Primary protease modulators and uses thereof

Abstract

The invention relates to a main protease regulator and application thereof, and particularly provides a compound shown as a formula O or a stereoisomer, a prodrug, a crystal form, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate of the compound, and the compound has excellent coronavirus (such as SARS-CoV-2 and a mutant strain thereof and MERS-CoV) 3CL protease inhibitory activity. Replication of coronaviruses (such as SARS-CoV-2 and mutant strains thereof and MERS-CoV) can be effectively inhibited, and good potential treatment effect is achieved in the aspect of treating diseases caused by the coronaviruses (such as SARS-CoV-2 and mutant strains thereof and MERS-CoV).

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a main protease regulator and application thereof. Background Art

[0005] In the early response, clinicians relied on existing antiviral drugs and supportive treatments. However, as the understanding of the pathology of SARS-CoV-2 deepened, the scientific community quickly concentrated resources to promote the development of specialized drugs and vaccines for the virus. Multiple pharmaceutical companies and research institutions participated in the race to develop COVID-19 vaccines, such as Pfizer and Moderna's mRNA vaccines, Oxford-AstraZeneca's adenovirus vector vaccines, etc., which successfully entered the market in a very short period of time, which is unprecedented in the history of modern medicine. By mid-2021, billions of doses of vaccines had been administered worldwide, which to some extent alleviated the spread of the epidemic.

[0006] In addition, drugs for critically ill patients, such as Remdesivir and Dexamethasone, have also become core drugs for the treatment of COVID-19. Remdesivir, as a broad-spectrum antiviral drug, was originally used to treat Ebola virus, but has shown certain efficacy in clinical studies of COVID-19, especially in reducing the length of hospital stay for critically ill patients. Dexamethasone, as a steroid drug, is mainly used to suppress overactive immune responses, especially to prevent the occurrence of "cytokine storms", which are more common in critically ill COVID-19 patients.

[0007] Comparison with Middle East Respiratory Syndrome (MERS)

[0008] SARS-CoV-2 belongs to the same coronavirus family as the Middle East respiratory syndrome coronavirus (MERS-CoV), which was first discovered in 2012, but its transmissibility and lethality differ. The spread of MERS is relatively limited, mainly concentrated in the Middle East, especially in Saudi Arabia, and its lethality is about 36%, much higher than SARS-CoV-2. However, MERS is relatively less contagious, has far fewer cases than COVID-19, and has not yet caused a global pandemic.

[0009] Although MERS has a very high mortality rate, the global spread of SARS-CoV-2 makes its impact on human society more profound. SARS-CoV-2 spreads extremely quickly, has a long incubation period, and some infected people are asymptomatic or have mild symptoms, which makes the prevention and control of the epidemic more complicated. In contrast, most MERS infected people show severe respiratory symptoms, making them easier to track and isolate. The COVID-19 pandemic has exposed the vulnerability of the global public health system in responding to the new coronavirus, and has also prompted governments and international organizations to re-examine their strategies and capabilities for responding to similar pandemics in the future.

[0010] Current status and future prospects of research and development of antiviral drugs

[0011] Although the successful development of COVID-19 vaccines has largely controlled the spread of the epidemic, the development of specific drugs for coronavirus infection is still ongoing. Currently, the treatment drugs for SARS-CoV-2 mainly include antiviral drugs, immunomodulators and supportive treatments.

[0012] Among them, the research and development of antiviral drugs is particularly important. Researchers have developed several new antiviral drug candidates targeting the replication mechanism of the coronavirus and the interaction with host cells. In addition, the variability of the virus further increases the complexity of drug development. From the end of 2020 to 2021, multiple variants of SARS-CoV-2 (such as the Delta and Omicron variants) appeared one after another. Some variants showed partial escape from existing vaccines and drugs, forcing the scientific community to quickly adjust the composition of the vaccine and develop more broad-spectrum antiviral drugs.

[0013] In terms of antiviral drug development, in addition to drugs such as remdesivir and monoclonal antibody therapy that have been used in clinical practice, research on coronavirus protease inhibitors and RNA-dependent RNA polymerase inhibitors is also progressing rapidly. With a deeper understanding of the structure and replication mechanism of coronaviruses, more targeted drugs may appear in the future to directly inhibit viral replication or prevent the virus from entering host cells.

[0014] In addition, the development of antiviral drugs has also promoted large-scale international cooperation and the advancement of drug screening technology. In particular, the application of artificial intelligence technology has accelerated the screening and optimization process of drug molecules. For example, through cooperation, many pharmaceutical companies and scientific research institutions around the world quickly analyzed the genome sequence and structural proteins of SARS-CoV-2, and designed highly targeted drug molecules based on this.

[0015] In short, although vaccines have played a key role in the response to COVID-19, effective antiviral drugs remain the cornerstone of future public health security, especially in response to possible new coronavirus variants and other unknown coronavirus infections. In the next few years, multidisciplinary collaboration based on virology, immunology and pharmacology will continue to promote the development of new drugs and provide more complete solutions to global public health challenges. Summary of the invention

[0016] Through in-depth research, the inventors of the present application found that the compounds of the present invention have excellent coronavirus (such as SARS-CoV-2 and its mutants and MERS-CoV) 3CL protease inhibitory activity, can effectively inhibit the virus activity of coronavirus (such as SARS-CoV-2 and its mutants and MERS-CoV), and have good potential therapeutic effects in treating diseases caused by coronavirus (such as SARS-CoV-2 and its mutants and MERS-CoV).

[0017] To this end, in the first aspect of the present invention, the present invention provides a compound represented by formula O or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound,

[0018]

[0019] in:

[0020] R 1 is selected from phenyl, C3-C6 cycloalkyl, 5-10 membered heteroaryl, pyridyl C1-C6 alkylene, and the phenyl, C3-C6 cycloalkyl, 5-10 membered heteroaryl are each independently optionally substituted by 1-2 (preferably 1) substituents selected from C1-C6 alkyl, nitro, and phenyl;

[0021] Preferably, R 1 is selected from phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl, The phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl are each independently optionally substituted by 1-2 (preferably 1) substituents selected from methyl, nitro, phenyl;

[0022] More preferably, R 1 is selected from phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl, The phenyl, pyrrolyl and pyridyl groups are each independently optionally substituted by 1-2 (preferably 1) substituents selected from methyl, nitro and phenyl;

[0023] Most preferably, R 1 Selected from

[0024] R 2 is selected from phenyl, naphthyl, 5-10 membered heteroaryl, The phenyl, naphthyl, and 5-10 membered heteroaryl groups are each independently and optionally substituted by 1-3 substituents selected from the following: C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-,

[0025]

[0026] Preferably, R 2 Selected from phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoquinolyl, indolyl, The phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoquinolyl, indolyl are each independently optionally substituted by 1-3 substituents selected from the following: -CH3, -F, -Cl, -Br, -OCH3, -SCH3, -CF3, -NO2, Phenyl,

[0027] Preferably, R 2 Selected from:

[0028] 1) in:

[0029] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any one, any two or any three are selected from hydrogen, C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, The rest is hydrogen;

[0030] Preferably, Z 1 , Z2 , Z 3 , Z 4 , Z 5 In any one (such as Z 2 or Z 3 ) is selected from hydrogen, C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, The remainder is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In any two (such as Z 2 and Z 3 , or Z 2 and Z 4 ) is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, phenyl-C1-C6 alkylene-O-, and the rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any three (such as Z 2 , Z 3 and Z 4 ) is selected from halogen, the remainder being hydrogen;

[0031] More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In any one (such as Z 2 or Z 3 ) is selected from hydrogen, -CH3, -Cl, -Br, -OCH3, -SCH3, -CF3, -NO2, Phenyl, The rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In any two (such as Z 2 and Z 3 , or Z 2 and Z 4 ) is selected from -CH3, -F, -Cl, -Br, -OCH3, -CF3, The remainder is hydrogen; or, Z 1, Z 2 , Z 3 , Z 4 , Z 5 Among them, any three (such as Z 2 , Z 3 and Z 4 ) is selected from -F, the rest are hydrogen;

[0032] Most preferably, As a whole, selected from:

[0033]

[0034] 2) in:

[0035] Z 1 is selected from C1-C6 alkyl; preferably, Z 1 is -CH3;

[0036] 3) in:

[0037] Z 1 is selected from halogen; preferably, Z 1 is -Cl;

[0038] 4) in:

[0039] Z 1 is selected from C1-C6 alkyl; preferably, Z 1 is -CH3;

[0040] 5)

[0041] Most preferably, R 2 Selected from

[0042] Ring A is selected from a benzene ring, a 5-9 membered heteroaromatic ring, and a C4-C6 cycloolefin;

[0043] Preferably, ring A is selected from a benzene ring, a pyridine ring, a benzofuran ring, a benzothiophene ring, a benzothiazole ring, an indole ring, a furan ring, a thiophene ring, a pyrrole ring, and a cyclopentene ring;

[0044] More preferably, Ring A is selected from Among them, carbon atom No. 1 corresponds to carbon atom No. 1 in the parent nucleus, and carbon atom No. 2 corresponds to carbon atom No. 2 in the parent nucleus;

[0045] n is selected from 0 and 1;

[0046] R 3is selected from halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 heterocycloalkyl, phenyl, naphthyl, 5-6 membered heteroaryl, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 heterocycloalkyl, phenyl, naphthyl, 5-6 membered heteroaryl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group;

[0047] Preferably, R 3 is selected from halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group;

[0048] More preferably, R 3 is selected from halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, pyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group;

[0049] R a , R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0050] Preferably, R a , R b Each independently selected from C1-C6 alkyl;

[0051] More preferably, R a , R b All are methyl;

[0052] More preferably, R 3is selected from -Br, -I, -NO2, cyano, methyl, cyclopropyl, cyclohexyl, -CF3, methoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridinyl, pyrrolyl, and the methyl, cyclohexyl, methoxy, pyrrolyl, morpholinyl, phenyl, naphthyl, pyridinyl are each independently optionally substituted by 1-2 selected from -F, -Cl, cyano, methyl, methoxy, substituted by a group;

[0053] Most preferably, R 3 Selected from -Br, -I, -NO2, cyano, -CH3, cyclopropyl, -CF3, -OCH3,

[0054]

[0055] Phenyl,

[0056] Most preferably, the A ring together with R 3 and n as a whole, selected from

[0057]

[0058] Among them, carbon atom No. 1 corresponds to carbon atom No. 1 in the parent nucleus, and carbon atom No. 2 corresponds to carbon atom No. 2 in the parent nucleus.

[0059] In some embodiments, the compound has the structural formula shown in Formula I,

[0060]

[0061] in:

[0062] R 1 is selected from phenyl, C3-C6 cycloalkyl, 5-10 membered heteroaryl, pyridyl C1-C6 alkylene, and the phenyl, C3-C6 cycloalkyl, 5-10 membered heteroaryl are each independently optionally substituted by 1-2 (preferably 1) substituents selected from C1-C6 alkyl, nitro, and phenyl;

[0063] Preferably, R 1 is selected from phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl, The phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl are each independently optionally substituted by 1-2 (preferably 1) substituents selected from methyl, nitro, phenyl;

[0064] More preferably, R 1 is selected from phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl, The phenyl, pyrrolyl and pyridyl groups are each independently optionally substituted by 1-2 (preferably 1) substituents selected from methyl, nitro and phenyl;

[0065] Most preferably, R 1 Selected from

[0066] R 2 is selected from phenyl, naphthyl, 5-10 membered heteroaryl, The phenyl, naphthyl, and 5-10 membered heteroaryl groups are each independently and optionally substituted by 1-3 substituents selected from the following: C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-,

[0067]

[0068] Preferably, R 2 Selected from phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoquinolyl, indolyl, The phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoquinolyl, indolyl are each independently optionally substituted by 1-3 substituents selected from the following: -CH3, -F, -Cl, -Br, -OCH3, -SCH3, -CF3, -NO2, Phenyl,

[0069] Preferably, R 2 Selected from:

[0070] 1) in:

[0071] Z 1 , Z 2 , Z 3 , Z 4 , Z 5Among them, any one, any two or any three are selected from hydrogen, C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, The rest is hydrogen;

[0072] Preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any one (such as Z 2 or Z 3 ) is selected from hydrogen, C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, The rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In any two (such as Z 2 and Z 3 , or Z 2 and Z 4 ) is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, phenyl-C1-C6 alkylene-O-, and the rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any three (such as Z 2 , Z 3 and Z 4 ) is selected from halogen, the remainder being hydrogen;

[0073] More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any one (such as Z 2 or Z 3 ) is selected from hydrogen, -CH3, -Cl, -Br, -OCH3, -SCH3, -CF3, -NO2, Phenyl, The rest is hydrogen; or, Z1 , Z 2 , Z 3 , Z 4 , Z 5 In any two (such as Z 2 and Z 3 , or Z 2 and Z 4 ) is selected from -CH3, -F, -Cl, -Br, -OCH3, -CF3, The remainder is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any three (such as Z 2 , Z 3 and Z 4 ) is selected from -F, the rest are hydrogen;

[0074] Most preferably, As a whole, selected from:

[0075]

[0076] 2) in:

[0077] Z 1 is selected from C1-C6 alkyl; preferably, Z 1 is -CH3;

[0078] 3) in:

[0079] Z 1 is selected from halogen; preferably, Z 1 is -Cl;

[0080] 4) in:

[0081] Z 1 is selected from C1-C6 alkyl; preferably, Z 1 is -CH3;

[0082] 5)

[0083] Most preferably, R 2 Selected from

[0084] R 3a , R 3b , R 3c , R 3d In any one (such as R 3a, R 3b or R 3c ) is selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 heterocycloalkyl, phenyl, naphthyl, 5-6 membered heteroaryl, the rest is hydrogen, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 heterocycloalkyl, phenyl, naphthyl, 5-6 membered heteroaryl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group;

[0085] Preferably, R 3a , R 3b , R 3c , R 3d In any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl, the rest is hydrogen, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group;

[0086] More preferably, R 3a , R 3b , R 3c , R 3d In any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl, the rest is hydrogen, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, pyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group;

[0087] R a , R bEach is independently selected from hydrogen, C1-C6 alkyl;

[0088] Preferably, R a , R b Each independently selected from C1-C6 alkyl;

[0089] More preferably, R a , R b All are methyl;

[0090] More preferably, R 3a , R 3b , R 3c , R 3d In any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, -I, -NO2, cyano, methyl, cyclopropyl, cyclohexyl, -CF3, methoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridinyl, pyrrolyl, the rest is hydrogen, and the methyl, cyclohexyl, methoxy, pyrrolyl, morpholinyl, phenyl, naphthyl, pyridinyl are each independently optionally substituted by 1-2 selected from -F, -Cl, cyano, methyl, methoxy, substituted by a group;

[0091] Most preferably, R 3a , R 3b , R 3c , R 3d In any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, -I, -NO2, cyano, -CH3, cyclopropyl, -CF3, -OCH3, The remainder is hydrogen.

[0092] In some embodiments, the compound has the structural formula shown in Formula I-1,

[0093]

[0094] in:

[0095] R 2 is selected from phenyl, naphthyl, 5-10 membered heteroaryl, The phenyl, naphthyl, and 5-10 membered heteroaryl groups are each independently and optionally substituted by 1-3 substituents selected from the following: C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-,

[0096]

[0097] Preferably, R 2 Selected from phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoquinolyl, indolyl, The phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoquinolyl, indolyl are each independently optionally substituted by 1-3 substituents selected from the following: -CH3, -F, -Cl, -Br, -OCH3, -SCH3, -CF3, -NO2, Phenyl,

[0098] Preferably, R 2 Selected from:

[0099] 1) in:

[0100] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any one, any two or any three are selected from hydrogen, C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, The rest is hydrogen;

[0101] Preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In any one (such as Z 2 or Z 3 ) is selected from hydrogen, C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, The remainder is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In any two (such as Z 2 and Z 3 , or Z2 and Z 4 ) is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, phenyl-C1-C6 alkylene-O-, and the rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any three (such as Z 2 , Z 3 and Z 4 ) is selected from halogen, the remainder being hydrogen;

[0102] More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any one (such as Z 2 or Z 3 ) is selected from hydrogen, -CH3, -Cl, -Br, -OCH3, -SCH3, -CF3, -NO2, Phenyl, The rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In any two (such as Z 2 and Z 3 , or Z 2 and Z 4 ) is selected from -CH3, -F, -Cl, -Br, -OCH3, -CF3, The rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any three (such as Z 2 , Z 3 and Z 4 ) is selected from -F, the rest are hydrogen;

[0103] Most preferably, As a whole, selected from:

[0104]

[0105] 2) in:

[0106] Z 1 is selected from C1-C6 alkyl; preferably, Z 1 is -CH3;

[0107] 3) in:

[0108] Z 1 is selected from halogen; preferably, Z 1 is -Cl;

[0109] 4) in:

[0110] Z 1 is selected from C1-C6 alkyl; preferably, Z 1 is -CH3;

[0111] 5)

[0112] Most preferably, R 2 Selected from

[0113] R 3a , R 3b , R 3c , R 3d In any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 heterocycloalkyl, phenyl, naphthyl, 5-6 membered heteroaryl, the rest is hydrogen, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 heterocycloalkyl, phenyl, naphthyl, 5-6 membered heteroaryl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group;

[0114] Preferably, R 3a , R 3b , R 3c , R 3d In any one (such as R 3a , R 3b or R 3c) is selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl, the rest is hydrogen, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group;

[0115] More preferably, R 3a , R 3b , R 3c , R 3d In any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl, the rest is hydrogen, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, pyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group;

[0116] R a , R b Each is independently selected from hydrogen, C1-C6 alkyl;

[0117] Preferably, R a , R b Each independently selected from C1-C6 alkyl;

[0118] More preferably, R a , R b All are methyl;

[0119] More preferably, R 3a , R 3b , R 3c , R 3d In any one (such as R 3a , R 3b or R 3c) is selected from hydrogen, -I, -NO2, cyano, methyl, cyclopropyl, cyclohexyl, -CF3, methoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridinyl, pyrrolyl, the rest is hydrogen, and the methyl, cyclohexyl, methoxy, pyrrolyl, morpholinyl, phenyl, naphthyl, pyridinyl are each independently optionally substituted by 1-2 selected from -F, -Cl, cyano, methyl, methoxy, substituted by a group;

[0120] Most preferably, R 3a , R 3b , R 3c , R 3d In any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, -I, -NO2, cyano, -CH3, cyclopropyl, -CF3, -OCH3, The remainder is hydrogen.

[0121] In some embodiments, the compound has the structural formula shown in Formula I-2,

[0122]

[0123] in:

[0124] R 1 is selected from phenyl, C3-C6 cycloalkyl, 5-10 membered heteroaryl, pyridyl C1-C6 alkylene, and the phenyl, C3-C6 cycloalkyl, 5-10 membered heteroaryl are each independently optionally substituted by 1-2 (preferably 1) substituents selected from C1-C6 alkyl, nitro, and phenyl;

[0125] Preferably, R 1 is selected from phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl, The phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl are each independently optionally substituted by 1-2 (preferably 1) substituents selected from methyl, nitro, phenyl;

[0126] More preferably, R 1 is selected from phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl, The phenyl, pyrrolyl and pyridyl groups are each independently optionally substituted by 1-2 (preferably 1) substituents selected from methyl, nitro and phenyl;

[0127] Most preferably, R 1 Selected from

[0128] In some embodiments, the compound has the structural formula shown in Formula II,

[0129]

[0130]

[0131] in:

[0132] R 1 is selected from 6-10 membered heteroaryl;

[0133] Preferably, R 1 is selected from pyridyl, isoquinolyl;

[0134] More preferably, R 1 Selected from

[0135] Ring A is selected from a 5-9 membered heteroaromatic ring, a C4-C6 cycloolefin;

[0136] Preferably, ring A is selected from a pyridine ring, a benzofuran ring, a benzothiophene ring, a benzothiazole ring, an indole ring, a furan ring, a thiophene ring, a pyrrole ring, and a cyclopentene ring;

[0137] More preferably, Ring A is selected from Among them, carbon atom No. 1 corresponds to carbon atom No. 1 in the parent nucleus, and carbon atom No. 2 corresponds to carbon atom No. 2 in the parent nucleus;

[0138] n is selected from 0 and 1;

[0139] R 3 is selected from halogen, C1-C6 alkyl, and phenyl, wherein the C1-C6 alkyl and phenyl are each independently optionally substituted by 1-2 (preferably 1) groups selected from C1-C6 alkoxy;

[0140] Preferably, R 3 is selected from halogen, C1-C6 alkyl, phenyl, wherein the phenyl is optionally substituted by 1-2 (preferably 1) groups selected from C1-C6 alkoxy;

[0141] More preferably, R 3 Selected from -Br, -CH3, phenyl,

[0142] Most preferably, the A ring together with R 3 and n as a whole, selected from

[0143] Among them, carbon atom No. 1 corresponds to carbon atom No. 1 in the parent nucleus, and carbon atom No. 2 corresponds to carbon atom No. 2 in the parent nucleus.

[0144] In some embodiments, the compound is selected from:

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152] In the second aspect of the present invention, the present invention provides a pharmaceutical composition comprising the aforementioned compound or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, and optionally a pharmaceutically acceptable excipient.

[0153] In the third aspect of the present invention, the present invention provides the use of the aforementioned compound or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound or the aforementioned pharmaceutical composition in the preparation of a medicament for treating a disease or infection caused by a coronavirus (preferably SARS-CoV-2 and its mutants and MERS-CoV).

[0154] In some embodiments, the disease caused by SARS-CoV-2 and its mutants is COVID-19.

[0155] In some embodiments, the disease or infection caused by SARS-CoV-2 and its mutants is a respiratory disease, such as simple infection, mild pneumonia, severe pneumonia, acute respiratory infection, severe acute respiratory infection (SARI), hypoxic respiratory failure, acute respiratory distress syndrome, sepsis, septic shock, etc.

[0156] In some embodiments, the simple infection includes but is not limited to fever, cough, sore throat, nasal congestion, fatigue, headache, muscle pain or discomfort; preferably, the mild pneumonia includes but is not limited to cough, dyspnea and / or shortness of breath; preferably, the severe pneumonia includes but is not limited to increased respiratory rate, severe respiratory failure or dyspnea, central cyanosis, drowsiness, unconsciousness or convulsions, convulsions; preferably, the acute respiratory distress syndrome includes but is not limited to pulmonary edema; preferably, the sepsis includes but is not limited to organ dysfunction.

[0157] In some embodiments, the disease caused by MERS-CoV is Middle East Respiratory Syndrome (MERS).

[0158] In some embodiments, the disease or infection caused by MERS-CoV is a respiratory disease, such as fever, cough, shortness of breath, pneumonia, respiratory failure, etc.

[0159] In the fourth aspect of the present invention, the present invention provides the use of the aforementioned compound or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound or the aforementioned pharmaceutical composition in the preparation of a reagent for inhibiting coronavirus (preferably SARS-CoV-2 and its mutants and MERS-CoV) 3CL protease. Wherein, the reagent can be, for example, an experimental reagent, for example, a coronavirus (preferably SARS-CoV-2 and its mutants and MERS-CoV) 3CL protease inhibitor.

[0160] In the fifth aspect of the present invention, the present invention provides the aforementioned compound or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound or the aforementioned pharmaceutical composition, which is used to treat diseases or infections caused by coronaviruses (preferably SARS-CoV-2 and its mutants and MERS-CoV).

[0161] In some embodiments, the disease caused by SARS-CoV-2 and its mutants is COVID-19.

[0162] In some embodiments, the disease or infection caused by SARS-CoV-2 and its mutants is a respiratory disease, such as simple infection, mild pneumonia, severe pneumonia, acute respiratory infection, severe acute respiratory infection (SARI), hypoxic respiratory failure, acute respiratory distress syndrome, sepsis, septic shock, etc.

[0163] In some embodiments, the simple infection includes but is not limited to fever, cough, sore throat, nasal congestion, fatigue, headache, muscle pain or discomfort; preferably, the mild pneumonia includes but is not limited to cough, dyspnea and / or shortness of breath; preferably, the severe pneumonia includes but is not limited to increased respiratory rate, severe respiratory failure or dyspnea, central cyanosis, drowsiness, unconsciousness or convulsions, convulsions; preferably, the acute respiratory distress syndrome includes but is not limited to pulmonary edema; preferably, the sepsis includes but is not limited to organ dysfunction.

[0164] In some embodiments, the disease caused by MERS-CoV is Middle East Respiratory Syndrome (MERS).

[0165] In some embodiments, the disease or infection caused by MERS-CoV is a respiratory disease, such as fever, cough, shortness of breath, pneumonia, respiratory failure, etc.

[0166] In the sixth aspect of the present invention, the present invention provides the aforementioned compound or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound or the aforementioned pharmaceutical composition, which is used to inhibit coronavirus (preferably SARS-CoV-2 and its mutants and MERS-CoV) 3CL protease.

[0167] In the seventh aspect of the present invention, the present invention provides a method for treating a disease or infection caused by a coronavirus (preferably SARS-CoV-2 and its mutants and MERS-CoV), comprising administering to a subject in need thereof an effective amount of the aforementioned compound or a stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound or the aforementioned pharmaceutical composition.

[0168] In some embodiments, the disease caused by SARS-CoV-2 and its mutants is COVID-19.

[0169] In some embodiments, the disease or infection caused by SARS-CoV-2 and its mutants is a respiratory disease, such as simple infection, mild pneumonia, severe pneumonia, acute respiratory infection, severe acute respiratory infection (SARI), hypoxic respiratory failure, acute respiratory distress syndrome, sepsis, septic shock, etc.

[0170] In some embodiments, the simple infection includes but is not limited to fever, cough, sore throat, nasal congestion, fatigue, headache, muscle pain or discomfort; preferably, the mild pneumonia includes but is not limited to cough, dyspnea and / or shortness of breath; preferably, the severe pneumonia includes but is not limited to increased respiratory rate, severe respiratory failure or dyspnea, central cyanosis, drowsiness, unconsciousness or convulsions, convulsions; preferably, the acute respiratory distress syndrome includes but is not limited to pulmonary edema; preferably, the sepsis includes but is not limited to organ dysfunction.

[0171] In some embodiments, the disease caused by MERS-CoV is Middle East Respiratory Syndrome (MERS).

[0172] In some embodiments, the disease or infection caused by MERS-CoV is a respiratory disease, such as fever, cough, shortness of breath, pneumonia, respiratory failure, etc.

[0173] In the eighth aspect of the present invention, the present invention provides a method for inhibiting coronavirus (preferably SARS-CoV-2 and its mutants and MERS-CoV) 3CL protease, which comprises contacting the aforementioned compound or the stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound or the aforementioned pharmaceutical composition with coronavirus (preferably SARS-CoV-2 and its mutants and MERS-CoV) 3CL protease.

[0174] Beneficial Effects

[0175] The compounds of the present invention (such as the target compounds prepared in Examples 1 to 58) have excellent coronavirus (such as SARS-CoV-2 and its mutants and MERS-CoV) 3CL protease inhibitory activity, can effectively inhibit the virus activity of coronavirus (such as SARS-CoV-2 and its mutants and MERS-CoV), and have good potential therapeutic effects in treating diseases caused by coronavirus (such as SARS-CoV-2 and its mutants and MERS-CoV). BRIEF DESCRIPTION OF THE DRAWINGS

[0176] Figure 1 The results of cytotoxicity evaluation of the compounds of the present invention are shown. DETAILED DESCRIPTION

[0177] It should be understood that the terminology used herein is intended to describe specific embodiments and is not intended to be limiting. In addition, although any method, device and material similar or equivalent to that described herein can be used to implement or test the present invention, preferred methods, devices and materials are now described.

[0178] In the present invention, unless explicitly stated otherwise, the description method "...are independently selected from" used throughout this article can mean that in different groups, the specific options expressed by the same or different symbols do not affect each other, and can also mean that in the same group, the specific options expressed by the same or different symbols do not affect each other.

[0179] The substituents of the compounds of the present invention are disclosed in terms of group types or ranges. It is particularly noted that the present invention includes each independent secondary combination of the individual members of these group types and ranges. For example, the term "C1-C6 alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.

[0180] The term "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, preferably a "C1-C4 alkyl", more preferably a "C1-C3 alkyl", and most preferably a "C1-C2 alkyl". Examples of "C1-C6 alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. Examples of "C1-C4 alkyl" include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl), and the like. Examples of "C1-C3 alkyl" include methyl, ethyl, propyl (e.g., n-propyl, isopropyl), and the like. Examples of "C1-C2 alkyl" include methyl, ethyl.

[0181] The term "C1-C6 haloalkyl" refers to a group obtained by replacing one or more (such as 2, 3 or 4) hydrogen atoms in any of the above C1-C6 alkyl groups with halogen (preferably fluorine), examples of which include monofluoromethyl, difluoromethyl, difluoroethyl, trifluoromethyl, etc., preferably trifluoromethyl.

[0182] The term "C1-C6 alkoxy" refers to any of the above C1-C6 alkyl groups connected to the rest of the molecule through an oxygen atom (-O-), and examples include methoxy, ethoxy, isopropoxy, and the like.

[0183] The term "C1-C6 alkylthio group" refers to a group obtained by replacing the oxygen atom in any of the above C1-C6 alkoxy groups with a sulfur atom, such as C1-C6 alkylthio group, C1-C4 alkylthio group, C1-C3 alkylthio group, and the like.

[0184] The term "C1-C6 alkylene" refers to a divalent group obtained by removing a hydrogen atom from any of the above C1-C6 alkyl groups (e.g., C1-C4 alkyl, C1-C3 alkyl, etc.), for example wait.

[0185] The term "C3-C6 cycloalkyl" refers to

[0186] The term "C3-C6 heterocycloalkyl" refers to a group obtained by replacing at least one carbon atom in any of the above C3-C6 cycloalkyl groups with a heteroatom (N, O or S), such as tetrahydropyrrolyl, morpholinyl and the like.

[0187] The term "C4-C6 cycloolefin" refers to a saturated alicyclic hydrocarbon containing 4 to 6 carbon atoms and containing a carbon-carbon double bond, such as cyclopentene.

[0188] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0189] The term "heteroaryl" refers to a 5-, 6-, 7-, 8-, 9- or 10-membered aromatic monocyclic group, bicyclic group and tricyclic group or more ring groups having at least one heteroatom (N, O or S) in at least one ring, and the heteroatom-containing ring optionally further has 1, 2 or 3 heteroatoms selected from N, O or S. For a heteroaryl group that is bicyclic or tricyclic or more, each ring in the bicyclic or tricyclic or polycyclic ring is required to constitute an aromatic system. Non-limiting examples of the heteroaryl group are, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thioxazolyl, pyrrolyl, phenyl-pyrrolyl, furanyl, phenyl-furanyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzofuranyl, benzothienyl, benzimidazolyl, indazolyl, quinolyl, isoquinolyl, The term "heteroaromatic ring" can be understood accordingly with reference to the aforementioned term "heteroaryl".

[0190] The term "heteroatom" refers to N, O or S.

[0191] From all the above descriptions, it is obvious to a person skilled in the art that any group whose name is a composite name, such as "pyridyl C1-C6 alkylene", should refer to the conventional construction from the part derived therefrom from left to right, such as from "C1-C6 alkylene" substituted with "pyridyl", wherein "C1-C6 alkylene" is as defined above. Specifically, "pyridyl C1-C6 alkylene" can be, for example, Other similar composite groups can be understood by referring to the above content.

[0192] The term "substituted" means that any one or more hydrogens on the designated atom or group are replaced with the selection of designated groups, provided that the normal valence of the designated atom is not exceeded.

[0193] In the present invention, “R 2 Selected from phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoquinolyl, indolyl, The phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoquinolyl, indolyl are each independently optionally substituted by 1-3 substituents selected from the following: -CH3, -F, -Cl, -Br, -OCH3, -SCH3, -CF3, -NO2, Phenyl, ", which means that the phenyl, naphthyl, pyridyl, furanyl, thienyl, pyrrolyl, isoquinolyl or indolyl may be substituted or unsubstituted, and if the phenyl, naphthyl, pyridyl, furanyl, thienyl, pyrrolyl, isoquinolyl or indolyl is substituted, the respective substituents may be the same or different. Further, when the phenyl, naphthyl, pyridyl, furanyl, thienyl, pyrrolyl, isoquinolyl or indolyl is substituted with 2 or 3 substituents, the 2 substituents or the 3 substituents may be the same or different. Other similar definitions can be understood with reference to the above content.

[0194] In the present invention, the structural formula shown in formula O In the formula, n is selected from 0 and 1, which means that if n is 0, the A ring is not substituted by a substituent, and if n is 1, the A ring is substituted by a substituent, namely R 3 replaced, and R 3 The substitution site on ring A is not specifically limited. Other similar definitions can be understood by referring to the above content.

[0195] In the present invention, in the compound represented by formula O, "A ring is selected from Among them, carbon atom No. 1 corresponds to carbon atom No. 1 in the parent nucleus, and carbon atom No. 2 corresponds to carbon atom No. 2 in the parent nucleus." This means that, for example, if ring A is When carbon atom No. 1 corresponds to carbon atom No. 1 in the parent nucleus, and carbon atom No. 2 corresponds to carbon atom No. 2 in the parent nucleus, then the structural formula shown in formula O becomes Other similar definitions can be understood by referring to the above content.

[0196] In the present invention, "treatment" generally refers to obtaining the desired pharmacological and / or physiological effects. "Treatment" as used herein covers any treatment of a patient's disease, including: (a) preventing a disease or symptom from occurring in a patient who is susceptible to the disease or symptom but has not yet been diagnosed with the disease; (b) inhibiting the symptoms of the disease, i.e., preventing its development; or (c) alleviating the symptoms of the disease, i.e., causing the disease or symptom to regress.

[0197] In the present invention, "subject" refers to a vertebrate. In certain embodiments, a vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, a mammal refers to a human.

[0198] In the present invention, "effective amount" refers to an amount that is effective in achieving the desired therapeutic effect at the necessary dosage and time. The "therapeutically effective amount" of the substance / molecule of the present invention may vary according to factors such as the disease state, age, sex and weight of the individual and the ability of the substance / molecule to induce a desired response in the individual. The therapeutically effective amount also encompasses the amount in which the therapeutically beneficial effects of the substance / molecule outweigh any toxic or harmful consequences. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce tumor volume; inhibit (i.e., slow down to a certain extent, preferably stop) cancer cell infiltration into surrounding organs; inhibit (i.e., slow down to a certain extent, preferably stop) tumor metastasis; inhibit tumor growth to a certain extent; and / or alleviate one or more symptoms associated with cancer to a certain extent.

[0199] The pharmaceutical composition of the present invention may contain pharmaceutically acceptable excipients, including but not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, lanolin, etc.

[0200] The pharmaceutical composition of the present invention can be prepared into various forms according to different administration routes. For example, the pharmaceutical composition can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or administration via an explanted reservoir. Among them, oral or intravenous administration is preferred.

[0201] The compounds of the present invention may optionally be used in combination with one or more other active ingredients, and the respective dosages and ratios thereof may be adjusted by those skilled in the art according to specific symptoms, patient conditions, clinical needs, etc.

[0202] As used herein, unless otherwise indicated, the term "prodrug" refers to a derivative that can be hydrolyzed, oxidized or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the present invention. Prodrugs become active compounds only under biological conditions through this reaction, or they have no or only low activity in their unreactive form. Prodrugs can generally be prepared using known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, 5th edition).

[0203] When the stereoisomers in the compounds described herein are specifically designated as (R)- or (S)-isomers in the chemical name, it should be understood that the major configuration is the (R)-isomer or (S)-isomer, respectively. Any asymmetric carbon atom may exist in the (R)-, (S)- or (R, S)-configuration, preferably in the (R)- or (S)-configuration.

[0204] "Solvate" or "solvate" are used interchangeably and refer to a compound that exists in combination with certain solvent molecules. The combination may include a stoichiometric amount of a certain solvent, such as a monohydrate or a dihydrate, or may include any amount of water; for example, methanol or ethanol may form an "alcoholate", which may also be stoichiometric or non-stoichiometric. The term "solvate" as used herein refers to a solid form, i.e., a compound in a solution of a solvent, although it may be solvated, it is not a solvate as the term is used herein.

[0205] As used herein, the term "pharmaceutically acceptable salt" refers to (i) a salt formed by an acidic functional group (e.g., -COOH) present in the compounds provided by the present invention and a suitable inorganic or organic cation (base), and includes, but is not limited to, alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic base salts, such as ammonium salts; organic base salts, such as tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenethylamine salts, piperazine salts, tetramethylamine salts, tris(hydroxymethyl)aminomethane salts. And, (ii) salts formed by basic functional groups (e.g. -NH2) present in the compounds provided by the present invention and appropriate inorganic or organic anions (acids), and including but not limited to, hydrohalides, such as hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, etc.; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkane sulfonates, such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, etc.; aryl sulfonates, such as benzenesulfonates, p-toluenesulfonates, etc.; organic acid salts, such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, maleates, etc.; amino acid salts, such as glycine, trimethylglycine, arginine, ornithine, glutamate, aspartate, etc.

[0206] As used herein, the term "crystal form" refers to the crystal structure of a substance. When a substance crystallizes, various factors may affect the intramolecular or intermolecular bonding mode, causing molecules or atoms to be arranged differently in the lattice space, forming different crystal structures. The compounds of the present invention may exist in one crystal structure or in multiple crystal structures, i.e., have "polymorphism". The compounds of the present invention may exist in different crystal forms.

[0207] The present invention is further explained below in conjunction with specific examples. Unless otherwise specified, the raw materials used in the following examples can be obtained commercially.

[0208] Example 1: Preparation of 1-phenyl-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A1)

[0209]

[0210] Step 1: Preparation of 3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (Int 1)

[0211] Triphosgene (1.48 g, 5 mmol) and toluene (20 mL) were added to a pear-shaped bottle, and compound 1-1 (methyl 2-aminobenzoate) (1.50 g, 10 mmol) was added under an ice bath, and then refluxed at 115 ° C for 6 h. After adding 3-aminopyridine (0.95 g, 10 mmol) to the reaction solution, a beige solid was quickly precipitated, and then refluxed for overnight reaction. After TLC detection, the reaction was completed, cooled to room temperature, filtered, and the filter cake was washed with a small amount of ethanol to obtain 2.7 g of beige solid. The obtained beige solid and sodium methoxide (0.38 g, 6 mmol) were added to methanol (25 mL), and the reaction was stirred at room temperature overnight. After TLC detection, the reaction was completed, filtered, and the filter cake was separated by silica gel column chromatography (PE / EA=1 / 2~pure EA) to obtain 1.5 g of off-white solid, with a yield of 60%.

[0212] Step 2: Preparation of 1-phenyl-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A1)

[0213] 3-(Pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (Int 1) (0.10 g, 0.4 mmol), phenylboronic acid (0.15 g, 0.8 mmol), copper acetate (0.16 g, 0.8 mmol), TEA (0.10 g, 0.8 mmol), DCM (8 mL) were added to a pear-shaped bottle and stirred overnight at room temperature. After the reaction was completed by TLC, the mixture was filtered, the filtrate was dried and sanded, and purified by silica gel column chromatography (PE / EA = 2:1 to 1:2) to obtain the target product M1-A1 (30 mg) with a yield of 20%.

[0214] 1 H NMR (400MHz, Chloroform-d) δ8.67(t,J=5.0Hz,2H),8.30(dd,J=7.9,1.6Hz,1H),7.74(dt,J=8.2,1.9Hz,1H),7.62(dd,J=8.3,6.5H z,2H),7.56(ddt,J=8.6,7.2,1.6Hz,2H),7.46(dd,J=8.1,4.8Hz,1H),7.44–7.37(m,2H),7.34–7.27(m,1H),6.66(d,J=8.4Hz,1H). 13 C NMR (101MHz, CDCl3) δ161.87,150.44,149.70,149.51,141.74,136.43,136.06,135.41,130.43,129.59,129.06,128.99,123.65,115.80,115.27.

[0215] Example 2: Preparation of 1-(4-chlorophenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A2)

[0216]

[0217] The preparation method is the same as that of Example 1, except that 4-chlorophenylboronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a white solid (80 mg), with a two-step yield of 50%.

[0218] 1 H NMR (400MHz, DMSO-d6) δ8.62(dd,J=4.8,1.6Hz,1H),8.60(d,J=2.4Hz,1H),8.13(dd,J=8.0,1.6Hz,1H),7.86(dt,J=8.0,2.0H z,1H),7.72–7.69(m,2H),7.66(ddd,J=8.8,7.2,1.6Hz,1H),7.59–7.53(m,3H),7.34(t,J=7.2Hz,1H),6.57(d,J=8.4Hz,1H). 13 C NMR (101MHz, CDCl3) δ161.69,150.30,149.60,149.57,141.40,136.39,135.61,1 35.52,134.49,131.85,130.70,130.48,129.22,123.88,123.83,115.53,115.31.

[0219] Example 3: Preparation of 1-(3-chlorophenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A3)

[0220]

[0221] The preparation method is the same as that of Example 1, except that 3-chlorophenylboronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a white solid (40 mg), with a two-step yield of 30%.

[0222] 1H NMR (400MHz, DMSO-d6) δ8.62(d,J=11.7Hz,2H),8.14(dd,J=7.9,1.6Hz,1H),7.87(dt,J=8.3,1.8Hz,1H),7.72–7.64 (m,4H),7.59(dd,J=8.1,4.7Hz,1H),7.52(dt,J=7.1,2.1Hz,1H),7.36(td,J=7.6,1.0Hz,1H),6.58(d,J=8.4Hz,1H). 13 C NMR(101MHz,DMSO)δ162.08,150.35,150.11,149.63,141.98,138.32,137.26,136.0 2,134.56,132.24,129.96,129.94,128.79,128.51,124.44,123.74,115.78,115.56.

[0223] Example 4: Preparation of 1-(3-chlorophenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A4)

[0224]

[0225] The preparation method is the same as that of Example 1, except that 3-methylphenylboronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a white solid (69 mg), with a two-step yield of 43%.

[0226] 1 H NMR (400MHz, CDCl3) δ8.65–8.62(m,2H),8.26(dd,J=7.6,1.6Hz,1H),7.71(ddd,J=8.0,2.4,1.6Hz,1H),7.53(ddd,J=8.4,7.2,1.6Hz,1H),7.47 (t,J=8.0Hz,1H),7.43(dd,J=8.0,4.8Hz,1H),7.33(d,J=7.6Hz,1H),7.29–7.25(m,1H),7.20–7.16(m,2H),6.66(d,J=8.4Hz,1H),2.42(s,3H). 13C NMR (101MHz, CDCl3) δ161.89,150.45,149.70,149.47,141.78,140.67,136.45,135.92,135. 39,132.02,130.37,130.20,129.41,128.97,125.82,123.76,123.59,115.93,115.20,21.37.

[0227] Example 5: Preparation of 1-(3-bromophenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A5)

[0228]

[0229] The preparation method is the same as that of Example 1, except that 3-bromophenylboronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a yellow solid (8.7 mg), with a two-step yield of 5%.

[0230] 1 H NMR(400MHz, DMSO-d6)δ8.63–8.59(m,2H),8.13(dd,J=8.0,1.6Hz,1H),7.86(dt,J=8.4,2.0Hz,1H),7 .83–7.75(m,2H),7.70–7.65(m,1H),7.64–7.54(m,3H),7.35(t,J=7.6Hz,1H),6.57(d,J=8.4Hz,1H). 13 C NMR(101MHz,DMSO)δ162.09,150.36,150.11,149.65,141.99,138.41,137.28,136.04,13 3.05,132.81,132.75,132.51,129.16,128.50,124.44,123.75,122.76,115.78,115.54.

[0231] Example 6: Preparation of 1-(3-methoxyphenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A6)

[0232]

[0233] The preparation method is the same as that of Example 1, except that 3-methoxyphenylboronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a white solid (25 mg), with a two-step yield of 13%.

[0234] 1H NMR (400MHz, DMSO-d6) δ8.63–8.61(m,2H),8.12(d,J=8.0Hz,1H),7.87(d,J=8.4Hz,1H),7.66(t,J=8.0Hz,1H),7.61–7.50(m,2 H),7.33(t,J=7.6Hz,1H),7.14(dd,J=8.0,2.4Hz,1H),7.11(s,1H),7.06(d,J=8.0Hz,1H),6.57(d,J=8.4Hz,1H),3.80(s,3H). 13 C NMR (101MHz, CDCl3) δ161.85,161.20,150.28,149.68,149.48,141.65,137.01,136.46,135. 42,131.96,131.11,128.99,123.77,123.65,120.94,115.88,115.55,115.19,114.40,55.55.

[0235] Example 7: Preparation of 1-(3-methylthiophenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A7)

[0236]

[0237] The preparation method is the same as that of Example 1, except that 3-methylthiophenylboronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a white solid (13 mg), with a two-step yield of 6%.

[0238] 1 H NMR (400MHz, DMSO-d6) δ8.69–8.56(m,2H),8.13(dd,J=8.0,1.6Hz,1H),7.87(dt,J=8.0,2.0Hz,1H),7.67(ddd,J=8.8,7.2,1.6Hz,1H),7.60–7.55 (m,2H),7.45(dt,J=8.4,1.2Hz,1H),7.42(t,J=2.0Hz,1H),7.34(t,J=7. 6Hz,1H),7.27(dt,J=8.0,1.2Hz,1H),6.57(d,J=8.4Hz,1H),2.51(s,3H). 13C NMR(101MHz,DMSO)δ162.12,150.34,150.17,149.58,142.20,141.11,137.63,137.30,135.9 4,133.13,130.98,128.43,126.84,126.61,125.93,124.38,123.58,115.90,115.52,14.97.

[0239] Example 8: Preparation of 1-(3-trifluoromethylphenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A8)

[0240]

[0241] The preparation method is the same as that of Example 1, except that 3-trifluoromethylphenylboronic acid is used instead of phenylboronic acid in the second step to obtain the title compound as a white solid (25 mg), with a two-step yield of 15%.

[0242] 1 H NMR (400MHz, DMSO-d6) δ8.64(d,J=4.8Hz,1H),8.62(d,J=2.4Hz,1H),8.16(dd,J=8.0,1.6Hz,1H),8.00(s,1H),7.97(d,J=7 .6Hz,1H),7.94–7.83(m,3H),7.72–7.64(m,1H),7.59(dd,J=8.4,4.8Hz,1H),7.37(t,J=7.6Hz,1H),6.54(d,J=8.4Hz,1H). 13 CNMR(101MHz, CDCl3)δ162.11,150.51,150.13,149.67,142.01,137.84,137.28,136.07,134.36,133.04,132.02,131.42( q,J=32.5Hz),128.60,126.97(q,J=3.8Hz),126.66(q,J=3.8Hz),124.67(q,J=176.2Hz),124.43,123.80,115.69,115.66. 19 F NMR (376 MHz, DMSO) δ-61.09.

[0243] Example 9: Preparation of 1-(3-nitrophenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A9)

[0244]

[0245] The preparation method is the same as that of Example 1, except that 3-nitrobenzeneboronic acid is used instead of phenylboronic acid in the second step to obtain the title compound as a yellow solid (13 mg), with a two-step yield of 8%.

[0246] 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=14.4Hz,2H),8.48(t,J=2.0Hz,1H),8.45(d dd,J=8.4,2.4,1.2Hz,1H),8.16(dd,J=8.0,1.6Hz,1H),8.02(dt,J=8.0,1.6Hz ,1H),7.96(t,J=8.0Hz,1H),7.88(dt,J=8.0,2.0Hz,1H),7.66(ddd,J=8.8,7. 2,1.6Hz,1H),7.61–7.58(m,1H),7.38(t,J=7.6Hz,1H),6.61(d,J=8.4Hz,1H). 13 C NMR (101MHz, DMSO) δ162.10,150.48,150.09,149.69,149.42,141.86,138.04,137.26,13 6.99,136.01,132.15,129.69,128.58,126.90,125.39,124.79,123.88,115.80,115.69.

[0247] Example 10: Preparation of 1-(3-acetylphenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A10)

[0248]

[0249] The preparation method is the same as that of Example 1, except that 3-acetylphenylboronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a yellow solid (9.4 mg), with a two-step yield of 5%.

[0250] 1 H NMR(400MHz,DMSO-d6)δ8.63(d,J=6.4Hz,2H),8.18–8.14(m,2H),8.10(s,1H),7.89(dd,J=8.0,2.0Hz,1H),7.84–7.78 (m,2H),7.66(t,J=8.0Hz,1H),7.58(dd,J=8.0,4.8Hz,1H),7.36(t,J=7.6Hz,1H),6.53(d,J=8.4Hz,1H),2.64(s,3H). 13C NMR(101MHz,DMSO)δ197.61,162.14,150.49,150.16,149.62,142.12,139.20,137.48,137.31,1 35.95,134.61,131.19,129.67,129.41,128.53,124.43,123.68,120.78,115.79,115.64,27.31.

[0251] Example 11: Preparation of 1-(3-methoxycarbonylphenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A11)

[0252]

[0253] The preparation method is the same as that of Example 1, except that 3-methoxycarbonylphenylboronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a beige solid (15 mg), with a two-step yield of 10%.

[0254] 1 H NMR (400MHz, DMSO-d6) δ8.64–8.62(m,2H),8.19–8.09(m,3H),7.89(dt,J=8.0,2.0Hz,1H),7.82–7.81(m,2H),7.65( ddd,J=8.8,7.2,1.6Hz,1H),7.58(dd,J=8.0,4.8Hz,1H),7.35(t,J=7.6Hz,1H),6.53(d,J=8.4Hz,1H),3.89(s,3H). 13 C NMR (101MHz, DMSO) δ165.87,162.14,150.50,150.18,149.60,142.10,137.47,137.29,135.9 1,134.85,133.14,132.19,131.26,130.74,130.37,128.54,124.38,123.66,115.72,52.90.

[0255] Example 12: Preparation of 1-([1,1'-biphenyl]-3-yl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A12)

[0256]

[0257] The preparation method is the same as that of Example 1, except that [1,1'-biphenyl]-3-phenylboronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a pink solid (17 mg), with a two-step yield of 12%.

[0258] 1 H NMR (400MHz, DMSO-d6) δ8.64–8.62(m,2H),8.14(dd,J=8.0,1.6Hz,1H),7.89(dd,J=8.0,1.6Hz,2H),7.85(d,J=2.0Hz,1H),7.77–7.70(m,3H),7. 67(td,J=7.6,1.6Hz,1H),7.58(dd,J=8.4,4.8Hz,1H),7.49(t,J=7.6Hz,3H),7.40(t,J=7.2Hz,1H),7.34(t,J=7.6Hz,1H),6.64(d,J=8.8Hz,1H). 13 C NMR (101MHz, DMSO) δ162.17,150.49,150.18,149.60,142.60,142.32,139.24,137.68,137.33,135.99,13 3.18,131.25,129.57,128.67,128.52,128.47,127.88,127.81,127.16,124.42,123.60,115.99,115.56.

[0259] Example 13: Preparation of 3-(2,4-dioxo-3-(pyridin-3-yl)-3,4-dihydroquinazoline-1(2H)-yl)phenyl acetate (M1-A13)

[0260]

[0261] The preparation method is the same as that of Example 1, except that 3-methoxyphenylboronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a yellow solid (11 mg), with a two-step yield of 5%.

[0262] 1 H NMR(400MHz, DMSO-d6)δ8.63(d,J=6.4Hz,2H),8.18–8.10(m,3H),7.89(dd,J=8.0,2.0Hz,1H),7.84–7.78(m,2H ),7.66(t,J=8.0Hz,1H),7.58(dd,J=8.0,4.8Hz,1H),7.34(t,J=7.6Hz,1H),6.53(d,J=8.4Hz,1H),2.63(s,3H). 13CNMR(101MHz,DMSO)δ167.31,161.84,150.19,149.86,149.32,141.82,138.90,137.18,137.01,1 35.65,134.31,130.89,129.37,129.11,128.23,124.13,123.38,120.48,115.49,115.34,27.01.

[0263] Example 14: Preparation of 1-(3-(dibenzo[b,d]furan-2-yl)phenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A14)

[0264]

[0265] The preparation method is the same as that of Example 1, except that 3-(dibenzo[b,d]furan-2-yl)phenylboronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a white solid (9.5 mg), with a two-step yield of 7%.

[0266] 1 H NMR (400MHz, DMSO-d6) δ8.64(d,J=6.0Hz,2H),8.23–8.16(m,4H),8.06(t,J=2.0Hz,1H),7.91(dt,J=8.0,2.0Hz,1H),7.85(t,J=8.0H z,1H),7.78–7.68(m,3H),7.63–7.60(m,1H),7.60–7.52(m,3H),7.45(t,J=7.6Hz,1H),7.38(t,J=7.6Hz,1H),6.77(d,J=8.4Hz,1H). 13 C NMR (101MHz, DMSO) δ162.17,155.87,152.90,150.53,150.21,149.58,142. 30,138.09,137.52,137.33,135.99,135.26,134.97,131.10,129.78,129.5 7,129.29,128.51,128.33,127.38,125.05,124.39,124.29,124.23,123.88,123.81,123.66,121.80,121.46,118.84,118.17,116.02,115.67,112.25.

[0267] Example 15: Preparation of 1-(3-benzyloxyphenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A15)

[0268]

[0269] The preparation method is the same as that of Example 1, except that 3-benzyloxyphenylboronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a pink solid (17 mg), with a two-step yield of 6%.

[0270] 1 H NMR(400MHz,Chloroform-d)δ8.76–8.55(m,2H),8.27(dd,J=7.9,1.6Hz,1H),7.72(ddd,J=8.1,2.5,1.5Hz,1H),7.57–7.52(m,1H),7.52–7.48(m,1H),7 .48–7.36(m,5H),7.36–7.32(m,1H),7.31–7.26(m,1H),7.15(ddd,J=8.4,2 .4,1.0Hz,1H),7.06–6.94(m,2H),6.67(d,J=8.4Hz,1H),5.16–5.02(m,2H). 13 CNMR (101MHz, CDCl3) δ161.84,160.33,150.30,149.70,149.51,141.62,137.01,136.44,136.23,135. 41,131.16,129.01,128.68,128.24,127.61,123.65,121.27,116.37,115.86,115.43,115.22,70.39.

[0271] Example 16: Preparation of 1-(3,4-dimethylphenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A16)

[0272]

[0273] The preparation method is the same as that of Example 1, except that 3,4-dimethylphenylboronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a yellow solid (70 mg), with a two-step yield of 38%.

[0274] 1H NMR (400MHz, CDCl3) δ8.66(d,J=4.8Hz,2H),8.27(d,J=8.0Hz,1H),7.73(dd,J=8.4,2.0Hz,1H),7.54(t,J=8.0Hz,1H),7.45(dd,J=8.0,4.8 Hz,1H),7.36(d,J=8.0Hz,1H),7.28(t,J=7.6Hz,1H),7.17(s,1H),7.12(d,J=8.0Hz,1H),6.71(d,J=8.4Hz,1H),2.36(s,3H),2.34(s,3H). 13 C NMR (101MHz, CDCl3) δ161.94,150.53,149.71,149.41,141.95,139.10,138.33,136.46,135.34, 133.53,132.08,131.44,129.60,128.90,125.97,123.75,123.49,116.01,115.18,19.94,19.63.

[0275] Example 17: Preparation of 1-(3-chloro-5-methoxyphenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A17)

[0276]

[0277] The preparation method is the same as that of Example 1, except that 3-methoxyphenylboronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a yellow solid (8.1 mg), with a two-step yield of 5%.

[0278] 1 H NMR (400MHz, CDCl3) δ8.67(s,2H),8.28(dd,J=2.0,1.6Hz,1H),7.72(d,J=8.0Hz,1H),7.58(ddd,J=8.8,7.2,1.6Hz,1H),7.48(s ,1H),7.33–7.29(m,1H),7.07(t,J=2.0Hz,1H),7.00(t,J=2.0Hz,1H),6.84(t,J=2.0Hz,1H),6.70(d,J=8.4Hz,1H),3.84(s,3H). 13C NMR (101MHz, CDCl3) δ162.61,161.66,161.63,150.08,149.53,141.19,137.60,136.49,1 36.45,135.58,129.79,129.18,123.93,121.47,115.92,115.65,115.19,113.60,55.89.

[0279] Example 18: Preparation of 1-(3,4-dichlorophenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A18)

[0280]

[0281] The preparation method is the same as that of Example 1, except that 3,4-dichlorophenylboronic acid is used instead of phenylboronic acid in the second step to obtain the title compound as a yellow solid (30 mg), with a two-step yield of 18%.

[0282] 1 H NMR (400MHz, DMSO-d6) δ8.63(dd,J=4.8,1.6Hz,1H),8.59(d,J=2.4Hz,1H),8.13(dd,J=8.0,1.6Hz,1H),7.93(d,J=8.4Hz,1H),7.91(d,J=2. 4Hz,1H),7.85(ddd,J=8.0,2.4,1.2Hz,1H),7.67(ddd,J=8.4,7.2,1.6Hz,1H),7.60–7.55(m,2H),7.38–7.41(m,1H),6.66(d,J=8.4Hz,1H). 13 C NMR (101MHz, CDCl3) δ161.52,150.16,149.68,149.56,141.02,136.34,135.66,1 35.17,134.43,134.30,132.07,131.33,129.39,128.61,124.13,115.36,115.30.

[0283] Example 19: Preparation of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A19)

[0284]

[0285] The preparation method is the same as that of Example 1, except that 3,4-dichlorophenylboronic acid is used instead of phenylboronic acid in the second step to obtain the title compound as a yellow solid (77 mg), with a two-step yield of 25%.

[0286] 1 H NMR(400MHz,Chloroform-d)δ8.64(br,2H),8.27(dd,J=8.0,1.6Hz,1H),7.79–7.65( m,3H),7.62–7.51(m,2H),7.45(br,1H),7.32(t,J=7.6Hz,1H),6.60(d,J=8.4Hz,1H). 13 C NMR (101MHz, CDCl3) δ161.46,150.24,149.65,149.52,140.91,136.31,135.75,134.77,133.90,133.80,133.6 3,130.63(q,J=32.6Hz),129.47,128.77(q,J=5.0Hz),124.24,123.85,122.11(q,J=274.7Hz),115.40,115.15. 19 F NMR (376MHz,CDCl3)δ-62.93.

[0287] Example 20: Preparation of 1-(3,4-dichlorophenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A20)

[0288]

[0289] The preparation method is the same as that of Example 1, except that 3,4,5-trifluorophenylboric acid is used instead of phenylboric acid in the second step to obtain the title compound as a yellow solid (20 mg), with a two-step yield of 15%.

[0290] 1 H NMR(400MHz,Chloroform-d)δ8.72(s,2H),8.32(dd,J=7.9,1.6Hz,1H),7.96(d,J=8.4Hz,1H),7.73(d,J= 8.1Hz,1H),7.67–7.58(m,2H),7.48(dd,J=8.3,2.1Hz,1H),7.37(t,J=7.6Hz,1H),6.65(d,J=8.4Hz,1H). 13C NMR (101MHz, CDCl3) δ161.38, 149.99, 149.62 (d, J = 17.3Hz), 140.64, 139.93, 136.30, 135.74, 134.39, 132.49 ,129.79(d,J=32.1Hz),129.53,129.42(q,J=5.2Hz),127.89,124.33,122.34(d,J=274.7Hz),115.37,115.18. 19 F NMR(376MHz,DMSO)δ-133.22,-159.52.

[0291] Example 21: Preparation of 1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A21)

[0292]

[0293] The preparation method is the same as that of Example 1, except that 3-chloro-4-trifluoromethylphenylboronic acid is used instead of phenylboronic acid in the second step to obtain the title compound as a yellow solid (14 mg), with a two-step yield of 5%.

[0294] 1 H NMR (400MHz, DMSO-d6) δ8.63(d,J=14.4Hz,2H),8.19–8.14(m,2H),8.03(d,J=2.0Hz,1H),7.87(dt,J=8.4,2.0Hz,1H),7.77(dd, J=8.4,2.0Hz,1H),7.69(ddd,J=8.4,7.2,1.6Hz,1H),7.60(dd,J=8.4,4.8Hz,1H),7.39(t,J=7.6Hz,1H),6.67(d,J=8.4Hz,1H). 13 C NMR (101MHz, DMSO) δ162.01,150.22,150.06,149.72,141.75,141.49,137.23,136.14,133.23,132.90,132.63,132.61 ,130.31(q,J=5.4Hz),129.78,128.58,127.95(q,J=31.3Hz),124.47,124.01,123.11(q,J=274.7Hz),115.85,115.61. 19 F NMR (376 MHz, DMSO) δ -61.24.

[0295] Example 22: Preparation of 1-(3-benzyloxy-5-methylphenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A22)

[0296]

[0297] The preparation method is the same as that of Example 1, except that 3,4-dichlorophenylboronic acid is used instead of phenylboronic acid in the second step to obtain the title compound as a yellow solid (50 mg), with a two-step yield of 20%.

[0298] 1 H NMR(400MHz,Chloroform-d)δ8.66(s,2H),8.26(dd,J=8.0,1.6Hz,1H),7.72(dt,J=8.4,1.6Hz,1H),7.53(ddd,J=8.8,7.2 ,1.6Hz,1H),7.47–7.27(m,7H),6.98(d,J=2.0Hz,1H),6.82(s,2H),6.70(d,J=8.4Hz,1H),5.12–5.02(m,2H),2.40(s,3H). 13 C NMR (101MHz, CDCl3) δ161.86,160.20,150.32,149.66,149.41,141.75,141.66,136.73,136.49,136.38,135.39, 132.07,128.94,128.65,128.17,127.59,123.79,123.59,121.99,117.17,115.98,115.17,112.30,70.30,21.60.

[0299] Example 23: Preparation of 1-(2-naphthyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A23)

[0300]

[0301] The preparation method is the same as that of Example 1, except that 2-naphthaleneboronic acid is used instead of phenylboronic acid in the second step to obtain the title compound. Grey solid (10 mg), two-step yield 5%.

[0302] 1H NMR (400MHz, DMSO-d6) δ8.67(br,2H),8.19(d,J=8.8Hz,1H),8.18–8.15(m,1H),8.11(d,J=2.0Hz,1H),8.08(d,J=7.6 Hz,1H),8.04(d,J=8.0Hz,1H),7.92(d,J=8.0Hz,1H),7.72–7.56(m,5H),7.35(t,J=7.6Hz,1H),6.59(d,J=8.4Hz,1H). 13 C NMR(101MHz,DMSO)δ162.18,150.63,150.22,149.59,142.35,137.31,135.91,134.37,133.92,13 3.28,130.57,128.72,128.55,128.48,128.32,127.71,127.33,127.18,123.62,116.05,115.62.

[0303] Example 24: Preparation of 1,3-di(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A24)

[0304]

[0305] The preparation method is the same as that of Example 1, except that pyridine-3-boric acid is used in place of phenylboric acid in the second step to obtain the title compound as a yellow solid (7 mg), with a two-step yield of 4%.

[0306] 1 H NMR(400MHz,Chloroform-d)δ8.81(t,J=1.9Hz,1H),8.72(dd,J=1.9,1.0Hz,1H),8.41–8.36(m,2H),8.11(dd,J=8.5,1.6Hz,1H),7.71 (ddt,J=7.3,3.8,2.1Hz,2H),7.60(td,J=7.6,1.5Hz,1H),7.45(dd,J=7.5,1.5Hz,1H),7.36–7.34(m,2H),7.30(td,J=8.3,1.4Hz,1H). 13 C NMR (101MHz, CDCl3) δ161.72,152.13,147.74,146.78,144.73,144.73,141.95,136.4 8,133.17,131.51,130.66,128.77,127.31,124.49,124.58,123.35,120.85,118.91.

[0307] Example 25: Preparation of 1-(1-methyl-1H-pyrrol-3-yl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A25)

[0308]

[0309] The preparation method is the same as that of Example 1, except that 3,4-dichlorophenylboronic acid is used instead of phenylboronic acid in the second step to obtain the title compound as a yellow solid (13 mg), with a two-step yield of 8%.

[0310] 1 H NMR(400MHz,Chloroform-d)δ8.81(dd,J=1.9,1.0Hz,1H),8.38(ddd,J=4.2,1.9,1 .0Hz,1H),8.13(dd,J=8.6,1.6Hz,1H),7.71(dt,J=7.3,1.9Hz,1H),7.65–7.56(m,1 H),7.44(dd,J=7.4,1.4Hz,1H),7.38–7.25(m,2H),6.96(ddd,J=6.2,3.9,1.8Hz,1 H),6.47(dd,J=5.9,3.9Hz,1H),6.28(dd,J=5.9,1.7Hz,1H).3.65(d,J=0.6Hz,1H). 13 C NMR (101MHz, CDCl3) δ161.55,150.77,147.62,144.95,141.41,134.32,134.21,131. 40,130.60,126.95,123.87,123.85,120.06,119.54,119.46,107.72,106.01,33.23.

[0311] Example 26: Preparation of 1-(furan-2-yl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A26)

[0312]

[0313] The preparation method is the same as that of Example 1, except that furan-2-boric acid is used in place of phenylboric acid in the second step to obtain the title compound as a yellow solid (10 mg), with a two-step yield of 5%.

[0314] 1H NMR(400MHz,Chloroform-d)δ8.80(dd,J=2.0,1.0Hz,1H),8.38(ddd,J=4.2,1.9,1.0Hz ,1H),8.13(dd,J=8.5,1.6Hz,1H),7.77(dt,J=7.5,2.0Hz,1H),7.59(td,J=7.6,1.5Hz,1 H),7.54(dd,J=7.3,1.6Hz,1H),7.49(t,J=1.8Hz,1H),7.35(dd,J=7.3,4.2Hz,1H),7.3 0(ddd,J=8.5,7.8,1.6Hz,1H),7.03(dd,J=4.5,1.7Hz,1H),6.56(dd,J=4.4,1.9Hz,1H). 13 C NMR (101MHz, CDCl3) δ161.46,151.14,147.42,145.36,144.51,142.16,139.88,1 34.15,131.18,130.05,127.01,123.8,123.28,119.53,117.94,115.14,104.83.

[0315] Example 27: Preparation of 1-(Benzo[d][1,3]dioxolan-5-yl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A27)

[0316]

[0317] The preparation method is the same as that of Example 1, except that benzo[d][1,3]dioxolane-5-boronic acid is used in place of phenylboronic acid in the second step to obtain the title compound as a yellow solid (13 mg), with a two-step yield of 6%.

[0318] 1 H NMR(400MHz,Chloroform-d)δ8.81(dd,J=2.4,1.6Hz,1H),8.38(ddd,J=4.0,2.2 ,1.6Hz,1H),8.11(dd,J=8.5,1.6Hz,1H),7.72(dt,J=7.3,2.3Hz,1H),7.60(ddd ,J=8.1,7.4,1.5Hz,1H),7.45(dd,J=7.4,1.5Hz,1H),7.39–7.25(m,2H),7.00(d ,J=2.2Hz,1H),6.91(dd,J=8.6,2.3Hz,1H),6.80(d,J=8.6Hz,1H),5.97(s,2H). 13C NMR(101MHz,Chloroform-d)δ161.68,152.26,147.77,147.72,144.41,142.27,141.87,137.25,1 33.70,131.10,130.62,127.09,124.90,123.48,121.89,120.53,118.52,109.07,107.26,101.24.

[0319] Example 28: Preparation of 1-(isoquinolin-7-yl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A28)

[0320]

[0321] The preparation method is the same as that of Example 1, except that isoquinoline-7-boric acid is used in place of phenylboric acid in the second step to obtain the title compound as a yellow solid (15 mg), with a two-step yield of 7%.

[0322] 1 H NMR(404MHz,Chloroform-d)δ8.93(dd,J=1.5,0.9Hz,1H),8.83–8.74(m,2H),8.38(d dd,J=4.1,2.2,1.6Hz,1H),8.11(dd,J=8.5,1.5Hz,1H),8.03(t,J=2.0Hz,1H),7.92(d d,J=7.6,1.1Hz,1H),7.72(dt,J=7.4,2.2Hz,1H),7.65–7.56(m,1H),7.60–7.55(m,1 H),7.52(ddd,J=7.7,2.2,0.6Hz,1H),7.45(dd,J=7.4,1.5Hz,1H),7.39–7.26(m,2H). 13 C NMR(101MHz,Chloroform-d)δ161.51,151.13,148.93,147.22,146.03,144.50,141.41,137.94,134.22,1 31.22,131.03,130.33,130.00,127.36,127.07,125.49,123.78,123.58,121.68,120.81,120.38,118.56.

[0323] Example 29: Preparation of 1-(5-chlorothiophene-3-yl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A29)

[0324]

[0325] The preparation method is the same as that of Example 1, except that 5-chlorothiophene-3-boric acid is used in place of phenylboric acid in the second step to obtain the title compound as a yellow solid (18 mg), with a two-step yield of 9%.

[0326] 1 H NMR (404MHz, Chloroform-d) δ8.81(dd,J=2.3,1.6Hz,1H),8.38(ddd,J=4.0,2.2,1.6Hz,1H),8.11(dd,J=8.5,1.5Hz,1H),7.72(dt,J= 7.4,2.2Hz,1H),7.65–7.56(m,2H),7.45(dd,J=7.4,1.3Hz,1H),7.35(dd,J=7.4,4.3Hz,1H),7.34–7.25(m,1H),6.51(d,J=1.6Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ161.51,150.95,147.22,144.50,141.56,138.85,134.2 2,131.01,130.00,128.27,126.99,123.79,123.78,120.88,120.83,119.24,115.11.

[0327] Example 30: Preparation of 1-(1-methyl-1H-indol-6-yl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-A30)

[0328]

[0329] The preparation method is the same as that of Example 1, except that isoquinoline-7-boric acid is used in place of phenylboric acid in the second step to obtain the title compound as a yellow solid (15 mg), with a two-step yield of 7%.

[0330] 1H NMR (404MHz, Chloroform-d) δ8.81(t,J=1.9Hz,1H),8.38(dt,J=4.0,2.1Hz,1H),8.11(dd,J=8.5,1.6Hz,1H),7.75–7.67(m,2H),7.65–7. 56(m,2H),7.54–7.48(m,1H),7.45(dd,J=7.5,1.5Hz,1H),7.39–7.25(m,2H),7.23–7.17(m,1H),6.54–6.48(m,1H),3.76(d,J=0.6Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ161.51,150.94,147.22,144.50,141.71,138.04,136.40,134.22,131. 03,130.00,129.19,127.07,124.77,123.78,123.58,121.09,120.39,119.19,118.28,102.44,32.98.

[0331] Example 31: Preparation of 1-(3,4-dichlorophenyl)-3-(p-tolyl)quinazoline-2,4(1H,3H)-dione (M1-B1)

[0332]

[0333] The preparation method is the same as that of Example 1, except that p-methylaniline is used in place of 3-aminopyridine in the first step to obtain the title compound as a white solid (30 mg), with a two-step yield of 13%.

[0334] 1 H NMR(400MHz,Chloroform-d)δ8.11(dd,J=8.5,1.6Hz,1H),7.72(d,J=2.1Hz,1H),7.60(td ,J=7.8,1.6Hz,1H),7.52–7.38(m,5H),7.34–7.25(m,1H),7.20–7.13(m,2H),2.39(s,3H). 13 C NMR(101MHz,Chloroform-d)δ161.64,151.44,141.71,138.75,137.85,133.44,132.47,131. 03,130.01,129.50,127.86,127.07,126.13,126.00,125.95,123.58,120.38,118.41,20.71.

[0335] Example 32: 1-(3,4-dichlorophenyl)-3-cyclohexylquinazoline-2,4(1H,3H)-dione

[0336] Preparation of (M1-B2)

[0337]

[0338] The preparation method is the same as that of Example 1, except that cyclohexylamine is used in place of 3-aminopyridine in the first step to obtain the title compound as a white solid (220 mg), with a two-step yield of 70%.

[0339] 1 H NMR(400MHz,Chloroform-d)δ8.17(dd,J=8.0,1.6Hz,1H),7.62(d,J=8.4Hz,1H),7.46–7.42(m,2H),7.21–7.17(m,2H),6.50(d,J=8.4Hz,1 H),4.90(tt,J=12.0,3.6Hz,1H),2.49–2.38(m,2H),1.80(dt,J=13.2,3.2Hz,2H),1.71–1.60(m,3H),1.39–1.30(m,2H),1.23–1.15(m,1H). 13 C NMR (101MHz, CDCl3) δ161.95,150.44,140.80,135.99,134.63,134.14,133.75,131 .91,131.43,128.98,128.84,123.42,115.60,114.67,55.01,28.80,26.40,25.34.

[0341] Example 33: Preparation of 1-(3,4-dichlorophenyl)-3-(3-nitrophenyl)quinazoline-2,4(1H,3H)-dione (M1-B3)

[0342]

[0343] The preparation method is the same as that of Example 1, except that 3-nitroaniline is used in place of 3-aminopyridine in the first step to obtain the title compound as a yellow solid (150 mg), with a two-step yield of 63%.

[0344] 1H NMR(400MHz,Chloroform-d)δ8.24(t,J=1.9Hz,1H),8.11(dd,J=8.4,1.5Hz,1H),7.78(dt,J=8.8,1.8Hz,1H) ,7.72(d,J=2.3Hz,1H),7.68(dd,J=8.7,7.5Hz,1H),7.64–7.56(m,2H),7.50–7.38(m,2H),7.34–7.25(m,1H). 13 C NMR(101MHz,Chloroform-d)δ161.64,151.24,148.01,141.71,138.65,137.58,132.47,131.03,1 30.79,130.01,129.97,127.07,126.13,126.00,125.95,123.58,121.96,121.91,120.38,118.60.

[0345] Example 34: Preparation of 1-(3,4-dichlorophenyl)-3-(pyridin-2-yl)quinazoline-2,4(1H,3H)-dione (M1-B4)

[0346]

[0347] The preparation method is the same as that of Example 1, except that 2-aminopyridine is used instead of 3-aminopyridine in the first step to obtain the title compound as a yellow solid (30 mg), with a two-step yield of 13%.

[0348] 1 H NMR (400MHz, Chloroform-d) δ8.41 (dd, J=4.5, 1.7Hz, 1H), 8.13 (dd, J=8.5, 1.6Hz, 1H), 7.74–7. 65(m,2H),7.68–7.56(m,2H),7.50–7.42(m,2H),7.42(dd,J=8.5,2.1Hz,1H),7.34–7.25(m,2H). 13 C NMR(101MHz,Chloroform-d)δ161.08,151.45,148.67,148.57,141.86,138.69,137.92,132.4 7,131.03,130.01,127.09,126.13,126.00,125.98,125.67,123.65,120.40,119.44,117.17.

[0350] Example 35: Preparation of 1-(3,4-dichlorophenyl)-3-(pyridin-3-ylmethylene)quinazoline-2,4(1H,3H)-dione (M1-B5)

[0351]

[0352] The preparation method is the same as that of Example 1, except that pyridin-3-ylmethylamine is used in place of 3-aminopyridine in the first step to obtain the title compound as a white solid (30 mg), with a two-step yield of 12%.

[0353] 1 H NMR(400MHz,Chloroform-d)δ8.66–8.60(m,1H),8.46(dt,J=4.2,1.9Hz,1H),8.03(dd,J=8.4,1.6Hz,1H),7.75(dt,J= 7.9, 2.2Hz, 1H), 7.66–7.58 (m, 2H), 7.47 (d, J=8.5Hz, 1H), 7.38 (dd, J=8.7, 2.0Hz, 2H), 7.32–7.20 (m, 2H), 5.10 (s, 2H). 13 C NMR(101MHz,Chloroform-d)δ161.63,152.10,149.27,148.21,141.48,139.17,135.08,132.47,1 31.56,130.96,130.00,126.86,126.13,126.01,125.45,123.44,123.21,120.02,118.39,41.40.

[0354] Example 36: Preparation of 1-(3,4-dichlorophenyl)-3-(pyridazin-4-yl)quinazoline-2,4(1H,3H)-dione (M1-B6)

[0355]

[0356] The preparation method is the same as that of Example 1, except that 4-aminopyridazine is used in place of 3-aminopyridine in the first step to obtain the title compound as a white solid (40 mg), with a two-step yield of 10%.

[0357] 1H NMR(400MHz,Chloroform-d)δ9.35(d,J=5.6Hz,1H),9.25(d,J=2.8Hz,1H),8.28(d,J=8.0Hz,1H),7.71(d,J=8.4H z,1H),7.66–7.57(m,2H),7.55(d,J=2.4Hz,1H),7.36(t,J=7.6Hz,1H),7.30–7.27(m,1H),6.68(d,J=8.4Hz,1H). 13 CNMR (101MHz, CDCl3) δ160.75,151.84,151.36,149.29,140.92,136.18,135.06,134. 78,134.56,134.55,132.22,131.20,129.41,128.50,126.24,124.48,115.58,114.90.

[0358] Example 37: Preparation of 1-(3,4-dichlorophenyl)-3-(pyridazin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-B7)

[0359]

[0360] The preparation method is the same as that of Example 1, except that 3-aminopyridazine is used in place of 3-aminopyridine in the first step to obtain the title compound as a white solid (30 mg), with a two-step yield of 10%.

[0361] 1 H NMR(400MHz,Chloroform-d)δ8.84(dd,J=4.2,2.2Hz,1H),8.13(dd,J=8.5,1.6Hz,1H) ,7.76–7.69(m,2H),7.60(td,J=7.7,1.5Hz,1H),7.55–7.38(m,3H),7.34–7.25(m,1H). 13 C NMR(101MHz,Chloroform-d)δ161.03,150.96,149.16,146.35,141.77,138.65,132.47,1 31.03,130.01,129.19,127.09,126.13,126.00,125.98,125.91,123.65,120.40,117.14.

[0362] Example 38: Preparation of 1-(3,4-dichlorophenyl)-3-(pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione (M1-B8)

[0363]

[0364] The preparation method is the same as that of Example 1, except that aminopyrazine is used in place of 3-aminopyridine in the first step to obtain the title compound as a white solid (25 mg), with a two-step yield of 10%.

[0365] 1 H NMR(400MHz,Chloroform-d)δ8.77(d,J=1.7Hz,1H),8.41(dd,J=3.7,1.7Hz,1H),8.36(d,J=3.6Hz,1H),8.13(d d,J=8.6,1.6Hz,1H),7.72(d,J=2.1Hz,1H),7.60(td,J=7.8,1.6Hz,1H),7.50–7.39(m,2H),7.34–7.25(m,1H). 13 C NMR(101MHz,Chloroform-d)δ161.09,151.14,145.23,141.81,141.48,140.70,138.65,1 38.17,132.47,131.03,130.01,127.09,126.13,126.00,125.98,123.65,120.40,116.99.

[0366] Example 39: Preparation of 1-(3,4-dichlorophenyl)-3-(isoquinolin-4-yl)quinazoline-2,4(1H,3H)-dione (M1-B9)

[0367]

[0368] The preparation method is the same as that of Example 1, except that 4-aminoisoquinoline is used in place of 3-aminopyridine in the first step to obtain the title compound as a pale yellow solid (25 mg), with a two-step yield of 13%.

[0369] 1 H NMR(400MHz,Chloroform-d)δ8.93(d,J=1.9Hz,1H),8.77(t,J=2.0Hz,1H),8.15–8.03( m,2H),7.94–7.84(m,1H),7.72(d,J=2.1Hz,1H),7.65–7.38(m,5H),7.34–7.25(m,1H). 13C NMR(101MHz,Chloroform-d)δ161.48,150.43,145.35,143.35,141.83,138.65,132.47,131.76,131.03,1 30.71,130.01,127.08,126.83,126.74,126.52,126.13,126.00,125.95,124.51,123.58,120.39,117.84.

[0370] Example 40: Preparation of 1-(3,4-dichlorophenyl)-3-(quinolin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-B10)

[0371]

[0372] The preparation method is the same as that of Example 1, except that 3-aminoquinoline is used in place of 3-aminopyridine in the first step to obtain the title compound as a pale yellow solid (23 mg), with a two-step yield of 13%.

[0373] 1 H NMR(400MHz,Chloroform-d)δ8.79(d,J=2.0Hz,1H),8.21(t,J=2.0Hz,1H),8.11(dd,J=8.5,1.6Hz,1H),7.93(dd, J=7.3,1.3Hz,1H),7.79–7.69(m,2H),7.65–7.54(m,2H),7.50–7.42(m,1H),7.46–7.38(m,2H),7.34–7.25(m,1H). 13 C NMR(101MHz,Chloroform-d)δ161.62,150.85,145.48,142.10,141.71,138.65,134.09,132.47,131.03,130.9 2,130.01,129.38,127.71,127.07,126.49,126.13,126.00,125.95,124.45,123.97,123.58,120.38,118.28.

[0374] Example 41: Preparation of 1-(3,4-dichlorophenyl)-3-(1,5-naphthyridin-4-yl)quinazoline-2,4(1H,3H)-dione (M1-B11)

[0375]

[0376] The preparation method is the same as that of Example 1, except that 1,5-naphthyridin-4-amine is used instead of 3-aminopyridine in the first step to obtain the title compound as a pale yellow solid (15 mg), with a two-step yield of 10%.

[0377] 1 H NMR(400MHz,Chloroform-d)δ8.80(dd,J=4.5,2.2Hz,1H),8.61(d,J=5.3Hz,1H),8.11(dd,J=8.5,1.6Hz,1H),8.01(dd,J=7.3,2. 2Hz,1H),7.76–7.66(m,3H),7.64–7.56(m,1H),7.49–7.43(m,2H),7.41(dd,J=8.5,1.9Hz,1H),7.30(ddd,J=8.5,7.9,1.4Hz,1H). 13 C NMR (101MHz, CDCl3) δ161.54,150.53,148.32,148.12,142.07,140.51,139.61,138.17,137.59,1 36.46,132.58,131.00,130.10,127.81,126.17,126.03,126.40,123.66,120.44,117.78,117.66.

[0378] Example 42: Preparation of 1-(3,4-dichlorophenyl)-3-(1-methyl-1H-pyrrol-2-yl)quinazoline-2,4(1H,3H)-dione (M1-B12)

[0379]

[0380] The preparation method is the same as that of Example 1, except that 2-amino-N-methylpyrrole is used in place of 3-aminopyridine in the first step to obtain the title compound as a pale yellow solid (12 mg), with a two-step yield of 9%.

[0381] 1 H NMR(400MHz,Chloroform-d)δ8.13(dd,J=8.5,1.6Hz,1H),7.72(d,J=1.9Hz,1H),7.64–7.57(m,1H),7.50–7.39(m,3H),7.33–7 .26(m,1H),7.16(ddd,J=5.0,1.4,0.7Hz,1H),6.51(dd,J=6.1,1.6Hz,1H),6.29(dd,J=6.1,5.3Hz,1H),3.65(d,J=0.5Hz,3H). 13C NMR (101MHz, CDCl3) δ159.53,150.75,141.18,138.47,134.38,132.15,131.50,130.06,1 27.12,126.41,126.30,126.40,123.77,123.41,120.14,117.90,112.25,108.03,33.71.

[0382] Example 43: Preparation of 1-(3,4-dichlorophenyl)-3-(furan-2-yl)quinazoline-2,4(1H,3H)-dione (M1-B13)

[0383]

[0384] The preparation method is the same as that of Example 1, except that 2-aminofuran is used in place of 3-aminopyridine in the first step to obtain the title compound as a pale yellow solid (14 mg), with a two-step yield of 9%.

[0385] 1 H NMR(400MHz,Chloroform-d)δ8.13(dd,J=8.5,1.6Hz,1H),7.73(d,J=1.9Hz,1H),7.64–7.56(m,1H),7.52(t,J=1.8Hz,1H), 7.49–7.44(m,2H),7.42(dd,J=8.4,1.8Hz,1H),7.34–7.25(m,1H),7.01(dd,J=4.6,1.7Hz,1H),6.60(dd,J=4.6,1.8Hz,1H). 13 C NMR (101MHz, CDCl3) δ160.77,151.81,148.44,142.11,141.93,138.48,132.55,131.6 2,130.40,127.16,126.11,126.04,125.39,123.47,120.43,116.83,115.55,106.64.

[0386] Example 44: Preparation of 1-(3,4-dichlorophenyl)-3-(benzothiophene-2-yl)quinazoline-2,4(1H,3H)-dione (M1-B14)

[0387]

[0388] The preparation method is the same as that of Example 1, except that 2-aminofuran is used in place of 3-aminopyridine in the first step to obtain the title compound as a white solid (14 mg), with a two-step yield of 8%.

[0389] 1 H NMR(400MHz,Chloroform-d)δ8.13(dd,J=8.6,1.6Hz,1H),7.73(d,J=1.9Hz,1H ),7.67–7.57(m,2H),7.54–7.39(m,5H),7.37–7.26(m,2H),6.66–6.60(m,1H). 13 C NMR (101MHz, CDCl3) δ160.46,154.71,152.33,150.17,141.29,138.68,132.54,131.27,130.14,130. 30,127.61,126.34,126.51,126.07,125.89,124.60,123.77,120.94,120.54,116.18,112.31,98.53.

[0390] Example 45: Preparation of 1-(3,4-dichlorophenyl)-3-(5-phenylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-B15)

[0391]

[0392] The preparation method is the same as that of Example 1, except that 3-amino-5-phenylpyridine is used in place of 3-aminopyridine in the first step to obtain the title compound as a yellow solid (14 mg), with a two-step yield of 8%.

[0393] 1 H NMR (404MHz, Chloroform-d) δ8.80(t,J=1.9Hz,1H),8.58(t,J=1.8Hz,1H),8.23(t,J=2.0Hz,1H),8.11(dd,J=8 .5,1.6Hz,1H),7.72(d,J=2.1Hz,1H),7.59(ddd,J=16.0,8.0,1.6Hz,3H),7.50–7.34(m,4H),7.38–7.25(m,1H). 13 CNMR(101MHz,Chloroform-d)δ161.60,150.85,145.92,145.08,141.71,138.65,136.25,135.71,134.23,132. 47,131.03,130.01,128.82,128.01,127.07,126.81,126.13,126.00,125.95,125.77,123.58,120.38,118.28.

[0394] Example 46: 1-(3,4-dichlorophenyl)-6-methoxy-3-(pyridin-3-yl)quinazoline-2,4

[0395] Preparation of (1H,3H)-dione (M1-C1)

[0396]

[0397] The preparation method is the same as that of Example 1, except that methyl 2-amino-5-methoxybenzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a beige solid (54 mg), with a two-step yield of 32%.

[0398] 1 H NMR(400MHz,Chloroform-d)δ8.71(s,2H),7.69–7.60(m,3H),7.51(d,J=2.4Hz,2H),7.2 3(dd,J=8.4,2.4Hz,1H),7.13(dd,J=9.2,3.0Hz,1H),6.57(d,J=9.2Hz,1H),3.82(s,3H). 13 C NMR (101MHz, CDCl3) δ161.46,156.19,149.90,149.47,136.30,135.39,135.11,134.24,134. 08,132.01,131.33,130.40,130.30,130.24,128.69,124.46,116.99,115.97,110.12,55.98.

[0399] Example 47: Preparation of 1-(3,4-dichlorophenyl)-6-nitro-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-C2)

[0400]

[0401] The preparation method is the same as that of Example 1, except that methyl 2-amino-5-nitrobenzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (5.4 mg), with a two-step yield of 4%. 1 H NMR(400MHz,Chloroform-d)δ9.12(d,J=2.8Hz,1H),8.39(dd,J=9.2,2.8Hz,1H),7.72(t,J=8 .4Hz,2H),7.55(d,J=2.4Hz,1H),7.33–7.27(m,2H),7.13(d,J=2.8Hz,1H),6.90–6.78(m,2H).13 C NMR (101MHz, CDCl3) δ159.86,149.63,144.90,143.76,136.16,135.22,134.99,134.30,1 33.29,132.47,131.06,130.96,130.06,128.15,125.69,118.94,117.02,116.56,115.62.

[0402] Example 48: Preparation of 1-(3,4-dichlorophenyl)-6-nitro-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-C3)

[0403]

[0404] The preparation method is the same as that of Example 1, except that methyl 2-amino-5-trifluoromethylbenzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (100 mg), with a two-step yield of 40%.

[0405] 1 H NMR(400MHz,Chloroform-d)δ8.54(d,J=2.4Hz,1H),7.85–7.74(m,2H),7.72(d,J=8.4Hz,1H),7.55(d,J=2.4Hz,1 H),7.28(dd,J=8.4,2.4Hz,1H),7.17(d,J=8.0Hz,1H),6.88(s,1H),6.81(d,J=8.8Hz,1H),6.64(d,J=8.4Hz,1H). 13 CNMR(101MHz, CDCl3)δ160.55,156.48,149.89,148.91,143.21,136.39,134.82,134.70,134.55,132.47,132.34,132.15( q, J=3.5Hz), 130.65, 128.35, 127.08 (q, J=4.0Hz), 126.61 (q, J=34.4Hz), 123.25 (q, J=273.3Hz), 122.53, 116.24, 115.36. 19 FNMR (376MHz,CDCl3)δ-62.34.

[0406] Example 49: Preparation of 1-(3,4-dichlorophenyl)-6-iodo-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-C4)

[0407]

[0408] The preparation method is the same as that of Example 1, except that methyl 2-amino-5-iodobenzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a white solid (15 mg), with a two-step yield of 12%.

[0409] 1 H NMR (404MHz, Chloroform-d) δ8.81(t,J=1.9Hz,1H),8.38(dd,J=3.2,2.2Hz,2H),7.88(dd,J=8.2,2.2Hz,1H),7.75–7.68(m,2H),7.50–7.31(m,3H). 13 CNMR(101MHz,Chloroform-d)δ160.77,151.07,145.52,144.15,142.93,139.99,138.59,136. 24,136.23,132.69,129.85,128.88,125.81,125.76,125.60,123.71,121.72,118.36,89.30.

[0410] Example 50: Preparation of 1-(3,4-dichlorophenyl)-6-methyl-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-C5)

[0411]

[0412] The preparation method is the same as that of Example 1, except that methyl 2-amino-5-methylbenzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a white solid (70 mg), with a two-step yield of 38%.

[0413] 1 H NMR(400MHz,Chloroform-d)δ8.74–8.54(m,2H),8.07(t,J=1.2Hz,1H),7.73–7.65(m,2H),7.54(d,J=2.4Hz,1H),7.4 5(dd,J=8.4,4.8Hz,1H),7.39(dd,J=8.4,2.0Hz,1H),7.27(dd,J=8.4,2.4Hz,1H),6.57(d,J=8.4Hz,1H),2.42(s,3H). 13C NMR (101MHz, CDCl3) δ161.61,150.11,149.59,149.56,138.91,136.66,136.38,135.35,1 34.26,134.13,134.09,131.99,131.32,128.93,128.66,123.85,115.33,115.09,20.55.

[0414] Example 51: 1-(3,4-dichlorophenyl)-3-(pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4

[0415] Preparation of (1H,3H)-dione (M1-C6)

[0416]

[0417] The preparation method is the same as that of Example 1, except that methyl 2-aminonicotinate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (7.1 mg), with a two-step yield of 4%.

[0418] 1 H NMR(404MHz,Chloroform-d)δ8.81(dd,J=2.2,1.6Hz,1H),8.50(dd,J=4.7,2.2Hz,1H),8.38(dt,J=4.0,1.9Hz,1H),8.31(dd,J=8.4,2.2Hz,1 H),7.95(d,J=2.1Hz,1H),7.72(dt,J=7.3,2.2Hz,1H),7.61(dd,J=8.4,4.7Hz,1H),7.42(dd,J=8.4,2.2Hz,1H),7.35(dd,J=7.3,4.2Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ160.39,150.97,149.65,149.11,147.19,144.50,137.96,1 34.55,134.22,132.51,130.21,130.10,126.38,126.33,126.12,123.78,118.11,109.70.

[0419] Example 52: Preparation of 1-(3,4-dichlorophenyl)-3-(pyridin-3-yl)benzofurano[3,2-d]pyrimidine-2,4(1H,3H)-dione (M1-C7)

[0420]

[0421] The preparation method is the same as that of Example 1, except that methyl 3-aminobenzofuran-2-carboxylate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (9.2 mg), with a two-step yield of 4%.

[0422] 1 H NMR(404MHz,Chloroform-d)δ8.81(t,J=1.9Hz,1H),8.41–8.35(m,1H),8.01(dd,J=9.7,1.4Hz,1H),7.80–7.70(m,2H),7.57(d d,J=6.8,1.7Hz,1H),7.51(ddd,J=8.9,6.9,1.3Hz,1H),7.47(d,J=8.4Hz,1H),7.43(dd,J=8.5,2.1Hz,1H),7.39–7.30(m,2H). 13 C NMR(101MHz,Chloroform-d)δ154.71,153.45,150.08,147.29,144.48,138.13,133.66,132.94,132.5 7,130.84,130.26,130.05,128.09,126.25,126.17,125.79,123.76,123.68,122.87,120.34,113.67.

[0423] Example 53: Preparation of 1-(3,4-dichlorophenyl)-3-(pyridin-3-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (M1-C8)

[0424]

[0425] The preparation method is the same as that of Example 1, except that methyl 3-aminothiophene-2-carboxylate is used in place of methyl anthranilate in the first step to obtain the title compound as a white solid (40 mg), with a two-step yield of 18%.

[0426] 1 H NMR(400MHz,Chloroform-d)δ8.65(s,1H),8.59(s,1H),7.71(d,J=5.2Hz,1H),7.68(ddd,J=8.0,2.4,1.2Hz,1H),7.63( d,J=8.8Hz,1H),7.58(d,J=2.4Hz,1H),7.44(dd,J=8.0,4.8Hz,1H),7.31(dd,J=8.4,2.4Hz,1H),6.50(d,J=5.6Hz,1H). 13C NMR (101MHz, CDCl3) δ157.46,150.96,149.65,145.92,136.47,136.03,135.83,1 34.22,134.08,133.64,131.74,130.32,128.45,127.58,123.93,117.46,113.59.

[0427] Example 54: Preparation of 1-(3,4-dichlorophenyl)-3-(pyridin-3-yl)furo[3,2-d]pyrimidine-2,4(1H,3H)-dione (M1-C9)

[0428]

[0429] The preparation method is the same as that of Example 1, except that methyl 3-aminofuran-2-carboxylate is used in place of methyl anthranilate in the first step to obtain the title compound as a white solid (15 mg), with a two-step yield of 5%.

[0430] 1 H NMR (400MHz, Chloroform-d) δ8.81(br,2H),7.87–7.39(m,5H),7.33(dd,J=8.4,2.4Hz,1H),6.24(d,J=2.0Hz,1H). 13 C NMR (101MHz, CDCl3) δ152.72,150.66,149.80,148.26,138.62,136.26,135.18,1 34.06,134.00,132.16,130.99,130.26,129.61,127.84,127.62,126.80,102.53.

[0431] Example 55: 1-(3,4-dichlorophenyl)-3-(pyridin-3-yl)furo[3,2-d]pyrimidine-2,4

[0432] Preparation of (1H,3H)-dione (M1-C10)

[0433]

[0434] The preparation method is the same as that of Example 1, except that methyl 3-aminofuran-2-carboxylate is used instead of methyl anthranilate in the first step, and 4-aminoisoquinoline is used instead of 3-aminopyridine in the second step to obtain the title compound as a yellow solid (15 mg), with a two-step yield of 5%.

[0435] 1H NMR(404MHz,Chloroform-d)δ8.91(d,J=1.9Hz,1H),8.77(t,J=2.0Hz,1H),8.12–8.04(m,1H),8.04–7.97(m,1H),7.94–7.84(m,1H),7.7 7(d,J=2.3Hz,1H),7.57(dd,J=6.6,1.5Hz,1H),7.56–7.46(m,3H),7.47(d,J=8.4Hz,1H),7.43(dd,J=8.5,2.1Hz,1H),7.39–7.30(m,1H). 13 C NMR(101MHz,Chloroform-d)δ154.23,153.45,149.90,145.35,143.45,138.11,132.77,132.57,131.76,130.94,130.6 4,130.18,130.04,128.09,126.79,126.75,126.52,126.25,126.17,125.79,124.54,123.68,122.87,120.34,113.67.

[0436] Example 56: Preparation of 1-(3,4-dichlorophenyl)-6-phenyl-3-(pyridin-3-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (M1-C11)

[0437]

[0438] The preparation method is the same as that of Example 1, except that methyl 3-aminothiophene-5-phenyl-2-carboxylate is used in place of methyl anthranilate in the first step to obtain the title compound as a white solid (15 mg), with a two-step yield of 5%.

[0439] 1 H NMR(400MHz,Chloroform-d)δ8.81(t,J=1.9Hz,1H),8.41–8.35(m,1H),7.91(s,1H),7.77–7.68( m,2H),7.68–7.59(m,2H),7.47(d,J=8.4Hz,1H),7.47–7.38(m,4H),7.35(dd,J=7.3,4.2Hz,1H). 13C NMR(101MHz,Chloroform-d)δ157.83,150.88,147.25,145.32,144.50,139.99,139.72,134.94,133.9 3,132.53,130.16,130.05,128.83,127.74,126.73,126.70,126.19,126.09,123.78,116.85,112.19.

[0440] Example 57: Preparation of 1-(3,4-dichlorophenyl)-3-(pyridin-3-yl)-1,5,6,7-tetrahydro-2H-cyclopentadienyl[d]pyrimidine-2,4(3H)-dione (M1-C12)

[0441]

[0442] The preparation method is the same as that of Example 1, except that methyl 2-aminocyclopent-1-ene-1-carboxylate is used in place of methyl anthranilate in the first step to obtain the title compound as a white solid (18 mg), with a two-step yield of 5%.

[0443] 1 H NMR(400MHz,Chloroform-d)δ8.86–8.81(m,1H),8.38(dt,J=4.0,1.9Hz,1H),7.73–7.63(m,2H) ,7.48(d,J=8.6Hz,1H),7.34(ddd,J=9.9,8.0,3.3Hz,2H),2.77–2.62(m,4H),1.73–1.53(m,2H). 13 C NMR(101MHz,Chloroform-d)δ163.59,155.06,151.25,146.59,144.50,137.85,134.07, 132.20,129.97,129.39,126.46,125.98,125.51,123.85,112.53,32.43,29.08,22.41.

[0444] Example 58: Preparation of 1-(3,4-dichlorophenyl)-3-(pyridin-3-yl)-1,7-dihydro-2H-pyrrolo[2,3-d]pyrimidine-2,4(3H)-dione (M1-C13)

[0445]

[0446] The preparation method is the same as that of Example 1, except that methyl 2-amino-N-methylpyrrole-3-carboxylate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (19 mg), with a two-step yield of 7%.

[0447] 1 H NMR (400MHz, Chloroform-d) δ8.81(dd,J=2.2,1.6Hz,1H),8.38(ddd,J=4.0,2.2,1.6Hz,1H),7.86(d,J=1.9Hz,1H),7.72(dt, J=7.3,2.2Hz,1H),7.48(s,1H),7.40–7.31(m,2H),7.18(dd,J=6.6,4.5Hz,1H),6.30(d,J=4.5Hz,1H),3.73(d,J=0.5Hz,3H). 13 C NMR (101MHz, CDCl3) δ158.59,151.73,147.23,145.41,144.85,138.27,134.41,132. 18,130.33,130.12,126.62,125.55,124.72,123.68,120.13,108.14,102.30,35.43.

[0448] Example 59: Preparation of 1-(3,4-dichlorophenyl)-2,4-dioxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydroquinazoline-7-carbonitrile (M1-C14)

[0449]

[0450] The preparation method is the same as that of Example 1, except that methyl 2-amino-4-cyanobenzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (19 mg), with a two-step yield of 7%. 1 H NMR(400MHz,Chloroform-d)δ8.81(t,J=2.0Hz,1H),8.41–8.35(m,1H),8.28(d,J=9.0Hz,1H),7.98(d,J=2.2Hz ,1H),7.75–7.68(m,2H),7.63(dd,J=9.1,2.2Hz,1H),7.41(dd,J=8.4,2.2Hz,1H),7.35(dd,J=7.3,4.2Hz,1H). 13CNMR(101MHz,Chloroform-d)δ161.59,151.07,147.22,144.50,140.48,138.54,134.42,132.47,1 30.01,130.00,127.37,126.13,126.00,125.88,125.55,123.78,120.04,118.43,117.71,115.68.

[0451] Example 60: Preparation of 5-cyclopropyl-1-(3,4-dichlorophenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-C15)

[0452]

[0453] The preparation method is the same as that of Example 1, except that methyl 2-amino-6-cyclopropylbenzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a white solid (23 mg), with a two-step yield of 8%.

[0454] 1 H NMR(400MHz,Chloroform-d)δ8.81(t,J=1.9Hz,1H),8.41–8.35(m,1H),7.75–7.68(m,2 H),7.50–7.31(m,4H),7.30–7.23(m,1H),2.85(p,J=6.1Hz,1H),0.92(d,J=5.9Hz,4H). 13 C NMR(101MHz,Chloroform-d)δ161.94,150.91,147.06,144.38,142.62,141.91,138.88,134.68,132 .47,132.25,130.19,130.01,126.13,126.03,125.81,123.64,121.00,119.37,116.90,15.46,8.32.

[0455] Example 61: Preparation of 1-(3,4-dichlorophenyl)-5-(pyrrolidin-1-yl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-C16)

[0456]

[0457] The preparation method is the same as that of Example 1, except that methyl 2-amino-4-(pyrrolidin-1-yl)benzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (19 mg), with a two-step yield of 9%.

[0458] 1 H NMR(404MHz,Chloroform-d)δ8.83–8.78(m,1H),8.38(dt,J=4.0,1.8Hz,1H),8.09–8.02(m,1H),7.75–7.68(m,2H),7.47(d,J=8.4Hz,1H ),7.40(dd,J=8.4,2.2Hz,1H),7.35(dd,J=7.3,4.2Hz,1H),6.94–6.87(m,2H),3.48(dq,J=4.2,1.9Hz,4H),2.07(dt,J=4.0,2.2Hz,4H). 13 C NMR(101MHz,Chloroform-d)δ161.63,152.53,151.07,147.22,144.50,140.17,138.49,134.42,132. 47,130.01,129.99,128.52,126.13,126.01,125.88,123.78,113.12,109.99,105.06,48.27,25.37.

[0459] Example 62: Preparation of 1-(3,4-dichlorophenyl)-7-(3-(dimethylamino)phenyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-C17)

[0460]

[0461] The preparation method is the same as that of Example 1, except that methyl 3-amino-3'-(dimethylamino)-[1,1'-biphenyl]-4-carboxylate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (15 mg), with a two-step yield of 7%.

[0462] 1 H NMR(404MHz,Chloroform-d)δ8.83–8.78(m,1H),8.41–8.35(m,1H),8.22(d,J=9.0Hz,1H),7.75–7.67(m,3 H),7.50–7.31(m,4H),7.30–7.21(m,1H),6.90(t,J=1.9Hz,1H),6.72(dt,J=7.3,1.6Hz,1H),2.96(s,5H). 13C NMR(101MHz,Chloroform-d)δ161.68,150.93,150.85,147.22,144.50,140.30,139.77,138.45,137.92,134.22,132.47,1 30.01,130.00,129.39,128.72,126.13,126.00,125.98,123.78,123.76,122.14,117.16,116.04,114.07,112.09,40.70.

[0463] Example 63: Preparation of 1-(3,4-dichlorophenyl)-5-(4-methoxyphenyl)-3-(pyridin-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (M1-C18)

[0464]

[0465] The preparation method is the same as that of Example 1, except that methyl 2-amino-4-(4-methoxyphenyl)thiophene-3-carboxylate is used in place of methyl anthranilate in the first step to obtain the title compound as a white solid (19 mg), with a two-step yield of 8%.

[0466] 1 H NMR(400MHz,Chloroform-d)δ8.81(t,J=2.0Hz,1H),8.41–8.35(m,1H),7.77– 7.68(m,2H),7.42–7.31(m,4H),7.21(s,1H),7.01–6.93(m,2H),3.82(s,3H). 13 C NMR(101MHz,Chloroform-d)δ160.15,159.57,153.58,150.58,147.08,144.38,138.46,136.25,134.72,1 32.56,132.13,130.25,129.89,128.77,126.00,125.85,125.37,124.54,123.64,114.19,113.69,55.33.

[0468] Example 64: Preparation of 1-(3,4-dichlorophenyl)-7-(5-chloropyridin-3-yl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-C19)

[0469]

[0470] The preparation method is the same as that of Example 1, except that methyl 2-amino-4-(5-chloropyridin-3-yl)benzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (15 mg), with a two-step yield of 7%.

[0471] 1 H NMR(404MHz,Chloroform-d)δ8.83–8.78(m,1H),8.74(t,J=1.7Hz,1H),8.45(t,J=1.8Hz,1H),8.41–8.35(m,1H),8.25(d,J=9.0Hz,1H),7. 88(t,J=1.8Hz,1H),7.76(d,J=2.3Hz,1H),7.74–7.68(m,2H),7.54–7.46(m,1H),7.41(dd,J=8.4,2.2Hz,1H),7.35(dd,J=7.3,4.2Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ161.68,150.85,147.21,147.13,145.42,144.50,140.65,138.66,138.45,134.22,1 33.10,132.47,131.04,130.83,130.01,130.00,129.45,126.13,126.00,125.98,124.04,123.78,117.72,116.23.

[0473] Example 65: Preparation of 2-((1-(3,4-dichlorophenyl)-2,4-dioxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydroquinazolin-6-yl)oxy)acetonitrile (M1-C20)

[0474]

[0475] The preparation method is the same as that of Example 1, except that methyl 2-amino-5-(cyanomethoxy)benzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (15 mg), with a two-step yield of 7%.

[0476] 1H NMR(404MHz,Chloroform-d)δ8.81(t,J=1.9Hz,1H),8.41–8.35(m,1H),7.77–7.68(m,3H),7.57–7.46(m ,1H),7.41(dd,J=8.4,2.2Hz,1H),7.35(dd,J=7.3,4.2Hz,1H),7.04(dd,J=8.8,1.9Hz,1H),4.94(s,2H). 13 C NMR(101MHz,Chloroform-d)δ161.07,153.01,151.12,147.09,144.50,138.61,136.96,134.56,132. 47,130.09,130.01,126.13,126.03,125.86,123.78,120.99,120.41,119.30,115.04,111.60,53.73.

[0477] Example 66: Preparation of 1-(3,4-dichlorophenyl)-6-(methoxymethoxy)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-C21)

[0478]

[0479] The preparation method is the same as that of Example 1, except that methyl 2-amino-5-(methoxymethoxy)benzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a white solid (18 mg), with a two-step yield of 9%.

[0480] 1 H NMR(400MHz,Chloroform-d)δ8.83–8.78(m,1H),8.41–8.35(m,1H),7.77–7.68(m,3H),7.56–7.46(m,1H),7. 41(dd,J=8.4,2.2Hz,1H),7.35(dd,J=7.3,4.2Hz,1H),6.98(dd,J=8.9,2.7Hz,1H),5.00(s,2H),3.46(s,3H). 13C NMR(101MHz,Chloroform-d)δ161.09,154.07,151.12,147.09,144.50,138.61,136.88,134.56,132. 47,130.09,130.01,126.13,126.03,125.86,123.78,121.14,119.96,119.49,111.49,94.62,56.05.

[0481] Example 67: Preparation of 1-(3,4-dichlorophenyl)-7-(4,4-difluorocyclohexyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-C22)

[0482]

[0483] The preparation method is the same as that of Example 1, except that methyl 2-amino-4-(4,4-difluorocyclohexyl)benzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a white solid (18 mg), with a two-step yield of 9%.

[0484] 1 H NMR(400MHz,Chloroform-d)δ8.83–8.78(m,1H),8.41–8.35(m,1H),8.06(d,J=8.8Hz,1H),7.75–7.68(m,2H),7.5 0–7.31(m,3H),7.16(ddd,J=8.9,2.2,0.7Hz,1H),2.81–2.69(m,1H),2.19–2.06(m,1H),2.10–1.97(m,3H),2.01–

[0485] 1.90(m,2H),1.94–1.86(m,2H),1.90–1.81(m,1H). 13 C NMR(101MHz,Chloroform-d)δ161.62,150.85,147.82,147.22,144.50,139.93,138.40,134.22,132.47,130.01,130.00,126.83,126.13, 126.00,125.95,123.78,122.08,122.00,119.35,119.18,116.70,11 6.68,41.79,41.77,41.75,32.40,32.13,31.86,27.42,27.33,27.23. 19F NMR(381MHz,Chloroform-d)δ-100.44.

[0486] Example 68: Preparation of 1-(3,4-dichlorophenyl)-7-(1-methyl-1H-pyrrol-2-yl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-C23)

[0487]

[0488] The preparation method is the same as that of Example 1, except that methyl 2-amino-4-(1-methyl-1H-pyrrol-2-yl)benzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (18 mg), with a two-step yield of 13%.

[0489] 1 H NMR(400MHz,Chloroform-d)δ8.83–8.78(m,1H),8.41–8.35(m,1H),8.21(d,J=8.5Hz,1H),7.75–7.68(m,2H),7.60(d,J=2.2Hz,1H),7.41(dd,J= 8.4,2.2Hz,1H),7.35(dd,J=7.3,4.2Hz,1H),7.08–6.98(m,2H),6.43(dd,J=6.4,1.8Hz,1H),6.18(dd,J=6.4,4.7Hz,1H),3.67(d,J=0.7Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ161.71,150.85,147.22,144.50,139.54,138.45,136.39,134.22,132.47,130.82,1 30.01,130.00,127.53,126.26,126.13,126.00,125.98,124.83,123.78,118.38,117.05,110.15,107.11,33.25.

[0490] Example 69: Preparation of 1-(3,4-dichlorophenyl)-7-(3,5-dimethylmorpholinyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-C24)

[0491]

[0492] The preparation method is the same as that of Example 1, except that methyl 2-amino-4-(3,5-dimethylmorpholinyl)benzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (18 mg), with a two-step yield of 13%.

[0493] 1 H NMR(400MHz,Chloroform-d)δ8.83–8.78(m,1H),8.41–8.35(m,1H),8.07(d,J=8.9Hz,1H),7.75–7.68(m,2H),7.47(d,J=8.4Hz,1H),7.40(dd ,J=8.4,2.2Hz,1H),7.35(dd,J=7.3,4.2Hz,1H),6.96(d,J=2.2Hz,1H),6.73(dd,J=8.9,2.2Hz,1H),3.81–3.59(m,6H),1.17(d,J=6.7Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ161.63,151.07,149.98,147.22,144.50,139.49,138.49,134.42,132.47, 130.01,129.99,128.54,126.13,126.01,125.88,123.78,113.57,112.35,107.20,71.56,50.19,17.64.

[0494] Example 70: Preparation of 1-(3,4-dichlorophenyl)-7-(3,5-dimethylmorpholinyl)-3-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione (M1-C25)

[0495]

[0496] The preparation method is the same as that of Example 1, except that methyl 2-amino-4-(3,5-dimethylmorpholinyl)benzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (15 mg), with a two-step yield of 10%.

[0497] 1 H NMR(404MHz,Chloroform-d)δ8.83–8.78(m,1H),8.41–8.35(m,1H),7.99(dt,J =2.1,1.0Hz,1H),7.75–7.68(m,2H),7.50–7.29(m,4H),3.78(t,J=1.0Hz,2H). 13C NMR(101MHz,Chloroform-d)δ161.23,151.07,147.22,144.50,140.85,138.66,135.53,134.42,132. 47,132.04,130.01,130.00,126.16,126.13,126.00,125.84,123.78,119.37,116.24,63.56,45.08.

[0498] Example 71: Preparation of 4-(1-(3,4-dichlorophenyl)-2,4-dioxo-3-(pyridin-3-yl)-1,2,3,4-tetrahydroquinazolin-7-yl)-1-naphthalenecarbonitrile (M1-C26)

[0499]

[0500] The preparation method is the same as that of Example 1, except that methyl 2-amino-4-(4-cyanonaphthalen-1-yl)benzoate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (15 mg), with a two-step yield of 8%.

[0501] 1 H NMR(400MHz,Chloroform-d)δ8.83–8.78(m,1H),8.41–8.35(m,1H),8.27–8.19(m,2H),8.00–7.93(m,1H),7.89–7.81(m,2 H),7.78(d,J=2.2Hz,1H),7.75–7.68(m,2H),7.61–7.46(m,3H),7.41(dd,J=8.4,2.2Hz,1H),7.35(dd,J=7.3,4.2Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ161.68,150.85,147.22,144.50,140.84,140.09,138.45,136.25,134.50,134.22,132.47,131.80,131.20,1 30.01,130.00,128.48,127.72,127.66,126.96,126.13,126.00,125. 98,125.55,125.42,123.78,123.60,117.58,117.17,116.29,108.34.

[0502] Example 72: Preparation of 8-bromo-1-(3,4-dichlorophenyl)-3-(pyridin-3-yl)benzothieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (M1-C27)

[0503]

[0504] The preparation method is the same as that of Example 1, except that 5-bromo-3-aminobenzothiophene-2-carboxylic acid methyl ester is used in place of methyl anthranilate in the first step to obtain the title compound as a white solid (15 mg), with a two-step yield of 8%.

[0505] 1 H NMR(400MHz,Chloroform-d)δ8.81(t,J=2.0Hz,1H),8.41–8.35(m,1H),8.12(dd,J=7.8,1.3Hz,1H) ,7.85(dd,J=6.4,1.6Hz,1H),7.78(d,J=2.2Hz,1H),7.72(dt,J=7.3,2.2Hz,1H),7.55–7.31(m,4H). 13 C NMR(101MHz,Chloroform-d)δ158.10,150.24,147.25,144.50,141.93,140.53,138.19,133.93,132.5 1,130.77,130.16,130.03,126.93,126.42,126.17,125.73,125.48,124.87,124.27,123.78,115.64.

[0506] Example 73: Preparation of 1-(3,4-dichlorophenyl)-9-methyl-3-(pyridin-3-yl)-1,9-dihydro-2H-pyrrolo[3,2-h]quinazoline-2,4(3H)-dione (M1-C28)

[0507]

[0508] The preparation method is the same as that of Example 1, except that methyl 7-amino-1-methyl-1H-indole-6-carboxylate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (15 mg), with a two-step yield of 8%.

[0509] 1H NMR(400MHz,Chloroform-d)δ8.81(t,J=1.9Hz,1H),8.41–8.35(m,1H),8.25(d,J=8.4Hz,1H),7.78(d,J=2.0Hz,1H),7.72(dt,J=7.3,2.2Hz, 1H),7.50–7.40(m,1H),7.35(dd,J=7.3,4.2Hz,1H),7.24–7.18(m,1H),7.15(dd,J=4.8,0.8Hz,1H),6.49–6.43(m,1H),3.79(d,J=0.6Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ161.42,150.56,147.11,144.50,137.73,135.20,134.48,132.55,130. 22,129.99,126.74,126.65,126.05,125.68,125.60,123.78,120.62,119.06,117.05,103.39,33.94.

[0510] Example 74: Preparation of 5-(3,4-dichlorophenyl)-7-(pyridin-3-yl)thiazolo[4,5-g]quinazoline-6,8(5H,7H)-dione (M1-C29)

[0511]

[0512] The preparation method is the same as that of Example 1, except that methyl 6-aminobenzo[d]thiazole-5-carboxylate is used in place of methyl anthranilate in the first step to obtain the title compound as a yellow solid (15 mg), with a two-step yield of 8%.

[0513] 1 H NMR(404MHz,Chloroform-d)δ9.40(s,1H),8.83–8.78(m,2H),8.41–8.35(m,1H),8.0 0(s,1H),7.75–7.68(m,2H),7.41(dd,J=8.4,2.2Hz,1H),7.35(dd,J=7.3,4.2Hz,1H). 13C NMR(101MHz,Chloroform-d)δ161.02,159.18,151.10,149.28,147.11,144.50,139.89,138.37,1 36.62,134.46,132.47,130.01,129.99,126.13,126.01,125.86,123.78,121.74,116.49,110.57.

[0514] Test Example 1 SARS-CoV-2 3CL protease inhibition activity test

[0515] 1. Experimental materials:

[0516] SARS-CoV-2 3CL protease cDNA was synthesized by Hienzyme Biotech, plasmid pET-21a and Escherichia coli strain BL21 <de3>purchased from Novagen, nickel ion affinity column and S-200 gel filtration column were purchased from GE Healthcare, Dabcyl-KTSAVLQSGFRKM-Edans fluorescent substrate was synthesized by GL Biochemistry Ltd, the multifunctional microplate reader was Synergy 4 model from Biotek, and the 96-well black board was purchased from Corning.

[0517] 2. Experimental methods:

[0518] 1) Expression and purification of SARS-CoV-2 3CL protease:

[0519] Construction of SARS-CoV-2 pET 3CL-21x expression plasmid and transformation into Escherichia coli BL21 <de3>The strain was cultured to the logarithmic growth phase, and IPTG (isopropyl-β-D-thiogalactoside) was added to the culture medium at a final concentration of 0.5 mM. After inducing expression at 30°C for 3 hours, the bacterial sludge was collected by centrifugation. The lysate was added to resuspend the bacterial sludge, and the supernatant was collected by centrifugation after ultrasonic disruption. The SARS-CoV-23CL protein with a 6xHis tag at the C-terminus was purified by a nickel ion affinity column and an S-200 gel filtration column.

[0520] 2) Test of compound's inhibitory activity against SARS-CoV-2 3CL protease:

[0521] Different concentrations of compounds or DMSO were added to the dilution of SARS-CoV-2 3CL protease (the final concentration of SARS-CoV-2 3CL protease was 0.5 μM), and the diluent was a buffer containing 40 mM PBS, 100 mM NaCl, 1 mM EDTA, 0.1% Triton X-100, pH 7.3. After incubation for a certain period of time, Dabcyl-KTSAVLQSGFRKM-Edans fluorescent substrate (the final concentration of the substrate was 20 μM) was added to start the reaction, and the change in fluorescence intensity at 460 nm was measured by excitation at 360 nm. The reading was taken every 36 seconds and recorded continuously for 20 minutes, and then the inhibition rate (RFU / min) and IC were calculated based on the average rate of the entire interval. 50 The Hill1 formula was used for fitting.

[0522] 3. Experimental results

[0523] The experimental results are shown in the following table.

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535] A:0.01μM <IC 50 <0.1 μM

[0536] B:0.1μM <IC 50 <1μM

[0537] C:1μM <IC 50 <10 μM

[0538] D:10μM <IC 50 <100 μM

[0539] As can be seen from the above table, the compounds of the present invention have excellent SARS-CoV-2 3CL protease inhibitory activity.

[0540] Test Example 2 In vitro antiviral test

[0541] The 20 mM compound in DMSO was diluted to 200 μM to 0.00256 μM using DMEM containing 1% fetal bovine serum. DMSO medium (1%) was used as a negative control. Vero cells cultured overnight in a 96-well plate were infected with 0.01 MOI virus for 2 h, the culture medium was removed, and fresh culture medium containing inhibitors was added. The experiment was performed in quadruplicate. After 48 h, three replicate cells were lysed in lysis buffer. Viral RNA was extracted from the supernatant of 100 infected cells using an automated nucleic acid extraction system (TIANLONG, China). SARS-CoV-2 detection was performed using a one-step PrimeScript RT-PCR kit (TaKaRa, Japan) using Real-time PCR system (Roche, Rotkreuz, Switzerland). ORF1ab was amplified from cDNA, cloned into MS2-nCoV-ORF1ab, and used as a plasmid standard after sequencing and identification. The plasmid was serially diluted (103-109 copies), the copy number was determined, and a standard curve was obtained. The primers used for quantitative PCR were as follows: ORF1ab-F: 5'-AGAAGATTGGTTAGATGATGATAGT-3', ORF1ab-R: 5'-TTCCATCTCTAATTGAGGTTGAACC-3', and probe 5"-FAM-TCCTCACTGCCGTCTTGTTGACCA-BHQ1-3". After 72 h, the changes in the pathological effects of the remaining replicating cells were observed under a microscope.

[0542] Microsoft Excel 2016 was used to convert the Ct value into the viral copy number (10 y ), formula y = (Ct-35.461) / -3.4546. The percentage of viral copies of different concentrations of inhibitors was divided by the viral copy number of the negative control using Microsoft Excel 2016 to obtain the inhibition rate or relative RNA copy number percentage. GraphPad Prism 8.0 was used to fit the log (inhibitor) mode and the response (three-parameter) mode to draw the inhibition curve. EC50 was also calculated in the result table using GraphPad Prism 8.0. GraphPad Prism 8.0 performed a bar graph of relative RNA copies in the percentage of inhibitors and an unpaired t-test between two bars.

[0543] The compounds of the present invention can effectively inhibit the activity of SARS-CoV-2 virus.

[0544] Test Example 3 Plaque Reduction Test

[0545] 2×10 5 Vero cells were seeded in 24-well plates and cultured overnight in 24-well plates. The cells were infected with 200 μL SARSCoV-2 (100 PFU) for 2 hours, and then the culture medium was removed and the inhibitors of fresh culture medium (DMEM containing 2% fetal bovine serum and 1.2% Avicell) at appropriate concentrations were added to the cells. The cells were incubated at 37°C in 5% CO2 for 72 hours. The overlay was discarded. The cells were fixed with 4% polyformaldehyde (Solarbio, P1110) for 30 minutes and stained with crystal violet working solution for 15 minutes.

[0546] The compounds of the present invention can effectively inhibit the activity of SARS-CoV-2 virus.

[0547] Test Example 4 SARS-CoV-2 3CL protease mutant and MERS-CoV 3CL protease inhibitory activity test

[0548] 1. Experimental materials:

[0549] SARS-CoV-2 3CL protease E166V mutant and MRES-CoV 3CL protease cDNA were purchased from Hienzyme Biotech, and the activity was determined according to the method of Experimental Example 1.

[0550] 2. Experimental results

[0551] Some experimental results are shown in the following table.

[0552]

[0553]

[0554] A:0.01μM <IC 50 <0.1 μM

[0555] B:0.1μM <IC 50 <1μM

[0556] C:1μM <IC 50 <10 μM

[0557] As can be seen from the above table, the compounds of the present invention have excellent coronavirus 3CL protease inhibitory activity (such as SARS-CoV-2 3CL protease mutants and MERS-CoV 3CL protease inhibitory activity).

[0558] Test Example 5 Cytotoxicity Evaluation

[0559] 1. Cell culture and passaging

[0560] Vero E6 cells were cultured in DMEM medium containing penicillin (final concentration of 100U / mL), streptomycin (final concentration of 100μg / mL) and 10% FBS, and cultured at 37°C in a humidified atmosphere of 95% air and 5% carbon dioxide. When the cells grew to 90%, discard the old medium, wash the cells 2-3 times with 1-3mL PBS, discard PBS, add 1-3mL 0.02% EDTA / 0.25% trypsin mixed digestion solution, incubate at 37°C for 2-3 minutes, observe the cells become round, quickly add the same amount of complete medium as the digestion solution to terminate digestion, gently blow and collect the cells. Centrifuge at 1000rpm for 4min, discard the supernatant, resuspend the cells with complete medium, culture in bottles, and change the medium every other day.

[0561] 2. Cytotoxicity evaluation

[0562] The cytotoxicity of the compound was detected by the CCK-8 method. Vero E6 cells were seeded at a density of 10,000 / well in a 96-well plate. After incubation overnight to allow the cells to adhere, the original culture medium was removed and complete culture medium containing a given concentration of the test compound or an equal amount of DMSO (control group) was added to each well. Three replicate wells were set for each compound. Cell viability was detected by the CCK-8 method 48 hours after administration. The blank group was a well containing no cells but only culture medium and CCK-8 reagent, and its OD value was then read at 450nm using an enzyme reader. The formula for calculating cell viability is: Cell viability (%) = OD to be tested - OD blank / OD control - OD blank × 100.

[0563] Some experimental results are as follows Figure 1 shown.

[0564] The experimental results show that the compound of the present invention has lower cytotoxicity.

Claims

1. A compound represented by formula O or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, in: R 1 is selected from phenyl, C3-C6 cycloalkyl, 5-10 membered heteroaryl, pyridyl C1-C6 alkylene, and the phenyl, C3-C6 cycloalkyl, 5-10 membered heteroaryl are each independently optionally substituted by 1-2 (preferably 1) substituents selected from C1-C6 alkyl, nitro, and phenyl; Preferably, R 1 is selected from phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl, The phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl are each independently optionally substituted by 1-2 (preferably 1) substituents selected from methyl, nitro, phenyl; More preferably, R 1 is selected from phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl, The phenyl, pyrrolyl and pyridyl groups are each independently optionally substituted by 1-2 (preferably 1) substituents selected from methyl, nitro and phenyl; Most preferably, R 1 Selected from R 2 is selected from phenyl, naphthyl, 5-10 membered heteroaryl, The phenyl, naphthyl, and 5-10 membered heteroaryl groups are each independently and optionally substituted by 1-3 substituents selected from the following: C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, Preferably, R 2 Selected from phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoquinolyl, indolyl, The phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoquinolyl, indolyl are each independently optionally substituted by 1-3 substituents selected from the following: -CH3, -F, -Cl, -Br, -OCH3, -SCH3, -CF3, -NO2, Phenyl, Preferably, R 2 Selected from: 1) in: Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any one, any two or any three are selected from hydrogen, C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, The rest is hydrogen; Preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any one (such as Z 2 or Z 3 ) is selected from hydrogen, C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, The rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In any two (such as Z 2 and Z 3 , or Z 2 and Z 4 ) is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, phenyl-C1-C6 alkylene-O-, and the rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any three (such as Z 2 , Z 3 and Z 4 ) is selected from halogen, the remainder being hydrogen; More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any one (such as Z 2 or Z 3 ) is selected from hydrogen, -CH3, -Cl, -Br, -OCH3, -SCH3, -CF3, -NO2, Phenyl, The rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In any two (such as Z 2 and Z 3 , or Z 2 and Z 4 ) is selected from -CH3, -F, -Cl, -Br, -OCH3, -CF3, The rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any three (such as Z 2 , Z 3 and Z 4 ) is selected from -F, the rest are hydrogen; Most preferably, As a whole, selected from: 2) in: Z 1 is selected from C1-C6 alkyl; preferably, Z 1 is -CH3; 3) in: Z 1 is selected from halogen; preferably, Z 1 is -Cl; 4) in: Z 1 is selected from C1-C6 alkyl; preferably, Z 1 is -CH3; 5) Most preferably, R 2 Selected from Ring A is selected from a benzene ring, a 5-9 membered heteroaromatic ring, and a C4-C6 cycloolefin; Preferably, ring A is selected from a benzene ring, a pyridine ring, a benzofuran ring, a benzothiophene ring, a benzothiazole ring, an indole ring, a furan ring, a thiophene ring, a pyrrole ring, and a cyclopentene ring; More preferably, Ring A is selected from Among them, carbon atom No. 1 corresponds to carbon atom No. 1 in the parent nucleus, and carbon atom No. 2 corresponds to carbon atom No. 2 in the parent nucleus; n is selected from 0 and 1; R 3 is selected from halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 heterocycloalkyl, phenyl, naphthyl, 5-6 membered heteroaryl, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 heterocycloalkyl, phenyl, naphthyl, 5-6 membered heteroaryl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group; Preferably, R 3 is selected from halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group; More preferably, R 3 is selected from halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, pyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group; R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, R a , R b Each independently selected from C1-C6 alkyl; More preferably, R a , R b All are methyl; More preferably, R 3 is selected from -Br, -I, -NO2, cyano, methyl, cyclopropyl, cyclohexyl, -CF3, methoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridinyl, pyrrolyl, and the methyl, cyclohexyl, methoxy, pyrrolyl, morpholinyl, phenyl, naphthyl, pyridinyl are each independently optionally substituted by 1-2 selected from -F, -Cl, cyano, methyl, methoxy, substituted by a group; Most preferably, R 3 Selected from -Br, -I, -NO2, cyano, -CH3, cyclopropyl, -CF3, -OCH3, Phenyl, Most preferably, the A ring together with R 3 and n as a whole, selected from Among them, carbon atom No. 1 corresponds to carbon atom No. 1 in the parent nucleus, and carbon atom No. 2 corresponds to carbon atom No. 2 in the parent nucleus.

2. The compound according to claim 1, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, wherein: The compound has the structural formula shown in Formula I, in: R 1 is selected from phenyl, C3-C6 cycloalkyl, 5-10 membered heteroaryl, pyridyl C1-C6 alkylene, and the phenyl, C3-C6 cycloalkyl, 5-10 membered heteroaryl are each independently optionally substituted by 1-2 (preferably 1) substituents selected from C1-C6 alkyl, nitro, and phenyl; Preferably, R 1 is selected from phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl, The phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl are each independently optionally substituted by 1-2 (preferably 1) substituents selected from methyl, nitro, phenyl; More preferably, R 1 is selected from phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl, The phenyl, pyrrolyl and pyridyl groups are each independently optionally substituted by 1-2 (preferably 1) substituents selected from methyl, nitro and phenyl; Most preferably, R 1 Selected from R 2 is selected from phenyl, naphthyl, 5-10 membered heteroaryl, The phenyl, naphthyl, and 5-10 membered heteroaryl groups are each independently and optionally substituted by 1-3 substituents selected from the following: C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, Preferably, R 2 Selected from phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoquinolyl, indolyl, The phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoquinolyl, indolyl are each independently optionally substituted by 1-3 substituents selected from the following: -CH3, -F, -Cl, -Br, -OCH3, -SCH3, -CF3, -NO2, Phenyl, Preferably, R 2 Selected from: 1) in: Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any one, any two or any three are selected from hydrogen, C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, The rest is hydrogen; Preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any one (such as Z 2 or Z 3 ) is selected from hydrogen, C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, The rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In any two (such as Z 2 and Z 3 , or Z 2 and Z 4 ) is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, phenyl-C1-C6 alkylene-O-, and the rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any three (such as Z 2 , Z 3 and Z 4 ) is selected from halogen, the remainder being hydrogen; More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any one (such as Z 2 or Z 3 ) is selected from hydrogen, -CH3, -Cl, -Br, -OCH3, -SCH3, -CF3, -NO2, Phenyl, The rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In any two (such as Z 2 and Z 3 , or Z 2 and Z 4 ) is selected from -CH3, -F, -Cl, -Br, -OCH3, -CF3, The rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any three (such as Z 2 , Z 3 and Z 4 ) is selected from -F, the rest are hydrogen; Most preferably, As a whole, selected from: 2) in: Z 1 is selected from C1-C6 alkyl; preferably, Z 1 is -CH3; 3) in: Z 1 is selected from halogen; preferably, Z 1 is -Cl; 4) in: Z 1 is selected from C1-C6 alkyl; preferably, Z 1 is -CH3; 5) Most preferably, R 2 Selected from R 3a , R 3b , R 3c , R 3d Any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 heterocycloalkyl, phenyl, naphthyl, 5-6 membered heteroaryl, the rest is hydrogen, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 heterocycloalkyl, phenyl, naphthyl, 5-6 membered heteroaryl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group; Preferably, R 3a , R 3b , R 3c , R 3d Any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl, the rest is hydrogen, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group; More preferably, R 3a , R 3b , R 3c , R 3d Any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl, the rest is hydrogen, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, pyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group; R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, R a , R b Each independently selected from C1-C6 alkyl; More preferably, R a , R b All are methyl; More preferably, R 3a , R 3b , R 3c , R 3d Any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, -I, -NO2, cyano, methyl, cyclopropyl, cyclohexyl, -CF3, methoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridinyl, pyrrolyl, the rest is hydrogen, and the methyl, cyclohexyl, methoxy, pyrrolyl, morpholinyl, phenyl, naphthyl, pyridinyl are each independently optionally substituted by 1-2 selected from -F, -Cl, cyano, methyl, methoxy, substituted by a group; Most preferably, R 3a , R 3b , R 3c , R 3d Any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, -I, -NO2, cyano, -CH3, cyclopropyl, -CF3, -OCH3, The remainder is hydrogen.

3. The compound according to claim 2, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, wherein: The compound has the structural formula shown in Formula I-1, in: R 2 is selected from phenyl, naphthyl, 5-10 membered heteroaryl, The phenyl, naphthyl, and 5-10 membered heteroaryl groups are each independently and optionally substituted by 1-3 substituents selected from the following: C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, Preferably, R 2 Selected from phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoquinolyl, indolyl, The phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, isoquinolyl, indolyl are each independently optionally substituted by 1-3 substituents selected from the following: -CH3, -F, -Cl, -Br, -OCH3, -SCH3, -CF3, -NO2, Phenyl, Preferably, R 2 Selected from: 1) in: Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any one, any two or any three are selected from hydrogen, C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, The rest is hydrogen; Preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any one (such as Z 2 or Z 3 ) is selected from hydrogen, C1-C6 alkyl, halogen, nitro, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkyl, C1-C6 alkyl-C(=O)-, C1-C6 alkyl-OC(=O)-, C1-C6 alkyl-C(=O)-O-, phenyl, phenyl-C1-C6 alkylene-O-, The rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In any two (such as Z 2 and Z 3 , or Z 2 and Z 4 ) is selected from C1-C6 alkyl, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, phenyl-C1-C6 alkylene-O-, and the rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any three (such as Z 2 , Z 3 and Z 4 ) is selected from halogen, the remainder being hydrogen; More preferably, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any one (such as Z 2 or Z 3 ) is selected from hydrogen, -CH3, -Cl, -Br, -OCH3, -SCH3, -CF3, -NO2, Phenyl, The rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 In any two (such as Z 2 and Z 3 , or Z 2 and Z 4 ) is selected from -CH3, -F, -Cl, -Br, -OCH3, -CF3, The rest is hydrogen; or, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Among them, any three (such as Z 2 , Z 3 and Z 4 ) is selected from -F, the rest are hydrogen; Most preferably, As a whole, selected from: 2) in: Z 1 is selected from C1-C6 alkyl; preferably, Z 1 is -CH3; 3) in: Z 1 is selected from halogen; preferably, Z 1 is -Cl; 4) in: Z 1 is selected from C1-C6 alkyl; preferably, Z 1 is -CH3; 5) Most preferably, R 2 Selected from R 3a , R 3b , R 3c , R 3d Any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 heterocycloalkyl, phenyl, naphthyl, 5-6 membered heteroaryl, the rest is hydrogen, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 heterocycloalkyl, phenyl, naphthyl, 5-6 membered heteroaryl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group; Preferably, R 3a , R 3b , R 3c , R 3d Any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl, the rest is hydrogen, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group; More preferably, R 3a , R 3b , R 3c , R 3d Any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, halogen, nitro, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl, pyrrolyl, the rest is hydrogen, and the C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, pyrrolyl, morpholinyl, phenyl, naphthyl, pyridyl are each independently optionally substituted by 1-2 selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -NR a R b substituted by a group; R a , R b Each is independently selected from hydrogen, C1-C6 alkyl; Preferably, R a , R b Each independently selected from C1-C6 alkyl; More preferably, R a , R b All are methyl; More preferably, R 3a , R 3b , R 3c , R 3d Any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, -I, -NO2, cyano, methyl, cyclopropyl, cyclohexyl, -CF3, methoxy, tetrahydropyrrolyl, morpholinyl, phenyl, naphthyl, pyridinyl, pyrrolyl, the rest is hydrogen, and the methyl, cyclohexyl, methoxy, pyrrolyl, morpholinyl, phenyl, naphthyl, pyridinyl are each independently optionally substituted by 1-2 selected from -F, -Cl, cyano, methyl, methoxy, substituted by a group; Most preferably, R 3a , R 3b , R 3c , R 3d Any one (such as R 3a , R 3b or R 3c ) is selected from hydrogen, -I, -NO2, cyano, -CH3, cyclopropyl, -CF3, -OCH3, The remainder is hydrogen.

4. The compound according to claim 2, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, wherein: The compound has the structural formula shown in Formula I-2, in: R 1 is selected from phenyl, C3-C6 cycloalkyl, 5-10 membered heteroaryl, pyridyl C1-C6 alkylene, and the phenyl, C3-C6 cycloalkyl, 5-10 membered heteroaryl are each independently optionally substituted by 1-2 (preferably 1) substituents selected from C1-C6 alkyl, nitro, and phenyl; Preferably, R 1 is selected from phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl, The phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl are each independently optionally substituted by 1-2 (preferably 1) substituents selected from methyl, nitro, phenyl; More preferably, R 1 is selected from phenyl, cyclohexyl, pyridyl, pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, pyrrolyl, benzothienyl, The phenyl, pyrrolyl and pyridyl groups are each independently optionally substituted by 1-2 (preferably 1) substituents selected from methyl, nitro and phenyl; Most preferably, R 1 Selected from 5. The compound of claim 1 or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, wherein: The compound has the structural formula shown in Formula II, in: R 1 is selected from 6-10 membered heteroaryl; Preferably, R 1 is selected from pyridyl, isoquinolyl; More preferably, R 1 Selected from Ring A is selected from a 5-9 membered heteroaromatic ring, a C4-C6 cycloolefin; Preferably, ring A is selected from a pyridine ring, a benzofuran ring, a benzothiophene ring, a benzothiazole ring, an indole ring, a furan ring, a thiophene ring, a pyrrole ring, and a cyclopentene ring; More preferably, Ring A is selected from Among them, carbon atom No. 1 corresponds to carbon atom No. 1 in the parent nucleus, and carbon atom No. 2 corresponds to carbon atom No. 2 in the parent nucleus; n is selected from 0 and 1; R 3 is selected from halogen, C1-C6 alkyl, and phenyl, wherein the C1-C6 alkyl and phenyl are each independently optionally substituted by 1-2 (preferably 1) groups selected from C1-C6 alkoxy; Preferably, R 3 is selected from halogen, C1-C6 alkyl, phenyl, wherein the phenyl is optionally substituted by 1-2 (preferably 1) groups selected from C1-C6 alkoxy; More preferably, R 3 Selected from -Br, -CH3, phenyl, Most preferably, the A ring together with R 3 and n as a whole, selected from Among them, carbon atom No. 1 corresponds to carbon atom No. 1 in the parent nucleus, and carbon atom No. 2 corresponds to carbon atom No. 2 in the parent nucleus.

6. The compound according to any one of claims 1 to 5, or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, wherein: The compound is selected from:

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, and optionally a pharmaceutically acceptable excipient.

8. Use of the compound according to any one of claims 1 to 6, or the stereoisomer, prodrug, crystal form, pharmaceutically acceptable salt or pharmaceutically acceptable solvate of the compound, or the pharmaceutical composition according to claim 7, in one or more of the following (1) to (2): (1) Use in the preparation of drugs for treating diseases or infections caused by coronaviruses (preferably SARS-CoV-2 and its mutants and MERS-CoV); (2) Use in the preparation of reagents for inhibiting coronavirus (preferably SARS-CoV-2 and its mutants and MERS-CoV) 3CL protease.

9. The use according to claim 8, wherein The disease caused by SARS-CoV-2 and its mutant strains is COVID-19; Preferably, the disease or infection caused by SARS-CoV-2 and its mutants is a respiratory disease, such as simple infection, mild pneumonia, severe pneumonia, acute respiratory infection, severe acute respiratory infection (SARI), hypoxic respiratory failure, acute respiratory distress syndrome, sepsis, septic shock, etc.; Preferably, the simple infection includes but is not limited to fever, cough, sore throat, nasal congestion, fatigue, headache, muscle pain or discomfort; preferably, the mild pneumonia includes but is not limited to cough, dyspnea and / or shortness of breath; preferably, the severe pneumonia includes but is not limited to increased respiratory rate, severe respiratory failure or dyspnea, central cyanosis, drowsiness, unconsciousness or convulsions, convulsions; preferably, the acute respiratory distress syndrome includes but is not limited to pulmonary edema; preferably, the sepsis includes but is not limited to organ dysfunction; Alternatively, the disease caused by the MERS-CoV is Middle East Respiratory Syndrome (MERS); Preferably, the disease or infection caused by MERS-CoV is a respiratory disease, such as fever, cough, shortness of breath, pneumonia, respiratory failure, etc.

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