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

Abstract

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

Technical Field

[0001] The present invention relates to innovative drugs, preparation methods and uses, and in particular to quinazolinone compounds or pharmaceutically acceptable salts and isomers thereof, preparation methods, pharmaceutical compositions and uses thereof. Background Art

[0002] 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 colds, lower respiratory tract infections, and diarrhea. HCoV-229E and HCoV-OC43 are the first zoonotic virus strains discovered since 1995. In 2003, severe acute respiratory syndrome coronavirus, now named SARS-CoV-1, caused the first global human coronavirus pandemic, resulting in more than 8,000 people with progressive respiratory failure and 916 deaths (case fatality rate of 10-15%). In the following 8 years, people discovered zoonotic coronaviruses HCoV-NL64 and HCoV-HKU1 with significantly lower lethality. In 2012, the SARs-like Middle East respiratory syndrome coronavirus (MERS-CoV) was discovered. Although this type of virus has a lower transmission rate, it has a high mortality rate. Since its appearance in 2012 to February 2, 2021, there have been 2,567 confirmed infected patients and 882 deaths worldwide (mortality rate of 34%). In 2020, the novel coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is currently spreading around the world and has become a global pandemic, posing severe challenges to global public health defense and medical systems, and bringing uncertainty to the world economy. SARS-CoV-2 is a highly pathogenic, pandemic zoonotic virus that belongs to the Coronaviridae family along with SARS-CoV-1 and MERS-CoV. These three viruses are different from several other coronaviruses HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoVHKU1, which 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 hypoxemic respiratory failure, acute respiratory distress syndrome, multisystem organ failure, and ultimately death. What is more terrifying is that this virus is not only highly contagious, but can also be spread by asymptomatic carriers and those in the symptomatic and pre-symptomatic stages. Since the emergence of SARS-CoV in 2003, researchers have been committed to the research and development of anti-coronavirus drugs, but unfortunately, there is no effective targeted therapeutic drug or vaccine. This is also the main reason why we are helpless when facing an outbreak of SARS-CoV-infection. Although remdesivir was recently officially approved by the FDA for marketing, its clinical efficacy is not significant and is ineffective for critically ill patients. Therefore, it is urgent to find new and effective anti-SARS-CoV-2 infection strategies.

[0003] CoVs have high mutation and RNA recombination rates. So, can the vaccines or drugs currently under development effectively resist future "packaged" coronaviruses? This is a question worthy of attention. Therefore, compared with drug research targeting specific coronaviruses, the development of broad-spectrum antiviral drugs is a more reasonable and effective strategy to fight coronavirus infection. The key factors that control the host spectrum and viral pathogenicity are highly different in CoVs, such as different receptors that the virus relies on to infect the host, poor conservation of structural proteins (antigens), and high mutation and recombination rates of the CoVs genome. These factors make the research and development of broad-spectrum anti-coronavirus drugs very challenging. However, it is gratifying that as the gene replication and pathogenic mechanism of coronaviruses continue to be analyzed, people have found that there are some key proteins in pathogenic CoVs that are essential to the life cycle of CoVs and are highly conserved in structure and function. These key proteins can serve as potential effective targets for the development of broad-spectrum antiviral drugs.

[0004] After entering the host cell, the coronavirus will be decomposed to release the nucleocapsid and viral genome. The host cell ribosomes translate the open reading frames (ORF) 1a and ORF1b of the viral genome into polyproteins pp1a and pp1b, respectively, which are used to encode 16 non-structural proteins (nsps), while the remaining ORFs encode structural proteins and accessory proteins. 3C-like cysteine ​​protease (3CLpro) and papaya-like cysteine ​​protease (PLpro) catalyze the cleavage of PP to generate nsp2-16, which in turn forms the replication-transcription complex (RTC). The loss of these protease activities will cause the viral life cycle to stop. In addition, the structure and function of 3CLpro are highly conserved in coronaviruses. Therefore, 3CLpro has become a potential effective target for the development of anti-broad-spectrum coronavirus drugs. Currently reported 3CLpro inhibitors include covalent peptidomimetic inhibitors and non-covalent small molecule inhibitors. Although peptidomimetic covalent inhibitors have significant inhibitory activity against 3CLpro, the covalent inhibitors have poor target selectivity and unpredictable toxic side effects. However, there is a lack of non-covalent small molecule inhibitors, which have problems such as single structure, weak enzyme inhibition activity, and poor drugability. Currently, only three 3CLpro covalent inhibitors, GC-376, PF-00835231, and PF-07304814, have entered the early clinical research stage, and there are no marketed drugs yet. Therefore, finding non-covalent, non-peptidomic, active, and drugable 3CLpro small molecule inhibitors is of great significance for the development of broad-spectrum anti-coronavirus drugs.

[0005] Summary of the invention

[0006] Purpose of the invention: The purpose of the present invention is to provide a quinazolinone compound or a pharmaceutically acceptable salt or isomer thereof. Another purpose of the present invention is to provide a preparation method, a pharmaceutical composition and use of the quinazolinone compound or a pharmaceutically acceptable salt or isomer thereof.

[0007] Technical solution: The present invention provides a quinazolinone compound having a structure shown in general formula I or a pharmaceutically acceptable salt or isomer thereof, the structure of which is as follows:

[0008]

[0009] Among them, R 1 is hydrogen, hydroxyl, amino, thiol, OR 1-1 、-NHR 1-2 ;

[0010] R 1-1 is unsubstituted or R 1-1-1 Substituted C 1-6 Alkyl, unsubstituted or R 1-1-2 Substituted C 3-10 Cycloalkyl, "heteroatoms selected from one or more of N, O and S, with 1 to 3 heteroatoms" 5-10 membered heteroaryl, heterocycloalkyl, heterocycloalkyl-(C 1-4 alkyl)-, The 4- to 10-membered heterocycloalkyl group is a 4- to 10-membered heterocycloalkyl group having a heteroatom selected from one or more of N, O and S and a heteroatom number of 1 to 3;

[0011] R 1-2 A 5- to 10-membered heteroaryl group having a heteroatom selected from one or more of N, O and S and having 1 to 3 heteroatoms;

[0012] R 1-1-1 Hydroxyl, thiol, carboxyl, amino, C 1-4 Alkoxy or C 1-4 Haloalkoxy;

[0013] R 1-1-2 is a hydroxyl group, a thiol group, a carboxyl group or an amino group;

[0014] m is 1, 2 or 3; n is 0, 1, 2, 3 or 4;

[0015] R 2 is hydrogen, hydroxyl, amino, thiol, OR 2-1 , -O(C=O)R 2-2 ,

[0016] R 2-1 is unsubstituted or R 2-1-1 Substituted C1-6 Alkyl, or

[0017] R 2-1-1 Hydroxyl, thiol, carboxyl, amino C 1-4 Alkoxy or C 1-4 Haloalkoxy;

[0018] R 2-2 ~R 2-5 Independently selected from C 1-6 alkyl;

[0019] R 2-6 ~R 2-9 are independently selected from hydrogen or C 1-6 alkyl;

[0020] q is 1, 2 or 3; r is 0, 1, 2, 3 or 4;

[0021] R 3 is hydrogen, hydroxyl, thiol, OR 3-1 , -O(C=O)R 3-2 ,

[0022] R 3-1 is unsubstituted or R 3-1-1 Substituted C 1-6 alkyl;

[0023] R 3-1-1 Hydroxyl, thiol, C 1-4 Alkoxy, C 1-4 Haloalkoxy, "a 4- to 10-membered heterocycloalkyl group having one or more heteroatoms selected from N, O and S, and 1 to 3 heteroatoms";

[0024] R 3-2 ~R 3-5 Independently selected from C 1-6 alkyl;

[0025] R 3-6 ~R 3-9 are independently selected from hydrogen or C 1-6 alkyl;

[0026] R 1 , R 2 and R 3 Not at the same time hydrogen;

[0027] A is unsubstituted or R 4 Substituted C 6-10 Aryl, C 3-10 Cycloalkyl, unsubstituted or R 5Substituted "heteroatom selected from one or more of N, O and S, with 1 to 3 heteroatoms" 5-10 membered heteroaryl, C 3-10 Cycloalkenyl, C 6-10 Aryl-(C 2-4 Alkynyl)-, C 6-10 Aryl-(C 2-4 alkenyl)-;

[0028] 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, "heteroatoms selected from one or more of N, O and S, with 1-3 heteroatoms" 4-10 membered heterocycloalkyl, "heteroatoms selected from one or more of N, O and S, with 1-3 heteroatoms" 5-10 membered heteroaryl, -NR 4-3 R 4-4 、-(C=O)R 4-5 、-(C=O)OR 4-6 , -O(C=O)R 4-7 、-(C=O)NR 4-8 R 4-9 、-S(=O)2NR 4-10 R 4-11 ;

[0029] R 4-1 is halogen, hydroxyl, or -NR 4-1-1 R 4-1-2 ;

[0030] R 4-2 is a halogen;

[0031] R 4-3 ~R 4-11 are independently selected from hydrogen or C 1-4 alkyl;

[0032] R 4-1-1 and R 4-1-2 are independently selected from hydrogen or C 1-4 alkyl;

[0033] X is hydrogen, C 1-6 Alkyl, unsubstituted or R 6 Substituted C 6-10 Aryl, C 6-10 Aryl-(C 1-4alkyl)-, "heteroatoms selected from one or more of N, O and S, with 1-3 heteroatoms" 4-10 membered heterocycloalkyl, "heteroatoms selected from one or more of N, O and S, with 1-3 heteroatoms" 5-10 membered heteroaryl;

[0034] R 6 is a halogen;

[0035] R 7 For hydrogen, C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl-(C 1-4 alkyl)-.

[0036] In some embodiments, when R 1-1 is unsubstituted or R 1-1-1 Substituted C 1-6 When alkyl, the R 1-1-1 The number of is one or more. When there are multiple R 1-1-1 When the R 1-1-1 Can be the same or different.

[0037] In some embodiments, when R 1-1 is unsubstituted or R 1-1-1 Substituted C 1-6 When the C 1-6 Alkyl is C 1-4 alkyl.

[0038] In some embodiments, when R 1-1 is unsubstituted or R 1-1-2 Substituted C 3-10 When cycloalkyl, the R 1-1-2 The number of is one or more. When there are multiple R 1-1-2 When the R 1-1-2 Can be the same or different.

[0039] In some embodiments, when R 1-1 is unsubstituted or R 1-1-2 Substituted C 3-10 When cycloalkyl, the C 6-10 Cycloalkyl is C 3-6 Cycloalkyl.

[0040] In some embodiments, when R 1-1 When it is a 4- to 10-membered heteroaryl group "whose heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3", when the 4- to 10-membered heterocycloalkyl group is a 4- to 6-membered heterocycloalkyl group.

[0041] In some embodiments, when R 1-1"a 4- to 10-membered heterocycloalkyl-(C 1-4 alkyl), the 4- to 10-membered heterocycloalkyl-(C 1-4 Alkyl) is 4 to 6 heterocycloalkyl-(C 1-3 alkyl).

[0042] and / or, when R 1-1 When it is a 5- to 10-membered heteroaryl group "having a heteroatom selected from one or more of N, O and S, and having 1 to 3 heteroatoms", the 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group.

[0043] In some embodiments, m is 1 or 2.

[0044] In some embodiments, n is 0, 1, or 2.

[0045] In some embodiments, when R 1-2 When it is a 5- to 10-membered heteroaryl group "having a heteroatom selected from one or more of N, O and S, and having 1 to 3 heteroatoms", the 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group.

[0046] In some embodiments, when R 2-1 is unsubstituted or R 2-1-1 Substituted C 1-6 When alkyl, the R 2-1-1 The number of is one or more. When there are multiple R 2-1-1 When the R 2-1-1 Can be the same or different.

[0047] In some embodiments, when R 2-1 is unsubstituted or R 2-1-1 Substituted C 1-6 When the C 1-6 Alkyl is C 1-4 alkyl.

[0048] In some embodiments, when R 2-2 ~R 2-5 Independently selected from C 1-6 When the C 1-6 Alkyl is C 1-4 alkyl.

[0049] In some embodiments, when R 2-6 ~R 2-9 Independently selected from C 1-6 When the C 1-6 Alkyl is C 1-4 alkyl.

[0050] In some embodiments, q is 1 or 2.

[0051] In some embodiments, r is 0, 1 or 2.

[0052] In some embodiments, when R 3-1 is unsubstituted or R 3-1-1 Substituted C 1-6 When alkyl, the R 3-1-1 The number of is one or more. When there are multiple R 3-1-1 When the R 3-1-1 Can be the same or different.

[0053] In some embodiments, when R 3-1 is unsubstituted or R 3-1-1 Substituted C 1-6 When the C 1-6 Alkyl is C 1-4 alkyl.

[0054] In some embodiments, when R 3-1-1 C 1-4 In the case of an alkoxy group, the C 1-4 Alkoxy is C 1-3 Alkoxy.

[0055] In some embodiments, when R 3-1-1 C 1-4 When the halogenated alkoxy group is 1-4 Haloalkoxy is C 1-3 Halogenated alkoxy.

[0056] In some embodiments, when R 3-1-1 When it is a 4- to 10-membered heterocycloalkyl group "having one or more heteroatoms selected from N, O and S, and having 1 to 3 heteroatoms", the 4- to 10-membered heterocycloalkyl group is a 4- to 6-membered heterocycloalkyl group.

[0057] In some embodiments, when R 3-2 ~R 3-5 Independently selected from C 1-6 When the C 1-6 Alkyl is C 1-4 alkyl.

[0058] In some embodiments, when R 3-6 ~R 3-9 Independently selected from C 1-6 When the C 1-6 Alkyl is C 1-4 alkyl.

[0059] In some embodiments, when A is unsubstituted or R 4 Substituted C 6-10 When the group is aryl, the R4 The number of is one or more. When there are multiple R 4 When the R 4 Can be the same or different.

[0060] In some embodiments, when A is unsubstituted or R 4 Substituted C 6-10 When the C 6-10 Aryl is phenyl or naphthyl.

[0061] In some embodiments, when A is C 3-10 When cycloalkyl, the C 3-10 Cycloalkyl is C 3-6 Cycloalkyl.

[0062] In some embodiments, when A is unsubstituted or R 5 In the case of a substituted "heteroatom selected from one or more of N, O and S, with 1 to 3 heteroatoms" 5-10 membered heteroaryl group, the R 5 The number of is one or more. When there are multiple R 5 When the R 5 Can be the same or different.

[0063] In some embodiments, when A is unsubstituted or R 5 When the substituted "heteroatom is selected from one or more of N, O and S, and the number of the heteroatoms is 1 to 3" 5- to 10-membered heteroaryl, the 5- to 10-membered heteroaryl is a 5- to 6-membered heteroaryl.

[0064] In some embodiments, when A is C 3-10 When the cycloalkenyl group is 3-10 Cycloalkenyl is C 3-6 Cycloalkenyl.

[0065] In some embodiments, when A is C 6-10 Aryl-(C 2-4 Alkynyl)-, the C 6-10 Aryl-(C 2-4 phenylethynyl)- is phenylethynyl.

[0066] In some embodiments, when A is C 6-10 Aryl-(C 2-4 alkenyl)-, the C 6-10 Aryl-(C 2-4 The styryl group)-is styryl.

[0067] In some embodiments, when R 4 and R 5 are independently selected from unsubstituted or R 4-1 Substituted C 1-6When alkyl, the R 4-1 The number of is one or more. When there are multiple R 4-1 When the R 4-1 Can be the same or different.

[0068] In some embodiments, when R 4 and R 5 are independently selected from unsubstituted or R 4-1 Substituted C 1-6 When the C 1-6 Alkyl is C 1-4 alkyl.

[0069] In some embodiments, when R 4 is unsubstituted or R 4-2 Substituted C 1-6 When the alkoxy group is 4-2 The number of is one or more. When there are multiple R 4-2 When the R 4-2 Can be the same or different.

[0070] In some embodiments, when R 4 is unsubstituted or R 4-2 Substituted C 1-6 In the case of an alkoxy group, the C 1-6 Alkoxy is C 1-4 Alkoxy.

[0071] In some embodiments, when R 4 C 6-10 When the C 6-10 Aryl is phenyl.

[0072] In some embodiments, when R 4 C 3-10 When cycloalkyl, the C 3-10 Cycloalkyl is C 3-6 Cycloalkyl.

[0073] In some embodiments, when R 4 When it is a 4- to 10-membered heterocycloalkyl group "having one or more heteroatoms selected from N, O and S, and having 1 to 3 heteroatoms", the 4- to 10-membered heterocycloalkyl group is a 4- to 6-membered heterocycloalkyl group.

[0074] In some embodiments, when R 4-1 When it is a halogen, the halogen is fluorine.

[0075] In some embodiments, when R 4-2 When it is a halogen, the halogen is fluorine.

[0076] In some embodiments, when R4-3 ~R 4-7 Independently selected from C 1-4 When the C 1-4 The alkyl group is methyl, ethyl or n-propyl.

[0077] In some embodiments, when R 4-1-1 and R 4-1-2 Independently for C 1-4 When the C 1-4 The alkyl group is methyl, ethyl or n-propyl.

[0078] In some embodiments, when X is C 1-6 When the C 1-6 Alkyl is C 1-4 alkyl.

[0079] In some embodiments, when X is unsubstituted or R 6 Substituted C 6-10 When the group is aryl, the R 6 The number of is one or more. When there are multiple R 6 When the R 6 Can be the same or different.

[0080] In some embodiments, when X is unsubstituted or R 6 Substituted C 6-10 When the C 6-10 Aryl is phenyl.

[0081] In some embodiments, when X is C 6-10 Aryl-(C 1-4 alkyl)-, the C 6-10 Aryl-(C 1-4 Alkyl)-phenyl-(C 1-3 alkyl)-.

[0082] In some embodiments, when R 6 When it is a halogen, the halogen is fluorine, chlorine, bromine or iodine.

[0083] In some embodiments, when X is a 4- to 10-membered heterocycloalkyl group "having one or more heteroatoms selected from N, O and S, and having 1 to 3 heteroatoms", the 4- to 10-membered heterocycloalkyl group is a 4- to 6-membered heterocycloalkyl group.

[0084] In some embodiments, when X is a 5- to 10-membered heteroaryl group "having a heteroatom selected from one or more of N, O and S, and having 1 to 3 heteroatoms", the 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group.

[0085] In some embodiments, when R 7 C1-6 When the C 1-6 Alkyl is C 1-4 alkyl.

[0086] In some embodiments, when R 1-1 is unsubstituted or R 1-1-1 Substituted C 1-6 When alkyl, the R 1-1-1 The number of is 1, 2 or 3.

[0087] In some embodiments, when R 1-1 is unsubstituted or R 1-1-1 Substituted C 1-6 When the C 1-6 The alkyl group is methyl, ethyl, n-propyl or n-butyl.

[0088] In some embodiments, when R 1-1 is unsubstituted or R 1-1-2 Substituted C 3-10 When cycloalkyl, the R 1-1-2 The number of 1, 2 or 3.

[0089] In some embodiments, when R 1-1 is unsubstituted or R 1-1-2 Substituted C 3-10 When cycloalkyl, the C 3-10 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0090] In some embodiments, when R 1-1 When it is a 4- to 10-membered heteroaryl group "whose heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3", when the 4- to 10-membered heterocycloalkyl group is a pyrrolidinyl, azetidine or piperidine ring.

[0091] In some embodiments, when R 1-1 "a 4- to 10-membered heterocycloalkyl-(C 1-4 alkyl), the 4- to 10-membered heterocycloalkyl-(C 1-4 The alkyl) is pyrrolidinylmethyl, azetidinylmethyl or piperidinylmethyl.

[0092] In some embodiments, when R 1-1 When it is a 5- to 10-membered heteroaryl group "having one or more heteroatoms selected from N, O and S, and having 1 to 3 heteroatoms", the 5- to 10-membered heteroaryl group is imidazolyl or pyrazolyl.

[0093] In some embodiments, when R 1-2When it is a 5- to 10-membered heteroaryl group "having one or more heteroatoms selected from N, O and S, and having 1 to 3 heteroatoms", the 5- to 10-membered heteroaryl group is imidazolyl or pyrazolyl.

[0094] In some embodiments, when R 2-1 is unsubstituted or R 2-1-1 Substituted C 1-6 When alkyl, the R 2-1-1 The number of 1, 2 or 3.

[0095] In some embodiments, when R 2-1 is unsubstituted or R 2-1-1 Substituted C 1-6 When the C 1-6 The alkyl group is methyl, ethyl, n-propyl or n-butyl.

[0096] In some embodiments, when R 2-2 ~R 2-5 Independently selected from C 1-6 When the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0097] In some embodiments, when R 2-6 ~R 2-9 Independently selected from C 1-6 When the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0098] In some embodiments, when R 3-1 is unsubstituted or R 3-1-1 Substituted C 1-6 When alkyl, the R 3-1-1 The number of 1, 2 or 3.

[0099] In some embodiments, when R 3-1 is unsubstituted or R 3-1-1 Substituted C 1-6 When the C 1-6 The alkyl group is methyl, ethyl, n-propyl or n-butyl.

[0100] In some embodiments, when R 3-1-1 C 1-4 In the case of an alkoxy group, the C 1-4 Alkoxy is methoxy, ethoxy or n-propoxy.

[0101] In some embodiments, when R 3-1-1 C 1-4 When the halogenated alkoxy group is1-4 The haloalkoxy group is trifluoromethoxy or difluoromethoxy.

[0102] In some embodiments, when R 3-1-1 When it is a 4- to 10-membered heterocycloalkyl group "having one or more heteroatoms selected from N, O and S, and having 1 to 3 heteroatoms", the 4- to 10-membered heterocycloalkyl group is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl or azetidine.

[0103] In some embodiments, when R 3-2 ~R 3-5 Independently selected from C 1-6 When the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0104] In some embodiments, when R 3-6 ~R 3-9 Independently selected from C 1-6 When the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

[0105] In some embodiments, when A is unsubstituted or R 4 Substituted C 6-10 When the group is aryl, the R 4 The number of is 1, 2 or 3.

[0106] In some embodiments, when A is C 3-10 When cycloalkyl, the C 3-6 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0107] In some embodiments, when A is C 3-10 When the cycloalkenyl group is 3-10 Cycloalkenyl is cyclobutenyl, cyclopentenyl or cyclobutenyl.

[0108] In some embodiments, when A is unsubstituted or R 5 In the case of a substituted "heteroatom selected from one or more of N, O and S, with 1 to 3 heteroatoms" 5-10 membered heteroaryl group, the R 5 The number of is 1, 2 or 3.

[0109] In some embodiments, when A is unsubstituted or R 5When the substituted "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-3" 5-10 membered heteroaryl, the 5-10 membered heteroaryl is pyridyl, pyrimidinyl, thienyl, thiazolyl, furanyl, pyrazolyl, pyrrolyl, pyridazinyl, pyrazinyl, oxazolyl, or, imidazolyl.

[0110] In some embodiments, when R 4 and R 5 are independently selected from unsubstituted or R 4-1 Substituted C 1-6 When alkyl, the R 4-1 The number of is 1, 2 or 3.

[0111] In some embodiments, when R 4 and R 5 are independently selected from unsubstituted or R 4-1 Substituted C 1-6 When the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0112] In some embodiments, when R 4 is unsubstituted or R 4-2 Substituted C 1-6 When the alkoxy group is 4-2 The number of is 1, 2 or 3.

[0113] In some embodiments, when R 4 is unsubstituted or R 4-2 Substituted C 1-6 In the case of an alkoxy group, the C 1-6 Alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0114] In some embodiments, when R 4 C 3-10 When cycloalkyl, the C 3-10 Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0115] In some embodiments, when R 4 When it is a 4- to 10-membered heterocycloalkyl group "having a heteroatom selected from one or more of N, O and S, and having 1 to 3 heteroatoms", the 4- to 10-membered heterocycloalkyl group is morpholinyl, piperidinyl, piperazinyl, azetidine, or pyrrolidinyl.

[0116] In some embodiments, when R 4 For-NR 4-3 R 4-4 When the -NR4-3 R 4-4 is -NH2, or

[0117] In some embodiments, when R 4 -(C=O)R 4-5 When the -(C=O)R 4-5 for

[0118] In some embodiments, when R 4 -(C=O)OR 4-6 When the -(C=O)OR 4-6 is -COOH or

[0119] In some embodiments, when R 4 -O(C=O)R 4-7 When the -O(C=O)R 4-7 for

[0120] In some embodiments, when R 4 -(C=O)NR 4-8 R 4-9 When the -(C=O)NR 4-8 R 4-9 for

[0121] In some embodiments, when R 4-1 and R 4-2 Independently selected from -NR 4-1-1 R 4-1-2 When the -NR 4-1-1 R 4-1-2 is -NH2, or

[0122] In some embodiments, when X is C 1-6 When the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

[0123] In some embodiments, when X is unsubstituted or R 6 Substituted C 6-10 When the group is aryl, the R 6 The number of is 1, 2 or 3.

[0124] In some embodiments, when X is C 6-10 Aryl-(C 1-4 alkyl)-, the C 6-10 Aryl-(C 1-4alkyl)- is benzyl.

[0125] In some embodiments, when X is a 4- to 10-membered heterocycloalkyl group "having a heteroatom selected from one or more of N, O and S, and having 1 to 3 heteroatoms", the 4- to 10-membered heterocycloalkyl group is morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl or azetidine.

[0126] In some embodiments, when X is a 5- to 10-membered heteroaryl group "having a heteroatom selected from one or more of N, O and S, with 1 to 3 heteroatoms", the 5- to 10-membered heteroaryl group is pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, furanyl, pyrrolyl, oxazolyl or isoxazolyl.

[0127] In some embodiments, when R 7 C 1-6 When the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

[0128] In some embodiments, when R 1-1 For R 1-1-1 Substituted C 1-6 When alkyl, the R 1-1-1 Substituted C 1-6 The alkyl group is

[0129] In some embodiments, when R 1-1 For R 1-1-2 Substituted C 3-10 When cycloalkyl, the R 1-1-2 Substituted C 3-10 Cycloalkyl is

[0130] In some embodiments, when R 1-1 When the 4- to 10-membered heteroaryl group is a 4- to 10-membered heteroaryl group having a heteroatom selected from one or more of N, O and S and having 1 to 3 heteroatoms, the 4- to 10-membered heterocycloalkyl group is

[0131] In some embodiments, when R 1-1 "a 4- to 10-membered heterocycloalkyl-(C 1-4 alkyl), the 4- to 10-membered heterocycloalkyl-(C 1-4 Alkyl) is

[0132] In some embodiments, when R 1-1When it is a 5- to 10-membered heteroaryl group "having one or more heteroatoms selected from N, O and S, and having 1 to 3 heteroatoms", the 5- to 10-membered heteroaryl group is

[0133] In some embodiments, when R 1-2 When it is a 5- to 10-membered heteroaryl group "having one or more heteroatoms selected from N, O and S, and having 1 to 3 heteroatoms", the 5- to 10-membered heteroaryl group is

[0134] In some embodiments, when R 2-1 For R 2-1-1 Substituted C 1-6 When alkyl, the R 2-1-1 Substituted C 1-6 The alkyl group is

[0135] In some embodiments, when R 3-1 For R 3-1-1 Substituted C 1-6 When alkyl, the R 3-1-1 Substituted C 1-6 The alkyl group is

[0136] In some embodiments, when A is C 3-10 When the cycloalkenyl group is 3-10 Cycloalkenyl is

[0137] In some embodiments, when R 4 For R 4-1 Substituted C 1-6 When alkyl, the R 4-1 Substituted C 1-6 Alkyl is trifluoromethyl, difluoromethyl,

[0138] In some embodiments, when R 4 For R 4-2 Substituted C 1-6 When the alkoxy group is 4-2 Substituted C 1-6 The alkoxy group is trifluoromethoxy.

[0139] In some embodiments, when R 5 For R 4-1 Substituted C 1-6 When alkyl, the R 4-1 Substituted C 1-6 The alkyl group is trifluoromethyl.

[0140] In some embodiments, when X is unsubstituted or R 6 Substituted C 6-10 When aryl, the unsubstituted or R 6 Substituted C 6-10 Aryl

[0141] In some embodiments, when X is a 4- to 10-membered heterocycloalkyl group having a heteroatom selected from one or more of N, O and S, and having 1 to 3 heteroatoms, the 4- to 10-membered heterocycloalkyl group is

[0142] In some embodiments, when X is a 5- to 10-membered heteroaryl group "having one or more heteroatoms selected from N, O and S, and having 1 to 3 heteroatoms", the 5- to 10-membered heteroaryl group is

[0143] In some embodiments, when A is unsubstituted or R 4 Substituted C 6-10 In the case of aryl, the unsubstituted or R4-substituted C 6-10 Aryl

[0144]

[0145] In some embodiments, when A is unsubstituted or R 5 In the case of a substituted "heteroatom selected from one or more of N, O and S, with 1 to 3 heteroatoms" 5-10 membered heteroaryl group, the unsubstituted or R 5 The substituted heteroaryl is

[0146]

[0147] In some embodiments, R 1 Hydroxyl, OR 1-1 、-NHR 1-2 .

[0148] In some embodiments, R 2 is hydrogen, hydroxyl, OR 2-1 , -O(C=O)R 2-2 ,

[0149] In some embodiments, R 2-6 ~R 2-9 For hydrogen.

[0150] In some embodiments, R 1-1-1 is hydroxyl, carboxyl, or

[0151] In some embodiments, R 1-1-2 It is hydroxyl.

[0152] In some embodiments, R 2-1-1 is hydroxyl, or

[0153] In some embodiments, m is 1.

[0154] In some embodiments, n is 0 or 1.

[0155] In some embodiments, q is 1.

[0156] In some embodiments, r is 0 or 1.

[0157] In some embodiments, R 3 is hydrogen, hydroxyl, OR 3-1 , -O(C=O)R 3-2 ,

[0158] In some embodiments, R 3-6 ~R 3-9 For hydrogen.

[0159] In some embodiments, R 3-1-1 Hydroxyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, "a 4- to 10-membered heterocycloalkyl group having a heteroatom selected from one or more of N, O and S and having 1 to 3 heteroatoms".

[0160] 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- to 10-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, with 1 to 3 heteroatoms", -NR 4-3 R 4-4 、-(C=O)R 4-5 、-(C=O)OR 4-6 , -O(C=O)R 4 -7 、-(C=O)NR 4-8 R 4-9 .

[0161] In some embodiments, R 5 is halogen, unsubstituted or R 5-1Substituted C 1-6 alkyl.

[0162] In some embodiments, R 4-1 is halogen or hydroxy.

[0163] In some embodiments, R 4-7 C 1-4 alkyl.

[0164] In some embodiments, R 4-8 For hydrogen.

[0165] In some embodiments, R 4-9 For hydrogen.

[0166] In some embodiments, R 1 Hydroxyl, OR 1-1 、-NHR 1-2 ;

[0167] R 1-1 is unsubstituted or R 1-1-1 Substituted C 1-6 Alkyl, unsubstituted or R 1-1-2 Substituted C 3-10 Cycloalkyl, "heteroatoms selected from one or more of N, O and S, with 1 to 3 heteroatoms" 5-10 membered heteroaryl, heterocycloalkyl, heterocycloalkyl-(C 1-4 Alkyl)-, or The 4- to 10-membered heterocycloalkyl group is a 4- to 10-membered heterocycloalkyl group having a heteroatom selected from one or more of N, O and S and a heteroatom number of 1 to 3;

[0168] R 1-2 A 5- to 10-membered heteroaryl group having a heteroatom selected from one or more of N, O and S and having 1 to 3 heteroatoms;

[0169] R 1-1-1 Hydroxyl, carboxyl,

[0170] R 1-1-2 is hydroxyl group;

[0171] m is 1;

[0172] n is 0 or 1;

[0173] R 2 is hydrogen, hydroxyl, OR 2-1 , -O(C=O)R 2-2 ,

[0174] R 2-1 is unsubstituted or R 2-1-1Substituted C 1-6 alkyl,

[0175] R 2-1-1 For hydroxyl,

[0176] q is 1;

[0177] r is 0 or 1;

[0178] R 2-2 ~R 2-5 Independently selected from C 1-6 alkyl;

[0179] R 2-6 ~R 2-9 are independently selected from hydrogen;

[0180] R 3 is hydrogen, hydroxyl, OR 3-1 , -O(C=O)R 3-2 ,

[0181] R 3-1 is unsubstituted or R 3-1-1 Substituted C 1-6 alkyl;

[0182] R 3-1-1 Hydroxyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, "a 4- to 10-membered heterocycloalkyl group having one or more heteroatoms selected from N, O and S, and 1 to 3 heteroatoms";

[0183] R 3-2 ~R 3-5 Independently selected from C 1-6 alkyl;

[0184] R 3-6 ~R 3-9 are independently selected from hydrogen;

[0185] A is unsubstituted or R 4 Substituted C 6-10 Aryl, C 3-10 Cycloalkyl, unsubstituted or R 5 Substituted "heteroatom selected from one or more of N, O and S, with 1 to 3 heteroatoms" 5-10 membered heteroaryl, C 3-10 Cycloalkenyl, C 6-10 Aryl-(C 2-4 Alkynyl)-, C 6-10 Aryl-(C 2-4 alkenyl)-;

[0186] 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- to 10-membered heterocycloalkyl having one or more heteroatoms selected from N, O and S, with 1 to 3 heteroatoms", -NR 4-3 R 4-4 、-(C=O)R 4-5 、-(C=O)OR 4-6 , -O(C=O)R 4-7 , or, -(C=O)NR 4-8 R 4-9 ;

[0187] R 5 is halogen, unsubstituted or R 4-1 Substituted C 1-6 alkyl;

[0188] R 4-1 is halogen or hydroxyl;

[0189] R 4-2 is a halogen;

[0190] R 4-3 ~R 4-6 are independently selected from hydrogen or C 1-4 alkyl;

[0191] R 4-7 C 1-4 alkyl;

[0192] R 4-8 is hydrogen;

[0193] R 4-9 is hydrogen;

[0194] X is hydrogen, C 1-6 Alkyl, unsubstituted or R 6 Substituted C 6-10 Aryl, C 6-10 Aryl-(C 1-4 alkyl)-, "heteroatoms selected from one or more of N, O and S, with 1-3 heteroatoms" 4-10 membered heterocycloalkyl, "heteroatoms selected from one or more of N, O and S, with 1-3 heteroatoms" 5-10 membered heteroaryl;

[0195] R 6 is a halogen;

[0196] R 7 is hydrogen or C1-6 alkyl.

[0197] In some embodiments, R 1 Hydroxyl, OR 1-1 、-NHR 1-2 ;

[0198] R 1-1 is unsubstituted or R 1-1-1 Substituted C 1-6 Alkyl, unsubstituted or R 1-1-2 Substituted C 3-10 Cycloalkyl, "heteroatoms selected from one or more of N, O and S, with 1 to 3 heteroatoms" 5-10 membered heteroaryl, heterocycloalkyl, heterocycloalkyl-(C 1-4 alkyl)-, The 4- to 10-membered heterocycloalkyl group is a 4- to 10-membered heterocycloalkyl group having a heteroatom selected from one or more of N, O and S and a heteroatom number of 1 to 3;

[0199] R 1-2 A 5- to 10-membered heteroaryl group having a heteroatom selected from one or more of N, O and S and having 1 to 3 heteroatoms;

[0200] R 1-1-1 Hydroxyl, carboxyl,

[0201] R 1-1-2 is hydroxyl group;

[0202] m is 1;

[0203] n is 0 or 1;

[0204] R 2 Hydroxyl, OR 2-1 , -O(C=O)R 2-2 ,

[0205] R 2-1 is unsubstituted or R 2-1-1 Substituted C 1-6 alkyl,

[0206] R 2-1-1 For hydroxyl,

[0207] q is 1;

[0208] r is 0 or 1;

[0209] R 2-2 ~R 2-5 Independently selected from C 1-6 alkyl;

[0210] R 2-6 ~R 2-9 are independently selected from hydrogen;

[0211] R 3 Hydroxyl, OR 3-1 , -O(C=O)R 3-2 ,

[0212] R 3-1 is unsubstituted or R 3-1-1 Substituted C 1-6 alkyl;

[0213] R 3-1-1 Hydroxyl, "a 4- to 10-membered heterocycloalkyl group having one or more heteroatoms selected from N, O and S, and having 1 to 3 heteroatoms";

[0214] R 3-2 ~R 3-5 Independently selected from C 1-6 alkyl;

[0215] R 3-6 ~R 3-9 are independently selected from hydrogen;

[0216] A is unsubstituted or R 4 Substituted C 6-10 Aryl, C 3-10 Cycloalkyl, unsubstituted or R 5 Substituted "heteroatom selected from one or more of N, O and S, with 1 to 3 heteroatoms" 5-10 membered heteroaryl, C 3-10 Cycloalkenyl, C 6-10 Aryl-(C 2-4 Alkynyl)-, C 6-10 Aryl-(C 2-4 alkenyl)-;

[0217] R 4 is halogen, nitro, hydroxyl, 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 ;

[0218] R 5 is halogen, unsubstituted or R 4-1 Substituted C 1-6 alkyl;

[0219] R 4-1is hydroxyl or halogen;

[0220] R 4-2 is a halogen;

[0221] R 4-6 is hydrogen or C 1-4 alkyl;

[0222] R 4-7 C 1-4 alkyl;

[0223] X is hydrogen, C 1-6 Alkyl, "a heteroatom selected from one or more of N, O and S, with 1 to 3 heteroatoms" 4-10 membered heterocycloalkyl, "a heteroatom selected from one or more of N, O and S, with 1 to 3 heteroatoms" 5-10 membered heteroaryl;

[0224] R 7 For hydrogen.

[0225] In some embodiments, the quinazolinone compound having the structure shown in Formula I or its pharmaceutically acceptable salt or isomer is any of the following:

[0226]

[0227]

[0228]

[0229] The method for preparing the quinazolinone compound having the structure shown in general formula I or its pharmaceutically acceptable salt or isomer,

[0230] Method 1: Compound II and compound III are reacted in a solvent under the action of a catalyst to generate compound I-1.

[0231]

[0232] Method 2: Compound IV reacts with compounds V and VI in a solvent to generate compound I-2;

[0233]

[0234] Among them, R 1 , R 2 , R 3 , R 7 , X and A are defined as above.

[0235] A pharmaceutical composition comprises a therapeutically effective amount of one or more quinazolinone compounds having a structure as shown in general formula I or a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier or excipient.

[0236] The use of the quinazolinone compound having the structure shown in the general formula I or its pharmaceutically acceptable salt or isomer in the preparation of 3C-like cysteine ​​protease inhibitors or in the preparation of drugs for treating and / or preventing viral infectious diseases. The viruses include but are not limited to Middle East respiratory syndrome-related coronavirus (MERS-CoV), severe acute respiratory syndrome-related coronavirus-1 (SARS-CoV-1), influenza A virus, influenza B virus, severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2), Spanish flu virus, arenavirus, bunyavirus, rabies virus, avian influenza virus, poliovirus, rhinovirus, adenovirus, Ebola virus, enterovirus, hepatitis A virus, hepatitis C virus, hepatitis E virus, enterovirus, HIV virus, echovirus, filovirus, measles virus, yellow fever virus, Japanese encephalitis virus, West Nile virus, Newcastle disease virus, RS virus, vesicular stomatitis virus, mumps virus, dengue virus, coxsackievirus, rotavirus or tobacco mosaic virus.

[0237] The use of the pharmaceutical composition in preparing a 3C-like cysteine ​​protease inhibitor or in preparing a drug for treating and / or preventing viral infectious diseases. The viruses include but are not limited to Middle East respiratory syndrome-related coronavirus (MERS-CoV), severe acute respiratory syndrome-related coronavirus-1 (SARS-CoV-1), influenza A virus, influenza B virus, severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2), Spanish flu virus, arenavirus, bunyavirus, rabies virus, avian influenza virus, poliovirus, rhinovirus, adenovirus, Ebola virus, enterovirus, hepatitis A virus, hepatitis C virus, hepatitis E virus, enterovirus, HIV virus, echovirus, filovirus, measles virus, yellow fever virus, Japanese encephalitis virus, West Nile virus, Newcastle disease virus, RS virus, vesicular stomatitis virus, mumps virus, dengue virus, coxsackievirus, rotavirus or tobacco mosaic virus.

[0238] The pharmaceutical excipients can be those widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following excipients: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0239] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0240] The pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be a controlled release or delayed release dosage form (e.g., liposomes or microspheres). Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of preparations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0241] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered by the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonate or bicarbonate), phosphoric acid (forming phosphate, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid (forming sulfate or bisulfate), hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid. Acids such as tartaric acid and methanesulfonic acid; organic acid salts also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and can be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubility in polar solvents.

[0242] The "pharmaceutically acceptable salts" of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0243] The term "isomers" refers to compounds that have the same chemical formula but different arrangements of the atoms.

[0244] The term "metabolite" refers to a pharmaceutically active product produced by the in vivo metabolism of a compound of Formula I or a salt thereof. Such a product may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a process of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain a metabolite thereof.

[0245] Metabolites are typically identified by preparing radiolabeled isotopes of the compounds of the invention, administering them parenterally to animals, such as rats, mice, guinea pigs, monkeys, or humans, at detectable doses (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 the conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies that can bind to antigenic epitopes present in the metabolites). The metabolite structure is determined in a conventional manner, for example, by MS, LC / MS or NMR analysis. Generally, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. As long as the metabolite products are not otherwise not found in vivo, they can be used in assays for therapeutic dosing of the compounds of the invention. The compounds of the invention may contain non-natural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds may be labeled with radioisotopes, 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 included within the scope of the present invention.

[0246] In addition to the form of salts, the compounds provided by the present invention also exist in the form of prodrugs. The prodrugs of the compounds described herein are easily chemically changed under physiological conditions to be converted into the compounds of the present invention. Any compound that can be converted in vivo to provide a bioactive substance (i.e., a compound shown in Formula I) is a prodrug within the scope and spirit of the present invention. For example, a carboxyl-containing compound can form a physiologically hydrolyzable ester, which acts as a prodrug by being hydrolyzed in vivo to obtain the compound shown in Formula I itself. The prodrug is preferably administered orally, because hydrolysis occurs mainly under the influence of digestive enzymes in many cases. When the ester itself is active or hydrolysis occurs in the blood, parenteral administration can be used.

[0247] Those skilled in the art will appreciate that, according to the conventions used in the art, the structural formulas used in this application to describe groups It means that the corresponding group is connected with other fragments and groups in the compound shown in formula I through this site.

[0248] The "substitution" in the present invention may be one or more. When there are multiple "substitutions", the "substitutions" may be the same or different.

[0249] The term "plurality" may include, 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 a specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, and the like. The term "alkoxy" refers to the group -OR Y , where R Y is an alkyl group as defined above. The term "cycloalkyl" refers to a saturated monocyclic or polycyclic alkyl group. The monocyclic cycloalkyl group preferably has 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 group is saturated and may be a bicyclic or tricyclic cycloalkyl group having 4 to 10 carbon atoms. The term "heterocycloalkyl" refers to a saturated monocyclic or polycyclic group having a heteroatom. The monocyclic ring preferably contains 1, 2 or 3 4-6 membered saturated monocyclic heterocyclic alkyl groups independently selected from N, O and S, and examples thereof include but are not limited to: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, dioxolanyl, dioxanyl, etc. The polycyclic ring preferably contains 1, 2 or 3 8-10 membered saturated polycyclic heterocyclic alkyl groups independently selected from N, O and S on at least one ring, and may be bicyclic or tricyclic, and examples thereof include but are not limited to octahydropyrrolo[1,2-a]pyrazinyl and (1R,5S)-3,8-diazabicyclo[3.2.1]octyl. The term "aryl" refers to an aromatic group having a specified number of carbon atoms, preferably a monocyclic, bicyclic or tricyclic aromatic group, and when it is a bicyclic or tricyclic aromatic group, each ring satisfies the Huckel rule. 6-10The term "aryl" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably an aromatic 5-6 membered monocyclic ring or a 9-10 membered bicyclic ring containing 1, 2 or 3 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-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazolyl, dithiazolyl, tetrazolyl, pyridyl, pyranyl, thiopyranyl, diazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl or tetrazinyl. The 9-10 membered bicyclic ring includes but is not limited to benzimidazolyl, indolyl, indazolyl, benzofuranyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolyl, isoquinolyl. The term "cycloalkenyl" refers to a monocyclic or polycyclic alkyl group containing at least one double bond. The monocyclic cycloalkenyl group preferably has an incompletely saturated cyclic alkyl group containing a double bond with 4 to 7 ring carbon atoms, more preferably 4-6 carbon atoms, such as cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl. At least one ring of the polycyclic cycloalkyl group contains a double bond, which may be a bicyclic or tricyclic cycloalkenyl group with 4 to 10 carbon atoms.

[0250] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0251] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0252] 1. The quinazolinone of the present invention has good inhibitory activity against 3C-like cysteine ​​proteases. 2. The compounds of the present invention have good therapeutic effects on viral infectious diseases. 3. The compounds of the present invention have less toxic and side effects. DETAILED DESCRIPTION

[0253] Example 1 Synthesis of Compound S1

[0254]

[0255] Step 1: Synthesis of compound 2

[0256] Compound 1 (25 g) was dissolved in glacial acetic acid (110 ml), and a mixed solution of glacial acetic acid and fuming nitric acid (110 ml + 220 ml) was slowly added dropwise to the above solution at 0°C. After the addition was complete, the mixture was reacted at 0°C for 2 h. The above reaction was poured into ice water and filtered to obtain a light yellow solid 2, which was directly used in the next step without purification.1 H NMR (300MHz, CDCl3) δ10.22 (s, 1H), 7.28 (s, 1H), 3.97 (s, 9H).

[0257] Step 2: Synthesis of compound 3

[0258] Compound 2 (15 g, 62 mmol) was dissolved in ethanol / water (132 ml / 47 ml), FeSO4·7H2O (3.8 g) was added to the above solution, and iron powder (38 g) was added under vigorous mechanical stirring. The mixture was heated under reflux for 4 h. After the reaction was completed, the mixture was filtered, the solvent was evaporated, and the mixture was separated and purified by column chromatography to obtain a light yellow solid 3 (11 g, 85%). 1 H 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).

[0259] Step 3: Synthesis of compound 4

[0260] At 0-5°C, compound 3 (5.32 g, 25.2 mmol) was dissolved in 20% HCl (50 ml), and 16 ml of an aqueous solution of sodium nitrite (1.9 g) was added to the above solution, and mechanical stirring was performed for 15 min. Then, 50 ml of an aqueous solution of potassium iodide (20 g) was slowly added dropwise to the above solution, and the reaction was allowed to proceed overnight. After the reaction was completed, Na2S2O3 was added to quench the reaction, and chloroform was extracted 3 times (50 ml×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain a light yellow solid 4 (6.79 g, 84%). 1 H NMR (300MHz, CDCl3) δ=10.05 (s, 1H), 7.29 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.87 (s, 3H).

[0261] Step 4: Synthesis of compound 5

[0262] Compound 4 (5 g, 15.58 mmol) and aminosulfonic acid (1.8 g, 18.70 mmol) were suspended in a water / acetonitrile mixed solvent, and sodium chlorite (3.5 g, 38.95 mmol) was added in batches at 0°C. The mixture was transferred to room temperature for 2 h. After the reaction was completed, saturated Na2S2O3 was added to quench the reaction, and EA was added for extraction 3 times (50 ml×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain a white solid 5 (4.2 g, 80%). 1H NMR (300MHz, CDCl3) δ8.91 (s, 1H), 7.11 (s, 1H), 3.90 (s, 3H), 3.85 (s, 6H).

[0263] Step 5: Synthesis of compound 7

[0264] 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), protected by nitrogen, and reacted overnight at room temperature. Saturated ammonium chloride solution (30 ml) was added, stirred for 30 min, and filtered to obtain white solid 7 (147 mg, 80%). 1 H 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).

[0265] Step 6: Synthesis of compound S1

[0266] Compound 7 (100 mg, 0.32 mmol) was suspended in anhydrous DCM (2 ml), and a dichloromethane solution of BBr3 (1 M, 3 ml) was slowly added dropwise at -10°C, and the mixture was reacted overnight at room temperature. After the reaction was completed, glacial methanol was slowly added dropwise to quench the reaction, the methanol was evaporated, DCM was added, and the mixture was stirred at room temperature for 30 min, and the target compound S1 (77 mg, 90%) was obtained by suction filtration. 1 H 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).

[0267] The synthesis of compounds S2 to S68 in the following Examples S2 to S68 refers to the synthesis method of Example 1, and only the corresponding raw materials need to be replaced.

[0268] Example 2: Synthesis of Compound S2

[0269]

[0270] 1H NMR (300MHz, DMSO-d6) δ 12.48 (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).

[0271] Example 3: Synthesis of Compound S3

[0272]

[0273] 1 H 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).

[0274] Example 4: Synthesis of Compound S4

[0275]

[0276] 1 H 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).

[0277] Example 5: Synthesis of Compound S5

[0278]

[0279] 1 H 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).

[0280] Example 6: Synthesis of Compound S6

[0281]

[0282] 1H NMR (300MHz, DMSO-d6) δ 12.51 (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).

[0283] Example 7: Synthesis of Compound S7

[0284]

[0285] 1 H 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).

[0286] Example 8: Synthesis of Compound S8

[0287]

[0288] 1 H 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).

[0289] Example 9: Synthesis of Compound S9

[0290]

[0291] 1 H 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).

[0292] Example 10: Synthesis of Compound S10

[0293]

[0294] 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).

[0295] Example 11: Synthesis of Compound S11

[0296]

[0297] 1 H NMR (300MHz, DMSO-d6) δ 12.37 (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).

[0298] Example 12: Synthesis of Compound S12

[0299]

[0300] 1 H NMR (300MHz, DMSO-d6) δ 12.47 (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).

[0301] Example 13: Synthesis of Compound S13

[0302]

[0303] 1 H 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).

[0304] Example 14: Synthesis of Compound S14

[0305]

[0306] 1 H NMR (300MHz, DMSO-d6) δ 12.49 (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).

[0307] Example 15: Synthesis of Compound S15

[0308]

[0309] 1 H NMR (300MHz, DMSO-d6) δ 12.46 (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).

[0310] Example 16: Synthesis of Compound S16

[0311]

[0312] 1 H 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).

[0313] Example 17: Synthesis of Compound S17

[0314]

[0315] 1 H 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).

[0316] Example 18: Synthesis of Compound S18

[0317]

[0318] 1 H 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).

[0319] Example 19: Synthesis of Compound S19

[0320]

[0321] 1 H NMR (300MHz, DMSO-d6) δ 12.47 (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).

[0322] Example 20: Synthesis of Compound S20

[0323]

[0324] 1 H 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).

[0325] Example 21: Synthesis of Compound S21

[0326]

[0327] 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).

[0328] Example 22: Synthesis of Compound S22

[0329]

[0330] 1 H NMR (300MHz, DMSO-d6) δ 12.49 (s, 1H), 11.53 (s, 1H), 10.26 (s, 1H), 8.82 (s, 1H), δ 8.40-8.32 (m, 2H), 8.17-8.10 (m, 2H), 6.55 (s, 1H).

[0331] Example 23: Synthesis of Compound S23

[0332]

[0333] 1 H NMR (300MHz, DMSO-d6) δ 12.44 (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).

[0334] Example 24: Synthesis of Compound S24

[0335]

[0336] 1 H NMR (300MHz, DMSO-d6) δ12.51(s, 1H), 11.52(s, 1H), 10.28(s, 1H), 8.87(s, 1H), 7.89(d d, 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).

[0337] Example 25: Synthesis of Compound S25

[0338]

[0339] 1 H 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).

[0340] Example 26: Synthesis of Compound S26

[0341]

[0342] 1 H 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).

[0343] Example 27: Synthesis of Compound S27

[0344]

[0345] 1 H 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 ​​(d dd, 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).

[0346] Example 28: Synthesis of Compound S28

[0347]

[0348] 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 (d dd, 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).

[0349] Example 29: Synthesis of Compound S29

[0350]

[0351] 1 H NMR (300MHz, DMSO-d6) δ12.47 (s, 1H), 11.53 (s, 1H), 10.23 (s, 1H), 8.86 (s, 1H), 7.86-7.8 0 (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).

[0352] Example 30: Synthesis of Compound S30

[0353]

[0354] 1 H NMR (300MHz, DMSO-d6) δ 12.43 (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).

[0355] Example 31: Synthesis of Compound S31

[0356]

[0357] 1 H 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).

[0358] Example 32: Synthesis of Compound S32

[0359]

[0360] 1 H NMR (300MHz, DMSO-d6) δ 12.45 (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).

[0361] Example 33: Synthesis of Compound S33

[0362]

[0363] 1 H 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).

[0364] Example 34: Synthesis of Compound S34

[0365]

[0366] 1 H NMR (300MHz, DMSO-d6) δ12.43 (s, 1H), 11.44 (s, 1H), 10.24 (s, 1H), 8.84 (s, 1 H), 7.77 (dd, J=7.7, 1.7Hz, 1H), 7.43-7.25 (m, 3H), 6.56 (s, 1H), 1.31 (s, 9H).

[0367] Example 35: Synthesis of Compound S35

[0368]

[0369] 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).

[0370] Example 36: Synthesis of Compound S36

[0371]

[0372] 1 H 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).

[0373] Example 37: Synthesis of Compound S37

[0374]

[0375] 1 H 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).

[0376] Example 38: Synthesis of Compound S38

[0377]

[0378] 1 H NMR (300MHz, DMSO-d6) δ 12.43 (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).

[0379] Example 39: Synthesis of Compound S39

[0380]

[0381] 1 H NMR (300MHz, DMSO-d6) δ 12.43 (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).

[0382] Example 40: Synthesis of Compound S40

[0383]

[0384] 1 H 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).

[0385] Example 41: Synthesis of Compound S41

[0386]

[0387] 1 H 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).

[0388] Example 42: Synthesis of Compound S42

[0389]

[0390] 1 H 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).

[0391] Example 43: Synthesis of Compound S43

[0392]

[0393] 1 H 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).

[0394] Example 44: Synthesis of Compound S44

[0395]

[0396] 1 H 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).

[0397] Example 45: Synthesis of Compound S45

[0398]

[0399] 1 H 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).

[0400] Example 46: Synthesis of Compound S46

[0401]

[0402] 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).

[0403] Example 47: Synthesis of Compound S47

[0404]

[0405] 1 H 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).

[0406] Example 48: Synthesis of Compound S48

[0407]

[0408] 1 H 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).

[0409] Example 49: Synthesis of Compound S49

[0410]

[0411] 1 H NMR (300MHz, DMSO-d6) δ 12.51 (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).

[0412] Example 50: Synthesis of Compound S50

[0413]

[0414] 1 H 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).

[0415] Example 51: Synthesis of Compound S51

[0416]

[0417] 1 H 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).

[0418] Example 52: Synthesis of Compound S52

[0419]

[0420] 1 H NMR (300MHz, DMSO-d6) δ 12.48 (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).

[0421] Example 53: Synthesis of Compound S53

[0422]

[0423] 1 H 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).

[0424] Example 54: Synthesis of Compound S54

[0425]

[0426] 1 H NMR (300MHz, DMSO-d6) δ 12.44 (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).

[0427] Example 55: Synthesis of Compound S55

[0428]

[0429] 1 H NMR (300MHz, DMSO-d6) δ 12.44 (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).

[0430] Example 56: Synthesis of Compound S56

[0431]

[0432] 1 H 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).

[0433] Example 57: Synthesis of Compound S57

[0434]

[0435] 1 H NMR (300MHz, DMSO-d6) δ 12.50 (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).

[0436] Example 58: Synthesis of Compound S58

[0437]

[0438] 1 H 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).

[0439] Example 59: Synthesis of Compound S59

[0440]

[0441] 1 H 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).

[0442] Example 60: Synthesis of Compound S60

[0443]

[0444] 1 H 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).

[0445] Example 61: Synthesis of Compound S61

[0446]

[0447] 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).

[0448] Example 62: Synthesis of Compound S62

[0449]

[0450] 1 H 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).

[0451] Example 63: Synthesis of Compound S63

[0452]

[0453] 1 H NMR (300MHz, DMSO-d6) δ 12.51 (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).

[0454] Example 64: Synthesis of Compound S64

[0455]

[0456] 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).

[0457] Example 65: Synthesis of Compound S65

[0458]

[0459] 1 H 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).

[0460] Example 66: Synthesis of Compound S66

[0461]

[0462] 1 H 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), 7.37-7.2 5 (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).

[0463] Example 67: Synthesis of Compound S67

[0464]

[0465] 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).

[0466] Example 68: Synthesis of Compound S68

[0467]

[0468] 1 H 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).

[0469] Example 69: Synthesis of Compound S69

[0470]

[0471] Step 1: Synthesis of compound 9

[0472] Compound 8 (10 g, 47.2 mmol) was added in batches to 90 ml of concentrated nitric acid (68%-70%) at 0°C, stirred at 0°C for 30 min, 500 ml of ice water was added to the above solution, stirred at 0°C for 1 h, and filtered to obtain a light yellow solid 9 (8.4 g, 69%), which was directly used in the next step without purification. 1H NMR (CDCl3, 300 MHz) δ9.52 (s, 1H), 7.55 (s, 1H), 4.15-3.98 (s, 9H).

[0473] Step 2: Synthesis of compound 10

[0474] Compound 9 (8 g, 31.1 mmol) was dissolved in ethanol / water (66 ml / 25 ml), FeSO4·7H2O (2.0 g) was added to the above solution, and iron powder (19 g) was added under vigorous mechanical stirring. The mixture was heated under reflux for 4 h. After the reaction was completed, the mixture was filtered, the solvent was evaporated, and the mixture was purified by column chromatography to obtain a light yellow solid 10 (6.3 g, 89%). 1H NMR (300MHz, CDCl3) δ7.53 (s, 1H), 3.89-3.83 (s, 6H), 3.63 (s, 3H).

[0475] Step 3: Synthesis of compound 11

[0476] 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, nitrogen was protected, and the temperature was raised to 70°C for reaction for 2 h. Aniline (1.3 ml, 14 mmol) was added dropwise to the above reaction solution, and the reaction was carried out at 70°C overnight. After the reaction was complete, the mixture was cooled to room temperature, the solvent was evaporated, ethyl acetate was added to dissolve the residue, and the mixture was washed with 3N hydrochloric acid solution (1×50 ml), washed with brine (2×50 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain compound 11 (2.3 g, 50%). 1 H 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).

[0477] Step 3: Synthesis of compound S69

[0478] Compound 11 (200 mg, 0.52 mmol) was suspended in anhydrous DCM (2 ml), and BBr3 / DCM solution (4.7 ml, 4.7 mmol) was slowly added dropwise to the suspension at -10°C. The mixture was allowed to react overnight at -10°C. After the reaction was complete, icy methanol was added to quench the reaction, the mixture was concentrated, DCM was added, and the mixture was stirred at room temperature for 30 min. The target compound S69 (162 mg, 90%) was obtained by suction filtration. 1 HNMR (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).

[0479] The synthesis of compounds S70-S80 in the following Examples S70-S80 can refer to the synthesis method of Example 69, except that only the corresponding raw materials need to be replaced.

[0480] Example 70: Synthesis of Compound S71

[0481]

[0482] 1 H 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).

[0483] Example 71: Synthesis of Compound S71

[0484]

[0485] 1 H 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).

[0486] Example 72: Synthesis of Compound S72

[0487]

[0488] 1 H 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, 1 H), 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).

[0489] Example 73: Synthesis of Compound S73

[0490]

[0491] 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).

[0492] Example 74: Synthesis of Compound S74

[0493]

[0494] 1 H 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).

[0495] Example 75: Synthesis of Compound S75

[0496]

[0497] 1 H 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).

[0498] Example 76: Synthesis of Compound S76

[0499]

[0500] 1 H NMR (300MHz, DMSO-d6) δ12..51(s, 1H), 11.58(s, 1H), 10.31(s, 1H), 8.84(s, 1 H), 7.76-7.68 (m, 2H), 7.52-7.42 (m, 4H), 6.54 (s, 1H), 6.39 (d, J=4.4Hz, 1H).

[0501] Example 77: Synthesis of Compound S77

[0502]

[0503] 1 H NMR (300MHz, DMSO-d6) δ11.52 (s, 1H), 10.25 (s, 1H), 8.80 (s, 1H), 8.85 (d, J=1.8H z, 1H), 7.75-7.67 (m, 2H), 7.52-7.42 (m, 3H), 6.60 (d, J=2.0Hz, 1H), 6.56 (s, 1H).

[0504] Example 78: Synthesis of Compound S78

[0505]

[0506] 1 H NMR (300MHz, DMSO-d6) δ12.51 (s, 1H), 11.50 (s, 1H), 10.27 (s, 1H), 8.80 (s, 1 H), 7.75-7.68 (m, 2H), 7.52-7.42 (m, 4H), 6.54 (s, 1H), 6.39 (d, J=4.4Hz, 1H).

[0507] Example 79: Synthesis of Compound S79

[0508]

[0509] 1 H 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).

[0510] Example 80: Synthesis of Compound S80

[0511]

[0512] 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).

[0513] Example 81: Synthesis of Compound 12

[0514]

[0515] Step 1: Synthesis of compound 12

[0516] Add dichlorodiphenylmethane (18 g, 52.5 mmol) to a solution of compound S1 (9.45 g, 35 mmol) in diphenyl ether (200 ml), heat to 175°C, stop the reaction after the reaction is complete, cool to room temperature, add petroleum ether (1000 ml), filter to obtain a filter cake, and further separate and purify by column chromatography to obtain compound 12 (12.9 g, 85%). 1 H NMR (300MHz, Chloroform-d) δ12.99 (s, 1H), 8.16-8.10 (m, 2H), 7.64-7.58 (m, 4H), 7.5 7-7.50(m, 2H), 7.54-7.44(m, 1H), 7.42-7.34(m, 4H), 7.38-7.28(m, 2H), 6.92(s, 1H).

[0517] Step 2: Synthesis of compound 13

[0518] Compound 12 (500 mg, 1.15 mmol) was dissolved in acetone (10 ml), and methyl bromoacetate (0.13 ml, 1.38 mmol) and potassium carbonate (476 mg, 3.45 mmol) were added in sequence, and the mixture was heated under reflux to react overnight. After the reaction was complete, the reaction was stopped, cooled to room temperature, the solvent was evaporated, 5 ml of water was added to the reaction residue, and DCM (3×10 ml) was used for extraction. The organic phases were combined, washed with saturated brine (1×10 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain compound 13 (518 mg, 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).

[0519] Step 3: Synthesis of compound 14

[0520] Compound 13 (506 mg, 1 mmol) was dissolved in methanol (5 ml), and sodium hydroxide aqueous solution (1 M, 2.0 ml) was added, and stirred at room temperature for 2 h. After the reaction was complete, the pH was adjusted to 2-3 with dilute hydrochloric acid at 0°C, and compound 14 was obtained by suction filtration, which was directly used in the next step without purification.

[0521] Step 4: Synthesis of compound S81

[0522] Compound 14 (400 mg, 0.81 mmol) was dissolved in ethanol (30 ml), Pd / C (40 mg, 10%) was added, and the mixture was reacted for 12 h under the action of hydrogen. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the mixture was purified by column chromatography to obtain compound S81. 1 H 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).

[0523] The synthesis of compounds S82 to S88 in the following Examples S82 to S88 refers to the synthesis method of Example 81, and only the corresponding raw materials need to be replaced.

[0524] Example 82: Synthesis of Compound S82

[0525]

[0526] 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 (d dd, 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).

[0527] Example 83: Synthesis of Compound S83

[0528]

[0529] 1 H 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).

[0530] Example 84: Synthesis of Compound S84

[0531]

[0532] 1 H 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).

[0533] Example 85: Synthesis of Compound S85

[0534]

[0535] 1 H 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).

[0536] Example 86: Synthesis of Compound S86

[0537]

[0538] 1 H NMR (300MHz, DMSO-d6) δ12.47 (s, 1H), 10.30 (s, 1H), 8.79 (s, 1H), 8.16-8.10 (m, 2H), 7.58-7.5 1 (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).

[0539] Example 87: Synthesis of Compound S87

[0540]

[0541] 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).

[0542] Example 88: Synthesis of Compound S88

[0543]

[0544] 1 H 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).

[0545] Example 89: Synthesis of Compound S89

[0546]

[0547] 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).

[0548] Example 90: Synthesis of Compound S90

[0549]

[0550] 1 H 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).

[0551] Example 91: Synthesis of Compound S91

[0552]

[0553] 1 H 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).

[0554] Example 92: Synthesis of Compound S92

[0555]

[0556] 1 H 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).

[0557] Example 93: Synthesis of Compound S93

[0558]

[0559] Step 1: Synthesis of compound 15

[0560] Compound S1 (9.45 g, 35 mmol) was dissolved in DMF (80 ml), and benzyl bromide (5.4 ml, 45.5 mmol) and potassium carbonate (7.24 mg, 52.5 mmol) were added, and the mixture was reacted overnight at room temperature. After the reaction was complete, the reaction was stopped, ethyl acetate (300 ml) was added, and the mixture was washed with water (3×100 ml), washed with saturated brine (1×100 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain compound 15 (10.1 g, 80%). 1 H 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)

[0561] Step 2: Synthesis of compound 16

[0562] Compound 15 (500 mg, 1.39 mmol) was dissolved in DMF (5 ml), and 2-iodoethanol (287 mg, 1.67 mmol) and potassium carbonate (288 mg, 2.1 mmol) were added in sequence, and the mixture was reacted overnight at room temperature. After the reaction was complete, water (10 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3×10 ml), washed with saturated brine (1×10 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain compound 16 (421 mg, 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).

[0563] Step 3: Synthesis of compound S93

[0564] Compound 16 (400 mg, 1 mmol) was dissolved in ethanol (10 ml), Pd / C (40 mg, 10%) was added, and the mixture was reacted for 8 h under the action of hydrogen. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the mixture was purified by column chromatography to obtain compound S89 (279 mg, 89%). 1 HNMR (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).

[0565] The synthesis of compounds S94 to S104 in the following Examples S94 to S104 can refer to the synthesis method of Example 93, and only the corresponding raw materials need to be replaced.

[0566] Example 94: Synthesis of Compound S94

[0567]

[0568] 1 H 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).

[0569] Example 95: Synthesis of Compound S95

[0570]

[0571] 1 H 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).

[0572] Example 96: Synthesis of Compound S96

[0573]

[0574] 1 H 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).

[0575] Example 97: Synthesis of Compound S97

[0576]

[0577] 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).

[0578] Example 98: Synthesis of Compound S98

[0579]

[0580] 1 H 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).

[0581] Example 99: Synthesis of Compound S99

[0582]

[0583] 1 H 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).

[0584] Example 100: Synthesis of Compound S100

[0585]

[0586] 1 H 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).

[0587] Example 101: Synthesis of Compound S101

[0588]

[0589] 1 H 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).

[0590] Example 102: Synthesis of Compound S102

[0591]

[0592] 1 H 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).

[0593] Example 103: Synthesis of Compound S103

[0594]

[0595] 1 H NMR (300MHz, DMSO-d6) δ12.41 (s, 1H), 11.53 (s, 1H), 10.38 (s, 1H), 8.16-8.1 0 (m, 2H), 7.58-7.44 (m, 3H), 6.59 (s, 1H), 6.14 (d, J=8.6Hz, 2H), 4.20 (s, 2H).

[0596] Example 104: Synthesis of Compound S104

[0597]

[0598] 1 H NMR (300MHz, DMSO-d6) δ 12.43 (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).

[0599] Example 105: Synthesis of Compound S105

[0600]

[0601] Step 1: Synthesis of compound 17

[0602] The 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°C, and the mixture was transferred to room temperature. After the reaction was complete, the reaction was stopped, ice water was added to quench the reaction, and the filter cake was filtered and dried to obtain compound 17 (3.76 g, 95%), which was directly used for the next step without purification.

[0603] Step 2: Synthesis of compound 18

[0604] Compound 17 (3 g, 7.58 mmol) was dissolved in anhydrous acetone (30 ml), potassium carbonate (7.3 g, 53 mmol) and benzyl bromide (1.6 g, 9.1 mmol) were added, and the mixture was refluxed for 6 h. After the reaction was complete, the reaction was stopped, the mixture was cooled to room temperature, the solvent was evaporated, water (50 ml) was added, and the mixture was extracted with ethyl acetate (3×50 ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 18 (2.4 g, 70%). 1 H 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).

[0605] Step 3: Synthesis of compound 19

[0606] Compound 19 (2.4 g, 5.41 mmol) was dissolved in ethanol (50 ml), Pd / C (24 mg, 10%) was added, and the mixture was reacted for 8 h under the action of hydrogen. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the mixture was purified by column chromatography to obtain compound 19 (1.5 mg, 80%). 1 H NMR (300MHz, DMSO-d6) δ12.88 (s, 1H), 8.99 (s, 1H), 6.81 (s, 1H), 2.39 (s, 3H), 2.29 (s, 3H).

[0607] Step 4: Synthesis of compound 20

[0608] 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-morpholine)ethyl bromide (1 g, 5.2 mmol) and potassium iodide (17 mg, 0.1 mmol) were added. The temperature was raised to 60°C, and after the reaction was complete, the reaction was stopped, cooled to room temperature, and water (30 ml) was added to quench the reaction, and extracted with ethyl acetate (3×30 ml), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain compound 20 (2.0 g, 65%). 1 H 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).

[0609] Step 5: Synthesis of compound S105

[0610] Compound 20 (200 mg, 0.43 mmol) was dissolved in methanol (2 ml), potassium carbonate (88.7 mg, 0.64 mmol) was added, and the mixture was reacted at room temperature. After the reaction was complete, dilute hydrochloric acid was added to adjust the pH to 2-3, and the mixture was filtered, the filter cake was washed with water, and the filter cake was dried to obtain compound S101 (165 mg, 90%). 1 H 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).

[0611] The synthesis of compounds S106 to S1110 in the following Examples S106 to S110 can refer to the synthesis method of Example 105, except that only the corresponding raw materials need to be replaced.

[0612] Example 106: Synthesis of Compound S106

[0613]

[0614] 1 H NMR (300MHz, DMSO-d6) δ12.49 (s, 1H), 11.54 (s, 1H), 8.81 (s, 1H), 8.16-8.10 (m, 2 H), 7.58-7.52(m, 2H), 7.55-7.44(m, 1H), 6.80(s, 1H), 6.10(s, 2H), 2.11(s, 3H).

[0615] Example 107: Synthesis of Compound S107

[0616]

[0617] 1 H 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).

[0618] Example 108: Synthesis of Compound S108

[0619]

[0620] 1 H NMR (300MHz, DMSO-d6) δ 12.57 (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).

[0621] Example 109: Synthesis of Compound S109

[0622]

[0623] 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).

[0624] Example 110: Synthesis of Compound S110

[0625]

[0626] 1 H 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).

[0627] Example 111: Synthesis of Compound S111

[0628]

[0629] 1 H 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).

[0630] Example 112: Synthesis of Compound S112

[0631]

[0632] 1 H 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).

[0633] Example 113: Synthesis of Compound S113

[0634]

[0635] 1 H 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).

[0636] Example 114: Synthesis of Compound 114

[0637]

[0638] Step 1: Synthesis of compound 21

[0639] Compound 12 (4.34 g, 10 mmol) was dissolved in anhydrous DCM (30 ml), trifluoromethanesulfonic anhydride (2.5 ml, 11 mmol) and TEA (2.1 ml, 15 mmol) were slowly added dropwise at 0°C, and the mixture was stirred for 1 h. After the reaction was completed, DCM (30 ml) was added, and the mixture was washed with water (3×30 ml), washed with saturated brine (1×30 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 21, which was directly used in the next step without purification.

[0640] Step 2: Synthesis of compound 22

[0641] Compound 21 (5.7 g, 10 mmol), 23 (2.0 g, 10 mmol), cesium carbonate (3.9 g, 12 mmol), Pd2(dba)3 (144 mg, 0.25 mmol), xantphos (289 mg, 0.5 mmol) were dissolved in anhydrous toluene (30 ml), nitrogen was protected, and the mixture was refluxed overnight for reaction. After the reaction was complete, the reaction was stopped, the solvent was evaporated, water (50 ml) was added, and ethyl acetate was extracted (3×30 ml), the organic phases were combined, washed with saturated brine ((1×30 ml)), dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography to obtain compound 22 (4.0 g, 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).

[0642] Step 3: Synthesis of compound S114

[0643] Compound 22 (619 mg, 1 mmol) was dissolved in ethanol (5 ml) / DCM (5 ml), Pd / C (62 mg, 10%) was added, and the mixture was reacted for 8 h under the action of hydrogen. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the mixture was purified by column chromatography to obtain compound S110 (453 mg, 80%). 1 H 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).

[0644] The synthesis of compounds S115 to S121 in the following Examples S115 to S121 can refer to the synthesis method of Example 114, and only the corresponding raw materials need to be replaced.

[0645] Example 115: Synthesis of Compound S115

[0646]

[0647] 1 H 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).

[0648] Example 116: Synthesis of Compound S116

[0649]

[0650] 1 H 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).

[0651] Example 117: Synthesis of Compound S117

[0652]

[0653] 1 H 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).

[0654] Example 118: Synthesis of Compound S118

[0655]

[0656] 1 H 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).

[0657] Example 119: Synthesis of Compound S119

[0658]

[0659] 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 (d td, 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).

[0660] Example 120: Synthesis of Compound S120

[0661]

[0662] 1 H 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).

[0663] Example 121: Synthesis of Compound S121

[0664]

[0665] 1 H 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).

[0666] Example 122: SARS-CoV-2 virus 3C-like cysteine ​​protease (3CLpro) enzyme inhibition activity test experiment

[0667] 1. 3CLpro protein expression and purification

[0668] The gene sequence of the full-length 3CLpro protein was constructed in the expression vector pET28a(+) and transferred into the competent cells of Escherichia coli BL21(DE3). After induction at a final concentration of 0.5 mM IPTG and 12 hours at 25°C, the purified protein was purified using a Ni-NTA column. The purified protein was tested by SDS, and the portion with a purity greater than 90% was further purified using the Superdex 200 10 / 300GL of the GE protein chromatography purification system AKTA Pure to obtain a protein with a purity greater than 95%. The protein concentration was determined using Nano Drop, and the protein was aliquoted and quickly frozen in liquid nitrogen and stored at -80°C.

[0669] 2. Establishment of SARS-CoV-2 3CLpro enzyme activity screening system and calculation of inhibitor inhibition rate and drug IC50

[0670] The activity of SARS-CoV-2 3CLpro and the inhibitory activity of the compounds on SARS-CoV-2 3CLpro were determined by fluorescence resonance energy transfer (FRET) technology. The fluorescent substrate (Dabcyl-KTSAVLQ↓SGFRKM-E(Edans)-NH2) with the SARS-CoV-2 3CLpro cleavage site (indicated by the arrow) and Tris-HCl buffer (20mMTris-HCl, 150mM NaCl, 10mM EDTA, pH7.5) were used in the assay. The compounds were dissolved in 100% DMSO. 10μl of the compound was incubated with 40μl of SARS-CoV-2 3CLpro (final concentration 0.5μM, diluted in Tris-HCl buffer) at 25°C for 10min, and the reaction was initiated by adding 50μl of the fluorescent substrate (final concentration 20μM). The Dabcyl fluorescence signal generated by the substrate cleavage catalyzed by 3CLpro was detected using a radio resonance energy transfer fluorescence spectrophotometer at an excitation wavelength of 340nm and an absorption wavelength of 490nm. The kinetic constants (Vmax and Km) of SARS-CoV-2 3CLpro were obtained by fitting the data to the Michaelis Menten equation, V = Vmax × [S] / (Km + [S]). kcat was then calculated according to the formula kcat = Vmax / [E]. The compounds were serially diluted using Tris-HCl buffer by the multiple dilution method and assayed using the same final concentrations of SARS-CoV-2 3CLpro and fluorescent substrate system as described above. The values ​​of the intrinsic (V0i) and apparent (Vappi, Kappi) catalytic parameters for 3CLpro-catalyzed hydrolysis of peptide substrates were determined in the presence and absence of the target compound, respectively. The apparent inhibition constant (Kappi) for the binding of the target compound to Mpro was obtained from the dependence of Vappi on the inhibitor concentration ([I]) at a fixed substrate concentration ([S]) according to the equation Vappi = Vapp × [I] / (Kappi + [I]). The intrinsic inhibition constant (Ki) of the target compound binding to 3CLpro was calculated according to the equation Kappi = Ki × (1 + [S] / Km). The inhibition curve of the compound was drawn by GraphPad Prism 8.0 software and the IC was calculated. 50 The results are shown in Table 1 below. The example compounds have good inhibitory activity against SARS-CoV-2 virus 3CLpro, and their activity is better than that of the positive drug Baicalin, or equivalent to that of Baicalin. A: IC 50 <0.001μM; B:IC 50 =0.001μM-0.01μM;

[0671] Table 1 SARS-CoV-2 virus 3CLpro enzyme inhibitory activity

[0672]

[0673]

[0674]

[0675] Example 123: Cytotoxicity and Anti-SARS-CoV-2 Virus Infection Efficacy Test Experiment

[0676] Vero E6 cytotoxicity test: CCK8 method was used to detect the cytotoxicity of the test compound in mammalian Vero E6 cells. Vero E6 cells were added to a 96-well plate and cultured overnight. Then, the cells were incubated with different concentrations of the test compound for 48 hours. The culture medium in the well plate was removed and replaced with fresh serum-free culture medium, 10% CCK8 reagent was added, and then incubated at 37°C for 1 hour, and then the absorbance value at 450nm was detected by an ELISA reader.

[0677] Screening of compounds with no cytotoxicity or less cytotoxicity for antiviral infection tests, the specific operation includes the following steps: ① Inoculation of cells: Take Vero-E6 cells in the logarithmic growth phase, aspirate the culture medium, digest the cells with trypsin, and the cell count is: 1×106 / ml; Take 4ml of the above cells, add 6ml of culture medium, prepare a cell suspension with a cell density of 4×105 / ml, and inoculate it into a 96-well plate, 100μl per well, 4×104 cells per well. ② Drug pretreatment of cells: Replace the cell culture medium with DMEM culture medium containing 2% FBS, add the corresponding concentration of drugs and DMSO, 100μl per well, and then place it in a 37℃ incubator for pretreatment for 1h. ③ Virus infection: Take 0.3ml of virus, add 45ml of culture medium, mix well, and dilute the virus to 100TCID50 / 0.05ml; discard the drug culture medium in the cell plate and vertically drop the virus dilution into the 96-well plate, add the sample volume 50μl / well, and add the corresponding drug culture medium (containing the corresponding concentration of drug), add the sample volume 50μl / well, and mix well; ④ Incubation: Mix the cell culture plate with the sample on the shaker, place it in a 37℃ incubator, and incubate for 1h. After the incubation, remove the virus-serum mixture inoculated with cells, add the corresponding concentration of drug and control group DMSO, add the sample volume 100μl / well (100TCID50 / well), and place it in a 37℃ CO2 incubator for 48h; ⑤ Collect the supernatant to detect viral RNA, and fix and stain with 4% paraformaldehyde for immunofluorescence staining analysis.

[0678] The specific experimental results are shown in Table 2. The example compounds have low cytotoxicity, good inhibitory activity against SARS-CoV-2 virus infection, and good selectivity index; A: IC 50 <0.1μM; B:IC 50 =0.1μM-1.0μM.

[0679] Table 2 Cytotoxicity and anti-SARS-CoV-2 virus infection activity of the tested compounds

[0680]

[0681]

[0682]

[0683]

[0684]

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: in, R 1 is hydroxyl group; R 2 is hydroxyl group; R 3 is hydroxyl group; A is unsubstituted or R 4 Substituted phenyl; or C 3-6 Cycloalkyl, Phenylethynyl, phenylethynyl, R 4 is selected from deuterium, halogen, hydroxyl, cyano, nitro, unsubstituted C 1-6 Alkyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, methoxy, phenyl, cyclopropyl, -NH2, -COOH, X is hydrogen, C 1-6 alkyl, Benzyl, R 7 is hydrogen or C 1-6 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; Among them, R 1 , R 2 , R 3 , R 7 , X and A are defined as above.

4. A pharmaceutical composition, characterized in that Contains a therapeutically effective amount of one or more quinazolinone compounds having a structure shown in 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.

Images