Patent Publication Number: US-2023138310-A1

Title: Pharmaceutical use of aldehyde-based compound

Description:
FIELD OF THE INVENTION 
     The invention relates to the field of medicine, in particular to a medical use of aldehyde compounds. 
     BACKGROUND OF THE INVENTION 
     Most of acute infectious diseases are viral infectious diseases. The viral infectious diseases are of high incidence rate and high mortality rate. Due to limited detection and diagnosis methods, new epidemic outbreaks caused by new viruses are often sudden, random and unpredictable. Once it outbroke, if there is no effective prevention and control method, it can easily cause large-scale epidemic and seriously threaten public health and safety. At the end of 2019, there was an outbreak of new coronavirus (2019-nCoV, also known as SARS-CoV-2) infection, which caused severe pneumonia (Covid). By 10:00 on Jan. 28, 2020, there were 4,529 domestic infections and 106 deaths. The transmission route of the 2019-nCoV virus is not fully understood. It is known to be transmitted through droplets and contact, and there are human-to-human transmission as well as medical staff infection exists, also possesses a certain risk of community transmission, and the virus may mutate. At present, there is no specific prevention and treatment for the diseases caused by the new coronavirus. 
     The 2019-nCoV coronavirus belongs to the genus Coronavirus of the Coronavirus family, is a single-stranded positive-sense RNA virus with an envelope. Similar to other known coronaviruses, the 2019-nCoV coronavirus also completes the proliferation of progeny viruses through several processes such as adsorption, penetration, uncoating, biosynthesis, and assembly and release of progeny viruses. The infection of host cells by the 2019-nCoV coronavirus starts with the spike glycoprotein on the surface of the virus envelope binds to the receptor on the surface of the host cell, then membrane fusion occurs. The virus enters the host cell and releases the genetic material of the virus (singlesense—stranded RNA) under the effect of organelles such as cell lysosomes, and the RNA is translated to produce polyproteins under the effect of protein synthesis elements such as mitochondria, ribosomes of host cell, and necessary raw materials. After that, the two essential cysteine protease of the 2019-nCoV coronavirus: papain-like protease (PL pro ) and 3C-like protease (3C-like protease, 3CL pro ) cleave and process polyprotein precursors at specific sites to produce several non-structural protein that are important to the virus life cycle. Under the effect of these non-structural proteins, the viral RNA replicates the nucleic acid material of progeny virus, and a large number of required structural proteins are translated to complete the assembly and release of the progeny virus. Any step or key enzyme in the life cycle of the 2019-nCoV coronavirus infected cell can be used as the research target of antiviral drugs, such as the cysteine proteases PL pro  and 3CL pro  that hydrolyze and cleave the polyprotein precursor, or RNA polymerase that is responsible for completing the genetic material replication of progeny viruses, etc. 
     3CL protease (3 chymotrypsin-like protease, 3CL pro ), also known as the main protease (M pro ), is key protease in the process of hydrolysis to produce multiple non-structural proteins after coronavirus RNA translation of the polyproteins pp1a and pp1ab, which is critical to virus replication and infection. Inhibiting the catalytic function of 3CL protease can effectively inhibit the cleavage of viral polyprotein precursors, block virus replication, and inhibit the generation of progeny viruses. 3CL pro  belongs to acysteine protease, which is key protease that catalyzes the proteolysis of single sense-strand RNA virus precursors, and plays an important role in the replication activity of coronaviruses such as 2019-nCoV. Therefore, 3CL pro  is currently recognized as an ideal target for the development of anti-coronavirus drugs. 
     At present, there are no specific vaccines or antiviral drugs for severe pneumonia caused by the 2019-nCoV coronavirus. These infectious diseases have seriously affected people&#39;s lives and health, and it is urgent for development of effective small-molecule antiviral drugs. It is of great social meaning to develop antiviral drugs with novel structure, low toxicity and high efficiency and independent intellectual property rights for the 2019-nCoV coronavirus 3CL pro  to meet the clinical needs of patients infected with 2019-nCoV coronavirus worldwide. 
     In conclusion, there is an urgent need in the art to develop inhibitors for the 2019-nCoV coronavirus 3CL protease for the treatment of pneumonia caused by novel coronavirus infection. 
     SUMMARY OF THE INVENTION 
     The purpose of the present invention is to provide a novel use of aldehyde compound. 
     Specifically, the present invention provides a use of aldehyde compound according to General Formula I as 2019-nCov 3CL protease inhibitors for preparing drugs for the treatment, and/or prevention, alleviation of related diseases (such as respiratory infection, pneumonia and the like) caused by 2019-nCov infection. 
     In the first aspect of the present invention, a use of aldehyde compound according to General Formula I, or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof is provided, wherein it is used for preparing (a) 2019-nCov 3CL protease inhibitors; and (b) drugs for the treatment, and/or prevention, alleviation of related diseases caused by 2019-nCov infection: 
     
       
         
         
             
             
         
       
     
     wherein, 
     the chiral carbon atoms C*, C* 2 , C* 3 , and C* 4  are each independently in S configuration, R configuration, or the combinations thereof; 
     n=0 or 1; 
     R 1  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of C3-C7 cycloalkyl, trifluoromethyl, C2-C6 alkynyl, 4-7 membered heterocyclyl, C5-C7 aryl, 5-7 membered heteroaryl; each heterocyclyl and heteroaryl contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen; and the substituents are each independently selected from the groups consisting of halogen, C1-C4 straight or branched alkyl, C1-C4 straight or branched alkenyl, C2-C4 straight or branched alkynyl, C1-C4 straight or branched alkoxy, C1-C4 straight or branched alkylcarbonyloxy, cyano, nitro, hydroxyl, amino, hydroxymethyl, trifluoromethyl, carboxyl, sulfydryl, C1-C4 acyl, acylamino, sulfonyl, aminosulfonyl, C1-C4 alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atoms to which they are connected form 5-7 membered ring; R 2  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of C3-C7 cycloalkyl, 5-12 membered heterocyclyl (preferably 5-7 membered heterocyclyl or 6-membered aryl fused 5-7 membered heterocyclyl), C6-C12 aryl, 5-12 membered heteroaryl, styryl, or -Cbz; wherein each of the heterocyclyl or heteroaryl contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen; the substituents are each independently selected from halogen, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl, C2-C6 straight or branched alkynyl, C1-C6 straight or branched alkoxy, C1-C6 straight or branched alkylcarbonyloxy, cyano, nitro, hydroxyl, amino, hydroxymethyl, trifluoromethyl, carboxyl, sulfydryl, C1-C4 acyl, amide, sulfonyl, aminosulfonyl, C1-C4 alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atoms to which they are connected form 5-7 membered ring; 
     R 3  is a group unsubstituted or substituted by 1-3 substituents, and the group is selected from the group consisting of C1-C6 straight or branched alkyl, C1-C6 straight or branched alkoxy, C3-C7 cycloalkyl, C6-C12 aryl, 5-12 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen; wherein, the substituents are each independently selected from halogen, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl, C2-C6 straight or branched alkynyl, C1-C6 straight or branched alkoxy, C1-C6 straight or branched alkylcarbonyloxy, cyano, nitro, hydroxyl, amino, hydroxymethyl, trifluoromethyl, carboxyl, sulfydryl, C1-C4 acyl, amide, sulfonyl, amino sulfonyl, C1-C4 alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atoms to which they are connected form 5-7 membered ring. 
     In another preferred embodiment, the related diseases caused by 2019 n-Cov infection are selected from the groups consisting of respiratory infection, pneumonia and complications thereof, or the combinations thereof. 
     In another preferred embodiment, R 1  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of trifluoromethyl, alkynyl, cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexyl, phenyl, thienyl, pyrazolyl, thiazolyl, pyridyl, furyl. 
     In another preferred embodiment, R 1  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of trifluoromethyl, alkynyl, cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexyl, phenyl, thienyl, pyrazolyl, thiazolyl, pyridyl, furyl; and/or 
     R 2  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of phenyl, styryl, benzoheterocyclyl, 5-12 membered heteroaryl; preferably, the benzoheterocycle and 5-12 membered heteroaromatic ring are selected from benzodioxole, indole, isoxazole, 2-hydroproppyran, pyridine, pyrazole, dihydroimidazopyridine, imidazopyridine, benzothiophene, dihydrobenzodioxane, quinoxaline, benzofuran, indazole, benzimidazole, quinoline. 
     In another preferred embodiment, one or more of the chiral carbon atoms C*, C* 2 , C* 3 , and C* 4  are in S configuration. 
     In another preferred embodiment, the chiral carbon atoms C*, C* 2 , C* 3 , and C* 4  are in S configuration, and/or 
     R 1  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of trifluoromethyl, alkynyl, cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexyl, phenyl, thienyl, pyrazolyl, thiazolyl, pyridyl, furyl; and/or 
     R 2  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of phenyl, styryl, benzoheterocyclyl, 5-12 membered heteroaryl; preferably, the benzoheterocycle and 5-12 membered heteroaromatic ring are selected from benzodioxole, indole, isoxazole, 2-hydroproppyran, pyridine, pyrazole, dihydroimidazopyridine, imidazopyridine, benzothiophene, dihydrobenzodioxane, quinoxaline, benzofuran, indazole, benzimidazole, quinoline; and/or 
     R 3  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of C1-C6 straight or branched alkyl, C3-C7 cycloalkyl, phenyl. 
     In another preferred embodiment, the compounds in General formula I are selected from the group consisting of: 
     
       
         
           
               
               
               
               
             
               
                   
                 TABLE A 
               
               
                   
                   
               
               
                   
                 No. 
                 Name 
                 Structure 
               
               
                   
                   
               
             
            
               
                   
                  1 
                 6-Chloro-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidine-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}amino}butan-2-yl}-2H-chromene-3- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                  2 
                 6-Chloro-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}-2H-chromene-3- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                  3 
                 6-Chloro-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclopentylpropan-2- yl}amino}butan-2-yl}-2H-chromene-3- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                  4 
                 6-Chloro-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-4fluorophenylpropan-2- yl}amino}butan-2-yl}-2H-chromene-3- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                  5 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                  6 
                 5-Methyl-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}isoxazole-3- carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                  7 
                 N-{(S)-3-fluoro-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                  8 
                 5-Methyl-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}amino}butan-2-yl}isoxazole-3- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                  9 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}amino}butan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 10 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}amino}butan-2-yl}benzofuran-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 11 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}amino}butan-2-yl}quinoline-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 12 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-(3,4-difluorophenyl)propan- 2-yl}-1H-indole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 13 
                 5-Methoxy-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}amino}butan-2-yl}indole-2- carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 14 
                 4,6-dichloro-N-{(S)-3-methyl-1-carbonyl- 1-{{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}amino}butan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 15 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-4fluorocyclohexylpropan-2- yl}amino}butan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 16 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}quinoline-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 17 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}benzofuran-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 18 
                 7-Bromo-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}benzofuran-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 19 
                 3-Methyl-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}quinoline-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 20 
                 5-Chloro-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}benzofuran-2- carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 21 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-ethynylpropan-2-yl}-1H- indole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 22 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2-yl}-1H- indole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 23 
                 5-Fluoro-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}amino}butan-2-yl}benzofuran-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 24 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}benzothiophene-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 25 
                 7-Bromo-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}amino}butan-2-yl}quinoline-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 26 
                 7-Methoxy-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}benzofuran-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 27 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}amino}butan-2-yl}benzothiophene-2- carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 28 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}amino}pentan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 29 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}pentan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 30 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-4fluorophenylpropan-2- yl}amino}butan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 31 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclopentylpropan-2- yl}amino}butan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 32 
                 5-Methyl-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-4fluorophenylpropan-2- yl}amino}butan-2-yl}isoxazole-3- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 33 
                 N-{(S)-3,3-dimethyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}amino}butan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 34 
                 N-{(S)-3,3-dimethyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}indole-2- carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 35 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-(3,4- difluorocyclohexyl)propan-2- yl}amino}butan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 36 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclobutylpropan-2- yl}amino}butan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 37 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 38 
                 1-Methyl-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3-phenylpropan-2- yl}-1H-indole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 39 
                 6-Trifluoromethyl-N-{(S)-1-carbonyl-1- {{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2-yl}-1H- indole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 40 
                 5-Methoxy-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3-phenylpropan-2- yl}-1H-indole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 41 
                 5-Chloro-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3-phenylpropan-2- yl}-1H-indole-2-carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 42 
                 4-Fluoro-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3-phenylpropan-2- yl}-1H-indole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 43 
                 7-Fluoro-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3-phenylpropan-2- yl}-1H-indole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 44 
                 5,7-Difluoro-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3-phenylpropan-2- yl}-1H-indole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 45 
                 5-Fluoro-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3-phenylpropan-2- yl}-1H-indole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 46 
                 6-Fluoro-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3-phenylpropan-2- yl}-1H-indole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 47 
                 4,6-Dichloro-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3- cyclohexylpropan-2-yl}-1H-indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 48 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2-yl}-1H- indole-2-carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 49 
                 1-Methyl-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3- cyclohexylpropan-2-yl}-1H-indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 50 
                 5-Methoxy-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3- cyclohexylpropan-2-yl}-1H-indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 51 
                 4-Fluoro-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3- cyclohexylpropan-2-yl}-1H-indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 52 
                 5-Fluoro-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3- cyclohexylpropan-2-yl}-1H-indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 53 
                 6-Fluoro-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3- cyclohexylpropan-2-yl}-1H-indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 54 
                 7-Fluoro-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3- cyclohexylpropan-2-yl}-1H-indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 55 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2-yl}- benzofuran-2-carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 56 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2-yl}- benzothiophene-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 57 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2-yl}- benzimidazole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 58 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2-yl}- quinoline-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 59 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl)amino}-3-cyclohexylpropan-2-yl}- quinoxaline-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 60 
                 N-{(S)-2-{{(S)-3-cyclohexyl-1-carbonyl-1- {{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-propan-2-yl}amino}-1- cyclopropylcarbonylethyl}-indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 61 
                 N-{(S)-2-{{(S)-3-cyclohexyl-1-carbonyl-1- {{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-propan-2-yl}amino}-1- cyclopropylcarbonylethyl}-benzodioxol-5- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 62 
                 5-Methyl-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3-phenylylpropan- 2-yl}-isoxazole-3-carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 63 
                 5-Fluoro-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3-phenylpropan-2- yl}nicotinamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 64 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylylpropan-2-yl}- benzofuran-5-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 65 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2-yl}-2,3- dihydrobenzo[b][1,4]dioxane-6- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 66 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2-yl}-2,3- dihydrobenzo[b][1,4]dioxane-5- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 67 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2-yl}-1H- indole-5-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 68 
                 6-Bromo-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3-phenylpropan-2- yl}imidazo[1,2-a]pyridine-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 69 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}benzo[b]thiophene-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 70 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}benzofuran-2-carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 71 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2- yl}quinoxaline-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 72 
                 3-Methyl-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3-phenylpropan-2- yl}quinoxaline-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 73 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2-yl}quinoline- 2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 74 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-phenylpropan-2-yl}-4- trifluoromethylquinoline-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 75 
                 7-Bromo-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3-phenylpropan-2- yl}quinoline-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 76 
                 6-Chloro-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3-phenylpropan-2- yl}-2H-chromene-3-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 77 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}-2,3- dihydrobenzo[b][1,4]dioxane-6- carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 78 
                 5-Methoxy-N-{(S)-3-methyl-1-carbonyl-1- {{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 79 
                 4,6-Dichloro-N-{(S)-3-methyl-1-carbonyl- 1-{{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 80 
                 N-{(S)-3-methyl-1-carbonyl-1-{{(S)-1- carbonyl-1-{{(S)-1-carbonyl-3-[(S)-2- carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-cyclohexylpropan-2- yl}amino}butan-2-yl}cinnamamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 81 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-3-fluorophenylpropan-2-yl}- 1H-indole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 82 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-4-fluorophenylpropan-2-yl}- 1H-indole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 83 
                 4,7-Difluoron-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3- 3fluorophenylpropan-2-yl}-1H-indole-2- carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 84 
                 4-Methyl-N-{(S)-1-carbonyl-1-{{(S)-1- carbonyl-3-[(S)-2-carbonylpyrrolidin-3- yl]propan-2-yl}amino}-3- cyclohexylpropan-2-yl}-1H-indole-2- carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 85 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-2-fluorophenylpropan-2-yl}- 1H-indole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 86 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-3-fluorophenylpropan-2-yl}- benzimidazole-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 87 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-3-fluorophenylpropan-2-yl}- benzofuran-2-carboxamide  
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
               
                   
                 88 
                 N-{(S)-1-carbonyl-1-{{(S)-1-carbonyl-3- [(S)-2-carbonylpyrrolidin-3-yl]propan-2- yl}amino}-3-3-fluorophenylpropan-2-yl}- quinoline-2-carboxamide 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
                   
               
            
           
         
       
     
     In the second aspect of the present invention, a pharmaceutical composition is provided, which comprising (a) a therapeutically effective amount of the aldehyde compounds according to Formula I, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates or prodrugs thereof; (b) a pharmaceutically acceptable carrier, wherein the aldehyde compounds according to Formula I are as described in the first aspect of the present invention. 
     In the third aspect of the present invention, the use of the pharmaceutical composition of the second aspect of the present invention is provided, which is used for preparing drugs for the treatment, prevention, and/or alleviation of diseases caused by 2019-nCov infection. 
     In another preferred embodiment, the diseases caused by 2019-nCov infection are selected from the groups consisting of respiratory tract infection, pneumonia and the complications thereof, or the combinations thereof. 
     In the third aspect of the present invention, an aldehyde compound according to Formula I, or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof is provided; 
     
       
         
         
             
             
         
       
     
     wherein, 
     the chiral carbon atoms C*, C* 2 , C* 3 , and C* 4  are each independently in S configuration, R configuration, or the combinations thereof; 
     n=0 or 1; 
     R 1  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of C3-C7 cycloalkyl, trifluoromethyl, C2-C6 alkynyl, 4-7 membered heterocyclyl, C5-C7 aryl, 5-7 membered heteroaryl; each of the heterocyclyl and heteroaryl contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen; the substituents are each independently selected from the group consisting of halogen, C1-C4 straight or branched alkyl, C1-C4 straight or branched alkenyl, C2-C4 straight or branched alkynyl, C1-C4 straight or branched alkoxy, C1-C4 straight or branched alkylcarbonyloxy, cyano, nitro, hydroxyl, amino, hydroxymethyl, trifluoromethyl, carboxyl, sulfydryl, C1-C4 acyl, amide, sulfonyl, aminosulfonyl, C1-C4 alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atoms to which they are connected form 5-7 membered ring; 
     R 2  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of C3-C7 cycloalkyl, 5-12 membered heterocyclyl (preferably 5-7 membered heterocyclyl or 6-membered aryl fused 5-7 membered heterocyclyl), C6-C12 aryl, 5-12 membered heteroaryl, styryl, or -Cbz; wherein each of the heterocyclyl or heteroaryl contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen; the substituents are each independently selected from halogen, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl, C2-C6 straight or branched alkynyl, C1-C6 straight or branched alkoxy, C1-C6 straight or branched alkylcarbonyloxy, cyano, nitro, hydroxyl, amino, hydroxymethyl, trifluoromethyl, carboxyl, sulfydryl, C1-C4 acyl, amide, sulfonyl, aminosulfonyl, C1-C4 alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atoms to which they are connected form 5-7 membered ring; 
     R 3  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of C1-C6 straight or branched alkyl, C1-C6 straight or branched alkoxy, C3-C7 cycloalkyl, C6-C12 aryl, 5-12 membered heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen; wherein, the substituents are each independently selected from halogen, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkenyl, C2-C6 straight or branched alkynyl, C1-C6 straight or branched alkoxy, C1-C6 straight or branched alkylcarbonyloxy, cyano, nitro, hydroxyl, amino, hydroxymethyl, trifluoromethyl, carboxyl, sulfydryl, C1-C4 acyl, amide, sulfonyl, aminosulfonyl, C1-C4 alkyl-substituted sulfonyl, or two adjacent substituents together with the carbon atoms to which they are connected form 5-7 membered ring. 
     In another preferred embodiment, R 1  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of trifluoromethyl, alkynyl, cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexyl, phenyl, thienyl, pyrazolyl, thiazolyl, pyridyl, furyl. 
     In another preferred embodiment, R 1  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of trifluoromethyl, alkynyl, cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexyl, phenyl, thienyl, pyrazolyl, thiazolyl, pyridyl, furyl; and/or 
     R 2  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of phenyl, styryl, benzoheterocyclyl, 5-12 membered heteroaryl; preferably, the benzoheterocycle and 5-12 membered heteroaromatic ring are selected from benzodioxole, indole, isoxazole, 2-hydroproppyran, pyridine, pyrazole, dihydroimidazopyridine, imidazopyridine, benzothiophene, dihydrobenzodioxane, quinoxaline, benzofuran, indazole, benzimidazole, quinoline. 
     In another preferred embodiment, the chiral carbon atoms C*, C* 2 , C* 3 , and C* 4  are in S configuration, and/or 
     R 1  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of trifluoromethyl, alkynyl, cyclopropanyl, cyclobutanyl, cyclopentyl, cyclohexyl, phenyl, thienyl, pyrazolyl, thiazolyl, pyridyl, furyl; and/or 
     R 2  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of phenyl, styryl, benzoheterocyclyl, 5-12 membered heteroaryl; preferably, the benzoheterocycle and 5-12 membered heteroaromatic ring are selected from benzodioxole, indole, isoxazole, 2-hydroproppyran, pyridine, pyrazole, dihydroimidazopyridine, imidazopyridine, benzothiophene, dihydrobenzodioxane, quinoxaline, benzofuran, indazole, benzimidazole, quinoline; and/or 
     R 3  is a group unsubstituted or substituted with 1-3 substituents, and the group is selected from the group consisting of C1-C6 straight or branched alkyl, C3-C7 cycloalkyl, phenyl. 
     In another preferred embodiment, the compound of formula I is any of compound 1-88 in Table A. 
     In the fifth aspect of the present invention, a method for treating, preventing, and/or alleviating diseases caused by 2019-nCov infection is provided, which comprises the steps: administering a safe and effective amount of the aldehyde compound according to Formula I, or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof, to the subject in need thereof, wherein the aldehyde compounds according to Formula I are as described above. 
     In another preferred embodiment, the subject is primate mammal, such as a human. 
     In the sixth aspect of the present invention, a method for inhibiting the 3CL protease activity of the 2019-nCov is provided, which comprises the steps: 
     contacting the 3CL protease of 2019-nCov with the aldehyde compound according to Formula I, or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof so as to inhibit the 3CL protease activity of the 2019-nCov. 
     In another preferred embodiment, the method is non-therapeutic and non-diagnostic. 
     In another preferred embodiment, the method is in vitro. 
     In another preferred embodiment, the 3CL protease of 2019-nCov is recombinant or expressed by 2019-nCov. 
     It should be understood that, within the scope of the present invention, the above-mentioned technical features herein and the technical features specifically described in the following (such as the examples) can be combined with each other, thereby constituting new or preferred technical solutions which need not be specified again herein. 
    
    
     
       DESCRIPTION OF THE DRAWINGS 
         FIG.  1    shows that the compounds of the present invention can inhibit the replication of 2019 nCoV virus. 
         FIG.  2    shows the inhibition curves and EC 50  values of some compounds of the present invention in inhibiting the 2019-nCov. 
         FIG.  3    shows the structure of the crystal complex formed by Compound 48, 81 with SARS-CoV-2 3Cl pro . 
     
    
    
     EMBODIMENTS FOR CARRYING OUT THE INVENTION 
     After extensive and in-depth research and extensive screening, the inventors first time unexpectedly developed a class of active ingredient that can effectively inhibit the 2019-nCov, that is, the compounds according to Formula I, or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates thereof. Tests have shown that the active ingredient of the present invention can effectively inhibit the 3CL protease activity of 2019-nCov, thereby inhibiting the replication and viability of 2019-nCov. The present invention has been completed on this basis. 
     Terms 
     Unless otherwise specified, the term “substituted” herein refers to the substitution of one or more hydrogen atoms on the group with substituents selected from the group consisting of C 1 -C 10  alkyl, C 3 -C 10  cycloalkyl, C 1 -C 10  alkoxy, halogen, hydroxyl, carboxyl (—COOH), C 1 -C 10  aldehyde group, C 2 -C 10  acyl, C 2 -C 10  ester group, amino, phenyl; the phenyl includes unsubstituted or substituted phenyl with 1-3 substituents, the substituents are selected from halogen, C 1 -C 10  alkyl, cyano, OH, nitro, C 3 -C 10  cycloalkyl, C 1 -C 10  alkoxy, and amino. 
     Unless otherwise specified, each chiral carbon atom in all the compounds herein may optionally be in the R configuration or the S configuration, or mixtures of the R configuration and the S configuration. 
     The term “C 1 -C 6  alkyl” refers to straight or branched chain alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups. 
     The term “3-8 membered heterocyclyl” refers to groups formed by losing one hydrogen atom of 3-8 membered saturated rings with 1-3 heteroatoms selected from the group consisting of N, S, O; for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or similar groups. 
     The term “6-10 membered aryl” refers to groups formed by losing one hydrogen atom of 6-10 membered aryl groups; for example, phenyl group, naphthyl group, or similar groups. 
     The term “5-10 membered heteroaryl” refers to groups formed by losing one hydrogen atom of 5-8 membered aryl groups h with 1-3 heteroatoms selected from the group consisting of N, S, O, where each ring system of heteroaryl can be monocyclic or polycyclic; for example, pyrrolyl, pyridyl, thienyl, furyl, imidazolyl, pyrimidinyl, benzothienyl, indolyl, imidazopyridyl, quinolinyl, or similar groups. 
     The term “C1-C6 alkoxy” refers to straight or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, tert-butoxy, or similar groups. 
     The term “C2-C6 ester group” refers to R—O—C(═O)— groups having 2-6 carbon atoms, such as —COOCH 3 , —COOC 2 H 5 , —COOC 3 H 7 , —COOC 4 H 9 , or similar groups. 
     The term “C2-C6 alkenyl” refers to groups formed by losing one or two hydrogen atoms of olefins with 2-6 carbon atoms. The olefin may be monoolefin, diolefin or triolefin, for example, —CH═CH 2 , —C 2 H 4 ═CH 2 , —CH═C 2 H 4 , or similar groups. 
     The term “halogen” refers to F, Cl, Br, and I. 
     Unless otherwise specified, the structural formula described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers)): for example, R, S configuration of asymmetrical centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers, etc. Therefore, the single stereochemical isomers or enantiomers, diastereomers or geometric isomers (or conformers) of the compounds of the invention, or mixtures thereof all fall within the scope of the invention. 
     The term “tautomer” means that structural isomers having different energies can exceed the low energy barrier and thereby transform between each other. For example, proton tautomers (proton shift) includes interconversion by proton transfer, such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole. Valence tautomers include interconversion through some bonding electron recombination. 
     The form “C1-C6” herein means that the group can have 1 to 6 carbon atoms, such as 1, 2, 3, 4, or 5. 
     Active Ingredient 
     In the present invention, an active ingredient that can effectively inhibit the replication of the 2019-nCov is provided. The active ingredient is the compound r according to General Formula I, and the active ingredient can effectively prevent, treat and/or alleviate 2019-nCov related diseases. 
     Tests have shown that the active ingredient of the present invention can effectively inhibit the 3CL protease of the 2019-nCov, thereby inhibiting the replication of the 2019-nCov, thereby preventing, treating and/or alleviating 2019-nCov related diseases. 2019-nCov is also known as SARS-CoV-2. 
     It should be understood that, the active ingredient of the present invention includes the aldehyde compounds according to Formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, or racemates thereof, or prodrugs thereof. It should be understood that, the active ingredient of the present invention also includes the crystalline forms, amorphous compounds, and deuterated compounds of the compound of Formula (I). 
     The “pharmaceutically acceptable salt” refers to the conventional non-toxic salts formed by reacting the compounds of Formula (I) with inorganic acids or organic acids. For example, the conventional non-toxic salts can be prepared by reacting the compounds of Formula (I) with inorganic acids or organic acids, the inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid and phosphoric acid, etc, organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and isethionic acid, etc.; or the sodium, potassium, calcium, aluminum or ammonium salts formed with inorganic bases after the compounds of Formula (I) formed esters with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid, or glutamic acid; or amine, ethylamine or ethanolamine salts formed by the compounds of Formula (I) with organic bases; or the corresponding inorganic acid salts formed with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid after the compounds of Formula (I) formed esters with lysine, arginine, ornithine or the corresponding organic acid salts formed with formic acid, acetic acid, picric acid, methanesulfonic acid or ethanesulfonic acid. 
     Pharmaceutical Composition and Use 
     The present invention also provides the use of the mixtures of one or more of the aldehyde compounds according to Formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers or racemates and prodrugs thereof as active ingredients for the preparation of drugs for the treatment and/or prevention, alleviation of respiratory infections, pneumonia and other related diseases caused by 2019 n-Cov infection. 
     The pharmaceutical composition provided by the present invention preferably contains the active ingredient in a weight ratio of 0.001-99 wt %, the preferred ratio is that the compound of Formula I as the active ingredient accounts for 0.1 wt %-90 wt % of the total weight, and the rest is pharmaceutically acceptable carrier, diluent, solution or salt solution. 
     When needed, one or more pharmaceutically acceptable carriers can be added to the drug. The carriers include conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and the like in the pharmaceutical field. 
     The compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in suitable solid or liquid carriers or diluents, also in the sterilization equipments for injection or drip infusion. 
     Various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit measurement of the preparation formula usually contains 0.05-400 mg of the compounds of Formula I, preferably, the unit measurement of the preparation formula contains 1 mg-500 mg of the compounds of Formula I. 
     The compounds and pharmaceutical compositions of the present invention can be used on mammals in clinical usage, including humans and animals, and can be administered via pathways such as oral, nose, skin, lung, or gastrointestinal. Most preferred is oral administration. The most preferred daily dose is 0.01-400 mg/kg body weight, taken at one time, or 0.01-200 mg/kg body weight, taken in divided doses. Regardless of the administration method, the individual&#39;s optimal dosage should be determined based on the specific treatment. Usually it should start with smaller dose and increase the dose gradually until the most suitable dose is found. The drugs or inhibitors of the present invention can be administered in various ways, for example, it can be introduced into the body such as muscle, intradermal, subcutaneous, vein, mucosal tissue by methods such as injection, spraying, nose drops, eye drops, penetration, absorption, physical or chemically mediation; or be introduced into the body by mixed or wrapped by other substances. 
     The main advantages of the present invention include: 
     (a) The compounds of the present invention can effectively inhibit 2019-nCoV 3CL protease, and some of the compounds have IC 50  values at about 70 nM. 
     (b) The compounds of the present invention has a higher inhibitory rate on 2019-nCoV at the viral level than the positive control CQ, showing a better anti-2019-nCoV potentiality. 
     (c) The compounds of the present invention have low toxic and side effects and good drug-making properties. 
     The present invention will be further illustrated below with reference to the specific examples. It should be understood that these examples are only to illustrate the invention but not to limit the scope of the invention. The experimental methods with no specific conditions described in the following examples are generally performed under the conventional conditions, or according to the manufacturer&#39;s instructions. Unless indicated otherwise, parts and percentage are calculated by weight. 
     The analytical data of samples were measured by the following instruments: NMR was measured by GEMINI-300, Bruker AMX-400 and INVOA-600 NMR instruments, TMS (tetramethylsilane) as the internal standard, the unit of chemical shift was ppm, the unit of coupling constant was Hz; the mass spectrum was measured by Finnigan MAT-711, MAT-95 and LCQ-DECA mass spectrometers and IonSpec 4.7 Tesla mass spectrometer. 200-300 Mesh silica gel (produced by Qingdao Ocean Chemical Plant) was used for column chromatography; TLC silica gel plate was HSGF-254 thin-layer chromatography prefabricated plate produced by Yantai Chemical Plant; boiling range of petroleum ether was 60-90° C.; UV lamp and iodine cylinder was used for color development. Unless otherwise specified, the conventional reagents and medicines used in the following examples were purchased from Sinopharm Group. The reagents and solvents used in the experiment were handled according to the specific conditions of the reaction. 
     Example 1: Synthesis of Compound 1 
     
       
         
         
             
             
         
       
     
     synthetic route: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Synthesis of Compound 1-2 
     Under argon protection, dimethyl N-tert-butoxycarbonyl-L-glutamate 1-1 (6 g, 21.8 mmol) was dissolved in 60 mL of anhydrous tetrahydrofuran, and LiHMDS (1M in THF) in tetrahydrofuran solution (47 mL, 47 mmol) was slowly added dropwise at −78° C., while the temperature was kept stable at −78° C. during the process for about 1 hour. The mixture was stirred at −78° C. for 1 hour. Bromoacetonitrile (2.79 g, 23.3 mmol) was dissolved in 20 ml of tetrahydrofuran, and then the solution was slowly added dropwise into the system for 1-2 hours. The temperature was controlled at −78° C., and the reaction was continued for 20 hours. After THL monitoring (alkaline potassium permanganate was used for color development) showed that the reaction was completed, 3 mL of methanol and 22.7 mL (v/v=1/7.5) of the mixture of glacial acetic acid and tetrahydrofuran were added to the reaction solution to quench. The mixture was warmed to room temperature after stirred for 10 min. 40 mL of saturated sodium chloride solution was poured and well stirred. The reaction system was observed to have layered. The organic layer was separated, and the aqueous phase was extracted with ethyl acetate (EA). The combined organic layer was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE:EA=4:1) to obtain a pale yellow oily substance 1-2 3.9 g, yield 58%. 
     Synthesis of Compound 1-3 
     Compound 1-2 (1 g, 3.15 mmol) was dissolved in 25 mL of anhydrous methanol, after stirred under an ice bath to 0° C., cobalt dichloride hexahydrate (450 mg, 1.89 mmol) was added and the solution turned to purple-red. 10 minutes later, sodium borohydride (715 mg, 18.9 mmol) was added in small portions, and the color of the solution turned to purple-black. The reaction solution continued to react in an ice bath for 1 hour and then warmed to room temperature. After 15 h, the mixture was quenched with 5 mL of saturated NH 4 Cl solution and stirred for 10 min. The solid was filtered off with diatomite, and the filtrate was evaporated to dryness under reduced pressure, anextracted with 20 mL of water and 30×3 mL of ethyl acetate. The combined organic phase was dried with anhydrous Na 2 SO 4  for 1 h, then concentrated under reduced pressure and separated by column chromatography [PE:EA=1:2] to obtain white powdery solid Compound 1-3 460 mg, yield 51%. 
     Synthesis of Compound 1-4 
     Intermediate 1-3 (1 g, 3.5 mmol) was dissolved in dichloromethane, 4 M HCl in dioxane solution (9 mL, 35 mmol) was added at 0° C., and the reaction was stirred at room temperature for 12 hours. The solution was evaporated to dryness to obtain Intermediate 1-4 and used directly to the next reaction. 
     Synthesis of Compound 1-6 
     Compound 1-5 (1.1 g, 3.5 mmol) was dissolved in dichloromethane (40 mL), the reaction solution was cooled to −20° C., then HATU (1.9 g, 4.9 mmol) was added to the reaction solution. After stirred for twenty minutes, Intermediate 1-4 obtained in the previous step was added to the reaction solution and stirred at −20° C. for 30 minutes. DIPEA (1.7 mL, 10.5 mmol) was added dropwise to the reaction solution. After stirred for 12 hours, the reaction was extracted with ammonium chloride (40×3 mL), sodium bicarbonate (40×3 mL), and sodium chloride (40×3 mL). The combined organic phase was dried with anhydrous sodium sulfate for 1 hour, then distillated under reduced pressure and separated by column chromatography (DCM: CH 3 OH, 40:1 v/v) to obtain white powder solid Compound 1-6 1.3 g, yield 83%. 
     Synthesis of Compound 1-7 
     Compound 1-6 (1.5 g, 3.5 mmol) was dissolved in dichloromethane, 4 M HCl dioxane solution (9 mL, 35 mmol) was added at 0° C., and the reaction was stirred at room temperature for 12 hours. Then the solution was evaporated to dryness to obtain Intermediate 1-7 and used directly to the next step. 
     Synthesis of Compound 1-9 
     Compound 1-8 (0.76 g, 3.5 mmol) was dissolved in dichloromethane (40 mL), and the reaction solution was cooled to −20° C., then HATU (1.9 g, 4.9 mmol) was added to the reaction solution. After stirred for twenty minutes, Intermediate 1-7 obtained in the previous step was added to the reaction solution, then stirred at −20° C. for 30 minutes. DIPEA (1.7 mL, 10.5 mmol) was added dropwise to the reaction solution. After the reaction was stirred for 12 hours, it was extracted with ammonium chloride (40×3 mL), sodium bicarbonate (40×3 mL) and sodium chloride (40×3 mL). The combined organic phase was dried with anhydrous sodium sulfate for 1 hour, then distillated under reduced pressure and separated by column chromatography (DCM: CH 3 OH, 40:1 v/v), to obtain white powder solid Compound 1-9 1.6 g, yield 85%. 
     Synthesis of Compound 1-10 
     Intermediate 1-9 (1.86 g, 3.5 mmol) was dissolved in dichloromethane, 4 M HCl dioxane solution (9 mL, 35 mmol) was added at 0° C., and the reaction was stirred at room temperature for 12 h. Then the solution was evaporated to dryness to obtain Intermediate 1-10 and used directly in the next step. 
     Synthesis of Compounds 1-12 
     Compound 1-11 (0.61 g, 3.5 mmol) was dissolved in dichloromethane (40 mL), the reaction solution was cooled to −20° C., then HATU (1.9 g, 4.9 mmol) was added to the reaction solution. After stirred for twenty minutes, Intermediate (10) obtained in the previous step was added to the reaction solution, stirred at −20° C. for 30 minutes, and then DIPEA (1.7 mL, 10.5 mmol) was added dropwise to the reaction solution. After stirred for 12 hours, the reaction was extracted with ammonium chloride (40×3 mL), sodium bicarbonate (40×3 mL) and sodium chloride (40×3 mL). The combined organic phase was dried with anhydrous sodium sulfate for 1 hour, distillated under reduced pressure and separated by column chromatography (DCM: CH 3 OH, 20:1 v/v) to obtain white powder solid compound (12) 1.7 g, yield 81%. 
     Synthesis of Compound 1-13 
     Compound 1-12 (304 mg, 0.51 mmol) was dissolved in 20 ml of dichloromethane, sodium borohydride (107 mg, 2.9 mmol) was slowly added in batches, then 1 ml of methanol was added dropwise. The mixture was stirred at room temperature for about 2 hours. After the reaction was completed, about 20 ml of saturated brine was added to quench the reaction, and dichloromethane was added for extraction. The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and separated by column chromatography (DCM: CH 3 OH, 20:1 v/v) to obtain white solid (13) 216 mg, yield 74%. 
     Synthesis of Compound 1 
     Compound 1-12 (165 mg, 0.29 mmol) was dissolved in 20 ml of dichloromethane, and Dess-Martin oxidant (147 mg, 0.35 mmol) was added, and stirred at room temperature. After TLC monitoring (UV) showed that the reaction was completed, the solution was extracted with sodium thiosulfate until clearation, then dried with anhydrous sodium sulfate and concentrated, column chromatography separated (DCM: CH 3 OH, 20:1 v/v) to obtain Compound 1 98 mg, yield 60%. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.66-7.57 (m, 3H), 7.25 (t, J=7.8 Hz, 1H), 7.07 (s, 1H), 7.00-6.93 (m, 2H), 6.55 (t, J=4.4 Hz, 1H), 4.91 (s, 2H), 4.76 (dd, J=9.1, 6.5 Hz, 1H), 4.28-4.14 (m, 2H), 3.29 (m, 1H), 3.16 (m, 1H), 2.35 (m, 1H), 2.11-1.95 (m, 3H), 1.85-1.43 (m, 10H), 1.40-1.18 (m, 5H), 0.67 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 566.31[M+H] +   
     Example 2: Synthesis of Compound 2 
     
       
         
         
             
             
         
       
     
     The Compound 2 was synthesized according to the synthesis of Compound 1 by using Compound 2-1 to replace the acid 1-11 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 7.73 (s, 1H), 7.67-7.59 (m, 3H), 7.31-7.23 (m, 2H), 6.91 (d, J=8.4 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.91 (s, 2H), 4.67 (dd, J=9.1, 6.5 Hz, 1H), 4.44 (dt, J=8.8, 6.4 Hz, 1H), 4.29 (dt, J=9.3, 6.9 Hz, 1H), 3.35-3.19 (m, 2H), 2.53 (m, 1H), 2.18 (dt, J=12.7, 6.3 Hz, 1H), 2.13-2.00 (m, 1H), 1.97 (dt, J=12.9, 6.4 Hz, 1H), 1.91-1.68 (m, 4H), 1.65-1.59 (m, 1H), 1.59-1.44 (m, 3H), 1.44-1.32 (m, 6H), 1.23 (m, 2H), 0.67 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 600.27[M+H] +   
     Example 3: Synthesis of Compound 3 
     
       
         
         
             
             
         
       
     
     The Compound 3 was synthesized according to the synthesis of Compound 1 by using Compound 2-1 to replace the acid 1-11 in Example 1, and using 3-1 to replace the 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 7.82 (d, J=9.2 Hz, 1H), 7.74 (s, 1H), 7.62 (dd, J=9.2, 2.2 Hz, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.23 (s, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.91 (s, 2H), 4.78 (dd, J=9.1, 6.5 Hz, 1H), 4.32 (dt, J=9.0, 6.4 Hz, 1H), 4.19 (dt, J=9.3, 6.9 Hz, 1H), 3.29 (m, 1H), 3.17 (m, 1H), 2.35 (m, 1H), 2.09 (dt, J=12.8, 6.3 Hz, 1H), 2.05-1.94 (m, 1H), 1.94-1.87 (m, 1H), 1.87-1.77 (m, 2H), 1.77-1.67 (m, 3H), 1.67-1.64 (m, 1H), 1.64-1.56 (m, 3H), 1.56-1.45 (m, 4H), 0.67 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 586.26[M+H] +   
     Example 4: Synthesis of Compound 4 
     
       
         
         
             
             
         
       
     
     The Compound 4 was synthesized according to the synthesis of Compound 3 by using Compound 4-1 to replace the 3-1 in Example 3. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 7.77 (d, J=9.3 Hz, 1H), 7.66-7.58 (m, 3H), 7.41 (s, 1H), 7.31-7.22 (m, 3H), 6.93 (t, J=8.1 Hz, 2H), 6.82 (d, J=8.4 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.97 (dd, J=9.2, 6.6 Hz, 1H), 4.91 (s, 2H), 4.73 (dt, J=9.3, 7.7 Hz, 1H), 4.40 (dt, J=9.0, 6.4 Hz, 1H), 3.33 (m, 1H), 3.21 (m, 1H), 3.04 (dd, J=14.0, 7.8 Hz, 1H), 2.92 (dd, J=14.0, 7.8 Hz, 1H), 2.44 (m, 1H), 2.16-2.01 (m, 2H), 1.96-1.81 (m, 2H), 1.73 (m, 1H), 0.86 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 612.22[M+H] +   
     Example 5: Synthesis of Compound 5 
     
       
         
         
             
             
         
       
     
     The Compound 5 was synthesized according to the synthesis of Compound 1 by using Compound 5-1 to replace the acid 1-11 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 9.12 (s, 1H), 8.55 (d, J=9.2 Hz, 1H), 7.69-7.55 (m, 3H), 7.44-7.32 (m, 2H), 7.28-7.12 (m, 2H), 6.55 (t, J=4.4 Hz, 1H), 5.11 (dd, J=9.2, 6.6 Hz, 1H), 4.50-4.23 (m, 2H), 3.34 (m, 1H), 3.20 (m, 1H), 2.40 (m, 1H), 2.29-2.19 (m, J=6.7 Hz, 1H), 2.14 (dt, J=12.9, 6.4 Hz, 1H), 1.99-1.70 (m, 5H), 1.58-1.32 (m, 10H), 1.26-1.18 (m, 2H), 0.87 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 552.31[M+H] +   
     Example 6: Synthesis of Compound 6 
     
       
         
         
             
             
         
       
     
     The Compound 6 was synthesized according to the synthesis of Compound 1 by using Compound 6-1 to replace the acid 1-11 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 8.18 (d, J=9.2 Hz, 1H), 7.86 (d, J=9.3 Hz, 1H), 7.65 (d, J=9.0 Hz, 1H), 6.58-6.52 (m, 2H), 5.18 (dd, J=9.1, 6.5 Hz, 1H), 4.41 (dt, J=8.8, 6.3 Hz, 1H), 4.33 (dt, J=9.3, 6.9 Hz, 1H), 3.31 (m, 1H), 3.19 (m, 1H), 2.47 (s, 3H), 2.39 (m, 1H), 2.18-2.04 (m, 2H), 1.92 (m, 2H), 1.82 (m, 1H), 1.78-1.69 (m, 2H), 1.55-1.43 (m, 5H), 1.43-1.31 (m, 5H), 1.19 (m, 2H), 0.88 (dd, J=24.9, 6.6 Hz, 6H). ESI-MS m/z 517.29 [M+H] +   
     Example 7: Synthesis of Compound 7 
     
       
         
         
             
             
         
       
     
     The Compound 7 was synthesized according to the synthesis of Compound 1 by using Compound 5-1 to replace the acid 1-11 in Example 1, and using Compound 7-1 to replace the 1-8 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 8.28 (d, J=9.0 Hz, 1H), 7.68 (d, J=9.3 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 6.39 (d, J=6.0 Hz, 1H), 6.30 (dd, J=8.7, 7.3 Hz, 1H), 6.21 (dd, J=8.7, 7.3 Hz, 1H), 6.14 (d, J=8.6 Hz, 1H), 6.06 (dd, J=8.7, 5.7 Hz, 1H), 5.84 (dd, J=8.7, 5.3 Hz, 1H), 4.61 (dd, J=25.3, 9.0 Hz, 1H), 4.50 (dt, J=9.3, 6.9 Hz, 1H), 4.31 (dt, J=8.8, 6.4 Hz, 1H), 3.77 (dt, J=8.6, 5.2 Hz, 1H), 3.37-3.29 (m, 2H), 3.20 (m, 1H), 2.41 (m, 1H), 2.13 (dt, J=12.7, 6.3 Hz, 1H), 1.95-1.71 (m, 5H), 1.65 (t, J=25.1 Hz, 6H), 1.59-1.34 (m, 9H), 1.29 (m, 2H). ESI-MS m/z 572.32[M+H] + . 
     Example 8: Synthesis of Compound 8 
     
       
         
         
             
             
         
       
     
     The Compound 8 was synthesized according to the synthesis of Compound 1 by using Compound 6-1 to replace the acid 1-11 in Example 1, and using compound 8-1 to replace the 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.35 (s, 1H), 8.30 (d, J=6.8 Hz, 1H), 7.81-7.69 (m, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.31-7.22 (m, 4H), 7.17 (t, J=7.1 Hz, 1H), 6.94 (s, 1H), 6.52 (d, J=0.7 Hz, 1H), 4.79 (m, 1H), 4.54-4.43 (m, 1H), 4.27 (m, 1H), 3.32-3.18 (m, 3H), 3.04 (dd, J=13.8, 8.1 Hz, 1H), 2.44-2.28 (m, 2H), 2.22 (dd, J=13.4, 6.7 Hz, 1H), 1.93 (d, J=5.6 Hz, 1H), 1.81-1.72 (m, 2H), 1.31 (s, 2H), 0.93 (dd, J=10.3, 6.8 Hz, 6H). ESI-MS m/z 511.24 [M+H] + . 
     Example 9: Synthesis of Compound 9 
     
       
         
         
             
             
         
       
     
     The Compound 9 was synthesized according to the synthesis of Compound 1 by using Compound 5-1 to replace the acid 1-11 in Example 1, and using Compound 8-1 to replace the 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 11.20 (s, 1H), 9.46 (s, 1H), 8.22 (d, J=7.4 Hz, 1H), 7.96-7.88 (m, 1H), 7.75 (dd, J=11.9, 4.0 Hz, 1H), 7.62 (m, 2H), 7.33-7.29 (m, 1H), 7.26-7.20 (m, 3H), 7.19-7.06 (m, 4H), 7.03 (dd, J=16.8, 9.5 Hz, 1H), 4.88-4.80 (m, 1H), 4.54-4.32 (m, 2H), 3.38 (dd, J=19.0, 10.1 Hz, 1H), 3.32-3.24 (m, 2H), 3.00 (m, 1H), 2.43 (m, 1H), 2.32 (m, 2H), 2.23 (m, 1H), 1.87-1.81 (m, 1H), 1.31 (d, J=1.7 Hz, 1H), 0.96 (dd, J=10.7, 6.9 Hz, 6H). ESI-MS m/z 546.26[M+H] + . 
     Example 10: Synthesis of Compound 10 
     
       
         
         
             
             
         
       
     
     The Compound 10 was synthesized according to the synthesis of Compound 1 by using Compound 10-1 to replace the acid 1-11 in Example 1, and using Compound 8-1 to replace the 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 2H), 8.32 (d, J=9.2 Hz, 2H), 7.74-7.67 (m, 4H), 7.63 (dd, J=12.5, 8.3 Hz, 4H), 7.58 (d, J=9.3 Hz, 2H), 7.39 (t, J=7.7 Hz, 2H), 7.33-7.23 (m, 7H), 7.23-7.18 (m, 1H), 7.16-7.08 (m, 4H), 6.55 (t, J=4.4 Hz, 2H), 5.01 (dd, J=9.2, 6.6 Hz, 2H), 4.75 (dt, J=9.3, 7.8 Hz, 2H), 4.38 (dt, J=8.8, 6.3 Hz, 2H), 3.38-3.28 (m, 4H), 3.26-3.10 (m, 4H), 2.42 (m, 2H), 2.28-2.16 (m, J=6.6 Hz, 2H), 2.13 (dt, J=12.8, 6.3 Hz, 2H), 1.92 (dt, J=12.8, 6.3 Hz, 2H), 1.83 (m, 2H), 1.74 (m, 2H), 0.88 (dd, J=25.1, 6.6 Hz, 12H). ESI-MS m/z 547.25[M+H]±. 
     Example 11: Synthesis of Compound 11 
     
       
         
         
             
             
         
       
     
     The Compound 11 was synthesized according to the synthesis of Compound 1 by using Compound 11-1 to replace the acid 1-11 in Example 1, and using compound 8-1 to replace the 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.40 (s, 1H), 8.74 (d, J=8.5 Hz, 1H), 8.52 (d, J=8.5 Hz, 1H), 8.27 (d, J=8.5 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.88-7.82 (m, 1H), 7.72 (dd, J=11.2, 4.0 Hz, 1H), 7.29 (d, J=7.4 Hz, 2H), 7.19 (t, J=7.6 Hz, 2H), 7.09 (d, J=7.5 Hz, 1H), 4.85 (dd, J=11.2, 5.0 Hz, 1H), 4.62-4.55 (m, 1H), 4.40-4.30 (m, 1H), 3.33-3.20 (m, 3H), 3.06-3.00 (m, 1H), 2.50-2.41 (m, 1H), 2.38-2.27 (m, 2H), 2.06-2.00 (m, 1H), 1.80 (dt, J=12.9, 9.6 Hz, 2H), 1.30 (d, J=5.1 Hz, 1H), 0.99 (dd, J=19.0, 6.8 Hz, 6H). ESI-MS m/z 547.25[M+H] + . 
     Example 12: Synthesis of Compound 12 
     
       
         
         
             
             
         
       
     
     synthetic route: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Synthesis of Compound 12-2 
     Compound 12-1 (1.05 g, 3.5 mmol) was dissolved in dichloromethane (40 mL), the reaction solution was cooled to −20° C., then HATU (1.9 g, 4.9 mmol) was added to the reaction solution. After stirred for twenty minutes, Compound 1-4 was added to the reaction solution, stirred at −20° C. for 30 minutes, and then DIPEA (1.7 mL, 10.5 mmol) was added dropwise to the reaction solution. After stirred for 12 hours, the reaction was extracted with ammonium chloride (40×3 mL), sodium bicarbonate (40×3 mL), and sodium chloride (40×3 mL). The combined organic phases was dried with anhydrous sodium sulfate for 1 hour, then distillated under reduced pressure and separated by column chromatography (DCM: CH 3 OH, 40:1 v/v) to obtain white powder solid Compound 12-2 1.3 g, yield 79%. 
     Synthesis of Compound 12-3 
     Compound 12-2 (1.64 g, 3 5 mmol) was dissolved in dichloromethane, 4 M HCl dioxane solution (9 mL, 35 mmol) was added at 0° C., and the reaction was stirred at room temperature for 12 hours. The solution was evaporated to dryness to obtain Compound 12-3 and used directly in the next step. 
     Synthesis of Compound 12-4 
     Compound 5-1 (0.56 g, 3.5 mmol) was dissolved in dichloromethane (40 mL), the reaction solution was cooled to −20° C., then HATU (1.9 g, 4.9 mmol) was added to the reaction solution. After stirred for twenty minutes, Intermediate 12-3 obtained in the previous step was added to the reaction solution, stirred at −20° C. for 30 minutes, and then DIPEA (1.7 mL, 10.5 mmol) was added dropwise to the reaction solution. After stirred for 12 hours, the reaction was extracted with ammonium chloride (40×3 mL), sodium bicarbonate (40×3 mL), and sodium chloride (40×3 mL). The combined organic phases was dried with anhydrous sodium sulfate for 1 hour, then distillated under reduced pressure and separated by column chromatography (DCM: CH 3 OH, 40:1 v/v) to obtain white powder solid Compound 12-4 1.4 g, with a yield of 78%. 
     Synthesis of Compound 12-5 
     Compound 12-4 (261 mg, 0.51 mmol) was dissolved in 20 ml of dichloromethane, sodium borohydride (107 mg, 2.9 mmol) was slowly added in batches, then 1 ml of methanol was added dropwise, and stirred at room temperature for about 2 hours. After the reaction was completed, about 20 ml of saturated brine was added to quench the reaction, and dichloromethane was added for extraction. The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and separated by column chromatography (DCM: CH 3 OH, 20:1 v/v) to obtain white solid compound 12-5 173 mg, yield 70% 
     Synthesis of Compound 12 
     Compound 12-5 (140 mg, 0.29 mmol) was dissolved in 20 ml of dichloromethane, and Dess-Martin oxidant (147 mg, 0.35 mmol) was added and stirred at room temperature. After TLC monitoring (UV) showed that the reaction was completed, the reaction solution was extracted with sodium thiosulfate until clearation, then dried with anhydrous sodium sulfate and concentrated. Column chromatography separated (DCM: CH 3 OH, 20:1 v/v) to obtain Compound 12 84 mg, yield 60%. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 9.11 (s, 1H), 8.63 (d, J=9.3 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.54 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.25-7.13 (m, 3H), 7.06 (m, 2H), 6.55 (t, J=4.4 Hz, 1H), 5.01 (dt, J=9.3, 7.8 Hz, 1H), 4.40 (dt, J=8.9, 6.4 Hz, 1H), 3.31 (m, 1H), 3.19 (m, 1H), 3.07 (dd, J=14.0, 7.8 Hz, 1H), 2.96 (dd, J=13.9, 7.7 Hz, 1H), 2.41 (m, 1H), 2.16 (dt, J=12.8, 6.3 Hz, 1H), 1.92 (dt, J=12.9, 6.4 Hz, 1H), 1.84-1.70 (m, 2H). ESI-MS m/z 482.18[M+H] + . 
     Example 13: Synthesis of Compound 13 
     
       
         
         
             
             
         
       
     
     The Compound 13 was synthesized according to the synthesis of Compound 11 by using Compound 13-1 to replace the Compound 11-1 in Example 11, and using Compound 15-1 to replace the 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.37 (s, 1H), 9.21 (s, 1H), 8.47 (d, J=9.1 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.58 (d, J=9.3 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.38 (s, 1H), 7.29 (s, 1H), 7.28-7.20 (m, 3H), 7.14-7.09 (m, 2H), 6.80 (d, J=8.4 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.98 (dd, J=9.2, 6.6 Hz, 1H), 4.74 (dt, J=9.3, 7.8 Hz, 1H), 4.39 (dt, J=8.8, 6.4 Hz, 1H), 3.83 (s, 3H), 3.39-3.29 (m, 2H), 3.27-3.10 (m, 2H), 2.44 (m, 1H), 2.26 (m, 1H), 2.11 (dt, J=12.7, 6.3 Hz, 1H), 1.94 (dt, J=12.9, 6.4 Hz, 1H), 1.83 (m, 1H), 1.75 (m, 1H), 0.88 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 576.27[M+H] + . 
     Example 14: Synthesis of Compound 14 
     
       
         
         
             
             
         
       
     
     The Compound 14 was synthesized according to the synthesis of Compound 11 by using Compound 14-1 to replace the Compound 11-1 in Example 11. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 9.04 (s, 1H), 8.44 (d, J=9.2 Hz, 1H), 7.67 (s, 1H), 7.63 (dd, J=9.1, 3.9 Hz, 2H), 7.43 (d, J=10.3 Hz, 2H), 7.28-7.20 (m, 3H), 7.14-7.08 (m, 2H), 6.55 (t, J=4.4 Hz, 1H), 4.93 (dd, J=9.2, 6.6 Hz, 1H), 4.71 (dt, J=9.3, 7.7 Hz, 1H), 4.42 (dt, J=9.0, 6.4 Hz, 1H), 3.38-3.29 (m, 2H), 3.23-3.11 (m, 2H), 2.40 (m, 1H), 2.18 (m, 2H), 1.97 (dt, J=12.9, 6.4 Hz, 1H), 1.85 (m, 1H), 1.74 (m, 1H), 0.90 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 614.18[M+H] +   
     Example 15: Synthesis of Compound 15 
     
       
         
         
             
             
         
       
     
     The Compound 15 was synthesized according to the synthesis of Compound 11 by using Compound 5-1 to replace the acid 1-11 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 2H), 9.12 (s, 2H), 8.54 (d, J=9.0 Hz, 2H), 7.64 (dd, J=12.7, 8.3 Hz, 4H), 7.58 (d, J=9.3 Hz, 2H), 7.42-7.36 (m, 4H), 7.22 (t, J=7.5 Hz, 2H), 7.19-7.13 (m, 2H), 6.55 (t, J=4.4 Hz, 2H), 4.92 (dd, J=9.1, 6.5 Hz, 2H), 4.68 (m, 1H), 4.58 (m, 1H), 4.46-4.33 (m, 4H), 3.33 (m, 2H), 3.21 (m, 2H), 2.41 (m, 2H), 2.19 (m, 2H), 2.12 (dd, J=12.9, 6.4 Hz, 2H), 2.01-1.55 (m, 22H), 1.47-1.38 (m, 2H), 1.32 (m, 4H), 0.87 (dd, J=25.0, 6.7 Hz, 12H). ESI-MS m/z 569.30[M+H] +   
     Example 16: Synthesis of Compound 16 
     
       
         
         
             
             
         
       
     
     The Compound 16 was synthesized according to the synthesis of Compound 1 by using Compound 11-1 to replace the Compound 1-11 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 8.61 (d, J=9.2 Hz, 1H), 8.30 (s, 2H), 8.15 (d, J=8.1 Hz, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.84 (dd, J=8.2, 7.4 Hz, 1H), 7.72-7.49 (m, 3H), 6.55 (t, J=4.4 Hz, 1H), 4.78 (dd, J=9.0, 6.6 Hz, 1H), 4.46-4.28 (m, 2H), 3.33 (m, 1H), 3.23 (m, 1H), 2.54 (m, 1H), 2.27-2.16 (m, J=6.6 Hz, 1H), 2.11 (dt, J=12.8, 6.3 Hz, 1H), 2.02-1.90 (m, 3H), 1.89-1.80 (m, 2H), 1.74 (m, 1H), 1.62-1.47 (m, 5H), 1.45-1.24 (m, 5H), 0.88 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 564.31[M+H] + . 
     Example 17: Synthesis of Compound 17 
     
       
         
         
             
             
         
       
     
     The Compound 17 was synthesized according to the synthesis of Compound 1 by using Compound 10-1 to replace the Compound 1-11 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 8.32 (d, J=9.2 Hz, 1H), 7.71 (s, 1H), 7.68-7.56 (m, 4H), 7.39 (t, J=7.7 Hz, 1H), 7.29 (t, J=7.5 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.82 (dd, J=9.0, 6.6 Hz, 1H), 4.50 (dt, J=9.3, 6.9 Hz, 1H), 4.37 (dt, J=8.8, 6.3 Hz, 1H), 3.32 (m, 1H), 3.19 (m, 1H), 2.40 (m, 1H), 2.22-2.08 (m, 2H), 1.92 (dt, J=12.9, 6.4 Hz, 1H), 1.88-1.79 (m, 2H), 1.78-1.68 (m, 2H), 1.58 (m, 2H), 1.54-1.37 (m, 7H), 1.27 (m, 2H), 0.88 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 553.29[M+H] + . 
     Example 18: Synthesis of Compound 18 
     
       
         
         
             
             
         
       
     
     The Compound 18 was synthesized according to the synthesis of Compound 1 by using Compound 18-1 to replace the Compound 1-11 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 8.44 (d, J=9.2 Hz, 1H), 7.66-7.58 (m, 3H), 7.55 (d, J=7.9 Hz, 1H), 7.46 (d, J=7.9 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.85 (dd, J=9.2, 6.6 Hz, 1H), 4.41 (dt, J=9.0, 6.3 Hz, 1H), 4.34 (dt, J=9.3, 6.9 Hz, 1H), 3.33 (m, 1H), 3.23 (m, 1H), 2.51 (m, 1H), 2.26 (m, 1H), 2.12 (dt, J=12.8, 6.3 Hz, 1H), 1.94 (dt, J=12.9, 6.4 Hz, 1H), 1.86-1.43 (m, 11H), 1.39-1.17 (m, 6H), 0.90 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 631.20[M+H] + . 
     Example 19: Synthesis of Compound 18 
     
       
         
         
             
             
         
       
     
     The Compound 19 was synthesized according to the synthesis of Compound 1 by using Compound 19-1 to replace the Compound 1-11 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 8.36 (d, J=9.0 Hz, 1H), 8.28 (s, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.81-7.74 (m, 2H), 7.62 (dd, J=9.2, 4.4 Hz, 2H), 7.52 (t, J=7.7 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.74 (dd, J=9.2, 6.6 Hz, 1H), 4.38 (dt, J=9.3, 6.9 Hz, 1H), 4.29 (dt, J=8.8, 6.4 Hz, 1H), 3.35 (m, 1H), 3.18 (m, 1H), 2.49 (s, 3H), 2.38 (m, 1H), 2.29-2.10 (m, 2H), 1.99-1.90 (m, 1H), 1.87-1.69 (m, 4H), 1.66-1.54 (m, 3H), 1.54-1.34 (m, 6H), 1.30-1.20 (m, 2H), 0.88 (dd, J=25.1, 6.6 Hz, 6H). ESI-MS m/z 578.33[M+H] + . 
     Example 20: Synthesis of Compound 20 
     
       
         
         
             
             
         
       
     
     The Compound 20 was synthesized according to the synthesis of Compound 1 by using Compound 20-1 to replace the Compound 1-11 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 8.31 (d, J=9.0 Hz, 1H), 7.82 (s, 1H), 7.76-7.71 (m, 2H), 7.60 (dd, J=11.4, 9.1 Hz, 2H), 7.42 (d, J=8.4 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 5.16 (dd, J=9.0, 6.6 Hz, 1H), 4.48-4.29 (m, 2H), 3.27 (m, 2H), 2.41 (m, 1H), 2.21 (m, 1H), 2.13 (dt, J=12.8, 6.3 Hz, 1H), 2.00-1.86 (m, 2H), 1.83 (m, 1H), 1.78-1.67 (m, 3H), 1.50 (m, 2H), 1.47-1.33 (m, 6H), 1.18 (m, 2H), 0.88 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 587 0.26 [M+H] + . 
     Example 21: Synthesis of Compound 21 
     
       
         
         
             
             
         
       
     
     The Compound 21 was synthesized according to the synthesis of Compound 12 by using Compound 21-1 to replace the Compound 12-1 in Example 12. 
       1 H NMR (500 MHz, Chloroform) δ 9.72 (s, 4H), 8.62 (s, 4H), 8.40 (s, 4H), 7.98 (s, 4H), 7.60 (s, 4H), 7.23 (s, 4H), 7.10 (s, 3H), 6.98 (s, 3H), 6.03 (s, 4H), 5.82 (s, 4H), 5.70 (s, 4H), 5.04 (s, 2H), 3.65 (s, 2H), 3.55 (s, 2H), 2.87 (d, J=12.0 Hz, 5H), 2.61 (s, 3H), 2.23 (s, 3H), 2.02 (s, 4H), 1.93 (d, J=15.1 Hz, 6H). ESI-MS m/z 395.16[M+H] + . 
     Example 22: Synthesis of Compound 22 
     
       
         
         
             
             
         
       
     
     The Compound 22 was synthesized according to the synthesis of Compound 12 by using Compound 3-1 to replace the Compound 12-1 in Example 12  1 H NMR (500 MHz, Chloroform) δ 9.72 (s, 7H), 8.63 (s, 7H), 7.98 (s, 7H), 7.60 (s, 7H), 7.10 (s, 6H), 7.00 (d, J=18.2 Hz, 14H), 6.62 (s, 7H), 6.16 (s, 7H), 6.02 (s, 7H), 5.29 (s, 5H), 4.65 (s, 4H), 3.65 (s, 4H), 3.55 (s, 4H), 2.80 (s, 4H), 2.22 (s, 5H), 2.02 (s, 13H), 1.91 (s, 3H), 1.76 (s, 13H), 1.64 (d, J=15.3 Hz, 18H), 1.53 (s, 3H), 1.33 (s, 7H). ESI-MS m/z 439.23 [M+H]±. 
     Example 23: Synthesis of Compound 23 
     
       
         
         
             
             
         
       
     
     The Compound 23 was synthesized according to the synthesis of Compound 12 by using Compound 8-1 to replace the Compound 12-1 in Example 12, and using Compound 23-1 to replace the 5-1 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 8.31 (d, J=9.0 Hz, 1H), 7.75 (s, 1H), 7.61 (m, 3H), 7.41 (d, J=8.1 Hz, 1H), 7.29-7.19 (m, 3H), 7.16-7.06 (m, 3H), 6.55 (t, J=4.4 Hz, 1H), 4.84 (dt, J=9.3, 7.8 Hz, 1H), 4.68 (dd, J=9.2, 6.6 Hz, 1H), 4.36 (dt, J=9.0, 6.4 Hz, 1H), 3.38-3.27 (m, 2H), 3.22-3.10 (m, 2H), 2.39 (m, 1H), 2.14 (dt, J=12.8, 6.3 Hz, 1H), 2.05 (m, 1H), 1.91 (dt, J=12.7, 6.3 Hz, 1H), 1.83 (m, 1H), 1.74 (m, 1H), 0.88 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 564.24[M+H] + . 
     Example 24: Synthesis of Compound 24 
     
       
         
         
             
             
         
       
     
     The Compound 24 was synthesized according to the synthesis of Compound 1 by using Compound 24-1 to replace the Compound 1-11 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 8.30 (s, 1H), 8.24 (d, J=9.0 Hz, 1H), 7.99-7.93 (m, 1H), 7.80-7.75 (m, 1H), 7.63 (d, J=9.0 Hz, 1H), 7.58 (d, J=9.3 Hz, 1H), 7.37-7.32 (m, 2H), 6.55 (t, J=4.4 Hz, 1H), 5.16 (dd, J=9.0, 6.6 Hz, 1H), 4.39 (m, 2H), 3.33 (m, 1H), 3.21 (m, 1H), 2.42 (m, 1H), 2.21-2.08 (m, 2H), 1.99-1.87 (m, 2H), 1.83 (m, 1H), 1.78-1.66 (m, 3H), 1.52 (m, 2H), 1.47-1.28 (m, 6H), 1.20 (m, 2H), 0.86 (dd, J=25.1, 6.6 Hz, 6H). ESI-MS m/z 569.27[M+H] + . 
     Example 25: Synthesis of Compound 25 
     
       
         
         
             
             
         
       
     
     The Compound 25 was synthesized according to the synthesis of Compound 1 by using Compound 25-1 to replace the Compound 1-11 in Example 1. 
     Example 26: Synthesis of Compound 26 
     
       
         
         
             
             
         
       
     
     The Compound 26 was synthesized according to the synthesis of Compound 1 by using Compound 26-1 to replace the Compound 1-11 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 8.60 (d, J=9.0 Hz, 1H), 8.30-8.19 (m, 3H), 7.90 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.63 (dd, J=9.2, 4.9 Hz, 2H), 6.55 (t, J=4.4 Hz, 1H), 4.90 (dd, J=9.1, 6.5 Hz, 1H), 4.41 (dt, J=9.0, 6.4 Hz, 1H), 4.30 (dt, J=9.3, 6.9 Hz, 1H), 3.34 (m, 1H), 3.23 (m, 1H), 2.47 (m, 1H), 2.26-2.16 (m, J=6.6 Hz, 1H), 2.12 (dt, J=12.9, 6.4 Hz, 1H), 1.94 (dt, J=12.9, 6.4 Hz, 1H), 1.90-1.78 (m, 3H), 1.74 (m, 1H), 1.68-1.57 (m, 1H), 1.54-1.41 (m, 4H), 1.41-1.34 (m, 4H), 1.22 (m, 2H), 0.90 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 642.22[M+H] + . 
     Example 27: Synthesis of Compound 27 
     
       
         
         
             
             
         
       
     
     The Compound 27 was synthesized according to the synthesis of Compound 1 by using Compound 24-1 to replace the Compound 1-11 in Example 1, and using Compound 8-1 to replace the 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 8.34 (s, 1H), 8.20 (d, J=9.2 Hz, 1H), 7.98-7.93 (m, 1H), 7.80-7.75 (m, 1H), 7.61 (dd, J=19.5, 9.1 Hz, 2H), 7.38-7.32 (m, 2H), 7.29-7.20 (m, 3H), 7.15-7.08 (m, 2H), 6.55 (t, J=4.4 Hz, 1H), 5.14 (dd, J=9.1, 6.5 Hz, 1H), 4.74 (dt, J=9.3, 7.7 Hz, 1H), 4.39 (dt, J=8.8, 6.4 Hz, 1H), 3.42-3.26 (m, 2H), 3.24-3.07 (m, 2H), 2.34 (m, 1H), 2.20-2.06 (m, 2H), 1.94 (dt, J=12.7, 6.3 Hz, 1H), 1.82 (m, 1H), 1.74 (m, 1H), 0.86 (dd, J=25.1, 6.6 Hz, 6H). ESI-MS m/z 562.22[M+H] + . 
     Example 28: Synthesis of Compound 28 
     
       
         
         
             
             
         
       
     
     The Compound 28 was synthesized according to the synthesis of Compound 9 by using Compound 28-1 to replace the Compound 1-8 in Example 9. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 9.16 (s, 1H), 8.46 (d, J=9.2 Hz, 1H), 7.68-7.56 (m, 3H), 7.39 (d, J=7.9 Hz, 1H), 7.32 (s, 1H), 7.29-7.14 (m, 5H), 7.14-7.08 (m, 2H), 6.55 (t, J=4.4 Hz, 1H), 4.90 (dd, J=9.1, 6.5 Hz, 1H), 4.72 (dt, J=9.3, 7.8 Hz, 1H), 4.44 (dt, J=9.0, 6.3 Hz, 1H), 3.40-3.30 (m, 2H), 3.21 (m, 1H), 3.12 (dd, J=14.0, 7.8 Hz, 1H), 2.43 (m, 1H), 2.17 (dt, J=12.8, 6.3 Hz, 1H), 1.97-1.80 (m, 3H), 1.79-1.61 (m, 2H), 1.46 (m, 1H), 0.90-0.83 (m, 6H). ESI-MS m/z 559.28[M+H] + . 
     Example 29: Synthesis of Compound 29 
     
       
         
         
             
             
         
       
     
     The Compound 29 was synthesized according to the synthesis of Compound 5 by using Compound 28-1 to replace the Compound 1-8 in Example 5. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.16 (s, 1H), 8.46 (d, J=9.2 Hz, 1H), 7.68-7.60 (m, 3H), 7.44 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 7.19-7.14 (m, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.83 (dd, J=9.0, 6.5 Hz, 1H), 4.41 (dt, J=8.9, 6.4 Hz, 1H), 4.30 (dt, J=9.3, 6.9 Hz, 1H), 3.38-3.10 (m, 2H), 2.42 (m, 1H), 2.08 (dt, J=12.9, 6.4 Hz, 1H), 2.00-1.91 (m, 2H), 1.86-1.62 (m, 5H), 1.60-1.42 (m, 7H), 1.35-1.20 (m, 5H), 0.91-0.84 (m, 6H). ESI-MS m/z 565.33[M+H] + . 
     Example 30: Synthesis of Compound 30 
     
       
         
         
             
             
         
       
     
     The Compound 30 was synthesized according to the synthesis of Compound 1 by using Compound 5-1 to replace the acid 1-11 in Example 1, and using Compound 4-1 to replace the 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 9.12 (s, 1H), 8.48 (d, J=9.0 Hz, 1H), 7.68-7.56 (m, 3H), 7.45 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.31-7.13 (m, 4H), 7.02-6.95 (m, 2H), 6.55 (t, J=4.4 Hz, 1H), 4.99 (dd, J=9.2, 6.6 Hz, 1H), 4.75 (dt, J=9.2, 7.7 Hz, 1H), 4.39 (dt, J=8.8, 6.4 Hz, 1H), 3.33 (m, 1H), 3.22 (m, 1H), 3.04 (dd, J=14.1, 7.7 Hz, 1H), 2.92 (dd, J=14.0, 7.8 Hz, 1H), 2.44 (m, 1H), 2.33-2.18 (m, J=6.6 Hz, 1H), 2.12 (dt, J=12.8, 6.3 Hz, 1H), 1.94 (dt, J=12.9, 6.3 Hz, 1H), 1.83 (m, 1H), 1.74 (m, 1H), 0.88 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 563.25[M+H] + . 
     Example 31: Synthesis of Compound 31 
     
       
         
         
             
             
         
       
     
     The Compound 31 was synthesized according to the synthesis of Compound 1 by using Compound 5-1 to replace the acid 1-11 in Example 1, and using Compound 3-1 to replace the 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 9.12 (s, 1H), 8.55 (d, J=9.2 Hz, 1H), 7.71-7.61 (m, 3H), 7.39 (d, J=7.9 Hz, 1H), 7.32 (s, 1H), 7.24-7.14 (m, 2H), 6.55 (t, J=4.4 Hz, 1H), 5.02 (dd, J=9.1, 6.5 Hz, 1H), 4.41 (dt, J=9.0, 6.4 Hz, 1H), 4.30 (dt, J=9.3, 6.9 Hz, 1H), 3.34 (m, 1H), 3.23 (m, 1H), 2.47 (m, 1H), 2.27-2.07 (m, 2H), 1.95 (dt, J=12.9, 6.4 Hz, 1H), 1.88-1.79 (m, 3H), 1.78-1.63 (m, 4H), 1.59-1.48 (m, 5H), 0.87 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 537.29[M+H] + . 
     Example 32: Synthesis of Compound 32 
     
       
         
         
             
             
         
       
     
     The Compound 32 was synthesized according to the synthesis of Compound 1 by using Compound 6-1 to replace the acid 1-11 in Example 1, and using Compound 4-1 to replace the 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 7.98 (d, J=9.3 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.28 (dd, J=8.4, 4.9 Hz, 2H), 7.03 (t, J=8.2 Hz, 2H), 6.58-6.52 (m, 2H), 4.75 (dd, J=9.0, 6.6 Hz, 1H), 4.58-4.44 (m, 2H), 3.30 (m, 1H), 3.18 (m, 1H), 3.09 (dd, J=13.9, 7.7 Hz, 1H), 2.92 (dd, J=14.1, 7.7 Hz, 1H), 2.55-2.47 (m, 4H), 2.24-2.11 (m, J=6.6 Hz, 1H), 2.01 (dt, J=12.8, 6.3 Hz, 1H), 1.87-1.76 (m, 2H), 1.73 (m, 1H), 0.88 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 529.23[M+H] + . 
     Example 33: Synthesis of Compound 33 
     
       
         
         
             
             
         
       
     
     The Compound 33 was synthesized according to the synthesis of Compound 9 by using Compound 33-1 to replace the Compound 1-8 in Example 9. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.12 (s, 1H), 8.49 (d, J=8.8 Hz, 1H), 7.81 (d, J=9.3 Hz, 1H), 7.69-7.60 (m, 2H), 7.41 (d, J=7.9 Hz, 1H), 7.32-7.08 (m, 8H), 6.55 (t, J=4.4 Hz, 1H), 4.79 (dt, J=9.3, 7.7 Hz, 1H), 4.48 (dt, J=9.0, 6.3 Hz, 1H), 4.42 (d, J=8.8 Hz, 1H), 3.37-3.30 (m, 2H), 3.24-3.11 (m, 2H), 2.43 (m, 1H), 2.24 (dt, J=12.7, 6.3 Hz, 1H), 1.99 (dt, J=12.9, 6.3 Hz, 1H), 1.87-1.71 (m, 2H), 0.98 (s, 9H). ESI-MS m/z 559.28[M+H] + . 
     Example 34: Synthesis of Compound 34 
     
       
         
         
             
             
         
       
     
     The Compound 34 was synthesized according to the synthesis of Compound 9 by using Compound 33-1 to replace the Compound 1-8 in Example 5. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.12 (s, 1H), 8.53 (d, J=8.8 Hz, 1H), 7.69-7.55 (m, 3H), 7.39 (d, J=7.9 Hz, 1H), 7.35 (s, 1H), 7.22 (t, J=7.5 Hz, 1H), 7.19-7.12 (m, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.61-4.55 (m, 2H), 4.33 (dt, J=9.3, 6.8 Hz, 1H), 3.34 (m, 1H), 3.22 (m, 1H), 2.46 (m, 1H), 2.06 (dt, J=12.8, 6.3 Hz, 1H), 1.98-1.79 (m, 3H), 1.78-1.58 (m, 5H), 1.57-1.39 (m, 3H), 1.34-1.17 (m, 5H), 0.98 (s, 9H). ESI-MS m/z 565.33[M+H] + . 
     Example 35: Synthesis of Compound 35 
     
       
         
         
             
             
         
       
     
     The Compound 35 was synthesized according to the synthesis of Compound 1 by using Compound 5-1 to replace the acid 1-11 in Example 1, and using Compound 35-1 to replace the 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 9.12 (s, 1H), 8.54 (d, J=9.0 Hz, 1H), 7.67-7.56 (m, 3H), 7.42-7.36 (m, 2H), 7.23 (t, J=7.6 Hz, 1H), 7.16 (dd, J=8.0, 7.4 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.89 (dd, J=9.0, 6.6 Hz, 1H), 4.74-4.52 (m, 2H), 4.52-4.43 (m, 1H), 4.33 (dt, J=8.8, 6.4 Hz, 1H), 3.33 (m, 1H), 3.19 (m, 1H), 2.40 (m, 1H), 2.20 (m, 1H), 2.15-2.09 (m, 1H), 2.00-1.56 (m, 12H), 0.87 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 587.29[M+H] + . 
     Example 36: Synthesis of Compound 36 
     
       
         
         
             
             
         
       
     
     The Compound 36 was synthesized according to the synthesis of Compound 35 by using Compound 36-1 to replace the Compound 35-1 in Example 35. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 9.07 (s, 1H), 8.54 (d, J=9.2 Hz, 1H), 7.73-7.62 (m, 3H), 7.39 (d, J=7.9 Hz, 1H), 7.32 (s, 1H), 7.25-7.14 (m, 2H), 6.55 (s, 1H), 4.99 (dd, J=9.2, 6.6 Hz, 1H), 4.46 (dt, J=8.8, 6.4 Hz, 1H), 4.42-4.32 (m, 1H), 3.38-3.18 (m, 2H), 2.45 (t, J=6.4 Hz, 1H), 2.25-2.15 (m, J=6.7 Hz, 1H), 2.10 (dt, J=12.9, 6.4 Hz, 1H), 2.01-1.91 (m, 2H), 1.89-1.55 (m, 10H), 0.87 (dd, J=25.0, 6.7 Hz, 6H). ESI-MS m/z 523.28[M+H] + . 
     Example 37: Synthesis of Compound 37 
     
       
         
         
             
             
         
       
     
     The Compound 37 was synthesized according to the synthesis of Compound 12 by using Compound 8-1 to replace the Compound 12-1 in Example 12. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 9.11 (s, 1H), 8.53 (d, J=9.3 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.36 (s, 1H), 7.29-7.12 (m, 7H), 6.55 (t, J=4.4 Hz, 1H), 5.04 (dt, J=9.3, 7.7 Hz, 1H), 4.36 (dt, J=8.8, 6.4 Hz, 1H), 3.25 (m, 1H), 3.15 (m, 1H), 3.11-3.01 (m, 2H), 2.41 (m, 1H), 2.18 (dt, J=12.8, 6.3 Hz, 1H), 1.87 (dt, J=12.9, 6.4 Hz, 1H), 1.82-1.68 (m, 2H). ESI-MS m/z 446.19[M+H] + . 
     Example 38: Synthesis of Compound 38 
     
       
         
         
             
             
         
       
     
     The Compound 38 was synthesized according to the synthesis of Compound 12 by using Compound 38-1 to replace the Compound 5-1 in Example 37. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 8.56 (d, J=9.3 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.30 (dd, J=8.2, 7.3 Hz, 1H), 7.27-7.18 (m, 6H), 6.55 (t, J=4.4 Hz, 1H), 4.97 (dt, J=9.3, 7.8 Hz, 1H), 4.60 (dt, J=8.8, 6.4 Hz, 1H), 3.94 (s, 3H), 3.33 (m, 1H), 3.16 (m, 1H), 3.10 (dd, J=13.9, 7.7 Hz, 1H), 3.00 (dd, J=14.1, 7.7 Hz, 1H), 2.37 (m, 1H), 2.13 (dt, J=12.9, 6.4 Hz, 1H), 1.88 (dt, J=12.9, 6.4 Hz, 1H), 1.82-1.69 (m, 2H). ESI-MS m/z 460.21 [M+H] + . 
     Example 39: Synthesis of Compound 39 
     
       
         
         
             
             
         
       
     
     The Compound 39 was synthesized according to the synthesis of Compound 12 by using Compound 39-1 to replace the Compound 5-1 in Example 37. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.14 (s, 1H), 8.53 (d, J=9.3 Hz, 1H), 7.86 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.52 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.27-7.18 (m, 5H), 6.55 (t, J=4.4 Hz, 1H), 4.91 (dt, J=9.3, 7.7 Hz, 1H), 4.53 (dt, J=9.0, 6.3 Hz, 1H), 3.37 (m, 1H), 3.22 (m, 1H), 3.09 (dd, J=14.0, 7.8 Hz, 1H), 3.00 (dd, J=13.9, 7.7 Hz, 1H), 2.44 (m, 1H), 2.17 (dt, J=12.9, 6.4 Hz, 1H), 1.97 (dt, J=12.9, 6.4 Hz, 1H), 1.84 (m, 1H), 1.76 (m, 1H). ESI-MS m/z 514.18[M+H] + . 
     Example 40: Synthesis of Compound 40 
     
       
         
         
             
             
         
       
     
     The Compound 40 was synthesized according to the synthesis of Compound 12 by using Compound 13-1 to replace the Compound 5-1 in Example 37. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 9.18 (s, 1H), 8.51 (d, J=9.3 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.33 (s, 1H), 7.30 (s, 1H), 7.28-7.18 (m, 5H), 6.80 (d, J=8.4 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 5.05 (dt, J=9.3, 7.8 Hz, 1H), 4.34 (dt, J=9.0, 6.3 Hz, 1H), 3.84 (s, 3H), 3.25 (m, 1H), 3.19-3.11 (m, 1H), 3.11-3.07 (m, 1H), 3.00 (dd, J=14.1, 7.7 Hz, 1H), 2.41 (m, 1H), 2.18 (dt, J=12.9, 6.4 Hz, 1H), 1.86 (dt, J=12.9, 6.4 Hz, 1H), 1.82-1.68 (m, 2H). ESI-MS m/z 476.21[M+H] + . 
     Example 41: Synthesis of Compound 41 
     
       
         
         
             
             
         
       
     
     The Compound 41 was synthesized according to the synthesis of Compound 37 by using Compound 20-1 to replace the Compound 5-1 in Example 37. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.15 (s, 1H), 8.53 (d, J=9.3 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.61 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.32-7.07 (m, 7H), 6.55 (t, J=4.4 Hz, 1H), 5.06 (dt, J=9.3, 7.8 Hz, 1H), 4.48 (dt, J=8.8, 6.4 Hz, 1H), 3.36 (m, 1H), 3.22 (m, 1H), 3.09 (dd, J=14.1, 7.7 Hz, 1H), 3.00 (dd, J=13.9, 7.7 Hz, 1H), 2.43 (m, 1H), 2.14 (dt, J=12.9, 6.4 Hz, 1H), 1.99 (dt, J=12.9, 6.3 Hz, 1H), 1.85-1.71 (m, 2H). ESI-MS m/z 480.16[M+H] + . 
     Example 42: Synthesis of Compound 42 
     
       
         
         
             
             
         
       
     
     The Compound 42 was synthesized according to the synthesis of Compound 37 by using Compound 42-1 to replace the Compound 5-1 in Example 37. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.13 (s, 1H), 8.61 (d, J=9.3 Hz, 1H), 7.83 (d, J=4.9 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.29-7.19 (m, 4H), 7.16-7.05 (m, 3H), 6.55 (t, J=4.4 Hz, 1H), 5.01 (dt, J=9.3, 7.7 Hz, 1H), 4.49 (dt, J=9.0, 6.4 Hz, 1H), 3.33 (m, 1H), 3.21-3.00 (m, 3H), 2.33 (m, 1H), 2.11 (dt, J=12.9, 6.4 Hz, 1H), 1.99 (dt, J=12.9, 6.3 Hz, 1H), 1.84-1.71 (m, 2H). ESI-MS m/z 464.19[M+H] + . 
     Example 43: Synthesis of Compound 43 
     
       
         
         
             
             
         
       
     
     The Compound 43 was synthesized according to the synthesis of Compound 37 by using Compound 43-1 to replace the Compound 5-1 in Example 37. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.77 (s, 1H), 9.21 (s, 1H), 8.61 (d, J=9.3 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.39 (s, 1H), 7.32 (td, J=7.9, 4.9 Hz, 1H), 7.29-7.18 (m, 5H), 7.01 (t, J=8.0 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 5.07 (dt, J=9.3, 7.7 Hz, 1H), 4.38 (dt, J=8.8, 6.4 Hz, 1H), 3.37 (m, 1H), 3.22 (m, 1H), 3.10 (dd, J=14.0, 7.8 Hz, 1H), 3.00 (dd, J=13.9, 7.7 Hz, 1H), 2.44 (m, 1H), 2.20 (dt, J=12.8, 6.3 Hz, 1H), 1.93 (dt, J=12.9, 6.4 Hz, 1H), 1.85-1.70 (m, 2H). ESI-MS m/z 464.19[M+H] + . 
     Example 44: Synthesis of Compound 44 
     
       
         
         
             
             
         
       
     
     The Compound 44 was synthesized according to the synthesis of Compound 37 by using Compound 44-1 to replace the Compound 5-1 in Example 37. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.76 (s, 1H), 9.21 (s, 1H), 8.58 (d, J=9.3 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.44-7.36 (m, 2H), 7.28-7.18 (m, 5H), 6.90 (t, J=8.1 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 5.06 (dt, J=9.3, 7.7 Hz, 1H), 4.41 (dt, J=9.0, 6.3 Hz, 1H), 3.37 (m, 1H), 3.22 (m, 1H), 3.10 (dd, J=13.9, 7.7 Hz, 1H), 3.00 (dd, J=14.1, 7.7 Hz, 1H), 2.44 (m, 1H), 2.19 (dt, J=12.9, 6.4 Hz, 1H), 1.92 (dt, J=12.8, 6.3 Hz, 1H), 1.85-1.70 (m, 2H). ESI-MS m/z 482.18[M+H] + . 
     Example 45: Synthesis of Compound 45 
     
       
         
         
             
             
         
       
     
     The Compound 45 was synthesized according to the synthesis of Compound 37 by using Compound 45-1 to replace the Compound 5-1 in Example 37. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.11 (s, 1H), 8.51 (d, J=9.3 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.50 (dd, J=8.4, 4.9 Hz, 1H), 7.36 (s, 1H), 7.29-7.18 (m, 3H), 7.13 (dd, J=6.1, 1.1 Hz, 2H), 7.03 (t, J=8.2 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 5.06 (dt, J=9.3, 7.8 Hz, 1H), 4.48 (dt, J=9.0, 6.4 Hz, 1H), 3.36 (m, 1H), 3.22 (m, 1H), 3.09 (dd, J=14.1, 7.7 Hz, 1H), 3.00 (dd, J=13.9, 7.7 Hz, 1H), 2.44 (m, 1H), 2.14 (dt, J=12.9, 6.3 Hz, 1H), 1.99 (dt, J=12.8, 6.3 Hz, 1H), 1.85-1.70 (m, 2H). ESI-MS m/z 464.19[M+H] + . 
     Example 46: Synthesis of Compound 46 
     
       
         
         
             
             
         
       
     
     The Compound 46 was synthesized according to the synthesis of Compound 37 by using Compound 46-1 to replace the Compound 5-1 in Example 37. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.23 (s, 1H), 8.51 (d, J=9.3 Hz, 1H), 7.93 (dd, J=8.4, 4.9 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.45 (s, 1H), 7.29-7.22 (m, 3H), 7.22-7.16 (m, 1H), 7.16-7.06 (m, 3H), 6.55 (t, J=4.4 Hz, 1H), 5.07 (dt, J=9.3, 7.8 Hz, 1H), 4.48 (dt, J=9.0, 6.4 Hz, 1H), 3.36 (m, 1H), 3.22 (m, 1H), 3.10 (dd, J=13.9, 7.7 Hz, 1H), 3.00 (dd, J=14.1, 7.7 Hz, 1H), 2.44 (m, 1H), 2.15 (dt, J=12.8, 6.3 Hz, 1H), 1.99 (dt, J=12.9, 6.3 Hz, 1H), 1.85-1.70 (m, 2H). ESI-MS m/z 464.19[M+H] + . 
     Example 47: Synthesis of Compound 47 
     
       
         
         
             
             
         
       
     
     The Compound 47 was synthesized according to the synthesis of Compound 37 by using Compound 14-1 to replace the Compound 5-1 in Example 37, and using 1-5 to replace the compound 8-1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.17 (s, 1H), 8.57 (d, J=9.3 Hz, 1H), 7.81 (s, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.41 (s, 1H), 7.31 (s, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.51 (dt, J=8.8, 6.4 Hz, 1H), 4.43 (dt, J=9.3, 6.9 Hz, 1H), 3.36 (m, 1H), 3.21 (m, 1H), 2.43 (m, 1H), 2.16 (dt, J=12.8, 6.3 Hz, 1H), 1.97 (dt, J=12.8, 6.3 Hz, 1H), 1.88-1.66 (m, 5H), 1.64-1.44 (m, 5H), 1.41-1.20 (m, 5H). ESI-MS m/z 520.16[M+H] + . 
     Example 48: Synthesis of Compound 48 
     
       
         
         
             
             
         
       
     
     The Compound 48 was synthesized according to the synthesis of Compound 37 by using Compound 5-1 to replace the Compound 5-1 in Example 37, and using 1-5 to replace the Compound 8-1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.11 (s, 1H), 8.58 (d, J=9.2 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.44 (s, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.25-7.13 (m, 2H), 6.55 (t, J=4.4 Hz, 1H), 4.48 (m, 2H), 3.35 (m, 1H), 3.20 (m, 1H), 2.42 (m, 1H), 2.15 (dt, J=12.9, 6.4 Hz, 1H), 2.02-1.89 (m, 2H), 1.85-1.44 (m, 9H), 1.39-1.20 (m, 5H). ESI-MS m/z 452.24[M+H] + . 
     Example 49: Synthesis of Compound 49 
     
       
         
         
             
             
         
       
     
     The Compound 49 was synthesized according to the synthesis of Compound 47 by using Compound 38-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 8.62 (d, J=9.3 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.33-7.26 (m, 2H), 7.20 (t, J=7.6 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.33 (m, 2H), 3.94 (s, 3H), 3.24 (m, 1H), 3.13 (m, 1H), 2.39 (m, 1H), 2.18 (dt, J=12.9, 6.3 Hz, 1H), 1.98 (dt, J=13.8, 6.9 Hz, 1H), 1.91-1.84 (m, 2H), 1.84-1.74 (m, 2H), 1.74-1.67 (m, 1H), 1.67-1.44 (m, 7H), 1.39-1.21 (m, 5H). ESI-MS m/z 466.26[M+H] + . 
     Example 50: Synthesis of Compound 50 
     
       
         
         
             
             
         
       
     
     The Compound 50 was synthesized according to the synthesis of Compound 47 by using Compound 50-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.15 (s, 1H), 8.58 (d, J=9.3 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.9 Hz, 2H), 7.27 (s, 1H), 6.80 (d, J=8.4 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.55 (dt, J=9.0, 6.4 Hz, 1H), 4.42 (dt, J=9.3, 6.9 Hz, 1H), 3.84 (s, 3H), 3.35 (m, 1H), 3.20 (m, 1H), 2.46 (m, 1H), 2.13 (dt, J=12.8, 6.4 Hz, 1H), 1.98 (dt, J=12.9, 6.4 Hz, 1H), 1.86-1.65 (m, 5H), 1.64-1.53 (m, 2H), 1.53-1.43 (m, 3H), 1.40-1.20 (m, 5H). ESI-MS m/z 482.25[M+H] + . 
     Example 51: Synthesis of Compound 51 
     
       
         
         
             
             
         
       
     
     The Compound 51 was synthesized according to the synthesis of Compound 47 by using Compound 42-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.13 (s, 1H), 8.63 (d, J=9.3 Hz, 1H), 7.80-7.71 (m, 2H), 7.27 (d, J=7.8 Hz, 1H), 7.21 (td, J=7.8, 4.9 Hz, 1H), 7.09 (t, J=7.8 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.51 (dt, J=9.0, 6.4 Hz, 1H), 4.43 (dt, J=9.3, 6.9 Hz, 1H), 3.36 (m, 1H), 3.21 (m, 1H), 2.42 (m, 1H), 2.16 (dt, J=12.9, 6.4 Hz, 1H), 2.00 (dt, J=12.9, 6.3 Hz, 1H), 1.86-1.66 (m, 5H), 1.64-1.44 (m, 5H), 1.41-1.20 (m, 5H). ESI-MS m/z 470.23[M+H] + . 
     Example 52: Synthesis of Compound 52 
     
       
         
         
             
             
         
       
     
     The Compound 52 was synthesized according to the synthesis of Compound 47 by using Compound 45-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.11 (s, 1H), 8.54 (d, J=9.2 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.47 (dd, J=8.4, 4.9 Hz, 1H), 7.37 (s, 1H), 7.03 (t, J=8.2 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.52 (dt, J=9.0, 6.4 Hz, 1H), 4.45 (dt, J=9.3, 6.9 Hz, 1H), 3.35 (m, 1H), 3.20 (m, 1H), 2.43 (m, 1H), 2.12 (dt, J=12.8, 6.3 Hz, 1H), 1.99 (dt, J=12.9, 6.3 Hz, 1H), 1.92-1.68 (m, 4H), 1.68-1.44 (m, 7H), 1.40-1.24 (m, 5H). ESI-MS m/z 470.23[M+H] + . 
     Example 53: Synthesis of Compound 53 
     
       
         
         
             
             
         
       
     
     The Compound 53 was synthesized according to the synthesis of Compound 47 by using Compound 46-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.23 (s, 1H), 8.54 (d, J=9.2 Hz, 1H), 7.90 (dd, J=8.4, 4.9 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.49 (s, 1H), 7.18-7.07 (m, 2H), 6.55 (t, J=4.4 Hz, 1H), 4.51 (dt, J=8.8, 6.3 Hz, 1H), 4.43 (dt, J=9.3, 6.9 Hz, 1H), 3.36 (m, 1H), 3.21 (m, 1H), 2.42 (m, 1H), 2.16 (dt, J=12.9, 6.4 Hz, 1H), 1.99 (dt, J=12.8, 6.3 Hz, 1H), 1.86-1.66 (m, 5H), 1.59 (m, 2H), 1.55-1.50 (m, 2H), 1.50-1.44 (m, 2H), 1.41-1.20 (m, 5H). ESI-MS m/z 470.23[M+H] + . 
     Example 54: Synthesis of Compound 54 
     
       
         
         
             
             
         
       
     
     The Compound 54 was synthesized according to the synthesis of Compound 47 by using Compound 43-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.78 (s, 1H), 9.21 (s, 1H), 8.63 (d, J=9.3 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.47 (s, 1H), 7.30 (td, J=7.9, 5.0 Hz, 1H), 7.00 (t, J=7.9 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.47-4.35 (m, 2H), 3.37 (m, 1H), 3.22 (m, 1H), 2.43 (m, 4.5 Hz, 1H), 2.21 (dt, J=12.8, 6.3 Hz, 1H), 1.94 (dt, J=12.9, 6.3 Hz, 1H), 1.88-1.66 (m, 5H), 1.64-1.44 (m, 5H), 1.41-1.21 (m, 5H). ESI-MS m/z 470.23[M+H] + . 
     Example 55: Synthesis of Compound 55 
     
       
         
         
             
             
         
       
     
     The Compound 55 was synthesized according to the synthesis of Compound 47 by using Compound 23-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 8.50 (d, J=9.3 Hz, 1H), 7.83-7.76 (m, 2H), 7.64 (dd, J=9.8, 7.7 Hz, 2H), 7.39 (t, J=7.5 Hz, 1H), 7.32 (t, J=7.4 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.38 (dt, J=8.8, 6.4 Hz, 1H), 4.25 (dt, J=9.3, 6.9 Hz, 1H), 3.32 (m, 1H), 3.20 (m, 1H), 2.42 (m, 1H), 2.16 (dt, J=12.9, 6.4 Hz, 1H), 1.98-1.65 (m, 6H), 1.59 (m, 2H), 1.57-1.44 (m, 3H), 1.41-1.18 (m, 5H). ESI-MS m/z 453.23[M+H] + . 
     Example 56: Synthesis of Compound 56 
     
       
         
         
             
             
         
       
     
     The Compound 56 was synthesized according to the synthesis of Compound 47 by using Compound 24-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 8.46 (d, J=9.3 Hz, 1H), 8.30 (s, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.83-7.77 (m, 2H), 7.42 (t, J=7.6 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.48 (dt, J=8.8, 6.4 Hz, 1H), 4.29 (dt, J=9.3, 6.9 Hz, 1H), 3.32-3.16 (m, 2H), 2.36 (m, 1H), 2.17 (dt, J=12.9, 6.4 Hz, 1H), 1.96 (m, 2H), 1.86-1.44 (m, 10H), 1.41-1.17 (m, 6H). ESI-MS m/z 469.20[M+H] + . 
     Example 57: Synthesis of Compound 57 
     
       
         
         
             
             
         
       
     
     The Compound 49 was synthesized according to the synthesis of Compound 47 by using Compound 38-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 8.63 (d, J=9.3 Hz, 1H), 7.83-7.73 (m, 2H), 7.65-7.57 (m, 1H), 7.29-7.21 (m, 2H), 6.55 (t, J=4.4 Hz, 1H), 4.56-4.47 (m, 2H), 3.36 (m, 1H), 3.21 (m, 1H), 2.42 (m, 1H), 2.15 (dt, J=12.8, 6.3 Hz, 1H), 1.98 (dt, J=12.8, 6.3 Hz, 1H), 1.85-1.66 (m, 5H), 1.63-1.45 (m, 6H), 1.42-1.21 (m, 6H). ESI-MS m/z 453 0.24 [M+H]±. 
     Example 58: Synthesis of Compound 58 
     
       
         
         
             
             
         
       
     
     The Compound 58 was synthesized according to the synthesis of Compound 47 by using Compound 11-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 8.57 (d, J=9.3 Hz, 1H), 8.35-8.26 (m, 2H), 8.15 (d, J=8.1 Hz, 1H), 7.93 (d, J=7.5 Hz, 1H), 7.85 (dd, J=8.2, 7.4 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.59 (t, J=7.4 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.45-4.35 (m, 2H), 3.27 (m, 1H), 3.12 (m, 1H), 2.40 (m, 1H), 2.10 (dt, J=12.8, 6.3 Hz, 1H), 2.00-1.89 (m, 2H), 1.84-1.65 (m, 3H), 1.65-1.43 (m, 6H), 1.39-1.19 (m, 5H). ESI-MS m/z 464.24[M+H]±. 
     Example 59: Synthesis of Compound 59 
     
       
         
         
             
             
         
       
     
     The Compound 59 was synthesized according to the synthesis of Compound 47 by using Compound 59-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.36 (s, 1H), 9.21 (s, 1H), 8.64 (d, J=9.3 Hz, 1H), 7.99 (dd, J=7.8, 3.7 Hz, 2H), 7.86 (t, J=7.6 Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.61-7.54 (m, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.43 (dt, J=9.3, 6.9 Hz, 1H), 4.37 (dt, J=8.8, 6.4 Hz, 1H), 3.23 (m, 1H), 3.02 (m, 1H), 2.36 (m, 1H), 2.09 (dt, J=12.7, 6.3 Hz, 1H), 1.99-1.89 (m, 2H), 1.83-1.44 (m, 10H), 1.40-1.19 (m, 6H). ESI-MS m/z 465.24[M+H] + . 
     Example 60: Synthesis of Compound 60 
     
       
         
         
             
             
         
       
     
     The Compound 60 was synthesized according to the synthesis of Compound 9 by using Compound 60-1 to replace the Compound 1-8 in Example 5. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.12 (s, 1H), 8.79 (d, J=9.1 Hz, 1H), 7.71-7.60 (m, 3H), 7.42-7.35 (m, 2H), 7.23 (t, J=7.6 Hz, 1H), 7.20-7.13 (m, 1H), 6.55 (t, J=4.4 Hz, 1H), 4.50 (dt, J=8.8, 6.4 Hz, 1H), 4.38 (dt, J=9.3, 6.8 Hz, 1H), 4.18 (dd, J=9.1, 5.2 Hz, 1H), 3.30 (m, 1H), 3.15 (m, 1H), 2.39 (m, 1H), 2.11 (dt, J=12.8, 6.3 Hz, 1H), 1.97 (dt, J=12.9, 6.3 Hz, 1H), 1.92-1.65 (m, 5H), 1.62-1.52 (m, 1H), 1.52-1.31 (m, 9H), 1.23-1.08 (m, 4H), 0.89-0.80 (m, 2H). ESI-MS m/z 549.29[M+H] + . 
     Example 61: Synthesis of Compound 61 
     
       
         
         
             
             
         
       
     
     The Compound 61 was synthesized according to the synthesis of Compound 47 by using Compound 61-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.21 (s, 1H), 8.48 (d, J=9.3 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.55 (t, J=4.4 Hz, 1H), 6.05 (d, J=6.8 Hz, 2H), 4.35 (m, 2H), 3.32 (m, 1H), 3.19 (m, 1H), 2.40 (m, 1H), 2.19 (dt, J=12.8, 6.3 Hz, 1H), 1.93-1.67 (m, 6H), 1.59 (m, 2H), 1.57-1.44 (m, 3H), 1.41-1.20 (m, 6H). ESI-MS m/z 457.22[M+H] + . 
     Example 62: Synthesis of Compound 62 
     
       
         
         
             
             
         
       
     
     The Compound 62 was synthesized according to the synthesis of Compound 47 by using Compound 6-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (600 MHz, Acetone-d6) δ 11.14 (d, J=8.4 Hz, 1H), 9.41 (s, 1H), 8.28-8.23 (m, 1H), 7.78 (dd, J=12.5, 8.8 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.37-7.33 (m, 2H), 7.23 (d, J=7.7 Hz, 2H), 7.16 (dd, J=6.3, 1.9 Hz, 4H), 5.44 (dd, J=70.6, 8.0 Hz, 1H), 5.06 (dd, J=7.1, 4.5 Hz, 1H), 4.51 (m, 1H), 4.13-3.99 (m, 1H), 3.32 (d, J=2.0 Hz, 1H), 3.20 (m, 2H), 2.44-2.34 (m, 1H), 2.33-2.25 (m, 1H), 1.79-1.55 (m, 2H). ESI-MS m/z 413.17[M+H] + . 
     Example 63: Synthesis of Compound 63 
     
       
         
         
             
             
         
       
     
     The Compound 63 was synthesized according to the synthesis of Compound 47 by using Compound 63-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.42 (s, 1H), 8.87 (d, J=12.0 Hz, 1H), 8.75 (d, J=6.0 Hz, 1H), 8.63 (d, J=2.7 Hz, 1H), 8.24 (d, J=8.1 Hz, 1H), 7.98-7.94 (m, 1H), 7.37 (d, J=7.3 Hz, 2H), 7.30 (dd, J=10.4, 4.7 Hz, 2H), 7.22 (m, 1H), 5.01 (m, 1H), 4.32-4.27 (m, 1H), 3.38-3.34 (m, 1H), 3.31-3.27 (m, 1H), 3.19 (dd, J=13.9, 8.9 Hz, 1H), 2.51-2.40 (m, 1H), 2.39-2.33 (m, 1H), 1.97-1.88 (m, 1H), 1.82 (m, 1H), 1.39 (s, 1H), 1.31 (d, J=2.5 Hz, 2H). ESI-MS m/z 427.16[M+H] + . 
     Example 64: Synthesis of Compound 64 
     
       
         
         
             
             
         
       
     
     The Compound 64 was synthesized according to the synthesis of Compound 12 by using Compound 64-1 to replace the Compound 5-1 in Example 12, and using Compound 8-1 to replace the Compound 12-1 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.43 (s, 1H), 8.59 (d, J=6.8 Hz, 1H), 8.18 (dd, J=15.6, 1.8 Hz, 1H), 8.08-7.99 (m, 1H), 7.92-7.82 (m, 2H), 7.53 (t, J=8.1 Hz, 1H), 7.38 (d, J=7.3 Hz, 2H), 7.28 (t, J=7.5 Hz, 2H), 7.19 (t, J=7.3 Hz, 1H), 7.13 (s, 1H), 6.97-6.90 (m, 1H), 5.07 (m, 1H), 4.37 (m, 1H), 3.37-3.33 (m, 1H), 3.29-3.20 (m, 3H), 2.52-2.24 (m, 2H), 2.05-1.98 (m, 1H), 1.87-1.62 (m, 2H). ESI-MS m/z 448.17[M+H] + . 
     Example 65: Synthesis of Compound 65 
     
       
         
         
             
             
         
       
     
     The Compound 65 was synthesized according to the synthesis of Compound 12 by using Compound 65-1 to replace the Compound 5-1 in Example 12, and using Compound 8-1 to replace the Compound 12-1 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.22 (s, 1H), 8.36 (d, J=6.3 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.23 (s, 5H), 7.02 (d, J=8.1 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.55 (s, 1H), 5.07 (m, 1H), 4.27-4.21 (m, 6H), 3.31-3.24 (m, 2H), 3.20 (dd, J=14.4, 6.7 Hz, 2H), 2.35-2.28 (m, 2H), 1.90 (dd, J=10.2, 6.4 Hz, 1H), 1.80 (m, 2H). ESI-MS m/z 466.18[M+H] + . 
     Example 66: Synthesis of Compound 66 
     
       
         
         
             
             
         
       
     
     The Compound 66 was synthesized according to the synthesis of Compound 12 by using Compound 66-1 to replace the Compound 5-1 in Example 12, and using Compound 8-1 to replace the Compound 12-1 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 11.14 (d, J=8.8 Hz, 1H), 9.41 (s, 1H), 8.28-8.23 (m, 1H), 7.78 (m, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.37-7.33 (m, 2H), 7.23 (d, J=7.7 Hz, 2H), 7.16 (dd, J=6.3, 1.9 Hz, 4H), 5.44 m, 1H), 5.06 (dd, J=7.1, 4.5 Hz, 1H), 4.51 (m, 1H), 4.13-3.99 (m, 1H), 3.32 (d, J=2.0 Hz, 1H), 3.20 (m, 2H), 2.44-2.34 (m, 1H), 2.33-2.25 (m, 1H), 1.79-1.55 (m, 2H). ESI-MS m/z 466.18[M+H] + . 
     Example 67: Synthesis of Compound 67 
     
       
         
         
             
             
         
       
     
     The Compound 67 was synthesized according to the synthesis of Compound 12 by using Compound 67-1 to replace the Compound 5-1 in Example 12, and using Compound 8-1 to replace the Compound 12-1 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 10.53 (s, 1H), 9.39 (s, 1H), 8.19-8.16 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.66 (dd, J=8.5, 1.7 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.40-7.38 (m, 1H), 7.37-7.33 (m, 2H), 7.26 (m, 2H), 7.19-7.15 (m, 1H), 6.96 (s, 1H), 6.54 (m, 1H), 5.01 (dt, J=8.2, 4.0 Hz, 1H), 4.31-4.26 (m, 1H), 3.31 (dd, J=8.2, 5.6 Hz, 1H), 3.26-3.18 (m, 3H), 2.45-2.36 (m, 1H), 2.32-2.21 (m, 1H), 1.98-1.95 (m, 1H), 1.81-1.68 (m, 2H). ESI-MS m/z 447.19[M+H] + . 
     Example 68: Synthesis of Compound 68 
     
       
         
         
             
             
         
       
     
     The Compound 68 was synthesized according to the synthesis of Compound 12 by using Compound 68-1 to replace the Compound 5-1 in Example 12, and using Compound 8-1 to replace the Compound 12-1 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.40 (s, 1H), 8.79 (s, 1H), 8.53 (d, J=6.2 Hz, 1H), 8.27 (d, J=4.9 Hz, 1H), 8.04 (d, J=7.3 Hz, 1H), 7.58-7.52 (m, 1H), 7.47-7.40 (m, 1H), 7.32 (t, J=6.4 Hz, 2H), 7.28-7.22 (m, 2H), 7.18 (t, J=7.2 Hz, 1H), 6.91 (s, 1H), 5.03-4.93 (m, 1H), 4.44 (m, 1H), 3.32 (t, J=6.9 Hz, 1H), 3.27-3.23 (m, 1H), 2.45-2.26 (m, 2H), 1.99-1.94 (m, 1H), 1.80-1.75 (m, 1H), 1.37 (s, 1H), 1.29 (d, J=3.3 Hz, 2H). ESI-MS m/z 526.11 [M+H] + . 
     Example 69: Synthesis of Compound 69 
     
       
         
         
             
             
         
       
     
     The Compound 69 was synthesized according to the synthesis of Compound 12 by using Compound 24-1 to replace the Compound 5-1 in Example 12, and using Compound 8-1 to replace the Compound 12-1 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 11.14 (d, J=8.4 Hz, 1H), 9.41 (s, 1H), 8.28-8.23 (m, 1H), 7.78 (dd, J=12.5, 8.8 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.37-7.33 (m, 2H), 7.23 (d, J=7.7 Hz, 2H), 7.16 (dd, J=6.3, 1.9 Hz, 4H), 5.44 (m, 1H), 5.06 (dd, J=7.1, 4.5 Hz, 1H), 4.51 (m, 1H), 4.13-3.99 (m, 1H), 3.32 (d, J=2.0 Hz, 1H), 3.20 (m, 2H), 2.44-2.34 (m, 1H), 2.33-2.25 (m, 1H), 1.79-1.55 (m, 2H). ESI-MS m/z 464.15[M+H] + . 
     Example 70: Synthesis of Compound 70 
     
       
         
         
             
             
         
       
     
     The Compound 70 was synthesized according to the synthesis of Compound 12 by using Compound 10-1 to replace the Compound 5-1 in Example 12, and using Compound 8-1 to replace the Compound 12-1 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.43 (s, 1H), 8.64 (d, J=6.8 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.56-7.50 (m, 1H), 7.49-7.41 (m, 2H), 7.37 (dd, J=9.2, 2.3 Hz, 2H), 7.32-7.22 (m, 3H), 7.19 (d, J=7.5 Hz, 1H), 7.12 (s, 1H), 5.10-5.01 (m, 1H), 4.58-4.32 (m, 1H), 3.38 (m, 1H), 3.25 (dd, J=9.0, 2.5 Hz, 3H), 2.53-2.27 (m, 2H), 2.04 (m, 1H), 1.86-1.62 (m, 2H). ESI-MS m/z 448.17[M+H] + . 
     Example 71: Synthesis of Compound 71 
     
       
         
         
             
             
         
       
     
     The Compound 71 was synthesized according to the synthesis of Compound 12 by using Compound 59-1 to replace the Compound 5-1 in Example 12, and using Compound 8-1 to replace the Compound 12-1 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.47 (s, 1H), 8.69 (d, J=8.0 Hz, 1H), 8.15 (m, 2H), 7.95 (m, 2H), 7.80 (d, J=8.0 Hz, 1H), 7.34 (d, J=7.3 Hz, 2H), 7.25 (t, J=7.3 Hz, 2H), 7.18 (t, J=7.3 Hz, 1H), 6.83 (s, 1H), 5.03-4.95 (m, 1H), 3.99 (dd, J=7.3, 4.3 Hz, 1H), 3.50 (m, 2H), 3.31-3.20 (m, 3H), 2.39-2.28 (m, 2H), 1.95-1.87 (m, 1H), 1.78-1.68 (m, 1H), 1.62-1.51 (m, 1H). ESI-MS m/z 460.18[M+H] + . 
     Example 72: Synthesis of Compound 72 
     
       
         
         
             
             
         
       
     
     The Compound 72 was synthesized according to the synthesis of Compound 1 by using Compound 72-1 to replace the acid 1-11 in Example 1, and using 
     Compound 8-1 to replace the Compound 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 8.63 (d, J=8.5 Hz, 1H), 8.33 (d, J=6.2 Hz, 1H), 8.06 (d, J=7.5 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.80 (m, 1H), 7.75 (dd, J=11.0, 4.0 Hz, 1H), 7.39-7.27 (m, 5H), 7.25 (d, J=7.1 Hz, 1H), 6.56 (s, 1H), 5.12 (q, J=7.1 Hz, 1H), 4.32 (m, 1H), 3.31 (dd, J=12.8, 6.2 Hz, 3H), 3.02 (s, 3H), 2.40-2.30 (m, 2H), 1.99-1.93 (m, 1H), 1.88-1.75 (m, 2H). ESI-MS m/z 474.21[M+H] + . 
     Example 73: Synthesis of Compound 73 
     
       
         
         
             
             
         
       
     
     The Compound 73 was synthesized according to the synthesis of Compound 1 by using Compound 11-1 to replace the acid 1-11 in Example 1, and using Compound 8-1 to replace the Compound 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.22 (s, 1H), 8.84 (d, J=8.5 Hz, 1H), 8.28 (d, J=8.5 Hz, 1H), 8.22 (dd, J=10.1, 6.0 Hz, 1H), 8.11 (m, 2H), 7.86 (d, J=8.1 Hz, 1H), 7.77 (dd, J=11.2, 4.1 Hz, 1H), 7.62 (m, 1H), 7.36-7.27 (m, 4H), 7.24 (t, J=7.2 Hz, 1H), 5.08 (m, 1H), 4.33-4.28 (m, 1H), 3.35-3.29 (m, 2H), 3.25 (t, J=6.8 Hz, 2H), 2.38-2.30 (m, 2H), 1.93-1.84 (m, 2H), 1.79-1.71 (m, 2H). ESI-MS m/z 459.19[M+H] + . 
     Example 74: Synthesis of Compound 74 
     
       
         
         
             
             
         
       
     
     The Compound 74 was synthesized according to the synthesis of Compound 1 by using Compound 74-1 to replace the acid 1-11 in Example 1, and using 
     Compound 8-1 to replace the Compound 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.46 (s, 1H), 8.91 (dd, J=7.9, 4.6 Hz, 1H), 8.71 (d, J=6.6 Hz, 1H), 8.44-8.39 (m, 1H), 8.24 (m, 1H), 8.17 (t, J=7.9 Hz, 1H), 7.98 (dd, J=14.5, 7.3 Hz, 1H), 7.90 (m, 1H), 7.42-7.38 (m, 2H), 7.30-7.25 (m, 2H), 7.20 (dd, J=10.4, 4.4 Hz, 1H), 7.02 (m, 1H), 5.16-5.07 (m, 1H), 4.62-4.32 (m, 1H), 3.42-3.37 (m, 1H), 3.30 (s, 2H), 2.53-2.30 (m, 2H), 1.99 (m, 1H), 1.88-1.62 (m, 2H). ESI-MS m/z 527.18[M+H] + . 
     Example 75: Synthesis of Compound 75 
     
       
         
         
             
             
         
       
     
     The Compound 75 was synthesized according to the synthesis of Compound 1 by using Compound 24-1 to replace the acid 1-11 in Example 1, and using Compound 8-1 to replace the Compound 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 11.14 (d, J=8.4 Hz, 1H), 9.41 (s, 1H), 8.28-8.23 (m, 1H), 7.78 (dd, J=12.5, 8.8 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.37-7.33 (m, 2H), 7.23 (d, J=7.7 Hz, 2H), 7.16 (dd, J=6.3, 1.9 Hz, 4H), 5.44 (m, 1H), 5.06 (dd, J=7.1, 4.5 Hz, 1H), 4.51 (m, 1H), 4.13-3.99 (m, 1H), 3.32 (d, J=2.0 Hz, 1H), 3.20 (m, 2H), 2.44-2.34 (m, 1H), 2.33-2.25 (m, 1H), 1.79-1.55 (m, 2H). ESI-MS m/z 537.10[M+H] + . 
     Example 76: Synthesis of Compound 76 
     
       
         
         
             
             
         
       
     
     The Compound 76 was synthesized according to the synthesis of Compound 1 by using Compound 2-1 to replace the acid 1-11 in Example 1, and using Compound 8-1 to replace the Compound 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.24 (s, 1H), 8.55 (d, J=6.0 Hz, 1H), 7.29-7.26 (m, 2H), 7.22 (m, 5H), 7.10 (m, 1H), 6.99 (d, J=2.6 Hz, 1H), 6.95 (s, 1H), 6.72 (d, J=8.6 Hz, 1H), 6.58 (s, 1H), 5.01 (dd, J=14.9, 6.9 Hz, 1H), 4.91-4.85 (m, 2H), 4.25-4.20 (m, 1H), 3.32-3.26 (m, 2H), 3.18 (m, 2H), 2.34-2.29 (m, 2H), 1.94-1.87 (m, 1H), 1.82-1.77 (m, 1H). ESI-MS m/z 496.15[M+H] + . 
     Example 77: Synthesis of Compound 77 
     
       
         
         
             
             
         
       
     
     The Compound 77 was synthesized according to the synthesis of Compound 1 by using Compound 65-1 to replace the acid 1-11 in Example 1, and using 
     Compound 8-1 to replace the Compound 1-5 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.72 (s, 1H), 8.05 (s, 1H), 7.65-7.46 (m, 3H), 7.21-7.09 (m, 3H), 5.99 (s, 1H), 5.78 (s, 1H), 5.08 (s, 1H), 4.91 (m, 2H), 4.29 (m, 4H), 3.64 (s, 1H), 3.54 (s, 1H), 3.29 (s, 1H), 3.04 (s, 1H), 2.81 (s, 1H), 2.73 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.91 (s, 1H), 0.96 (s, 6H). ESI-MS m/z 565.26[M+H] + . 
     Example 78: Synthesis of Compound 78 
     
       
         
         
             
             
         
       
     
     The Compound 78 was synthesized according to the synthesis of Compound 1 by using Compound 13-1 to replace the acid 1-11 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.69 (s, 1H), 8.57 (s, 1H), 8.39 (s, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 7.14 (s, 1H), 6.89 (s, 1H), 6.77 (s, 1H), 5.95 (s, 1H), 5.43 (s, 1H), 5.16 (s, 1H), 4.92 (s, 1H), 4.49 (s, 1H), 3.80 (s, 3H), 3.64 (s, 1H), 3.53 (s, 1H), 2.85 (s, 1H), 2.72 (s, 1H), 2.22 (s, 1H), 2.02 (s, 1H), 1.91 (s, 1H), 1.75 (s, 1H), 1.60 (s, 1H), 1.54-1.36 (m, 7H), 1.29 (s, 1H), 0.96 (s, 6H). ESI-MS m/z 582.32[M+H] + . 
     Example 79: Synthesis of Compound 79 
     
       
         
         
             
             
         
       
     
     The Compound 79 was synthesized according to the synthesis of Compound 1 by using Compound 14-1 to replace the acid 1-11 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.72 (s, 1H), 8.59 (s, 1H), 7.41 (s, 1H), 7.41-7.28 (m, 3H), 7.10 (s, 1H), 6.67 (s, 1H), 6.04 (s, 1H), 4.99 (s, 1H), 4.78 (s, 1H), 4.50 (s, 1H), 3.65 (s, 1H), 3.53 (s, 1H), 2.73 (s, 1H), 2.56 (s, 1H), 2.21 (s, 1H), 2.02 (s, 1H), 1.91 (s, 1H), 1.76 (s, 2H), 1.60 (s, 1H), 1.51 (m, 3H), 1.48-1.41 (m, 4H), 1.38 (s, 1H), 0.96 (s, 6H). ESI-MS m/z 620.23 [M+H] + . 
     Example 80: Synthesis of Compound 80 
     
       
         
         
             
             
         
       
     
     The Compound 80 was synthesized according to the synthesis of Compound 1 by using Compound 80-1 to replace the acid 1-11 in Example 1. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.72 (s, 1H), 7.91 (s, 2H), 7.59 (s, 2H), 7.51 (s, 1H), 7.32 (m, 1H), 6.99 (s, 1H), 6.08 (s, 1H), 6.01 (s, 1H), 5.53 (s, 1H), 4.91 (m, 2H), 4.59 (s, 1H), 3.65 (s, 1H), 3.54 (s, 1H), 2.73 (m, 2H), 2.22 (s, 1H), 2.02 (s, 1H), 1.92 (s, 1H), 1.76 (s, 1H), 1.58 (s, 1H), 1.55-1.41 (m, 5H), 1.28 (s, 1H), 0.96 (s, 6H). ESI-MS m/z 539.31[M+H] + . 
     Example 81: Synthesis of Compound 81 
     
       
         
         
             
             
         
       
     
     The Compound 81 was synthesized according to the synthesis of Compound 12 by using Compound 81-1 to replace the Compound 12-1 in Example 12. 
       1 H NMR (600 MHz, Acetone-d6) δ 9.30 (s, 1H), 9.11 (s, 1H), 8.57 (d, J=9.3 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.30 (td, J=7.9, 4.9 Hz, 1H), 7.25-7.13 (m, 2H), 6.98 (td, J=8.1, 2.9 Hz, 3H), 6.55 (t, J=4.4 Hz, 1H), 5.07 (dt, J=9.3, 7.7 Hz, 1H), 4.46 (dt, J=8.8, 6.3 Hz, 1H), 3.33 (m, 1H), 3.16 (m, 1H), 3.03 (dd, J=14.0, 7.8 Hz, 1H), 2.96 (dd, J=13.9, 7.7 Hz, 1H), 2.28 (m, 1H), 2.11 (dt, J=12.9, 6.4 Hz, 1H), 1.95 (dt, J=12.9, 6.3 Hz, 1H), 1.84-1.69 (m, 2H). ESI-MS m/z 464.19 [M+H] + . 
     Example 82: Synthesis of Compound 82 
     
       
         
         
             
             
         
       
     
     The Compound 82 was synthesized according to the synthesis of Compound 12 by using Compound 4-1 to replace the Compound 12-1 in Example 12. 
       1 H NMR (500 MHz, Chloroform) δ 11.66 (s, 1H), 9.72 (s, 1H), 7.98 (dt, J=14.9, 3.1 Hz, 1H), 7.60 (dd, J=14.9, 3.2 Hz, 1H), 7.31 (d, J=3.0 Hz, 1H), 7.29-6.93 (m, 7H), 6.44 (s, 1H), 5.20 (dd, J=25.8, 13.3 Hz, 1H), 5.04 (t, J=10.4 Hz, 1H), 3.76-3.48 (m, 2H), 3.29 (dd, J=24.7, 10.3 Hz, 1H), 3.04 (dd, J=24.8, 10.4 Hz, 1H), 2.59 (ddd, J=23.1, 15.0, 9.2 Hz, 1H), 2.32-2.14 (m, 1H), 2.07-1.88 (in, 3H). ESI-MS m/z 465.19[M+H] + . 
     Example 83: Synthesis of Compound 83 
     
       
         
         
             
             
         
       
     
     The Compound 83 was synthesized according to the synthesis of Compound 81 by using Compound 83-1 to replace the Compound 5-1 in Example 81. 
       1 H NMR (500 MHz, Chloroform) δ 10.96 (s, 1H), 9.72 (s, 1H), 7.86 (s, 1H), 7.43 (d, J=5.0 Hz, 1H), 7.39-7.26 (m, 2H), 7.14-6.95 (m, 5H), 5.04 (t, J=5.4 Hz, 1H), 4.84 (q, J=6.0 Hz, 1H), 3.69 (dt, J=12.7, 6.5 Hz, 1H), 3.56 (dt, J=12.7, 6.5 Hz, 1H), 3.29 (dd, J=12.4, 5.3 Hz, 1H), 3.04 (dd, J=12.4, 5.3 Hz, 1H), 2.61 (tt, J=9.1, 6.5 Hz, 1H), 2.23 (ddt, J=12.9, 9.1, 6.4 Hz, 1H), 2.02 (t, J=6.2 Hz, 2H), 1.99-1.88 (in, 1H). ESI-MS m/z 501.17[M+H] + . 
     Example 84: Synthesis of Compound 84 
     
       
         
         
             
             
         
       
     
     The Compound 84 was synthesized according to the synthesis of Compound 47 by using Compound 84-1 to replace the Compound 14-1 in Example 47. 
       1 H NMR (500 MHz, Chloroform) δ 11.97 (s, 1H), 9.72 (s, 1H), 7.50 (dd, J=14.9, 3.2 Hz, 1H), 7.11 (s, 1H), 7.03 (t, J=15.0 Hz, 1H), 6.85 (dd, J=15.0, 3.1 Hz, 1H), 6.45 (s, 2H), 5.09 (dd, J=25.7, 13.2 Hz, 1H), 4.46 (t, J=11.8 Hz, 1H), 3.74-3.48 (m, 2H), 2.66-2.53 (m, 4H), 2.21 (ddd, J=25.3, 16.7, 12.5 Hz, 1H), 2.07-1.88 (m, 4H), 1.86-1.63 (m, 7H), 1.31 (p, J=11.6 Hz, 2H), 1.17-0.97 (in, 3H). ESI-MS m/z 467 0.26 [M+H] + . 
     Example 85: Synthesis of Compound 85 
     
       
         
         
             
             
         
       
     
     The Compound 85 was synthesized according to the synthesis of Compound 12 by using Compound 85-1 to replace the Compound 12-1 in Example 12. 
       1 H NMR (500 MHz, Chloroform) 611.30 (s, 1H), 9.72 (s, 1H), 8.78 (s, 1H), 7.98 (dt, J=14.9, 3.1 Hz, 1H), 7.60 (dtd, J=14.7, 8.0, 3.2 Hz, 2H), 7.29-6.93 (m, 6H), 6.35 (s, 1H), 6.02 (s, 1H), 5.66 (s, 1H), 5.36 (dd, J=23.9, 11.7 Hz, 1H), 4.96 (t, J=10.8 Hz, 1H), 3.72-3.47 (m, 2H), 3.29 (dd, J=24.7, 10.8 Hz, 1H), 3.04 (dd, J=24.7, 10.8 Hz, 1H), 2.88 (tt, J=18.3, 12.5 Hz, 1H), 2.23 (ddt, J=25.5, 18.3, 12.8 Hz, 1H), 2.07-1.82 (in, 3H). ESI-MS m/z 465.19[M+H] + . 
     Example 86: Synthesis of Compound 86 
     
       
         
         
             
             
         
       
     
     The Compound 86 was synthesized according to the synthesis of Compound 81 by using Compound 57-1 to replace the Compound 5-1 in Example 81. 
       1 H NMR (500 MHz, Chloroform) δ 13.79 (s, 1H), 9.71 (s, 1H), 7.59 (dt, J=14.9, 7.4 Hz, 2H), 7.36-7.21 (m, 3H), 7.07-6.94 (m, 3H), 6.35 (s, 1H), 6.15 (s, 1H), 5.41 (s, 1H), 5.15 (dt, J=12.4, 10.3 Hz, 1H), 4.87 (t, J=14.7 Hz, 1H), 3.75-3.60 (m, 1H), 3.60-3.45 (m, 1H), 3.29 (dd, J=24.9, 14.5 Hz, 1H), 3.04 (dd, J=24.9, 14.5 Hz, 1H), 2.69 (tt, J=18.3, 6.8 Hz, 1H), 2.28-2.10 (m, 1H), 2.06-1.89 (in, 3H). ESI-MS m/z 466.18[M+H] + . 
     Example 87: Synthesis of Compound 87 
     
       
         
         
             
             
         
       
     
     The Compound 87 was synthesized according to the synthesis of Compound 81 by using Compound 10-1 to replace the Compound 5-1 in Example 81. 
       1 H NMR (500 MHz, Chloroform) δ 9.72 (s, 1H), 8.04 (s, 1H), 7.63-7.55 (m, 1H), 7.50 (dd, J=14.3, 3.6 Hz, 1H), 7.36-7.15 (m, 5H), 7.06-6.94 (m, 2H), 6.06 (s, 1H), 5.65 (td, J=15.4, 12.4 Hz, 1H), 5.55 (s, 1H), 4.90 (t, J=11.8 Hz, 1H), 3.70-3.44 (m, 2H), 3.29 (dd, J=24.8, 11.8 Hz, 1H), 3.04 (dd, J=24.8, 11.8 Hz, 1H), 2.54 (td, J=31.2, 16.3 Hz, 1H), 2.20 (ddt, J=25.0, 16.3, 13.0 Hz, 1H), 2.07-1.84 (in, 3H). ESI-MS m/z 466.18[M+H] + . 
     Example 88: Synthesis of Compound 88 
     
       
         
         
             
             
         
       
     
     The Compound 88 was synthesized according to the synthesis of Compound 81 by using Compound 11-1 to replace the Compound 5-1 in Example 81. 
       1 H NMR (500 MHz, Chloroform) δ 12.09 (s, 1H), 9.72 (s, 1H), 8.59 (dd, J=7.5, 1.5 Hz, 1H), 8.49 (s, 1H), 8.20 (dd, J=7.4, 1.3 Hz, 1H), 7.93-7.82 (m, 2H), 7.76 (d, J=7.5 Hz, 1H), 7.57 (td, J=7.5, 1.5 Hz, 1H), 7.39-7.26 (m, 2H), 7.00 (tdd, J=5.6, 2.9, 1.6 Hz, 2H), 6.10 (s, 1H), 5.23 (t, J=7.0 Hz, 1H), 4.55 (q, J=6.5 Hz, 1H), 3.65 (dt, J=12.8, 6.5 Hz, 1H), 3.52 (dt, J=12.6, 6.5 Hz, 1H), 3.29 (dd, J=12.5, 7.0 Hz, 1H), 3.04 (dd, J=12.5, 7.0 Hz, 1H), 2.44 (tt, J=9.1, 6.1 Hz, 1H), 2.21 (ddt, J=12.8, 9.1, 6.5 Hz, 1H), 2.02 (t, J=6.4 Hz, 2H), 1.92 (ddt, J=12.7, 9.3, 6.5 Hz, 1H). ESI-MS m/z 477.19[M+H] + . 
     Test Example 1: Evaluation of Inhibitory Activity to 3CL Protease of 2019 Novel Coronavirus 
     Determination of the inhibitory activity of the compound against the 3CL protease of 2019 Novel Coronavirus (2019-nCoV 3CL pro ): Fluorescence resonance energy transfer (FRET) technology was used to determine the enzyme level inhibitory activity of the 3C protease inhibitor. In a 96-well plate, 27.5 μL of buffer (20 mM Tris, 100 mM NaCl, 1 mM EDTA, pH 7.4) was added to each well, and 2.5 μL of compound (final concentrations 2 μM, 4 μM, 6 μM, 8 μM, 10 μM, 12 μM, 14 μM, 16 μM, 18 μM, 20 μM) and 5 μL of EV713Cpro (final concentration 3 μM) were added together. The system was incubated for 15 min at 37° C., and then 15 μL of fluorescent substrate diluted in buffer (of which the final concentration was 20 μM) was added. The fluorescence parameters were measured with a Ge n5 fluorometer at 340 nm excitation wavelength and 490 nm emission wavelength, respectively. The system was kept at 37° C. for 10 min before the data was read. A negative control without any compound was used (the rest are the same). The obtained data was processed using GraphPad Prism 5 software, and the experimental results are shown in Tables 1A and 1B. 
     
       
         
           
               
             
               
                 TABLE 1A 
               
             
            
               
                   
               
               
                 Inhibitory Activity of 3CL protease  
               
               
                 of 2019 Novel Coronavirus 
               
            
           
           
               
               
               
            
               
                   
                 Compound 
                 (1 μM)  
               
               
                   
                 number 
                 Inhibition rate 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                  5(DC402265) 
                 95.7 
               
               
                   
                  6(DC402264) 
                 95.8 
               
               
                   
                  7 
                 88.7 
               
               
                   
                  8 
                 86.5 
               
               
                   
                  9(DC402240) 
                 95.8 
               
               
                   
                 10(DC402237) 
                 88.2 
               
               
                   
                 11(DC402238) 
                 89.7 
               
               
                   
                 12 
                 103.1 
               
               
                   
                 16(DC402267) 
                 89.1 
               
               
                   
                   
                 (IC 50  = 74 nM)) 
               
               
                   
                 17(DC402266) 
                 105.7 
               
               
                   
                 18(DC402306) 
                 97.8 
               
               
                   
                 19(DC402308) 
                 98.3 
               
               
                   
                 20(DC402310) 
                 100.7 
               
               
                   
                 24(DC402307) 
                 93.3 
               
               
                   
                 25(DC402309) 
                 101.9 
               
               
                   
                 26(DC402311) 
                 101.8 
               
               
                   
                 35 
                 94.3 
               
               
                   
                 45 
                 85.2 
               
               
                   
                 46 
                 89.3 
               
               
                   
                 47 
                 90.4 
               
               
                   
                 48(DC402234) 
                 100.4 
               
               
                   
                 49 
                 91.2 
               
               
                   
                 50 
                 89.1 
               
               
                   
                 51 
                 84.6 
               
               
                   
                 56 
                 81.3 
               
               
                   
                 57 
                 92.3 
               
               
                   
                 58 
                 94.3 
               
               
                   
                 59 
                 86.7 
               
               
                   
                 60 
                 92.6 
               
               
                   
                 61(DC402207) 
                 88.3 
               
               
                   
                 65 
                 86.7 
               
               
                   
                 66 
                 68.4 
               
               
                   
                 81(DC402259) 
                 96.3 
               
               
                   
                 82 
                 100.7 
               
               
                   
                 83 
                 97.8 
               
               
                   
                   
               
            
           
         
       
     
     Note: Compound 48, or DC402234, or 2234 (“DC40” in “DC40XXXX” was omitted) referred to the same compound; other compounds were deduced by analogy. 
     The IC 50  values of some preferred compounds were listed in Table 1B. 
     
       
         
           
               
             
               
                 TABLE IB 
               
             
            
               
                   
               
               
                 Inhibition Activity(IC 50 ) of 2019  
               
               
                 n-Cov 3CL Protease Inhibitory 
               
            
           
           
               
               
               
            
               
                   
                 Compound 
                 IC 50  (nM) of SARS- 
               
               
                   
                 number 
                 CoV-2 3 CL protease 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 5 
                 33.61 ± 3.45  
               
               
                   
                 6 
                 48.53 ± 3.17  
               
               
                   
                 9 
                 68.14 ± 12.48 
               
               
                   
                 10 
                 67.46 ± 13.88 
               
               
                   
                 11 
                 178.90 ± 29.39  
               
               
                   
                 12 
                 87 ± 8  
               
               
                   
                 16 
                 74 
               
               
                   
                 17 
                 61.03 ± 12.50 
               
               
                   
                 18 
                 238.33 ± 18.67  
               
               
                   
                 19 
                 62.73 ± 8.97  
               
               
                   
                 20 
                 150.10 ± 9.55   
               
               
                   
                 24 
                 131.83 ± 14.73  
               
               
                   
                 25 
                 169.23 ± 37.87  
               
               
                   
                 26 
                 105.29 ± 10.12  
               
               
                   
                 48 
                  53 ± 0.5 
               
               
                   
                 81 
                  40 ± 0.2 
               
               
                   
                 82 
                 103 ± 13  
               
               
                   
                 83 
                 113 ± 9   
               
               
                   
                   
               
            
           
         
       
     
     The experimental results show that most compounds have good inhibitory activity against 2019-nCoV 3CL protease at 1 μM, and IC 50  values of some compounds (Compounds 48, 81, 5, 6, 9, 10, 12, 16, 17, 19) were less than 100 nM, in which the inhibitory activity (IC 50 ) of Compound 16 (DC402267) against 2019-nCoV 3CL protease reached 73.5 nM, and the IC 50  of Compound 48 and 81 reached 53 nM and 40 nM. 
     Test Example 2: Evaluation of the Inhibitory Activity of Compounds Against the Replication of 2019 n-Cov and Determination of Half Toxic Concentration Thereof 
     2.1 EC 50  Determination 
     Determination of the compound&#39;s inhibitory activity against the replication of 2019-nCov: 100 μl/well compounds at gradient concentration was added to 96 wells, then 50 μl/well of virus buffer was added, then 50 μl/well of cultured RD cells (rhabdomyosarcoma cells) was immediately added. The system was cultured at 37° C. for 3-4 days until the maximum cytopathic effect was observed. The medium was aspirated, 75 μl 5% MTS phenol red medium was added, and incubated at 37° C. with 5% CO 2  for 1.5 hours. The fluorescence value of each well was measured at 498 nM wavelength, and a graph of compound concentration vs. cell response was drawn, and the EC 50  of the compound against the virus was calculated using customized software purchased from Accelrys Corporation. 
     The test results are shown in  FIGS.  1  and  2   . 
     The results show that the aldehyde compounds of the present invention can effectively inhibit the replication of the 2019 n-Cov ( FIG.  1   ), and can inhibit different isolated virus strains to some extent. 
     The existing anti-2019-nCoV positive compound CQ has an inhibitory rate against 2019-nCoV virus replication at EC 50 =1.13 μM. The results showed that: when using CQ as a positive control to test the compounds of the application at different concentration gradients, all of Compound 2234 (DC402234, namely Compound 48), 2259 (DC402259, namely Compound 81), 2267 (DC402267, namely Compound 16) have shown excellent anti-virus activity, in which the EC 50  of 2234 was 0.29 μM, and the EC 50  of 2259 was 0.33±0.09 μM, respectively. Therefore, the inhibitory rate of Compounds 48 and 81 to 2019-nCoV at viral level was better than that of the positive control CQ, thus showing good anti-2019-nCoV potentiality ( FIG.  2   ). 
     2.2 Determination of Half-Toxic Concentration 
     In this example, the half-toxic concentrations (CC 50 ) of some compounds of the present invention to Vero E6 cells were determined with CCK8 kit in duplicate. The results were shown in  FIG.  2   . The CC 50  of Compounds 16, 48 and 81 are much more than 100 μM, suggesting the compounds of the present invention were of good safety. 
     Activity Example 3: Crystal Complex Formed by Compound and SARS-CoV-2 3CL pro    
     3.1 Cloning, Expression, Purification and Crystallization of SARS-CoV-2) 3CL pro  (M pro ) 
     The full-length gene encoding SARS-CoV-2 3CL pro  was optimized and synthesized, and inserted into the BamHI and XhoI sites of pGEX-6p-1 plasmid DNA (Amersham Biosciences) for  Escherichia coli  ( E. coli ) Expression (GENEWIZ). SARS-CoV-2 3CL pro  was further purified and then co-crystallized. SARS-CoV-2 3CL pro  was incubated with 10 mM of Compound 48 or Compound 81 for 30 mins, and the crystallized by pendant drop vapor diffusion method at 20° C. (5 mg/ml). The best crystals were grown with buffer containing 2% polyethylene glycol (PEG) 6000, 3% DMSO, 1 mM DTT, 0.1 M MES (pH 6.0). The cryoprotectant solution contained 30% PEG 400, 0.1 M MES (pH 6.0). 
     3.2 Data Collection and Refinement Statistics of Crystal Complexes 
     All data was collected on beamline BL19U1 of Shanghai Synchrotron Radiation Facility (SSRF) using Pilatus3 6M image plate detector at wavelength 0.9785 Å and 100 K. XDS25 program was used for data integration and expansion. SARS-CoV 3CL pro  (PDB: 2H2Z) was used as the search model and the PHASER26 program was used for molecular substitution (MR) to determine the structure. The output model of MR was manually adjusted and iterative looped by Coot27, and refined with Phenix. Compounds 48 and 81 were constructed according to the outline. 
     3.3 Results 
     The results are shown in Table 2 and  FIG.  3   . 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Data collection and refinement statistics of crystal complexes 
               
            
           
           
               
               
               
            
               
                   
                 Mpro-48 
                 Mpro-81 
               
               
                   
               
               
                 PDB code 
                 6LZE 
                 6M0K 
               
               
                 Data collection 
                   
                   
               
               
                 Space group 
                 C2 
                 C2 
               
               
                 Unit cell size 
                   
                   
               
               
                 a, b, c (Å) 
                 97.70, 80.94, 51.74 
                 98.15, 81.70, 51.67 
               
               
                 α, β, γ (°) 
                 90, 114.27, 90 
                 90, 114.69, 90 
               
               
                 Wavelength (Å) 
                 0.97852 
                 0.97852 
               
               
                 Resolution (Å) 
                 50.00-1.51 (1.54-1.51) a   
                 50.00-1.50 (1.54-1.50) a   
               
               
                 Completeness (%) 
                 98.0 (91.6) 
                 98.8 (90.3) 
               
               
                 R merge  (%) 
                  4.2 (55.5) 
                  3.0 (77.1) 
               
               
                 Redundancy 
                 3.3 (2.7) 
                 3.4 (2.8) 
               
               
                 I/σ(I) 
                 13.99 (1.80)  
                 18.69 (1.30)  
               
               
                 Refinement 
                   
                   
               
               
                 Resolution (Å) 
                 47.16-1.50 
                 43.45-1.50 
               
               
                 Number of reflections 
                 57,378 
                 58,412 
               
               
                 R work /R free  (%) 
                 17.8/20.1 
                 18.34/19.66 
               
               
                 Number of atoms 
                   
                   
               
               
                 Protein 
                 2340 
                 2,347 
               
               
                 Ligand 
                 49 
                 50 
               
               
                 Water 
                 209 
                 163 
               
               
                 B factor (Å 2 ) 
                   
                   
               
               
                 Protein 
                 28.75 
                 31.92 
               
               
                 Ligand 
                 37.60 
                 52.56 
               
               
                 Water 
                 37.95 
                 40.62 
               
               
                 R.m.s deviation 
                   
                   
               
               
                 Bond length (Å) 
                 0.014 
                 0.017 
               
               
                 Bond angle (°) 
                 1.280 
                 1.440 
               
               
                 Ramachandran graph (%) 
                   
                   
               
               
                 Favored 
                 98.0 
                 98.0 
               
               
                 Allowed 
                 2.0 
                 2.0 
               
               
                 Outliers 
                 0.0 
                 0.0 
               
               
                   
               
               
                   a The value in parentheses was for the highest resolution structure. 
               
            
           
         
       
     
     The coordinates and structure factors of SARS-CoV-2 3CL pro  and Compounds 48 and 81 have been stored in the protein database, of which the PDB numbers were 6LZE and 6M0K, respectively. 
     The structures of crystal complexes of Compounds 48, 81 and SARS-CoV-2 3CL pro  were shown in  FIG.  3   . 
     The experimental results showed that the aldehyde group C of Compound 48 formed a standard 1.8 Å C—S covalent bond with the catalytic site Cys145 of SARS-CoV-2 MP″ ( FIG.  3 B ), indicating that the Michael addition reaction has occurred. In addition, the oxygen atom of the aldehyde group formed hydrogen bond with the Cys145 residue and the Gly143 residue of the S1 pocket, which also plays vital role in stabilizing the conformation of the compound ( FIG.  3 B ). The five-membered lactam ring can insert into the S1 pocket smoothly ( FIG.  3 B ). The oxygen atom of lactam formed hydrogen bond with the His163 residue of the side chain. The main chain and side chain Glu166 of Phe140 also participated in stabilizing the five-membered ring lactam by forming hydrogen bonds with NH. In addition, the amide bond on the main chain of Compound 48 formed hydrogen bonds with His164 and the main chain of Glu166, respectively ( FIG.  3 B ). The cyclohexyl of Compound 48 has penetrated into the S2 pocket, and was surrounded by the side chains of Met49, Tyr54, Met165 and Asp187, thus leading to extensive hydrophobic interactions ( FIG.  3 B ). The indole group of Compound 48 was exposed to the solvent (S4 pocket) and stabilized by Glu166 through hydrogen bonding ( FIG.  3 B ). The side chains of Pro168 and Gln189 residues interacted with the indole group of Compound 48 through hydrophobic interactions. Also, multiple water molecules (named W1-W6) played an important role in binding Compound 48 ( FIG.  3 B ). W1 interacted with the amide bond of Compound 48 through hydrogen bond, while W2-6 formed multiple hydrogen bonds with the aldehyde group of Compound 48 and the residues of Asn142, Gly143, Thr26, Thr25, His41, and Cys44, which help stabilizing Compound 48 in the binding pocket ( FIG.  3 B ). 
     The crystal structure of Compound 81 and SARS-CoV-2 M″ was very similar that of Compound 48, which shows similar inhibitor binding modes ( FIG.  3 C,  3 D ). The difference in binding may be caused by aryl of Compound 81. Compared with cyclohexyl of Compound 48, aryl of Compound 81 has rotated significantly ( FIG.  3 C ). The side chains of His41, Met49, Met165, and Val186 residues interacted with aryl through hydrophobic interactions ( FIG.  3 D ). The side chain of Gln189 stabilized aryl by forming an additional hydrogen bond with fluorine atom ( FIG.  3 D ). 
     In short, these two crystal structures revealed a same inhibitory mechanism, that is, the two compounds occupying the substrate binding pocket, mimicking the intermediate in the catalytic reaction, thus blocking the enzyme activity of SARS-CoV-2 M pro . 
     All literatures mentioned in the present invention are incorporated herein by reference, as though each one is individually incorporated by reference. Additionally, it should be understood that after reading the above teachings, those skilled in the art can make various changes and modifications to the present invention. These equivalents also fall within the scope defined by the appended claims.