CN113754594B

CN113754594B - Quinazolinone compounds or their pharmaceutically acceptable salts, isomers, preparation methods, pharmaceutical compositions and uses thereof

Info

Publication number: CN113754594B
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: 2025-01-21
Anticipated expiration: 2041-09-16
Also published as: CN113754594A

Abstract

本发明公开了具有通式I所示结构的喹唑啉酮类化合物或其可药用的盐、异构体及其制备方法、药物组合物和用途，本发明克服了现有广谱抗病毒药物结构单一、非共价类高效小分子抑制剂缺乏等缺陷，对3C样半胱氨酸蛋白酶具有很好的抑制活性，对病毒感染性疾病具有良好的治疗作用，毒副作用较小。 The present invention discloses quinazolinone compounds having a structure as shown in general formula I or pharmaceutically acceptable salts and isomers thereof, and preparation methods, pharmaceutical compositions and uses thereof. The present invention overcomes the defects of existing broad-spectrum antiviral drugs such as single structure and lack of non-covalent highly effective small molecule inhibitors, has good inhibitory activity on 3C-like cysteine proteases, has good therapeutic effects on viral infectious diseases, and has less toxic and side effects.

Description

Quinazolinone compound or pharmaceutically acceptable salts and isomers thereof, preparation method, pharmaceutical composition and application thereof

Technical Field

The invention relates to innovative drugs, a preparation method and application thereof, in particular to a quinazolinone compound or pharmaceutically acceptable salts and isomers thereof, a preparation method, a pharmaceutical composition and application thereof.

Background

Coronaviruses (CoV) are a family of enveloped positive-strand RNA-pathogenic viruses that can cause acute and chronic diseases including central nervous system diseases, common cold, lower respiratory tract infections, and diarrhea. HCoV-229E and HCoV-OC43 are zoonotic strains first discovered since 1995. In 2003, severe acute respiratory syndrome coronavirus, now designated as SARS-CoV-1, caused the first global human coronavirus pandemic, resulting in 8000 or more progressive respiratory failures and 916 deaths (mortality rate 10-15%). In the next 8 years, human and animal zoonotic coronaviruses HCoV-NL64 and HCoV-HKU1 were found to have significantly reduced mortality. In 2012, the middle east respiratory syndrome coronavirus (MERS-CoV) like SARs was found to have a very high mortality rate, despite a low transmission rate, from 2012 to 2021, 2 months and a total of 2567 patients diagnosed with infection worldwide, with 882 deaths (mortality 34%). In 2020, a new type of coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is currently spreading worldwide, has become a world epidemic disease, brings serious challenges to the global public health defense and medical system, and brings uncertainty factors to the world economy. SARS-CoV-2 is a highly pathogenic, pandemic human and animal co-virus belonging to the coronaviridae family with SARS-CoV-1 and MERS-CoV. These three viruses, unlike the other several coronaviruses HCoV-NL63, HCoV-229E, HCoV-OC43 and HCoVHKU, 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. Even more terrible, the virus is not only highly contagious, but can be transmitted by asymptomatic infected persons and those in both symptomatic and pre-symptomatic stages. Since the advent of SARS-CoV in 2003, researchers have been working on the research and development of anti-coronavirus drugs, but unfortunately no effective targeted therapeutic drugs or vaccines are currently available. This is also a major reason we are faced with the diligence of explosive SARS-CoV-infection. Although adefovir has recently been approved by the FDA for sale, its clinical efficacy is not significant and is ineffective in critically ill patients. Therefore, it is urgent to find a new effective anti-SARS-CoV-2 infection strategy.

The mutation rate and RNA recombination rate of CoVs are high. Then, is it a matter of concern that the vaccine or drug currently being developed is effective against coronaviruses that are "packaged" in the future. Therefore, the development of broad-spectrum antiviral drugs is a more rational and effective strategy for anti-coronavirus infection than drug studies directed against specific coronaviruses. The key factors controlling host spectrum and viral pathogenicity are highly different in CoVs, such as receptor-dependent differences in the host infected by the virus, poor conservation of structural proteins (antigens), and the like, and high mutation and recombination rates of the CoVs genome, which make the research and development of broad-spectrum anti-coronavirus drugs very challenging. However, it is desirable that as coronavirus gene replication and pathogenesis are continuously resolved, some key proteins in pathogenic CoVs are found to be critical to the life cycle of CoVs and are highly conserved in structure and function, and these key proteins can serve as potential effective targets for the development of broad-spectrum antiviral drugs.

Coronaviruses are broken down to release nucleocapsids and viral genomes after entering host cells. The host cell ribosomes translate the Open Reading Frames (ORFs) 1a and 1b of the viral genome into the multimeric proteins pp1a and pp1b, respectively, which encode 16 nonstructural proteins (nsps), while the remaining ORFs encode structural and accessory proteins. The cleavage of PP to nsp2-16 is catalyzed by 3C-like cysteine protease (3 CLpro) and papain-like cysteine protease (PLpro) to form the replication-transcription complex (RTC). These protease activity deletions lead to a viral life cycle arrest. Furthermore, the structure and function of 3CLpro are highly conserved among coronaviruses. Thus, 3CLpro is a potentially effective target for the development of drugs against a broad spectrum of coronaviruses. The 3CLpro inhibitors reported to date include covalent peptidomimetic inhibitors and non-covalent small molecule inhibitors. Although the peptide-like covalent inhibitor has remarkable inhibitory activity on 3CLpro, the covalent inhibitor has poor target selectivity and unpredictable toxic and side effects. The noncovalent small molecule inhibitor is very deficient, and has the problems of single structure, weak enzyme inhibition activity, poor patentability and the like. At present, only three 3CLpro covalent inhibitors, GC-376, PF-00835231 and PF-07304814, enter the early clinical research stage, and no drug is yet marketed. Therefore, the searching of the 3CLpro small molecule inhibitor which is non-covalent, non-peptoid, remarkable in activity and excellent in patency has important significance for developing broad-spectrum anti-coronavirus medicaments.

Disclosure of Invention

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 invention provides a quinazolinone compound with a structure shown in a general formula I or pharmaceutically acceptable salts and isomers thereof, which has the following structure:

Wherein R ¹ is hydrogen, hydroxy, amino, mercapto, OR ^1-1、-NHR^1-2;

R ^1-1 is C _1-6 alkyl which is unsubstituted or substituted by R ^1-1-1, C _3-10 cycloalkyl which is unsubstituted or substituted by R ^1-1-2, one or more hetero atoms selected from N, O and S, and 1-3 hetero atoms of 5-10 membered heteroaryl, heterocycloalkyl- (C _1-4 alkyl) -, The 4-10 membered heterocycloalkyl group is a 4-10 membered heterocycloalkyl group with 1-3 hetero atoms, wherein the hetero atoms are one or more selected from N, O and S;

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

r ^1-1-1 is hydroxy, mercapto, carboxyl, amino, A C _1-4 alkoxy group or a C _1-4 haloalkoxy group;

R ^1-1-2 is hydroxy, mercapto, carboxyl or amino;

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

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

R ^2-1 is unsubstituted or R ^2-1-1 substituted C _1-6 alkyl, or,

R ^2-1-1 is hydroxy, mercapto, carboxyl, aminoA C _1-4 alkoxy group or a C _1-4 haloalkoxy group;

R ^2-2～R^2-5 is independently selected from C _1-6 alkyl;

R ^2-6～R^2-9 is independently selected from hydrogen or C _1-6 alkyl;

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

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

R ^3-1 is unsubstituted or R ^3-1-1 substituted C _1-6 alkyl;

R ^3-1-1 is hydroxyl, mercapto, C _1-4 alkoxy, C _1-4 halogenated alkoxy, one or more hetero atoms selected from N, O and S, and a hetero atom number of 1-3 is a 4-10 membered heterocycloalkyl;

r ^3-2～R^3-5 is independently selected from C _1-6 alkyl;

r ^3-6～R^3-9 is independently selected from hydrogen or C _1-6 alkyl;

R ¹、R² and R ³ are not simultaneously hydrogen;

A is C _6-10 aryl, C _3-10 cycloalkyl, or C _6-10 aryl- (C _2-4 alkenyl) which is unsubstituted or R ⁴ substituted and has 1-3 hetero atoms, wherein the hetero atoms are one or more selected from N, O and S;

R ⁴ and R ⁵ are independently selected from deuterium, halogen, hydroxy, cyano, nitro, unsubstituted or R ^4-1 substituted C _1-6 alkyl, unsubstituted or R ^4-2 substituted C _1-6 alkoxy, C _6-10 aryl, C _3-10 cycloalkyl, one or more of N, O and S as a hetero atom, 1-3 hetero atom of 4-10 membered heterocycloalkyl, one or more of N, O and S as a hetero atom, and 1-3 hetero atom of 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 ^4-1 is halogen, hydroxy, or-NR ^4-1-1R^4-1-2;

R ^4-2 is halogen;

R ^4-3～R^4-11 is independently selected from hydrogen or C _1-4 alkyl;

R ^4-1-1 and R ^4-1-2 are independently selected from hydrogen or C _1-4 alkyl;

X is hydrogen, C _1-6 alkyl, unsubstituted or R ⁶ substituted C _6-10 aryl, C _6-10 aryl- (C _1-4 alkyl) -, "heteroatom is selected from one or more of N, O and S," 4-10 membered heterocycloalkyl with 1-3 heteroatoms, "heteroatom is selected from one or more of N, O and S," 5-10 membered heteroaryl with 1-3 heteroatoms;

r ⁶ is halogen;

R ⁷ is hydrogen, C _1-6 alkyl, C _6-10 aryl, C _6-10 aryl- (C _1-4 alkyl) -.

In some embodiments, when R ^1-1 is unsubstituted or R ^1-1-1 substituted C _1-6 alkyl, the number of R ^1-1-1 is one or more, and when multiple R ^1-1-1 are present, the R ^1-1-1 may be the same or different.

In some embodiments, when R ^1-1 is unsubstituted or R ^1-1-1 substituted C _1-6 alkyl, the C _1-6 alkyl is C _1-4 alkyl.

In some embodiments, when R ^1-1 is unsubstituted or R ^1-1-2 substituted C _3-10 cycloalkyl, the number of R ^1-1-2 is one or more, and when multiple R ^1-1-2 are present, the R ^1-1-2 may be the same or different.

In some embodiments, when R ^1-1 is unsubstituted or R ^1-1-2 substituted C _3-10 cycloalkyl, the C _6-10 cycloalkyl is C _3-6 cycloalkyl.

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

In some embodiments, when R ^1-1 is "a heteroatom selected from one or more of N, O and S," 4-10 membered heterocycloalkyl- (C _1-4 alkyl) having 1-3 heteroatoms, the 4-10 membered heterocycloalkyl- (C _1-4 alkyl) is 4-6 heterocycloalkyl- (C _1-3 alkyl).

And/or, when R ^1-1 is a 5-to 10-membered heteroaryl group in which "heteroatom is selected from one or more of N, O and S and the number of heteroatom is 1 to 3", the 5-to 10-membered heteroaryl group is a 5-to 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 ^1-2 is a "5-to 10-membered heteroaryl having 1-3 heteroatoms" selected from one or more of N, O and S, the 5-to 10-membered heteroaryl is a 5-to 6-membered heteroaryl.

In some embodiments, when R ^2-1 is unsubstituted or R ^2-1-1 substituted C _1-6 alkyl, the number of R ^2-1-1 is one or more, and when multiple R ^2-1-1 are present, the R ^2-1-1 may be the same or different.

In some embodiments, when R ^2-1 is unsubstituted or R ^2-1-1 substituted C _1-6 alkyl, the C _1-6 alkyl is C _1-4 alkyl.

In some embodiments, when R ^2-2～R^2-5 is independently selected from C _1-6 alkyl, the C _1-6 alkyl is C _1-4 alkyl.

In some embodiments, when R ^2-6～R^2-9 is independently selected from C _1-6 alkyl, the C _1-6 alkyl is C _1-4 alkyl.

In some embodiments, q is 1 or 2.

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

In some embodiments, when R ^3-1 is unsubstituted or R ^3-1-1 substituted C _1-6 alkyl, the number of R ^3-1-1 is one or more, and when multiple R ^3-1-1 are present, the R ^3-1-1 may be the same or different.

In some embodiments, when R ^3-1 is unsubstituted or R ^3-1-1 substituted C _1-6 alkyl, the C _1-6 alkyl is C _1-4 alkyl.

In some embodiments, when R ^3-1-1 is C _1-4 alkoxy, the C _1-4 alkoxy is C _1-3 alkoxy.

In some embodiments, when R ^3-1-1 is C _1-4 haloalkoxy, the C _1-4 haloalkoxy is C _1-3 haloalkoxy.

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

In some embodiments, when R ^3-2～R^3-5 is independently selected from C _1-6 alkyl, the C _1-6 alkyl is C _1-4 alkyl.

In some embodiments, when R ^3-6～R^3-9 is independently selected from C _1-6 alkyl, the C _1-6 alkyl is C _1-4 alkyl.

In some embodiments, when a is unsubstituted or R ⁴ substituted C _6-10 aryl, the number of R ⁴ is one or more, and when multiple R ⁴ are present, the R ⁴ can be the same or different.

In some embodiments, when a is unsubstituted or R ⁴ substituted C _6-10 aryl, the C _6-10 aryl is phenyl or naphthyl.

In some embodiments, when a is C _3-10 cycloalkyl, the C _3-10 cycloalkyl is C _3-6 cycloalkyl.

In some embodiments, when a is an unsubstituted or R ⁵ substituted "heteroatom selected from one or more of N, O and S, the number of heteroatoms is 1-3" 5-10 membered heteroaryl, the number of R ⁵ is one or more, and when multiple R ⁵ are present, the R ⁵ may be the same or different.

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

In some embodiments, when a is C _3-10 cycloalkenyl, the C _3-10 cycloalkenyl is C _3-6 cycloalkenyl.

In some embodiments, when a is C _6-10 aryl- (C _2-4 alkynyl) -said C _6-10 aryl- (C _2-4 alkynyl) -is phenylethynyl.

In some embodiments, when a is C _6-10 aryl- (C _2-4 alkenyl) -said C _6-10 aryl- (C _2-4 alkenyl) -is styryl.

In some embodiments, when R ⁴ and R ⁵ are independently selected from unsubstituted or R ^4-1 substituted C _1-6 alkyl groups, the number of R ^4-1 is one or more, and when multiple R ^4-1 are present, the R ^4-1 groups may be the same or different.

In some embodiments, when R ⁴ and R ⁵ are independently selected from unsubstituted or R ^4-1 substituted C _1-6 alkyl, the C _1-6 alkyl is C _1-4 alkyl.

In some embodiments, when R ⁴ is unsubstituted or R ^4-2 substituted C _1-6 alkoxy, the number of R ^4-2 is one or more, and when multiple R ^4-2 are present, the R ^4-2 may be the same or different.

In some embodiments, when R ⁴ is unsubstituted or R ^4-2 substituted C _1-6 alkoxy, the C _1-6 alkoxy is C _1-4 alkoxy.

In some embodiments, when R ⁴ is C _6-10 aryl, the C _6-10 aryl is phenyl.

In some embodiments, when R ⁴ is C _3-10 cycloalkyl, the C _3-10 cycloalkyl is C _3-6 cycloalkyl.

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

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

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

In some embodiments, when R ^4-3～R^4-7 is independently selected from C _1-4 alkyl, the C _1-4 alkyl is methyl, ethyl, or n-propyl.

In some embodiments, when R ^4-1-1 and R ^4-1-2 are independently C _1-4 alkyl, the C _1-4 alkyl is methyl, ethyl, or n-propyl.

In some embodiments, when X is C _1-6 alkyl, the C _1-6 alkyl is C _1-4 alkyl.

In some embodiments, when X is unsubstituted or R ⁶ substituted C _6-10 aryl, the number of R ⁶ is one or more, and when a plurality of R ⁶ are present, the R ⁶ can be the same or different.

In some embodiments, when X is unsubstituted or R ⁶ substituted C _6-10 aryl, the C _6-10 aryl is phenyl.

In some embodiments, when X is C _6-10 aryl- (C _1-4 alkyl) -said C _6-10 aryl- (C _1-4 alkyl) -is phenyl- (C _1-3 alkyl) -.

In some embodiments, when R ⁶ is halogen, the halogen is fluorine, chlorine, bromine, or iodine.

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 a 4-6 membered heterocycloalkyl.

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

In some embodiments, when R ⁷ is C _1-6 alkyl, the C _1-6 alkyl is C _1-4 alkyl.

In some embodiments, when R ^1-1 is unsubstituted or R ^1-1-1 substituted C _1-6 alkyl, the number of R ^1-1-1 is 1, 2, or 3.

In some embodiments, when R ^1-1 is unsubstituted or R ^1-1-1 substituted C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, n-propyl, or n-butyl.

In some embodiments, when R ^1-1 is unsubstituted or R ^1-1-2 substituted C _3-10 cycloalkyl, the number of R ^1-1-2 is 1, 2, or 3.

In some embodiments, when R ^1-1 is unsubstituted or R ^1-1-2 substituted C _3-10 cycloalkyl, the C _3-10 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, when R ^1-1 is a "4-10 membered heteroaryl group having 1-3 heteroatoms" selected from one or more of N, O and S, the 4-10 membered heterocycloalkyl group is pyrrolidinyl, azetidine, or piperidine ring.

In some embodiments, when R ^1-1 is "a heteroatom selected from one or more of N, O and S," 4-10 membered heterocycloalkyl- (C _1-4 alkyl) having 1-3 heteroatoms, the 4-10 membered heterocycloalkyl- (C _1-4 alkyl) is pyrrolidinylmethyl, azetidinylmethyl, or piperidinylmethyl.

In some embodiments, when R ^1-1 is a "5-10 membered heteroaryl having 1-3 heteroatoms" selected from one or more of N, O and S, the 5-10 membered heteroaryl is imidazolyl or pyrazolyl.

In some embodiments, when R ^1-2 is a "5-10 membered heteroaryl having 1-3 heteroatoms" selected from one or more of N, O and S, the 5-10 membered heteroaryl is imidazolyl or pyrazolyl.

In some embodiments, when R ^2-1 is unsubstituted or R ^2-1-1 substituted C _1-6 alkyl, the number of R ^2-1-1 is 1,2, or 3.

In some embodiments, when R ^2-1 is unsubstituted or R ^2-1-1 substituted C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, n-propyl, or n-butyl.

In some embodiments, when R ^2-2～R^2-5 is independently selected from C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

In some embodiments, when R ^2-6～R^2-9 is independently selected from C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

In some embodiments, when R ^3-1 is unsubstituted or R ^3-1-1 substituted C _1-6 alkyl, the number of R ^3-1-1 is 1,2, or 3.

In some embodiments, when R ^3-1 is unsubstituted or R ^3-1-1 substituted C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, n-propyl, or n-butyl.

In some embodiments, when R ^3-1-1 is C _1-4 alkoxy, the C _1-4 alkoxy is methoxy, ethoxy, or n-propoxy.

In some embodiments, when R ^3-1-1 is C _1-4 haloalkoxy, the C _1-4 haloalkoxy is trifluoromethoxy or difluoromethoxy.

In some embodiments, when R ^3-1-1 is "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, piperidinyl, piperazinyl, pyrrolidinyl, or azetidine.

In some embodiments, when R ^3-2～R^3-5 is independently selected from C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

In some embodiments, when R ^3-6～R^3-9 is independently selected from C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

In some embodiments, when a is unsubstituted or R ⁴ substituted C _6-10 aryl, the number of R ⁴ is 1, 2, or 3.

In some embodiments, when a is C _3-10 cycloalkyl, the C _3-6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, when a is C _3-10 cycloalkenyl, the C _3-10 cycloalkenyl is cyclobutenyl, cyclopentenyl, or butadienyl.

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

In some embodiments, when a is an unsubstituted or R ⁵ -substituted "heteroatom selected from one or more of N, O and S, the heteroatom number is 1-3" 5-10 membered heteroaryl, the 5-10 membered heteroaryl is pyridinyl, pyrimidinyl, thienyl, thiazolyl, furanyl, pyrazolyl, pyrrolyl, pyridazinyl, pyrazinyl, oxazolyl, or imidazolyl.

In some embodiments, when R ⁴ and R ⁵ are independently selected from unsubstituted or R ^4-1 substituted C _1-6 alkyl, the number of R ^4-1 is 1, 2, or 3.

In some embodiments, when R ⁴ and R ⁵ are independently selected from unsubstituted or R ^4-1 substituted C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

In some embodiments, when R ⁴ is unsubstituted or R ^4-2 substituted C _1-6 alkoxy, the number of R ^4-2 is 1, 2, or 3.

In some embodiments, when R ⁴ is unsubstituted or R ^4-2 substituted C _1-6 alkoxy, the C _1-6 alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

In some embodiments, when R ⁴ is C _3-10 cycloalkyl, the C _3-10 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, when R ⁴ is "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, piperidinyl, piperazinyl, azetidine, or pyrrolidinyl.

In some embodiments, when R ⁴ is-NR ^4-3R^4-4, the-NR ^4-3R^4-4 is-NH ₂, or,

In some embodiments, when R ⁴ is- (c=o) R ^4-5, the- (c=o) R ^4-5 is

In some embodiments, when R ⁴ is- (c=o) OR ^4-6, the- (c=o) OR ^4-6 is-COOH OR

In some embodiments, when R ⁴ is-O (c=o) R ^4-7, said-O (c=o) R ^4-7 is

In some embodiments, when R ⁴ is- (c=o) NR ^4-8R^4-9, the- (c=o) NR ^4-8R^4-9 is

In some embodiments, when R ^4-1 and R ^4-2 are independently selected from-NR ^4-1-1R^4-1-2, the-NR ^4-1-1R^4-1-2 is-NH ₂, or,

In some embodiments, when X is a C _1-6 alkyl group, the C _1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

In some embodiments, when X is unsubstituted or R ⁶ substituted C _6-10 aryl, the number of R ⁶ is 1, 2, or 3.

In some embodiments, when X is C _6-10 aryl- (C _1-4 alkyl) -said C _6-10 aryl- (C _1-4 alkyl) -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 1-3 heteroatoms selected from one or more of N, O and S, the 5-10 membered heteroaryl group is pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, furanyl, pyrrolyl, oxazolyl or isoxazolyl.

In some embodiments, when R ⁷ is C _1-6 alkyl, the C _1-6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.

In some embodiments, when R ^1-1 is R ^1-1-1 substituted C _1-6 alkyl, the R ^1-1-1 substituted C _1-6 alkyl is

In some embodiments, when R ^1-1 is R ^1-1-2 substituted C _3-10 cycloalkyl, the R ^1-1-2 substituted C _3-10 cycloalkyl is

In some embodiments, when R ^1-1 is a "4-10 membered heteroaryl having 1-3 heteroatoms" selected from one or more of N, O and S, the 4-10 membered heterocycloalkyl is, where the 4-10 membered heterocycloalkyl is

In some embodiments, when R ^1-1 is "a heteroatom selected from one or more of N, O and S," 4-10 membered heterocycloalkyl- (C _1-4 alkyl) having 1-3 heteroatoms, the 4-10 membered heterocycloalkyl- (C _1-4 alkyl) is

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

In some embodiments, when R ^1-2 is a "5-10 membered heteroaryl having 1-3 heteroatoms" selected from one or more of N, O and S, the 5-10 membered heteroaryl is

In some embodiments, when R ^2-1 is R ^2-1-1 substituted C _1-6 alkyl, the R ^2-1-1 substituted C _1-6 alkyl is

In some embodiments, when R ^3-1 is R ^3-1-1 substituted C _1-6 alkyl, the R ^3-1-1 substituted C _1-6 alkyl is

In some embodiments, when A is C _3-10 cycloalkenyl, the C _3-10 cycloalkenyl is

In some embodiments, when R ⁴ is R ^4-1 substituted C _1-6 alkyl, the R ^4-1 substituted C _1-6 alkyl is trifluoromethyl, difluoromethyl,

In some embodiments, when R ⁴ is R ^4-2 substituted C _1-6 alkoxy, the R ^4-2 substituted C _1-6 alkoxy is trifluoromethoxy.

In some embodiments, when R ⁵ is R ^4-1 substituted C _1-6 alkyl, the R ^4-1 substituted C _1-6 alkyl is trifluoromethyl.

In some embodiments, when X is unsubstituted or R ⁶ -substituted C _6-10 aryl, the unsubstituted or R ⁶ -substituted C _6-10 aryl is

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

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

In some embodiments, when a is unsubstituted or R ⁴ substituted C _6-10 aryl, the unsubstituted or R4 substituted C _6-10 aryl is

In some embodiments, when A is an unsubstituted or R ⁵ -substituted "heteroatom selected from one or more of N, O and S, a 1-3 heteroatom number" 5-10 membered heteroaryl group, the unsubstituted or R ⁵ substituted heteroaryl group is

In some embodiments, R ¹ is hydroxy, OR ^1-1、-NHR^1-2.

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

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

In some embodiments, R ^1-1-1 is hydroxy, carboxy, or,

In some embodiments, R ^1-1-2 is hydroxy.

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

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

In some embodiments, R ^3-1-1 is hydroxy, C _1-4 alkoxy, C _1-4 haloalkoxy, one or more of N, O and S are "4-10 membered heterocycloalkyl having 1-3 heteroatoms".

In some embodiments, R ⁴ is halogen, hydroxy, cyano, nitro, unsubstituted or R ^4-1 substituted C _1-6 alkyl, unsubstituted or R ^4-2 substituted C _1-6 alkoxy, C _6-10 aryl, C _3-10 cycloalkyl, a "4-10 membered heterocycloalkyl having 1-3 heteroatoms selected from one or more of N, O and S 、-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, R ⁵ is halogen, unsubstituted or R ^5-1 substituted C _1-6 alkyl.

In some embodiments, R ^4-1 is halogen or hydroxy.

In some embodiments, R ^4-7 is C _1-4 alkyl.

In some embodiments, R ^4-8 is hydrogen.

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

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

r ^1-1 is C _1-6 alkyl which is unsubstituted or substituted by R ^1-1-1, C _3-10 cycloalkyl which is unsubstituted or substituted by R ^1-1-2, one or more hetero atoms selected from N, O and S, and 1-3 hetero atoms of 5-10 membered heteroaryl, heterocycloalkyl- (C _1-4 alkyl) -, or, The 4-10 membered heterocycloalkyl group is a 4-10 membered heterocycloalkyl group with 1-3 hetero atoms, wherein the hetero atoms are one or more selected from N, O and S;

r ^1-1-1 is hydroxy, carboxyl,

R ^1-1-2 is hydroxy;

m is 1;

n is 0 or 1;

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

R ^2-1 is unsubstituted or R ^2-1-1 substituted C _1-6 alkyl,

R ^2-1-1 is hydroxy,

Q is 1;

r is 0 or 1;

R ^2-2～R^2-5 is independently selected from C _1-6 alkyl;

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

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

R ^3-1 is unsubstituted or R ^3-1-1 substituted C _1-6 alkyl;

R ^3-1-1 is hydroxyl, C _1-4 alkoxy, C _1-4 halogenated alkoxy, one or more hetero atoms selected from N, O and S, and 4-10 membered heterocycloalkyl with 1-3 hetero atoms;

r ^3-2～R^3-5 is independently selected from C _1-6 alkyl;

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

r ⁴ is halogen, hydroxyl, cyano, nitro, C _1-6 alkyl which is unsubstituted or substituted by R ^4-1, C _1-6 alkoxy which is unsubstituted or substituted by R ^4-2, C _6-10 aryl, C _3-10 cycloalkyl, one or more of N, O and S are selected from the "hetero atoms", 4-10 membered heterocycloalkyl groups with 1-3 hetero atoms, -NR ^4-3R^4-4、-(C＝O)R^4-5、-(C＝O)OR^4-6、-O(C＝O)R^4-7, or- (C=O) NR ^4-8R^4-9;

R ⁵ is halogen, unsubstituted or R ^4-1 substituted C _1-6 alkyl;

R ^4-1 is halogen or hydroxy;

R ^4-2 is halogen;

R ^4-3～R^4-6 is independently selected from hydrogen or C _1-4 alkyl;

R ^4-7 is C _1-4 alkyl;

r ^4-8 is hydrogen;

r ^4-9 is hydrogen;

r ⁶ is halogen;

R ⁷ is hydrogen or C _1-6 alkyl.

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

r ^1-1-1 is hydroxy, carboxyl,

R ^1-1-2 is hydroxy;

m is 1;

n is 0 or 1;

R ² is hydroxy, OR ^2-1、-O(C＝O)R^2-2,

R ^2-1 is unsubstituted or R ^2-1-1 substituted C _1-6 alkyl,

R ^2-1-1 is hydroxy,

Q is 1;

r is 0 or 1;

R ^2-2～R^2-5 is independently selected from C _1-6 alkyl;

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

R ³ is hydroxy, OR ^3-1、-O(C＝O)R^3-2,

R ^3-1 is unsubstituted or R ^3-1-1 substituted C _1-6 alkyl;

r ^3-1-1 is hydroxyl, one or more hetero atoms selected from N, O and S, and 4-10 membered heterocycloalkyl with 1-3 hetero atoms;

r ^3-2～R^3-5 is independently selected from C _1-6 alkyl;

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

R ⁴ is halogen, nitro, hydroxy, unsubstituted OR R ^4-1 substituted C _1-6 alkyl, unsubstituted OR R ^4-2 substituted C _1-6 alkoxy, - (c=o) OR ^4-6、-O(C＝O)R^4-7;

R ⁵ is halogen, unsubstituted or R ^4-1 substituted C _1-6 alkyl;

R ^4-1 is hydroxy or halogen;

R ^4-2 is halogen;

R ^4-6 is hydrogen or C _1-4 alkyl;

R ^4-7 is C _1-4 alkyl;

X is hydrogen, C _1-6 alkyl, one or more of ' hetero atoms selected from N, O and S ', 1-3 ' 4-10 membered heterocyclic alkyl ', one or more of ' N, O and S ', and 1-3 ' 5-10 membered heteroaryl;

R ⁷ is hydrogen.

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

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

In the first method, a compound II and a compound III are reacted in a solvent to generate a compound I-1 under the action of a catalyst,

In a solvent, the compound IV reacts with the compounds V and VI to generate a compound I-2;

Wherein R ¹、R²、R³、R⁷, X and A are as defined above.

A pharmaceutical composition comprises a therapeutically effective amount of one or more quinazolinone compounds with a structure shown in a 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 salts and isomers thereof can be used for preparing 3C-like cysteine protease inhibitors or can be used for 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, bone marrow 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 use of the pharmaceutical composition in the preparation of a 3C-like cysteine protease inhibitor or in the preparation of a medicament for the treatment and/or prevention of viral 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, bone marrow 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 which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. 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 can include one or more of binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, binders, disintegrants, lubricants, anti-adherent agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill 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, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or delayed release dosage forms (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 formulations which may 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, aerosols such as nasal sprays or inhalants, liquid dosage forms suitable for parenteral administration, suppositories and lozenges.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of base in pure 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 the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogenphosphates, dihydrogenphosphates, sulfuric acid (forming sulfates or bisulphates), hydroiodic acid, phosphorous acid, and the like, and organic acid salts including, for example, 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, methanesulfonic acid, and the like, salts of amino acids (such as arginine and the like), and salts of organic acids such as glucuronic acid.

The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. Typically, such salts are 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 both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

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

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

Identification of metabolites typically occurs by preparing a radiolabeled isotope of a compound of the invention, parenterally administering it to an animal, such as a rat, mouse, guinea pig, monkey, or human, in a detectable dose (e.g., greater than about 0.5 mg/kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion product from urine, blood, or other biological samples. These products are easy to isolate because they are labeled (others are isolated by using antibodies that are capable of binding to epitopes present in the metabolite). The metabolite structures are determined in a conventional manner, for example by MS, LC/MS or NMR analysis. In general, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. So long as the metabolite products are not otherwise undetectable in vivo, they are useful in assays for therapeutic dosing of the compounds of the invention. The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with a radioisotope, such as tritium (³ H), iodine-125 (¹²⁵ I) or C-14 (¹⁴ C). 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 exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the 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 invention. For example, compounds containing a carboxyl group can form a physiologically hydrolyzable ester that acts as a prodrug by hydrolyzing in vivo to give the compound of formula I itself. The prodrugs are preferably administered orally, as hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.

Those skilled in the art will appreciate that, in accordance with the convention used in the art, the present application describes the structural formula of the group usedMeaning that the corresponding group is linked through this site to other fragments, groups in the compound of formula I.

"Substitution" in the present invention may be one or more, and when there are plural "substitution", the "substitution" may be the same or different.

The term "plurality" may enumerate, 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 ^Y, wherein R ^Y is alkyl 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 with 4-10 carbon atoms. The term "heterocycloalkyl" refers to a saturated, monocyclic or polycyclic group having heteroatoms. The monocyclic ring preferably contains 1, 2 or 3 4-6 membered saturated monocyclic heterocycloalkyl groups independently selected from N, O and S, examples of which include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyranyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxaazepanyl, dioxolanyl, dioxanyl, and the like. The polycyclic preferably contains 1,2 or 3 8-10 membered saturated polycyclic heterocycloalkyl groups independently selected from N, O and S on at least one ring, which may be bicyclic or tricyclic, examples include, but are not limited to, octahydropyrrolo [1,2-a ] pyrazinyl, (1 r, 5S) -3, 8-diazabicyclo [3.2.1] octyl. The term "aryl" refers to an aromatic group having the indicated number of carbon atoms, preferably a monocyclic, bicyclic or tricyclic aromatic group, and when bicyclic or tricyclic, each ring satisfies the shock rule. The aryl group of C _6-10 in the present invention means an aromatic group having 6 to 10 carbon atoms, such as phenyl or naphthyl. The term "heteroaryl" refers to aromatic groups containing heteroatoms, preferably aromatic 5-6 membered monocyclic rings or 9-10 membered bicyclic rings containing 1, 2 or 3 groups independently selected from nitrogen, oxygen and sulfur. The 5-to 6-membered monocyclic ring includes, but is not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, furazanyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, 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 9-10 membered bicyclic ring comprises, but is not limited to, benzimidazolyl, indolyl, indazolyl, benzofuranyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisozolyl, quinolinyl and isoquinolinyl. The term "cycloalkenyl" refers to a monocyclic or polycyclic alkyl group containing at least one double bond. The monocyclic cycloalkenyl group is preferably an unsaturated cyclic alkyl group having 4 to 7 ring carbon atoms, more preferably 4 to 6 carbon atoms, containing a double bond, such as cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl. At least one ring of the polycyclic cycloalkyl contains a double bond and can be a bicyclic or tricyclic alkenyl group with 4-10 carbon atoms.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

Compared with the prior art, the invention has the following advantages:

1. The quinazolinone has good inhibitory activity on 3C-like cysteine protease. 2. The compound has good therapeutic effect on viral infectious diseases. 3. The compound has small toxic and side effects.

Detailed Description

EXAMPLE 1 Synthesis of Compound S1

Step one Synthesis of Compound 2

Compound 1 (25 g) was dissolved in glacial acetic acid (110 ml), and a mixed solution of glacial acetic acid and fuming nitric acid (110ml+220 ml) was slowly added dropwise to the above solution at 0℃and reacted at 0℃for 2 hours after the addition. The reaction is poured into ice water, suction filtration is carried out, and the pale yellow solid 2 is prepared and 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 (15 g,62 mmol) was dissolved in ethanol/water (132 ml/47 ml), feSO ₄·7H₂ O (3.8 g) was added to the above solution, and iron powder (38 g) was added with vigorous mechanical stirring. And heating and refluxing for reaction for 4 hours. After the reaction is completed, the light yellow solid is prepared by suction filtration, evaporating the solvent, and separating and purifying by column chromatography 3(11g,85％).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 (5.32 g,25.2 mmol) was dissolved in 20% HCl (50 ml) at 0-5℃and 16ml of aqueous solution of sodium nitrite (1.9 g) was added to the solution and stirred mechanically for 15min. Then, 50ml of an aqueous solution of potassium iodide (20 g) was slowly dropped into the above solution, and the reaction was carried out overnight. After the completion of the reaction, na ₂S₂O₃ was added to quench the reaction, chloroform was extracted 3 times (50 ml. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to give a pale yellow solid 4(6.79g,84％).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 (5 g,15.58 mmol) and sulfamic acid (1.8 g,18.70 mmol) were suspended in a water/acetonitrile mixture and sodium chlorite (3.5 g,38.95 mmol) was added portionwise at 0 ℃. Transfer to room temperature and react for 2h. After completion of the reaction, the reaction was quenched with saturated Na ₂S₂O₃, extracted 3 times with EA (50 ml. Times.3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to give a white solid 5 (4.2 g, 80%). ¹H NMR(300MHz,CDCl₃ ) Delta 8.91 (s, 1H), 7.11 (s, 1H), 3.90 (s, 3H), 3.85 (s, 6H).

Step five, synthesis of the compound 7

Compound 5 (200 mg,0.59 mmol), compound 6 (184 mg,1.18 mmol), cuprous iodide (11 mg,0.059 mmol) and cesium carbonate (383 mg,1.48 mmol) were suspended in anhydrous DMF (4 ml), nitrogen-protected, and reacted overnight at room temperature. Adding saturated amine chloride solution (30 ml), stirring for 30min, and vacuum filtering to obtain white solid 7(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, synthesizing the compound S1

Compound 7 (100 mg,0.32 mmol) was suspended in anhydrous DCM (2 ml), and a solution of BBr3 in dichloromethane (1M, 3 ml) was slowly added dropwise at-10℃and reacted overnight at room temperature. After the reaction is completed, slowly dropwise adding ice methanol to quench the reaction, evaporating the methanol, adding DCM, stirring for 30min at room temperature, and carrying out suction filtration to obtain the target compound S1(77mg,90％).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 synthesis of the compounds S2 to S68 in the following examples S2 to S68 is performed by referring to the synthesis method of example 1, and only the corresponding raw materials are 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

Step one Synthesis of Compound 9

Compound 8 (10 g,47.2 mmol) was added in portions to 90ml of concentrated nitric acid (68% -70%) at 0 ℃, stirred at 0 ℃ for reaction for 30min, 500ml of ice water was added to the above solution, stirred at 0 ℃ for 1h, and suction filtered to give pale yellow solid 9 (8.4 g, 69%), which was directly put into the next reaction without purification. 1H NMR (CDCl ₃, 300 MHz) δ9.52 (s, 1H), 7.55 (s, 1H), 4.15-3.98 (s, 9H).

Step two Synthesis of Compound 10

Compound 9 (8 g,31.1 mmol) was dissolved in ethanol/water (66 ml/25 ml), feSO ₄·7H₂ O (2.0 g) was added to the above solution, and iron powder (19 g) was added with vigorous mechanical stirring. And heating and refluxing for reaction for 4 hours. After the completion of the reaction, the solvent was evaporated to dryness by suction filtration, and separated and purified by column chromatography to give 10 (6.3 g, 89%) as a pale yellow solid. ¹H NMR(300MHz,CDCl₃ ) Delta 7.53 (s, 1H), 3.89-3.83 (s, 6H), 3.63 (s, 3H).

Step three Synthesis of Compound 11

Compound 10 (2.7 g,11.7 mmol) and benzoic acid (1.42 g,11.7 mmol) were dissolved in pyridine (20 ml), TPP (7.64 mL,29.1 mmol) was added to the above solution, and the mixture was heated to 70℃under nitrogen protection and reacted for 2h. Aniline (1.3 ml,14 mmol) was added dropwise to the reaction solution and reacted overnight at 70 ℃. After the reaction was completed, cooling to room temperature, evaporating the solvent, dissolving the residue with ethyl acetate, washing with 3N hydrochloric acid solution (1X 50 ml), washing with saline solution (2X 50 ml), drying with anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by column chromatography to obtain the 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 (200 mg,0.52 mmol) was suspended in anhydrous DCM (2 ml), and a BBr3/DCM solution (4.7 ml,4.7 mmol) was slowly added dropwise to the suspension at-10 ℃. At-10 ℃ overnight, adding ice methanol to quench the reaction after the reaction is complete, concentrating, adding DCM, stirring for 30min at room temperature, and suction filtering to obtain the target 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 synthesis of the compounds S70 to S80 in the following examples S70 to S80 is performed by referring to the synthesis method of example 69, and only the corresponding raw materials are 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

Step one Synthesis of Compound 12

To a solution of compound S1 (9.45 g,35 mmol) in diphenyl ether (200 ml) was added dichlorodiphenylmethane (18 g,52.5 mmol), and the temperature was raised to 175℃and after completion of the reaction, the reaction was stopped and cooled to room temperature. Petroleum ether (1000 ml) is added, a filter cake is obtained by suction filtration, and the compound is obtained by further column chromatography separation and purification 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 (500 mg,1.15 mmol) was dissolved in acetone (10 ml), methyl bromoacetate (0.13 ml,1.38 mmol) and potassium carbonate (470 mg,3.45 mmol) were added sequentially, and the mixture was heated under reflux overnight. After the reaction was completed, the reaction was stopped, cooled to room temperature, the solvent was distilled off, 5ml of water was added to the reaction residue, DCM (3X 10 ml) was used for extraction, the organic phases were combined, washed with saturated brine (1X 10 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give the 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 (506 mg,1 mmol) was dissolved in methanol (5 ml), and aqueous sodium hydroxide (1M, 2.0 ml) was added thereto and stirred at room temperature for 2 hours. After the reaction is completed, the pH is regulated to 2-3 by dilute hydrochloric acid at the temperature of 0 ℃, and the compound 14 is obtained by suction filtration and directly put into the next reaction without purification.

Step four, synthesis of Compound S81

Compound 14 (400 mg,0.81 mmol) was dissolved in ethanol (30 ml), pd/C (40 mg, 10%) was added and reacted under the action of hydrogen for 12h. After the reaction is completed, carrying out suction filtration, concentrating filtrate, and purifying by column chromatography to obtain the 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 synthesis of the compounds S82 to S88 in the following examples S82 to S88 is performed by referring to the synthesis method of example 81, and only the corresponding raw materials are 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

Step one Synthesis of Compound 15

Compound S1 (9.45 g,35 mmol) was dissolved in DMF (80 ml), and bromobenzyl (5.4 ml,45.5 mmol) and potassium carbonate (7.24 mg,52.5 mmol) were added and reacted at room temperature overnight. After completion of the reaction, the reaction was stopped, ethyl acetate (300 ml) was added, washed with water (3X 100 ml), washed with saturated brine (1X 100 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give the 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 (500 mg,1.39 mmol) was dissolved in DMF (5 ml), 2-iodoethanol (287 mg,1.67 mmol) and potassium carbonate (288 mg,2.1 mmol) were added sequentially and reacted at room temperature overnight. After the reaction was completed, the reaction was quenched by adding water (10 ml), extracted with ethyl acetate (3X 10 ml), washed with saturated brine (1X 10 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give the 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 (400 mg,1 mmol) was dissolved in ethanol (10 ml), pd/C (40 mg, 10%) was added and reacted under the action of hydrogen for 8h. After the reaction is completed, carrying out suction filtration, concentrating filtrate, and purifying by column chromatography to obtain the 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 synthesis of the compounds S94 to S104 in the following examples S94 to S104 is performed by referring to the synthesis method of example 93, and only the corresponding raw materials are replaced.

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

Step one Synthesis of Compound 17

Raw material S1 (2.7 g,10 mmol) was dissolved in anhydrous pyridine (25 ml), acetic anhydride (25 ml) and DMAP (122 mg,0.1 mmol) were added at 0℃and transferred to room temperature. After the reaction is completed, stopping the reaction, adding ice water to quench the reaction, filtering to obtain a filter cake, and drying to obtain the compound 17 (3.76 g, 95%), wherein the compound is directly put into the next reaction without purification.

Step two, synthesis of Compound 18

Compound 17 (3 g,7.58 mmol) was dissolved in anhydrous acetone (30 ml), potassium carbonate (7.3 g,53 mmol) and bromobenzyl (1.6 g,9.1 mmol) were added and the mixture was reacted under reflux for 6h. Stopping the reaction after the reaction is completed, cooling to room temperature, evaporating the solvent, adding water (50 ml), extracting with ethyl acetate (3×50 ml), mixing the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, separating and purifying by column chromatography to obtain the 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 (2.4 g,5.41 mmol) was dissolved in ethanol (50 ml), pd/C (24 mg, 10%) was added and reacted under hydrogen for 8h. After the reaction is completed, carrying out suction filtration, concentrating filtrate, and purifying by column chromatography to obtain the 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 (1.5 g,4.33 mmol) was dissolved in DMF (10 ml), and potassium carbonate (1.2 g,8.66 mmol), 2- (4-morpholinyl) ethyl bromide (1 g,5.2 mmol) and potassium iodide (17 mg,0.1 mmol) were added. Heating to 60deg.C, stopping the reaction after the reaction is completed, cooling to room temperature, quenching the reaction with water (30 ml), extracting with ethyl acetate (3×30 ml), mixing the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, separating and purifying by column chromatography to obtain the 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 (200 mg,0.43 mmol) was dissolved in methanol (2 ml), and potassium carbonate (88.7 mg,0.64 mmol) was added thereto and reacted at room temperature. After the reaction is completed, adding dilute hydrochloric acid to regulate the pH to 2-3, filtering, washing a filter cake with water, and drying the filter cake to obtain the 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 synthesis of the compounds S106 to S1110 in the following examples S106 to S110 is performed by referring to the synthesis method of example 105, and only the corresponding raw materials are replaced.

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

Step one Synthesis of Compound 21

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

Step two Synthesis of Compound 22

Compound 21 (5.7 g,10 mmol), 23 (2.0 g,10 mmol), cesium carbonate (3.9 g,12 mmol) Pd ₂(dba)₃ (144 mg,0.25 mmol), xantphos (289 mg,0.5 mmol) were dissolved in anhydrous toluene (30 ml), nitrogen protected, and added to reflux overnight. After the reaction was completed, the reaction was stopped, the solvent was distilled off, water (50 ml) was added, extraction was performed with ethyl acetate (3X 30 ml), the organic phases were combined, washed with saturated brine ((1X 30 ml)), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the 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 (619 mg,1 mmol) was dissolved in ethanol (5 ml)/DCM (5 ml), pd/C (62 mg, 10%) was added and reacted under hydrogen for 8h. After the reaction is completed, carrying out suction filtration, concentrating filtrate, and purifying by column chromatography to obtain the 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 synthesis of the compounds S115 to S121 in the following examples S115 to S121 refers to the synthesis method of 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 test of SARS-CoV-2 Virus 3C-like cysteine protease (3 CLpro) enzyme inhibitory Activity

1.3 Expression and purification of CLpro protein

The gene sequence of the full-length 3CLpro protein was constructed in the expression vector pET28a (+) vector and transferred into competent cells of E.coli BL21 (DE 3), and after induction for 12 hours at a final concentration of 0.5mM IPTG at 25℃was purified using Ni-NTA column. The purified protein is detected by SDS, the part with the purity of more than 90 percent is further purified by Superdex 200 10/300GL of an AKTA Pure of a GE protein chromatography purification system, the protein with the purity of more than 95 percent is obtained, the protein concentration is measured by Nano Drop, and the protein is packaged and quick frozen by liquid nitrogen and then is put into-80 ℃ for preservation.

Establishment of SARS-CoV-2 3CLpro enzyme activity screening system and calculation of inhibitor inhibition rate and medicine IC50

The SARS-CoV-2 3CLpro activity and the inhibitory activity of the compound on SARS-CoV-2 3CLpro are determined by Fluorescence Resonance Energy Transfer (FRET) technique. A fluorogenic substrate (Dabcyl-KTSAVLQ ∈ SGFRKM-E (Edans) -NH ₂) with SARS-CoV-2 3CLpro cleavage site (arrow) and Tris-HCl buffer (20 mM Tris-HCl,150mM NaCl,10mM EDTA,pH7.5) were used in the assay. The compound was dissolved in 100% dmso. Mu.l of the compound was incubated with 40. Mu.l of SARS-CoV-2 3CLpro (final concentration 0.5. Mu.M, 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 fluorescent signal resulting from the cleavage of the substrate catalyzed by 3CLpro was detected using a radioresonance energy transfer fluorescence spectrophotometer at an excitation wavelength of 340nm and an absorption wavelength of 490 nm. SARS-CoV-2 3clpro kinetic constants (Vmax and Km) were obtained by fitting the data to MICHAELIS MENTEN equation, v=vmax× [ S ]/(km+ [ S ]). Kcat is then calculated according to the formula kcat=vmax/[ E ]. Compounds were diluted in a gradient by fold dilution using Tris-HCl buffer and assayed using the same final concentration of SARS-CoV-2 3CLpro and fluorogenic substrate system as described above. Values of intrinsic (V0 i) and apparent (Vappi, kappi) catalytic parameters of 3CLpro catalytic polypeptide substrate hydrolysis were determined in the presence and absence, respectively, of the compound of interest. The apparent inhibition constant (Kappi) for the binding of the target compound to Mpro is derived from the dependence of Vappi on the inhibitor concentration ([ I ]) at a fixed substrate concentration ([ S ]) according to the equation Vappi =Vappx [ I ]/(Kappi + [ I ]). The value of the intrinsic inhibition constant (Ki) for the binding of the target compound to 3CLpro is calculated according to equation Kappi = ki× (1+ [ S ]/Km). Inhibition curves for compounds were plotted by GRAPHPAD PRISM 8.0.0 software and IC ₅₀ values were calculated. As a result, as shown in Table 1 below, the compound of the example had a better inhibitory activity against SARS-CoV-2 virus 3CLpro, and the activity was superior to that of the positive drug baicalein or equivalent to that of baicalein. IC ₅₀＜0.001μM;B：IC₅₀ = 0.001 μm-0.01 μm;

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

EXAMPLE 123 cytotoxicity and anti-SARS-CoV-2 Virus infection efficacy test

And (3) testing the cytotoxicity of the Vero E6 by using a CCK8 method to test the cytotoxicity of the compound to be tested on the Vero E6 cells of the mammal. Vero E6 cells were added to 96-well plates and cultured overnight. Cells were then incubated with different concentrations of test compound for 48h. The medium in the well plate was removed, replaced with fresh serum-free medium, 10% cck8 reagent was added and incubated for 1h at 37 ℃ before detection of absorbance at 450nm using an enzyme-labeled instrument.

The method for screening compounds without cytotoxicity or with low cytotoxicity to perform antiviral infection test comprises inoculating ① cells, sucking out culture solution, digesting cells with pancreatin to obtain 1×106 cells/ml, adding 4ml of the cells into 6ml of culture medium to obtain cell suspension with cell density of 4×105 cells/ml, inoculating into 96 well plates with cell density of 100 μl per well and cell density of 4×104 per well. ② Drug pretreatment of cells were replaced with DMEM medium containing 2% fbs, drug and DMSO were added at corresponding concentrations of 100 μl per well, and then placed in a 37 ℃ incubator for pretreatment for 1h. ③ The virus infection comprises the steps of taking 0.3ml of virus, adding 45ml of culture medium, mixing uniformly, diluting the virus to 100TCID50/0.05ml, discarding the drug culture medium vertical hanging drop virus diluent in a cell plate to 96-well plates, adding 50 μl/hole of sample volume, adding corresponding drug culture medium (containing drug with corresponding concentration) simultaneously, adding 50 μl/hole of sample volume, mixing uniformly, carrying out ④ incubation, namely mixing the sample-added cell culture plate uniformly on a shaker, placing the cell culture plate in a 37 ℃ incubator, and incubating for 1h. After the incubation, the virus-serum mixture inoculated with cells was aspirated, the corresponding concentration of drug and control DMSO were added, 100. Mu.l/well (100 TCID 50/well) was placed in a 37℃CCO ₂ incubator for 48h, and the supernatant was collected ⑤ to detect viral RNA and subjected to immunofluorescent staining analysis by 4% paraformaldehyde fixation staining.

The specific experimental results are shown in Table 2, the compound of the example has smaller cytotoxicity, better inhibition activity on SARS-CoV-2 virus infection and better selection index, and A: IC ₅₀＜0.1μM;B：IC₅₀ = 0.1 mu M-1.0 mu M.

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

Claims

1. A quinazolinone compound having a structure shown in general formula I or a pharmaceutically acceptable salt thereof, the structure of which is as follows:

Wherein, R ¹ is a hydroxyl group;

^R2 is a hydroxyl group;

R ³ is a hydroxyl group;

A is unsubstituted or R ⁴ substituted phenyl; or C _3-6 cycloalkyl, Phenylethynyl, phenylethynyl,

R ⁴ is selected from deuterium, halogen, hydroxy, cyano, nitro, unsubstituted C _1-6 alkyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, methoxy, phenyl, cyclopropyl, -NH ₂ , -COOH,

X is hydrogen, C _1-6 alkyl, Benzyl,

^R7 is hydrogen or _C1-6 alkyl.

2. The quinazolinone compound having the structure shown in general formula I according to claim 1 or a pharmaceutically acceptable salt thereof is any of the following:

3. The method for preparing the quinazolinone compound having the structure shown in general formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that:

Method 1: Compound II and compound III are reacted in a solvent under the action of a catalyst to generate compound I-1.

Method 2: Compound IV reacts with compounds V and VI in a solvent to generate compound I-2;

Wherein, R ¹ , R ² , R ³ , R ⁷ , X and A are as defined above.

4. A pharmaceutical composition, characterized in that it contains a therapeutically effective amount of one or more quinazolinone compounds having a structure represented by general formula I according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

5. Use of the quinazolinone compound having the structure shown in general formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a 3C-like cysteine protease inhibitor or in the preparation of a drug for treating and/or preventing viral infectious diseases.

6. Use of the pharmaceutical composition according to claim 4 in the preparation of a 3C-like cysteine protease inhibitor or in the preparation of a drug for treating and/or preventing viral infectious diseases.