluoromethoxy;

and/or when R⁵Is R^4-1Substituted C_1-6When it is alkyl, said R^4-1Substituted C_1-6Alkyl is trifluoromethyl;

and/or, when X is unsubstituted or R⁶Substituted C_6-10When aryl, said is unsubstituted or R⁶Substituted C_6-10Aryl is

And/or, when X is 'one or more of N, O and S as a heteroatom, and the number of heteroatoms is 1-3,' 4-10 membered heterocycloalkyl, the 4-10 membered heterocycloalkyl is

And/or, when X is '5-10 membered heteroaryl with 1-3 heteroatoms and one or more heteroatoms selected from N, O and S', the 5-10 membered heteroaryl is

5. The quinazolinone compound or pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein said quinazolinone compound has the structure shown in formula I:

when A is unsubstituted or R⁴Substituted C_6-10When aryl, said is unsubstituted or R⁴Substituted C_6-10Aryl is

And/or, when A is unsubstituted or R⁵The substituted heteroatom is selected from one or more of N, O and S, and when the heteroatom is 1-3 and the heteroatom is 5-10 membered heteroaryl, the substituent is unsubstituted or R⁵Substituted heteroaryl is

6. The quinazolinone compound or pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein said quinazolinone compound has the structure shown in formula I:

R¹is hydroxy, OR^1-1、-NHR^1-2；

And/or, R²Is hydrogen, hydroxy, OR^2-1、-O(C＝O)R^2-2、

And/or, R^2-6～R^2-9Is hydrogen;

and/or, R^1-1-1Is hydroxy, carboxy, or

And/or, R^1-1-2Is a hydroxyl group;

and/or, R^2-1-1Is hydroxy, or

And/or, m is 1;

and/or n is 0 or 1;

and/or, q is 1;

and/or r is 0 or 1;

and/or, R³Is hydrogen, hydroxy, OR^3-1、-O(C＝O)R^3-2、

And/or, R^3-6～R^3-9Is hydrogen;

and/or, R^3-1-1Is hydroxy, C_1-4Alkoxy radical, C_1-4Halogenated alkoxy, one or more of N, O and S as heteroatoms, and 1-3 of 4-to 10-membered heterocycloalkyl as the heteroatoms;

and/or, R⁴Is halogen, hydroxy, cyano, nitro, unsubstituted or R^4-1Substituted C_1-6Alkyl, unsubstituted or R^4-2Substituted C_1-6Alkoxy radical, C_6-10Aryl radical, C_3-10Cycloalkyl, one or more of N, O heteroatoms selected from N, O and S, 4-to 10-membered heterocycloalkyl with 1-3 heteroatoms, and-NR^4-3R^4-4、-(C＝O)R^4-5、-(C＝O)OR^4-6、-O(C＝O)R^4-7、-(C＝O)NR^4-8R⁴ ^-9；

And/or, R⁵Is halogen, unsubstituted or R^5-1Substituted C_1-6An alkyl group;

and/or, R^4-1Is halogen or hydroxy;

and/or, R^4-7Is C_1-4An alkyl group;

and/or, R^4-8Is hydrogen;

and/or, R^4-9Is hydrogen.

7. The quinazolinone compound or pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein said quinazolinone compound has the structure shown in formula I:

R¹is hydroxy, OR^1-1、-NHR^1-2；

R^1-1-1is a hydroxyl group, a carboxyl group,

R^1-1-2Is a hydroxyl group;

m is 1;

n is 0 or 1;

R²is hydrogen, hydroxy, OR^2-1、-O(C＝O)R^2-2、

R^2-1-1Is a hydroxyl group,

q is 1;

r is 0 or 1;

R^2-2～R^2-5independently selected from C_1-6An alkyl group;

R^2-6～R^2-9independently selected from hydrogen;

R³is hydrogen, hydroxy, OR^3-1、-O(C＝O)R^3-2、

R^3-1Is unsubstituted or R^3-1-1Substituted C_1-6An alkyl group;

R^3-2～R^3-5independently selected from C_1-6An alkyl group;

R^3-6～R^3-9independently selected from hydrogen;

R⁴is halogen, hydroxy, cyano, nitro, unsubstituted or R^4-1Substituted C_1-6Alkyl, unsubstituted or R^4-2Substituted C_1-6Alkoxy radical, C_6-10Aryl radical, C_3-10Cycloalkyl, one or more of N, O heteroatoms selected from N, O and S, 4-to 10-membered heterocycloalkyl with 1-3 heteroatoms, and-NR^4-3R^4-4、-(C＝O)R^4-5、-(C＝O)OR^4-6、-O(C＝O)R^4-7Or, - (C ═ O) NR^4-8R^4-9；

R⁵Is halogen, unsubstituted or R^4-1Substituted C_1-6An alkyl group;

R^4-1is halogen or hydroxy;

R^4-2is halogen;

R^4-3～R^4-6independently selected from hydrogen or C_1-4An alkyl group;

R^4-7is C_1-4An alkyl group;

R^4-8is hydrogen;

R^4-9is hydrogen;

R⁶is halogen;

R⁷is hydrogen or C_1-6An alkyl group.

8. The quinazolinone compound or pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein said quinazolinone compound has the structure shown in formula I:

R¹is hydroxy, OR^1-1、-NHR^1-2；

R^1-1-1is a hydroxyl group, a carboxyl group,

R^1-1-2Is a hydroxyl group;

m is 1;

n is 0 or 1;

R²is hydroxy, OR^2-1、-O(C＝O)R^2-2、

R^2-1-1Is a hydroxyl group,

q is 1;

r is 0 or 1;

R^2-2～R^2-5independently selected from C_1-6An alkyl group;

R^2-6～R^2-9independently selected from hydrogen;

R³is hydroxy, OR^3-1、-O(C＝O)R^3-2、

R^3-1Is unsubstituted or R^3-1-1Substituted C_1-6An alkyl group;

R^3-2～R^3-5independently selected from C_1-6An alkyl group;

R^3-6～R^3-9independently selected from hydrogen;

R⁵Is halogen, unsubstituted or R^4-1Substituted C_1-6An alkyl group;

R^4-1is hydroxy or halogen;

R^4-2is halogen;

R^4-6is hydrogen or C_1-4An alkyl group;

R^4-7is C_1-4An alkyl group;

R⁷is hydrogen.

9. The quinazolinone compound or pharmaceutically acceptable salt and isomer thereof according to claim 1, having the structure shown in formula I, is any one of the following compounds,

10. the preparation method of quinazolinone compounds with the structure shown in the general formula I or pharmaceutically acceptable salts and isomers thereof according to claim 1, characterized in that:

wherein R is¹、R²、R³、R⁷X and A are as defined above.

11. A pharmaceutical composition, which comprises a therapeutically effective amount of one or more quinazolinone compounds having a structure shown in general formula I in any one of claims 1 to 9, or pharmaceutically acceptable salts and isomers thereof, and a pharmaceutically acceptable carrier or adjuvant.

12. Use of the quinazolinone compound with the structure shown in the general formula I or pharmaceutically acceptable salt and isomer thereof according to any one of claims 1 to 9 in preparation of 3C-like cysteine protease inhibitors or medicaments for treating and/or preventing viral infectious diseases.

13. Use of a pharmaceutical composition according to claim 11 for the preparation of a 3C-like cysteine protease inhibitor or for the preparation of a medicament for the treatment and/or prevention of a viral infectious disease.