Preparation and medical use of a class of furan[3,2-f]chromene compounds

Abstract

The application discloses a kind of SARS-CoV-2 3CLpro inhibitors (furo [3, 2-f] chromene compounds), its preparation method and its pharmaceutical composition and purposes.There are specifically disclosed a kind of compounds shown in general formula (I) and its pharmaceutically acceptable salt, the preparation process of this kind of compound, the pharmaceutical composition containing general formula (I) compound, and the application of this kind of compound and pharmaceutical composition in the direction of anti-SARS-CoV-2.

Description

Technical fields:

[0001] This invention relates to the field of pharmaceutical technology, and to a class of furano[3,2-f]chromene compounds and their pharmaceutically acceptable salts, as well as anti-SARS-CoV-2 preparations containing the above-mentioned compounds and their pharmaceutically acceptable salts. Background technology:

[0003] SARS-CoV-2 is a single-stranded, positive-sense RNA virus. Its viral particle consists of an envelope, spike protein (S protein), membrane protein (M protein), small envelope protein (E protein), and internal nucleocapsid protein (N protein) and viral genomic RNA. During the viral life cycle, after entering a host cell, the genomic RNA is translated, producing two polyproteins, pp1a and pp1ab. These polyproteins must be precisely cleaved by a 3C-like protease (3CLpro, also known as the main protease Mpro) to form 16 functional non-structural proteins. These non-structural proteins are crucial for viral replication, transcription, and assembly. Therefore, 3CLpro has become a key target for developing anti-SARS-CoV-2 drugs.

[0004] Currently, treatment for SARS-CoV-2 mainly includes vaccination, supportive care, and drug therapy. Vaccination plays a crucial role in preventing infection and reducing the severity of illness; however, with the continuous mutation of the virus, some variants have gradually increased their ability to evade the immune response to existing vaccines, thus affecting the protective efficacy of vaccines. Supportive care primarily addresses the relief of patients' symptoms, such as oxygen therapy and maintaining electrolyte balance, but it cannot fundamentally eliminate the virus.

[0005] Regarding drug treatment, although some drugs have been approved for clinical use, many limitations remain. For example, Remdesivir, a broad-spectrum antiviral drug, has been used to treat COVID-19 infection, but its efficacy varies across different studies, and it suffers from high cost and limited supply. Nirmatrelvir, the main component of the FDA-approved drug Paxlovid, specifically inhibits SARS-CoV-2's 3CLpro, blocking the cleavage of the viral polymer precursor and thus preventing viral replication. However, it must be used in combination with ritonavir, which may cause adverse reactions and contraindications, limiting its applicability, such as the risk of drug interactions and its unsuitability for patients already taking certain medications. Atitrelvir also requires combination with ritonavir, which to some extent limits its use for some patients. Ensitrelvir is an oral SARS-CoV-2 3CLpro inhibitor. Although it does not require combination with ritonavir, making it relatively convenient to administer, and has a good inhibitory effect on the novel coronavirus, effectively reducing viral load, its activity against certain variants may vary. Long-term safety and drug resistance issues require further observation and research, and drug accessibility may be uneven globally. Furthermore, some reported small-molecule inhibitors have insufficient inhibitory activity, making it difficult to achieve ideal therapeutic effects in clinical applications, or they have poor selectivity, easily causing serious adverse reactions, thus limiting their clinical application. While antibody drugs have some efficacy in early-stage infected patients, they are costly to prepare, require stringent storage conditions, and are easily affected by viral mutations, potentially losing their activity.

[0006] Given the current inadequacy of treatments for COVID-19 infection, there is an urgent need to develop novel, highly effective, safe, and pharmacokineticly compatible small-molecule inhibitors against SARS-CoV-2. Tuaimenal A, isolated from the deep-sea soft coral *Duvaflorida*, has been found to be an effective small-molecule inhibitor of SARS-CoV-2 3CLpro. Its unique chromene structure and SARS-CoV-2 3CLpro inhibitory activity make Tuaimenal A an attractive lead structure for developing novel SARS-CoV-2 3CLpro inhibitors. Our research group has previously completed the total synthesis of Tuaimenal A and conducted preliminary structure-activity relationship studies. This patent involves modifying its skeleton while retaining its active group to prepare a class of furano[3,2-f]chromene compounds with SARS-CoV-2 3CLpro inhibitory activity. This invention aims to provide a series of small-molecule inhibitors with excellent performance through innovative design ideas and synthetic methods, offering new and effective means to combat the SARS-CoV-2 epidemic. Summary of the Invention:

[0007] The first technical problem to be solved by the present invention is to provide a novel SARS-CoV-2 inhibitory active substance having general formula (Ⅰ) or a pharmaceutically usable salt thereof;

[0008] The second technical problem to be solved by the present invention is to provide a method for preparing such compounds or their pharmaceutically usable salts;

[0009] Another technical problem to be solved by the present invention is to provide a pharmaceutical composition containing a compound of general formula (I) or a pharmaceutically acceptable salt thereof;

[0010] Another technical problem to be solved by the present invention is to provide the use of compounds of general formula (I) or pharmaceutically usable salts thereof in the preparation of anti-SARS-CoV-2 drugs.

[0011] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0012]

[0013] This invention relates to a compound having general formula (Ⅰ) or a pharmaceutically usable salt thereof. Its structural feature is the retention of the chromene structure found in natural products, while introducing a furan ring at the benzene ring, thus altering the compound skeleton to a tricyclic structure, representing a significant innovation. Through R... 1 R 2 R 3 and R 4 Different groups are introduced into the compound, and the efficacy and toxic side effects of such compounds are improved by changing the substituents.

[0014] The compounds having general formula (Ⅰ) involved in this invention contain an asymmetric carbon atom, and therefore, these compounds can exist in enantiomeric or diastereomeric forms.

[0015] in,

[0016] R 1 Selected from: hydrogen, nitro, cyano, carboxyl, aldehyde, halogenated C 1-16 Alkyl, C 1-16 alkoxycarbonyl, carbamoyl, C 1-16 Alkylaminocarbonyl, (C 1-16 alkyl)2-aminocarbonyl, C 1-16 alkyl carbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 1-16 Alkyl)2-morpholinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, halopyrrolidinylcarbonyl, piperidinylcarbonyl, halopiperidinylcarbonyl, C 1-16 alkylpiperazinylcarbonyl, piperidinyl C 1-16 Alkoxycarbonyl, morpholinyl C 1-16 alkoxycarbonyl, C 1-16 Alkylpiperazine C 1-16 alkoxycarbonyl, oxadiazole, C 1-16 Alkyl oxadiazole group, halogenated C 1-16 Alkyl oxadiazolyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-substituted C 1-16 alkylaminocarbonyl, heteroaryl substituted C 1-16 Alkylaminocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl; the above aryl groups are selected from phenyl, naphthyl, and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyrroleyl, quinolinyl, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, amino, (C 1-16 alkyl)2-amino, C 1-16 Alkyl, Halogenated C 1-16 Alkyl, C 1-16 Alkoxy, halogenated C 1-16 Alkoxy;

[0017] R 2 Selected from: hydrogen, hydroxyl, C 1-16 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-16 Alkoxy C 1-16 Alkoxy, hydroxy C 1-16 Alkoxy, carboxyl C 1-16 Alkoxy, C 1-16 alkoxycarbonyl C 1-16 Alkoxy, piperidinyl carbonyl C1-16 Alkoxy, halopiperidinyl carbonyl C 1-16 Alkoxy, Morpholinyl Carbonyl C 1-16 Alkoxy, piperidinyl C 1-16 Alkoxy, Morpholinyl C 1-16 Alkoxy, C 1-16 Alkylpiperazine C 1-16 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-16 alkoxy and aryl substituted C 1-16 Alkoxy C 1-16 alkoxy- and heteroaryl-substituted C 1-16 alkoxy and aryl substituted C 1-16 alkylamino and heteroaryl substituted C 1-16 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrrolyl, quinolinyl, pyrimidinyl, pyridyl, indolyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-16 alkoxycarbonyl, amino, (C 1-16 alkyl)2-amino, hydroxy C 1-16 Alkyl, C 1-16 Alkyl, Halogenated C 1-16 Alkyl, C 1-16 Alkoxy, halogenated C 1-16 Alkoxy, C 1-16 alkylsulfonyl, C 1-16 alkylsulfonylamino;

[0018] R 3 Selected from: C 1-21 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-16 alkyl and heteroaryl substituted C 1-16 Alkyl; the above aryl group is selected from phenyl, naphthyl, and biphenyl; the above heteroaryl group is selected from furanyl, thiophene, pyrrolyl, quinolinyl, pyrimidinyl, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, and C. 1-16 alkoxycarbonyl, amino, (C 1-16 alkyl)2-amino, C 1-16 Alkyl, Halogenated C 1-16 Alkyl, C 1-16 Alkoxy, halogenated C 1-16 Alkoxy;

[0019] R 4 Selected from: hydrogen, C 1-16 alkyl;

[0020] Preferred R 1 Selected from: hydrogen, nitro, cyano, carboxyl, aldehyde, halogenated C 1-8 Alkyl, C 1-8 alkoxycarbonyl, carbamoyl, C 1-8 Alkylaminocarbonyl, (C 1-8 alkyl)2-aminocarbonyl, C 1-8 alkyl carbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 1-8 Alkyl)2-morpholinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, halopyrrolidinylcarbonyl, piperidinylcarbonyl, halopiperidinylcarbonyl, C 1-8 alkylpiperazinylcarbonyl, piperidinyl C 1-8 Alkoxycarbonyl, morpholinyl C 1-8 alkoxycarbonyl, C 1-8 Alkylpiperazine C 1-8 alkoxycarbonyl, oxadiazole, C 1-8 Alkyl oxadiazole group, halogenated C 1-8 Alkyl oxadiazolyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-substituted C 1-8 alkylaminocarbonyl, heteroaryl substituted C 1-8 Alkylaminocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl; the above aryl groups are selected from phenyl, naphthyl, and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, amino, (C 1-8 alkyl)2-amino, C 1-8 Alkyl, Halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 Alkoxy;

[0021] R 2 Selected from: hydrogen, hydroxyl, C 1-8 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-8 Alkoxy C 1-8 Alkoxy, hydroxy C 1-8 Alkoxy, carboxyl C 1-8 Alkoxy, C 1-8 alkoxycarbonyl C 1-8 Alkoxy, piperidinyl carbonyl C 1-8 Alkoxy, halopiperidinyl carbonyl C 1-8 Alkoxy, Morpholinyl Carbonyl C1-8 Alkoxy, piperidinyl C 1-8 Alkoxy, Morpholinyl C 1-8 Alkoxy, C 1-8 Alkylpiperazine C 1-8 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-8 alkoxy and aryl substituted C 1-8 Alkoxy C 1-8 alkoxy- and heteroaryl-substituted C 1-8 alkoxy and aryl substituted C 1-8 alkylamino and heteroaryl substituted C 1-8 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrimidinyl, pyridyl, indolyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-8 alkoxycarbonyl, amino, (C 1-8 alkyl)2-amino, hydroxy C 1-8 Alkyl, C 1-8 Alkyl, Halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 Alkoxy, C 1-8 alkylsulfonyl, C 1-8 alkylsulfonylamino;

[0022] R 3 Selected from: C 1-11 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-8 alkyl and heteroaryl substituted C 1-8 Alkyl; the above aryl group is selected from phenyl, naphthyl, and biphenyl; the above heteroaryl group is selected from furanyl, thiophene, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, and C. 1-8 alkoxycarbonyl, amino, (C 1-8 alkyl)2-amino, C 1-8 Alkyl, Halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 Alkoxy;

[0023] R 4 Selected from: hydrogen, C 1-8 alkyl;

[0024] More preferred R 1 Selected from: hydrogen, nitro, cyano, carboxyl, aldehyde, C 1-4 alkoxycarbonyl, carbamoyl, C 1-6 Alkylaminocarbonyl, (C 1-4 alkyl)2-aminocarbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 1-4 Alkyl)2-morpholinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, halopyrrolidinylcarbonyl, piperidinylcarbonyl, halopiperidinylcarbonyl, C 1-4 alkylpiperazinylcarbonyl, piperidinyl C 1-4 Alkoxycarbonyl, morpholinyl C 1-4 alkoxycarbonyl, C 1-4 Alkylpiperazine C 1-4 alkoxycarbonyl, oxadiazole, C 1-4 Alkyl oxadiazole group, halogenated C 1-4 Alkyl oxadiazolyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-substituted C 1-4 alkylaminocarbonyl, heteroaryl substituted C 1-4 Alkylaminocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl; the above aryl groups are selected from phenyl, naphthyl, and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0025] R 2 Selected from: hydrogen, hydroxyl, C 1-5 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-4 Alkoxy C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, carboxyl C 1-4 Alkoxy, C 1-4 alkoxycarbonyl C 1-4 Alkoxy, piperidinyl carbonyl C 1-4 Alkoxy, halopiperidinyl carbonyl C 1-4 Alkoxy, Morpholinyl Carbonyl C 1-4 Alkoxy, piperidinyl C 1-4 Alkoxy, Morpholinyl C 1-4 Alkoxy, C 1-4 Alkylpiperazine C 1-4 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-4alkoxy and aryl substituted C 1-4 Alkoxy C 1-4 alkoxy- and heteroaryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 alkylamino and heteroaryl substituted C 1-4 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrimidinyl, pyridinyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, carboxyl, C 1-4 alkoxycarbonyl, (C 1-4 alkyl)2-amino, hydroxy C 1-4 Alkyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino;

[0026] R 3 Selected from: C 1-6 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-4 alkyl and heteroaryl substituted C 1-4 Alkyl; the above aryl group is selected from phenyl, biphenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0027] R 4 Selected from: hydrogen, C 1-4 alkyl;

[0028] The preferred compounds represented by general formula (I) include, but are not limited to, the compounds represented by IA or their pharmaceutically acceptable salts.

[0029]

[0030] R 5 Selected from: hydrogen, hydroxyl, C 1-5 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-4 Alkoxy C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, carboxyl C 1-4Alkoxy, C 1-4 alkoxycarbonyl C 1-4 Alkoxy, piperidinyl carbonyl C 1-4 Alkoxy, halopiperidinyl carbonyl C 1-4 Alkoxy, Morpholinyl Carbonyl C 1-4 Alkoxy, piperidinyl C 1-4 Alkoxy, Morpholinyl C 1-4 Alkoxy, C 1-4 Alkylpiperazine C 1-4 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 Alkoxy C 1-4 alkoxy- and heteroaryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 alkylamino and heteroaryl substituted C 1-4 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrimidinyl, pyridinyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, carboxyl, C 1-4 alkoxycarbonyl, (C 1-4 alkyl)2-amino, hydroxy C 1-4 Alkyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino;

[0031] R 6 Selected from: C 1-6 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-4 alkyl and heteroaryl substituted C 1-4 Alkyl; the above aryl group is selected from phenyl, biphenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0032] R 7 Selected from: hydrogen, C 1-4 alkyl;

[0033] The preferred compounds represented by formula IA include, but are not limited to, the compounds represented by formula IB or their pharmaceutically acceptable salts.

[0034]

[0035] R 6a Selected from: C 1-6 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-4 alkyl and heteroaryl substituted C 1-4 Alkyl; the above aryl group is selected from phenyl, biphenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0036] R 7a Selected from: hydrogen, C 1-4 alkyl;

[0037] The preferred compounds represented by formula IB include, but are not limited to, the compounds represented by formula IC or their pharmaceutically acceptable salts.

[0038]

[0039] R 6b Selected from: aryl, heteroaryl; the above aryl group is selected from phenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, carboxyl, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0040] The preferred compounds represented by general formula (I) include, but are not limited to, the compounds represented by ID or their pharmaceutically acceptable salts.

[0041]

[0042] R 5c Selected from: hydrogen, hydroxyl, C 1-5 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-4 Alkoxy C 1-4 Alkoxy, hydroxy C1-4 Alkoxy, carboxyl C 1-4 Alkoxy, C 1-4 alkoxycarbonyl C 1-4 Alkoxy, piperidinyl carbonyl C 1-4 Alkoxy, halopiperidinyl carbonyl C 1-4 Alkoxy, Morpholinyl Carbonyl C 1-4 Alkoxy, piperidinyl C 1-4 Alkoxy, Morpholinyl C 1-4 Alkoxy, C 1-4 Alkylpiperazine C 1-4 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 Alkoxy C 1-4 alkoxy- and heteroaryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 alkylamino and heteroaryl substituted C 1-4 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrimidinyl, pyridinyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, carboxyl, C 1-4 alkoxycarbonyl, (C 1-4 alkyl)2-amino, hydroxy C 1-4 Alkyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino;

[0043] R 6c Selected from: C 1-6 Straight-chain or branched saturated or unsaturated alkyl or aryl-substituted C 1-4 alkyl and heteroaryl substituted C 1-4 Alkyl; the above aryl group is selected from phenyl, biphenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0044] The preferred compounds represented by formula ID include, but are not limited to, the compounds represented by IE or their pharmaceutically acceptable salts.

[0045]

[0046] R 5d Selected from: hydrogen, hydroxyl, C 1-5 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-4 Alkoxy C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, carboxyl C 1-4 Alkoxy, C 1-4 alkoxycarbonyl C 1-4 Alkoxy, piperidinyl C 1-4 Alkoxy, Morpholinyl C 1-4 Alkoxy, C 1-4 Alkylpiperazine C 1-4 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 Alkoxy C 1-4 alkoxy- and heteroaryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 alkylamino and heteroaryl substituted C 1-4 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrimidinyl, pyridinyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, carboxyl, C 1-4 alkoxycarbonyl, (C 1-4 alkyl)2-amino, hydroxy C 1-4 Alkyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino;

[0047] The preferred compounds represented by formula ID include, but are not limited to, the compounds represented by formula IF or their pharmaceutically acceptable salts.

[0048]

[0049] R 5e Selected from: hydroxyl, morpholino, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-4 alkoxy- and heteroaryl-substituted C1-4 alkoxy and aryl substituted C 1-4 alkylamino and heteroaryl substituted C 1-4 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, pyrazolyl, pyrimidinyl, pyridinyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-4 alkoxycarbonyl, hydroxy C 1-4 Alkyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylsulfonylamino;

[0050] R 8e Selected from: hydrogen, halogen, cyano, nitro, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0051] The preferred compounds represented by formula ID include, but are not limited to, the compounds represented by IG or their pharmaceutically acceptable salts.

[0052]

[0053] R 6f Selected from: C 1-6 Straight-chain or branched saturated or unsaturated alkyl or aryl-substituted C 1-4 alkyl and heteroaryl substituted C 1-4 Alkyl; the above aryl group is selected from phenyl, biphenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0054] Preferred compounds of general formula (I) include, but are not limited to, compounds represented by IH or their pharmaceutically acceptable salts.

[0055]

[0056] R 9 Selected from: hydrogen, nitro, cyano, carboxyl, aldehyde, C 1-4 alkoxycarbonyl, carbamoyl, C1-6 Alkylaminocarbonyl, (C 1-4 alkyl)2-aminocarbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 1-4 Alkyl)2-morpholinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, halopyrrolidinylcarbonyl, piperidinylcarbonyl, halopiperidinylcarbonyl, C 1-4 alkylpiperazinylcarbonyl, oxadiazolyl, C 1-4 Alkyl oxadiazole group, halogenated C 1-4 Alkyl oxadiazolyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-substituted C 1-4 alkylaminocarbonyl, heteroaryl substituted C 1-4 Alkylaminocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl; the above aryl groups are selected from phenyl, naphthyl, and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0057] R 10 Selected from: hydrogen, hydroxyl, C 1-5 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-4 Alkoxy C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, carboxyl C 1-4 Alkoxy, C 1-4 alkoxycarbonyl C 1-4 Alkoxy, piperidinyl carbonyl C 1-4 Alkoxy, halopiperidinyl carbonyl C 1-4 Alkoxy, Morpholinyl Carbonyl C 1-4 Alkoxy, piperidinyl C 1-4 Alkoxy, Morpholinyl C 1-4 Alkoxy, C 1-4 Alkylpiperazine C 1-4 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 Alkoxy C 1-4 alkoxy- and heteroaryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 alkylamino and heteroaryl substituted C 1-4Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrimidinyl, pyridinyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, carboxyl, C 1-4 alkoxycarbonyl, (C 1-4 alkyl)2-amino, hydroxy C 1-4 Alkyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino;

[0058] R 11 Selected from: C 1-6 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-4 alkyl and heteroaryl substituted C 1-4 Alkyl; the above aryl group is selected from phenyl, biphenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0059] Preferred compounds of formula IH include, but are not limited to, the compounds of formula II or their pharmaceutically acceptable salts.

[0060]

[0061] R 9a Selected from: hydrogen, nitro, cyano, carboxyl, aldehyde, C 1-4 alkoxycarbonyl, carbamoyl, C 1-6 Alkylaminocarbonyl, (C 1-4 alkyl)2-aminocarbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 1-4 Alkyl)2-morpholinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, halopyrrolidinylcarbonyl, piperidinylcarbonyl, halopiperidinylcarbonyl, C 1-4 alkylpiperazinylcarbonyl, oxadiazolyl, C 1-4 Alkyl oxadiazole group, halogenated C 1-4 Alkyl oxadiazolyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-substituted C 1-4alkylaminocarbonyl, heteroaryl substituted C 1-4 Alkylaminocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl; the above aryl groups are selected from phenyl, naphthyl, and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0062] R 11a Selected from: C 1-6 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-4 alkyl and heteroaryl substituted C 1-4 Alkyl; the above aryl group is selected from phenyl, biphenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0063] The preferred compounds represented by Formula II include, but are not limited to, the compounds represented by Formula IJ or their pharmaceutically acceptable salts.

[0064]

[0065] R 9b Selected from: hydrogen, nitro, cyano, carboxyl, aldehyde, C 1-4 alkoxycarbonyl, carbamoyl, C 1-6 Alkylaminocarbonyl, (C 1-4 alkyl)2-aminocarbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 1-4 Alkyl)2-morpholinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, halopyrrolidinylcarbonyl, piperidinylcarbonyl, halopiperidinylcarbonyl, C 1-4 alkylpiperazinylcarbonyl, oxadiazolyl, C 1-4 Alkyl oxadiazole group, halogenated C 1-4 Alkyl oxadiazolyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-substituted C 1-4 alkylaminocarbonyl, heteroaryl substituted C 1-4Alkylaminocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl; the above aryl groups are selected from phenyl, naphthyl, and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy;

[0066] The formation of pharmaceutically acceptable salts from the above-mentioned preferred compounds with acids also constitutes part of this invention. The basic nitrogen atom in the compound molecule of this invention can form salts with acids, as long as the acid can form a salt with a base and is pharmaceutically acceptable; there are no particular limitations. Examples include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid, and organic acids such as oxalic acid, fumaric acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid, and p-toluenesulfonic acid.

[0067] The second aspect of this invention discloses a method for preparing a compound having general formula (Ⅰ) or a pharmaceutically acceptable salt thereof, the specific preparation route of which is as follows:

[0068]

[0069] in,

[0070] R 1 Selected from: hydrogen, nitro, cyano, carboxyl, aldehyde, halogenated C 1-16 Alkyl, C 1-16 alkoxycarbonyl, carbamoyl, C 1-16 Alkylaminocarbonyl, (C 1-16 alkyl)2-aminocarbonyl, C 1-16 alkyl carbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 1-16 Alkyl)2-morpholinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, halopyrrolidinylcarbonyl, piperidinylcarbonyl, halopiperidinylcarbonyl, C 1-16 alkylpiperazinylcarbonyl, piperidinyl C 1-16 Alkoxycarbonyl, morpholinyl C 1-16 alkoxycarbonyl, C 1-16 Alkylpiperazine C 1-16 alkoxycarbonyl, oxadiazole, C 1-16 Alkyl oxadiazole group, halogenated C 1-16 Alkyl oxadiazolyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-substituted C 1-16 alkylaminocarbonyl, heteroaryl substituted C 1-16Alkylaminocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl; the above aryl groups are selected from phenyl, naphthyl, and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyrroleyl, quinolinyl, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, amino, (C 1-16 alkyl)2-amino, C 1-16 Alkyl, Halogenated C 1-16 Alkyl, C 1-16 Alkoxy, halogenated C 1-16 Alkoxy;

[0071] R 2 Selected from: hydrogen, hydroxyl, C 1-16 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-16 Alkoxy C 1-16 Alkoxy, hydroxy C 1-16 Alkoxy, carboxyl C 1-16 Alkoxy, C 1-16 alkoxycarbonyl C 1-16 Alkoxy, piperidinyl carbonyl C 1-16 Alkoxy, halopiperidinyl carbonyl C 1-16 Alkoxy, Morpholinyl Carbonyl C 1-16 Alkoxy, piperidinyl C 1-16 Alkoxy, Morpholinyl C 1-16 Alkoxy, C 1-16 Alkylpiperazine C 1-16 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-16 alkoxy and aryl substituted C 1-16 Alkoxy C 1-16 alkoxy- and heteroaryl-substituted C 1-16 alkoxy and aryl substituted C 1-16 alkylamino and heteroaryl substituted C 1-16 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrrolyl, quinolinyl, pyrimidinyl, pyridyl, indolyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-16 alkoxycarbonyl, amino, (C 1-16 alkyl)2-amino, hydroxy C 1-16 Alkyl, C 1-16 Alkyl, Halogenated C 1-16 Alkyl, C 1-16Alkoxy, halogenated C 1-16 Alkoxy, C 1-16 alkylsulfonyl, C 1-16 alkylsulfonylamino;

[0072] R 3 Selected from: C 1-21 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-16 alkyl and heteroaryl substituted C 1-16 Alkyl; the above aryl group is selected from phenyl, naphthyl, and biphenyl; the above heteroaryl group is selected from furanyl, thiophene, pyrrolyl, quinolinyl, pyrimidinyl, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, and C. 1-16 alkoxycarbonyl, amino, (C 1-16 alkyl)2-amino, C 1-16 Alkyl, Halogenated C 1-16 Alkyl, C 1-16 Alkoxy, halogenated C 1-16 Alkoxy;

[0073] R 4 Selected from: hydrogen, C 1-16 alkyl;

[0074] Step 1: Protect the phenolic hydroxyl group of sesamol A with MOM protecting group to obtain intermediate B;

[0075] Step 2: Intermediate B undergoes a methylation reaction to obtain intermediate C;

[0076] Step 3: Intermediate C undergoes a formylation reaction to obtain intermediate D;

[0077] Step 4: Remove the MOM protecting group from intermediate D to obtain intermediate E;

[0078] Step 5: Remove the methylene protecting group from intermediate E to obtain intermediate F;

[0079] Step 6: Intermediate F and G undergo a cascaded Knoevenagel-electrocyclization reaction to obtain intermediate H;

[0080] Step 7: Protect the phenolic hydroxyl group of intermediate H with a MOM protecting group to obtain intermediate I;

[0081] Step 8: Intermediate I and J undergo a cascade of nucleophilic substitution-condensation reaction to obtain intermediate K;

[0082] Step 9: Remove the MOM protecting group from intermediate K to obtain intermediate L;

[0083] Step 10: Intermediate L undergoes a nucleophilic substitution reaction with trifluoromethanesulfonic anhydride to obtain intermediate M;

[0084] Step 11: Intermediate M is used to prepare the target compound represented by general formula (Ⅰ) via a metal-catalyzed coupling reaction.

[0085] A third aspect of the invention also relates to pharmaceutical compositions in which the compounds of the invention are the active ingredients. These pharmaceutical compositions can be prepared according to methods known in the art. They can be formulated into any dosage form suitable for human or animal use by combining the compounds of the invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants. The content of the compounds of the invention in their pharmaceutical compositions is typically 0.1-95% by weight.

[0086] The compounds of the present invention or pharmaceutical compositions containing them can be administered in unit dose form via enteral or non-enteric routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0087] Dosage forms can be liquid, solid, or semi-solid. Liquid dosage forms can include solutions (including true solutions and colloidal solutions), emulsions (including o / w, w / o, and double emulsions), suspensions, injections (including aqueous injections, powder injections, and infusions), eye drops, nasal drops, lotions, and liniments, etc.; solid dosage forms can include tablets (including regular tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets), capsules (including hard capsules, soft capsules, and enteric-coated capsules), granules, powders, microcapsules, pellets, suppositories, films, patches, aerosols, and sprays, etc.; semi-solid dosage forms can include ointments, gels, and pastes, etc.

[0088] The compounds of this invention can be formulated into conventional formulations, as well as into sustained-release formulations, controlled-release formulations, targeted formulations, and various microparticle delivery systems.

[0089] To formulate the compounds of the present invention into tablets, a wide variety of excipients known in the art can be used, including diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and flow aids can be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc. Tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0090] To formulate the drug delivery unit into capsules, the active ingredient, the compound of the present invention, can be mixed with a diluent and a disintegrant, and the mixture can be placed directly into hard or soft capsules. Alternatively, the active ingredient, the compound of the present invention, can be first formed into granules or microspheres with a diluent, binder, and disintegrant, and then placed into hard or soft capsules. The diluents, binders, wetting agents, disintegrants, and disintegrants used to prepare tablets of the compounds of the present invention can also be used to prepare capsules of the compounds of the present invention.

[0091] To prepare the compounds of this invention into injectable formulations, water, ethanol, isopropanol, propylene glycol, or mixtures thereof can be used as solvents, and appropriate amounts of commonly used solubilizers, co-solvents, pH adjusters, and osmotic pressure regulators can be added. Solubilizers or co-solvents can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; pH adjusters can be phosphates, acetates, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulators can be sodium chloride, mannitol, glucose, phosphates, acetates, etc. If preparing lyophilized powder injections, mannitol, glucose, etc., can also be added as supporting agents.

[0092] In addition, colorants, preservatives, flavorings, tasters or other additives may be added to pharmaceutical preparations if necessary.

[0093] To achieve the purpose of medication and enhance the therapeutic effect, the drug or drug composition of the present invention can be administered using any known method of administration.

[0094] The compounds in this invention can be used in combination with other anti-SARS-CoV-2 drugs to treat COVID-19 infection, which is also part of this invention. These anti-SARS-CoV-2 drugs include, but are not limited to: nematamide / ritonavir (Paxlovid), monopravir (Molnupiravir), azvudine, senutamide / ritonavir (senutamide), deuterium remidevir hydrobromide (mindev), leretamide (lerelin), etc.

[0095] The dosage of the pharmaceutical compositions of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration, and the dosage form. Generally, the suitable daily dose range of the compounds of the present invention is 0.001-150 mg / kg body weight, preferably 0.1-100 mg / kg body weight, more preferably 1-60 mg / kg body weight, and most preferably 2-30 mg / kg body weight. The above dosage can be administered as a single dose unit or divided into several dose units, depending on the physician's clinical experience and the administration regimen, including the use of other treatment methods.

[0096] The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic or symptomatic drugs. When the compounds of the present invention have a synergistic effect with other therapeutic drugs, their dosage should be adjusted according to the actual situation. Detailed implementation method:

[0097] The present invention will be described in more detail below with reference to the embodiments listed below, but the present invention is not limited to these embodiments.

[0098] I. Preparation of Compounds 1-92

[0099] Example 1, Preparation of Compound 1:

[0100]

[0101] a) At 0 °C, sodium hydride (60% w / w, 0.48 g, 12.0 mmol) was added in portions to a solution of 1a (1.40 g, 10.0 mmol) in 20 mL of N,N-dimethylformamide and stirred for 30 min. At the same temperature, chloromethyl methyl ether (0.97 g, 12 mmol) was slowly added to the reaction mixture and stirring continued for 2 h. The reaction mixture was then quenched by slowly pouring it into 100 mL of water. The resulting mixture was extracted with ethyl acetate (30 mL × 3), and the combined organic layers were washed with saturated sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give compound 1b (1.75 g, 95% yield) as a colorless oil. 1H NMR(400MHz, CDCl3)δ6.70(d,J=8.4Hz,1H),6.62(d,J=2.4Hz,1H),6.49(dd,J=8.4,2.4Hz,1H),5.91(s,2H),5.08(s,2H),3.47(s,3H); HRMS(ESI)calcd for C9H 11 O4[M+H] + 183.0652, found 183.0658.

[0102] (b) Under nitrogen protection, n-butyllithium (2.5M n-hexane solution, 12.0 mL, 30.0 mmol) was slowly added to a mixed solution of compound 1b (2.75 g, 15.0 mmol) and TMEDA (3.50 g, 30.0 mmol) in anhydrous tetrahydrofuran (60 mL) at -60 °C. After stirring at this temperature for 30 minutes, iodomethane (8.52 g, 60.0 mmol) was slowly added to the reaction mixture, and then the reaction mixture was slowly brought to room temperature and stirred for 1 hour. The reaction mixture was quenched by slowly pouring it into water (60 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated sodium chloride solution (60 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give compound 1c (2.50 g, 85% yield) as a colorless oil. 1 H NMR(500MHz, CDCl3)δ6.58(d,J=8.5Hz,1H),6.52(d,J=8.5Hz,1H),5.90(s,2H),5.12(s,2H),3.50(s,3H),2.16(s,3H); HRMS(ESI)calcd for C 10 H 13 O4[M+H] + 197.0808, found 197.0814.

[0103] c) Under nitrogen protection, n-butyllithium (2.5M n-hexane solution, 12.0 mL, 30.0 mmol) was added dropwise to an anhydrous tetrahydrofuran (20 mL) solution of compound 1c (1.97 g, 10.0 mmol) at -78 °C. After stirring the reaction mixture for 2 hours, anhydrous N,N-dimethylformamide (3.65 g, 50.0 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for another 2 hours. Then, the temperature was slowly raised to 0 °C, and glacial acetic acid (3.0 mL) was added dropwise to neutralize the excess base. The reaction mixture was diluted with ethyl acetate (30 mL), and the resulting mixture was washed successively with saturated sodium bicarbonate aqueous solution (50 mL), water (50 mL), and saturated sodium chloride solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give compound 1d (1.34 g, yield 60%) as a pale yellow solid: mp = 90-92 °C; 1 H NMR(400MHz, CDCl3)δ10.14(s,1H),7.12(s,1H),6.02(s,2H),5.02(s,2H),3.59(s,3H),2.19(s,3H); HRMS(ESI)calcd forC 11 H 13 O5[M+H] + 225.0757, found 225.0762.

[0104] d) At 0 °C, methanesulfonic acid (2.02 g, 21.0 mmol) was added to compound 1d (3.36 g, 15.0 mmol) in a mixture of dichloromethane (35 mL) and water (0.7 mL). After stirring for 1 hour, the mixture was neutralized with saturated sodium bicarbonate aqueous solution (50 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (30 mL × 2). The combined organic layers were washed with saturated sodium chloride solution (60 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give compound 1e (2.59 g, 96% yield) as a white solid: mp = 93-95 °C; 1 H NMR(400MHz, CDCl3)δ11.94(s,1H),9.51(s,1H),6.63(s,1H),5.94(s,2H),2.05(s,3H); HRMS(ESI)calcd for C9H9O4[M+H] + 181.0495, found 181.0501.

[0105] e) Under nitrogen protection, boron tribromide (3.76 g, 15.0 mmol) was added to a solution of compound 1e (1.80 g, 10.0 mol) in dichloromethane (20 mL) at 0 °C. After reacting for 30 min, the reaction was quenched with water (60 mL). The resulting mixture was extracted with ethyl acetate (50 mL × 3), and the combined organic layers were concentrated under reduced pressure. The residue was dissolved in methanol (50 mL), and 1 M hydrochloric acid solution (20 mL) was added, and the mixture was stirred at room temperature for 8 h. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 2 / 1, v / v) to give compound 1f (1.20 g, yield 71%) as a yellow solid: mp = 96-98 °C; 1 H NMR(400MHz,DMSO-d6)δ11.24(s,1H),9.81(s,1H),9.65(s,1H),9.46(s,1H),6.89(s,1H),1.98(s,3H); HRMS(ESI)calcd for C8H9O4[M+H] + 169.0495, found 169.0502.

[0106] f) Compound 1f (1.52 g, 10.0 mmol) and cinnamaldehyde (1 g, 5.88 g, 20.0 mmol) were dissolved in pyridine (15 mL). The reaction mixture was heated to 120 °C and reacted for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1, v / v) to give compound 1h (2.96 g, 80% yield) as a yellow solid: mp: 103-105 °C; 1 H NMR (500MHz, CDCl3) δ12.31(s,1H),10.11(s,1H),7.45-7.37(m,5H),7.07(d,J=10.0Hz,1H),6.28(brs,1H),6.04(dd,J=10.0and 3.5Hz,1H),5.88-5.87(m,1H),2.12(s,3H); HRMS(ESI)m / z calcd for C 17 H 15 O4[M+H] + 283.0965, found 283.0975.

[0107] g) At room temperature, chloromethyl methyl ether (0.57 g, 7.1 mmol) was slowly added to a mixed solution of compound 1h (1.0 g, 3.6 mmol) and triethylamine (1.07 g, 10.6 mmol) in dichloromethane (10 mL). The reaction solution was reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain crude compound 1i, which was directly used in the next step: HRMS(ESI) m / z calcd for C 19 H 19 O5[M+H] + 327.1227, found 327.1238.

[0108] h) At room temperature, ethyl bromoacetate (0.28 g, 1.7 mmol) and anhydrous potassium carbonate (1.80 g, 13.1 mmol) were added to a 10 mL solution of compound 1i (0.85 g, 2.6 mmol) in ACN. The reaction mixture was heated to 80 °C and reacted for 12 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1, v / v) to give compound 1j (0.82 g, 80% yield) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ7.51 (s, 1H), 7.46-7.38 (m, 5H), 7.07 (d, J = 10.0Hz, 1H), 6.04 (dd, J = 10.0and 3.5Hz,1H),5.88(d,J=3.5Hz,1H),5.10(s,2H),4.42(q,J=7.2Hz,2H),3.61(s,3H),2.12(s,3H),1.40(t,J=7.2Hz,3H); HRMS(ESI)m / z calcd for C 23 H 23 O6[M+H] + 395.1489, found 395.1477.

[0109] i) At room temperature, p-toluenesulfonic acid (34 mg, 0.2 mmol) was added to an ethanol (10 mL) solution of compound 1j (0.80 g, 2.0 mmol). The reaction solution was heated to 50 °C and reacted for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature. The solution was diluted with ethyl acetate (30 mL), and the resulting mixture was washed successively with saturated sodium bicarbonate aqueous solution (20 mL), water (20 mL), and saturated sodium chloride solution (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated to give crude compound 1k, which was used directly for the next step: HRMS (ESI) m / z calcd for C 21 H 19 O5[M+H]+ 351.1227, found 351.1238.

[0110] j) At room temperature, 1M sodium hydroxide solution (2 mL) was added to an ethanol (5 mL) solution of compound 1k (0.50 g, 1.4 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, it was diluted with water (20 mL). The pH was adjusted to 2-3 with 1M hydrochloric acid solution, and then extracted with ethyl acetate (20 mL). The organic layer was washed with saturated sodium chloride solution (20 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give compound 1 (0.43 g, 95% yield) as a yellow solid: mp: 123-125℃; 1 H NMR (500MHz, CDCl3) δ12.31(brs,1H),7.50(s,1H),7.46-7.38(m,5H),7.07(d,J=10.0Hz,1H),6.23(brs,1H),6.03(dd,J=10.0and 3.5Hz,1H),5.84(d,J=3.5Hz,1H),2.12(s,3H); HRMS(ESI)m / z calcd for C 19 H 15 O5[M+H] + 323.0914, found 323.0908.

[0111] Example 2, Preparation of Compound 2:

[0112]

[0113] a) To a 10 mL solution of 4-fluorobenzaldehyde (2a, 1.0 g, 8.1 mmol) in toluene, formylmethyltriphenylphosphine (3.7 g, 12.2 mmol) was added, and the mixture was reacted at 80 °C for 5 hours. After the reaction was complete, the system was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give compound 2b (0.91 g, 75% yield) as a pale yellow solid; HRMS (ESI) m / z calcd for C9H8FO[M+H] + 151.0554, found 151.0559.

[0114] b) Compound 2c was prepared by a similar method to compound 1h, with compound 2b replacing compound 1g. Compound 2c was obtained as a yellow solid: mp: 115-116℃; 1H NMR (400MHz, CDCl3) δ12.30(s,1H),10.12(s,1H),7.45-7.39(m,2H),7.11-7.05(m,3H),6.20(brs,1H),6.01(dd,J=10.0and 4.0Hz,1H),5.86(dd,J=4.0and 1.6Hz,1H),2.11(s,3H); HRMS(ESI)m / z calcd for C 17 H 14 FO4[M+H] + 301.0871, found 301.0881.

[0115] c) Compound 2d was prepared using a similar method to compound 1i, with compound 2c replacing compound 1h. Crude compound 2d was obtained and used directly in the next step without purification: HRMS (ESI) m / z calcd for C 19 H 18 FO5[M+H] + 345.1133, found 345.1139.

[0116] d) Compound 2e was prepared by a similar method to compound 1j, with compound 2d replacing compound 1i. Compound 2e was obtained as a yellow oil. 1 H NMR (500MHz, CDCl3) δ7.51(s,1H),7.45-7.39(m,2H),7.11-7.05(m,3H),6.01(dd,J=10.0and 4.0Hz,1H),5.86(dd,J=4.0and 1.6Hz,1H),5.10(s,2H),4.42(q,J=7.2Hz,2H),3.61(s,3H),2.12(s,3H),1.40(t,J=7.2Hz,3H); HRMS(ESI)m / z calcdfor C 23 H 22 FO6[M+H] + 413.1395, found 413.1936.

[0117] e) Compound 2f was prepared using a similar method to compound 1k, with compound 2e replacing compound 1j. The crude compound 2f was obtained without purification and used directly in the next step: HRMS (ESI) m / z calcd for C 21 H 18 FO5[M+H] + 396.1133, found 396.1145.

[0118] f) Compound 2 was prepared by a similar method to compound 1, with compound 2f replacing compound 1k. Compound 2 was obtained as a yellow solid: mp: 114-116℃; 1 H NMR (500MHz, CDCl3) δ12.30(brs,1H),7.51(s,1H),7.45-7.39(m,2H),7.11-7.05(m,3H),6.23(brs,1H),6.01(dd,J=10.0and 4.0Hz,1H),5.86(dd,J=4.0and 1.6Hz,1H),2.12(s,3H); HRMS(ESI)m / z calcd for C 19 H 14 FO5[M+H] + 341.0820, found 341.0825.

[0119] Example 3, Preparation of Compound 3:

[0120]

[0121] Compound 3 was prepared by a similar method to compound 2, except that 4-methoxybenzaldehyde was used instead of 4-fluorobenzaldehyde (2a). Compound 3 was obtained as a yellow solid: mp: 131-133℃; 1 H NMR (500MHz, CDCl3) δ12.31(brs,1H),7.50(s,1H),7.28(d,J=7.6Hz,2H),6.90(d,J=7.6Hz,2H),6.60(d,J=10.0Hz,1H),6.22(brs,1H),6.01(dd,J=10.0and 4.0Hz,1H),5.86(d,J=4.0,1H),3.81(s,3H),2.12(s,3H); HRMS(ESI)m / z calcd for C 20 H 17 O6[M+H] + 353.1020, found 353.1005.

[0122] Example 4, Preparation of Compound 4:

[0123]

[0124] Compound 4 was prepared by a similar method to compound 2, except that 2-thiophenecarboxaldehyde was used instead of 4-fluorobenzaldehyde (2a). Compound 4 was obtained as a pale yellow solid: mp: 129-130℃; 1H NMR (500MHz, CDCl3) δ12.31(brs,1H),7.49(s,1H),7.53(d,J=7.2Hz,1H),7.10(d,J=7.6Hz,1H),7.00(dd,J=7.6and 7.2Hz,1H),6.61(d,J=10.0Hz,1H),6.32(brs,1H),6.04(dd,J=10.0and 4.0Hz,1H),5.86(d,J=4.0,1H),2.12(s,3H); HRMS(ESI)m / z calcd for C 17 H 13 O5S[M+H] + 329.0478, found 329.0480.

[0125] Example 5, Preparation of Compound 5:

[0126]

[0127] Compound 5 was prepared by a similar method to compound 2, except that 2-cyanobenzaldehyde was used instead of 4-fluorobenzaldehyde (2a). Compound 5 was obtained as a yellow solid with an mp of 139-141 °C. 1 H NMR (500MHz, CDCl3) δ12.29(brs,1H),7.52(s,1H),7.25(d,J=7.2Hz,2H),6.93(d,J=7.2Hz,2H),6.60(d,J=10.0Hz,1H),6.23(brs,1H),6.05(dd,J=10.0and 4.4Hz,1H),5.87(d,J=4.4,1H),2.10(s,3H); HRMS(ESI)m / zcalcd for C 20 H 14 NO5[M+H] + 348.0866, found 348.0871.

[0128] Example 6, Preparation of Compound 6:

[0129]

[0130] Compound 6 was prepared by a similar method to compound 2, except that methyl paraformylbenzoate was used instead of 4-fluorobenzaldehyde (2a). Compound 6 was obtained as a yellow solid: mp: 125-126℃; 1H NMR (500MHz, CDCl3) δ12.29(brs,1H),8.25(d,J=7.2Hz,2H),7.52(s,1H),7.40(d,J=7.2Hz,2H),6.61(d,J=10.0Hz,1H),6.23(brs,1H),6.06(dd,J=10.0and 4.4Hz,1H),5.89(d,J=4.4,1H),3.89(s,3H),2.10(s,3H); HRMS(ESI)m / z calcd for C 21 H 17 O7[M+H] + 381.0969, found 381.0973.

[0131] Example 7, Preparation of Compound 7:

[0132]

[0133] Compound 7 was prepared by a similar method to compound 2, except that 1-benzothiaphen-2-carboxaldehyde was used instead of 4-fluorobenzaldehyde (2a). Compound 7 was obtained as a pale yellow solid: mp: 142-145℃; 1 H NMR (500MHz, CDCl3) δ12.30(brs,1H),8.10-8.09(m,2H),7.60-7.49(m,3H),7.32(m,1H),6.65(d,J=10.0Hz,1H),6.21(brs,1H),6.00(dd,J=10.0and 4.4Hz,1H),5.91(d,J=4.4,1H),2.12(s,3H); HRMS(ESI)m / zcalcd for C 21 H 15 O5S[M+H] + 379.0635, found 379.0633.

[0134] Example 8, Preparation of Compound 8:

[0135]

[0136] a) Compound 3b was prepared by a similar method to compound 2c, using compound 3a instead of compound 2b. Compound 3b was obtained as a yellow oil. 1H NMR (400MHz, CDCl3) δ12.30(s,1H),10.07(s,1H),6.85(d,J=10.4Hz,1H),5.78(d,J=10.4Hz,1H),5.10-5.06(m ,1H),2.13(s,3H),2.12-2.02(m,2H),1.82-1.69(m,2H),1.67(s,3H),1.58(s,3H),1.42(s,3H); HRMS(ESI)m / z calcd forC 18 H 23 O4[M+H] + 303.1591, found 303.1596.

[0137] b) Compound 3c was prepared by a similar method to compound 2d, using compound 3b instead of compound 2c. Compound 3c was obtained as a yellow oil. 1 H NMR (400MHz, CDCl3) δ12.03(s,1H),10.19(s,1H),6.87(d,J=10.0Hz,1H),5.80(d,J=10.0Hz,1H),5.27(d,J=11.2Hz,1H),5.26(d,J=11.2Hz, 1H),5.12-5.07(m,1H),3.57(s,3H),2.19(s,3H),2.16-2.05(m,2H),1 .83-1.69(m,2H),1.67(s,3H),1.58(s,3H),1.39(s,3H); HRMS(ESI)m / z calcd for C 20 H 27 O5[M+H] + 347.1853, found 347.1856.

[0138] c) Compound 3d was prepared by a similar method to compound 2e, using compound 3c instead of compound 2d. Compound 3d was obtained as a yellow oil. 1H NMR (400MHz, CDCl3) δ7.47(s,1H),6.58(d,J=10.0Hz,1H),5.64(d,J=10.0Hz,1H),5 .18(d,J=8.4Hz,1H),5.16(d,J=8.4Hz,1H),5.12-5.09(m,1H),4.42(q,J=7.2Hz,2H ),3.62(s,3H),2.49(s,3H),2.24-2.04(m,2H),1.86-1.79(m,1H),1.73-1.69(m,1H ),1.66(s,3H),1.57(s,3H),1.42(t,J=7.2Hz,3H),1.41(s,3H); HRMS(ESI)m / zcalcd for C 24 H 31 O6[M+H] + 415.2116, found 415.2119.

[0139] d) Compound 3e was prepared by a similar method to compound 2f, with compound 3d used instead of compound 2e. Compound 3e was obtained as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.47(s,1H),6.58(d,J=10.0Hz,1H),5.84(s,1H),5.63(d,J=10.0Hz,1H),5.09(t,J=7.2Hz,1H),4.41(q,J= 7.2Hz,2H),2.43(s,3H),2.20-2.04(m,2H),1.83-1.71(m,2H),1.66(s,3H),1.56(s,3H),1.43-1.39(m,6H); HRMS(ESI)m / zcalcd for C 22 H 27 O5[M+H] + 371.1858, found 371.1858.

[0140] e) Compound 8 was prepared by a similar method to compound 2, with compound 3e replacing compound 2f. Compound 8 was obtained as a pale yellow solid: mp: 132-135℃; 1H NMR (400MHz, CDCl3) δ8.58(brs,1H),7.63(s,1H),6.59(d,J=10.0Hz,1H),5.65(d,J=10.0Hz,1H),5.09(t,J=7.2Hz, 1H),2.44(s,3H),2.20-2.02(m,2H),1.84-1.69(m,2H),1.66(s,3H),1.56(s,3H),1.44(s,3H); HRMS(ESI)m / zcalcd for C 20 H 23 O5[M+H] + 343.1540, found 343.1539.

[0141] Example 9, Preparation of Compound 9:

[0142]

[0143] a) At 0°C, trifluoromethanesulfonic anhydride (1.52 g, 5.4 mmol) was slowly added to a mixed solution of compound 3e (1.0 g, 2.7 mmol) and triethylamine (0.82 g, 8.1 mmol) in dichloromethane (10 mL). The reaction solution was reacted at 0°C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1, v / v) to give compound 4a (1.3 g, 95% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.49(s,1H),6.59(d,J=10.0Hz,1H),5.72(d,J=10.0Hz,1H),5.10(t,J=6.4Hz,1H),4.43(q,J=7.2Hz,2H),2.54(s,3 H),2.22-2.07(m,2H),1.90-1.82(m,1H),1.74-1.69(m,1H),1.66(s,3H),1.57(s,3H),1.45(s,3H),1.42(t,J=7.2Hz,3H); HRMS(ESI)m / z calcd for C 23 H 26 F3O7S[M+H] + 503.1351, found 503.1355.

[0144] b) Under nitrogen protection, anhydrous cesium carbonate (1.0 g, 3.0 mmol), palladium acetate (23 mg, 0.1 mmol), and BINAP (62 mg, 0.1 mmol) were added sequentially to a 5 mL solution of compound 4a (0.5 g, 1.0 mmol) in 1,4-dioxane. The reaction was carried out at 80 °C for 5 hours. After the reaction was complete, the system was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1, v / v) to give compound 4b (0.16 g, 45% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.49(s,1H),6.73(s,1H),6.58(d,J=10.0Hz,1H),5.61(d,J=10.0Hz,1H),5.10(t,J=7.6Hz,1H),4.43(q,J=7.2H z,2H),2.49(s,3H),2.20-2.05(m,2H),1.79-1.68(m,2H),1.66(s,3H),1.57(s,3H),1.42(t,J=7.2Hz,3H),1.40(s,3H); HRMS(ESI)m / z calcd forC 22 H 27 O4[M+H] + 355.1904, found 355.1913;

[0145] c) Compound 9 was prepared by a similar method to compound 2, using compound 4b instead of compound 2f. Compound 9 was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.65(s,1H),6.77(s,1H),6.58(d,J=10.0Hz,1H),5.62(d,J=10.0Hz,1H),5.10(t,J=7.6H z,1H),2.50(s,3H),2.19-2.07(m,2H),1.80-1.68(m,2H),1.66(s,3H),1.58(s,3H),1.41(s,3H); HRMS(ESI)m / z calcd for C 20 H 23 O4[M+H] + 327.1596, found 327.1599.

[0146] Example 10, Preparation of Compound 10:

[0147]

[0148] a) Under nitrogen protection, triphenylphosphine (106 mg, 0.41 mmol) and DEAD (71 mg, 0.41 mmol) were added sequentially to a mixed solution of compound 3e (100 mg, 0.27 mmol) and isopentenol (5b, 28 mg, 0.32 mmol) in tetrahydrofuran (5 mL). The reaction solution was reacted at 60 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1, v / v) to give compound 5a (99 mg, yield 84%) as a colorless oil. 1 HNMR (400MHz, CDCl3) δ7.47(s,1H),6.58(d,J=10.0Hz,1H),5.64(d,J=10.0Hz,1H),5.58(t, J=7.6,1H),5.11(t,J=7.2,1H),4.56(d,J=12.4Hz,1H),4.51(d,J=12.4Hz,1H), 4.41(q,J=7 .2Hz,2H),2.43(s,3H),2.25-2.09(m,2H),1.90-1.82(m,1H),1.78(s,3H),1.76-1.69(m,1H ),1.72(s,3H),1.66(s,3H),1.58(s,3H),1.43(s,3H),1.41(t,J=7.2Hz,3H); HRMS(ESI)m / z calcdfor C 27 H 35 O5[M+H] + 439.2484, found 439.2486.

[0149] b) Compound 10 was prepared by a similar method to compound 2, using compound 5a instead of compound 2f. Compound 10 was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ9.65(brs,1H),7.64(s,1H),6.60(d,J=10.0Hz,1H),5.66(d,J= 10.0Hz,1H),5.61-5.57(m,1H),5.14-5.09(m,1H),4.59(d,J=11.2Hz,1H),4.54(d,J =11.2Hz,1H),2.45(s,3H),2.25-2.10(m,2H),1.91-1.83(m,1H),1.78(s,3H),1.76- 1.69(m,1H),1.73(s,3H),1.66(s,3H),1.58(s,3H),1.44(s,3H); HRMS(ESI)m / zcalcd for C 25 H31 O5[M+H] + 411.2171, found 411.2168.

[0150] Example 11, Preparation of Compound 11:

[0151]

[0152] At room temperature, 1M sodium hydroxide solution (2 mL) was added to an ethanol (5 mL) solution of compound 3d (0.50 g, 1.2 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, it was diluted with water (20 mL). The pH was adjusted to 3-4 with 1M hydrochloric acid solution, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated sodium chloride solution (20 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give compound 11 (0.42 g, 91% yield) as a colorless oil. 1 HNMR (400MHz, CDCl3) δ9.83(brs,1H),7.62(s,1H),6.58(d,J=10.0Hz,1H),5.65(d,J=10.0Hz,1H),5.20(d,J=8.4Hz,1H),5.19(d,J=8.4Hz,1H),5.12- 5.08(m,1H),3.63(s,3H),2.50(s,3H),2.22-2.05(m,2H),1.86-1.79(m,1H ),1.74-1.68(m,1H),1.65(s,3H),1.57(s,3H),1.41(s,3H); HRMS(ESI)m / z calcd for C 22 H 27 O6[M+H] + 387.1802, found 387.1810.

[0153] Example 12, Preparation of Compound 12:

[0154]

[0155] Compound 12 was prepared by a similar method to compound 10, using isopropanol instead of isopentenol (5b). Compound 12 was obtained as a colorless oil. 1H NMR (400MHz, CDCl3) δ8.86(brs,1H),7.64(s,1H),6.60(d,J=10.0Hz,1H),5.65(d,J=10.0Hz,1H),5.12(t,J=7.6Hz,1H),4.58(hept,J=6.0Hz,1H ),2.45(s,3H),2.22-2.10(m,2H),1.87-1.79(m,1H),1.76-1.70(m,1H), 1.67(s,3H),1.59(s,3H),1.41(s,3H),1.36-1.32(m,6H); HRMS(ESI)m / z calcd for C 23 H 29 O5[M+H] + 385.2010, found 385.2011.

[0156] Example 13, Preparation of Compound 13:

[0157]

[0158] Compound 13 was prepared by a similar method to compound 10, using cyclopentanol instead of isopentenol (5b). Compound 13 was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ10.20(brs,1H),7.64(s,1H),6.59(d,J=10.0Hz,1H),5.65(d,J=10.0Hz,1H),5.14-5.11(t,J=7.6Hz,1H),4.98-4 .95(m,1H),2.44(s,3H),2.23-2.09(m,2H),1.97-1.70(m,8H),1.67(s,3H),1.65-1.61(m,2H),1.59(s,3H),1.42(s,3H); HRMS(ESI)m / z calcd for C 25 H 31 O5[M+H] + 411.2166, found 411.2173.

[0159] Example 14, Preparation of Compound 14:

[0160]

[0161] Compound 14 was prepared by a similar method to compound 10, using 1,3-propanediol instead of isopentenol (5b). Compound 14 was obtained as a colorless oil. 1H NMR (400MHz, CDCl3) δ7.58 (s, 1H), 6.58 (d, J = 10.0Hz, 1H), 5.65 (d, J = 10.0Hz, 1H),5.10(t,J=7.2Hz,1H),4.96(brs,1H),4.12(t,J=5.6Hz,2H),4.03-3.94(m ,2H),2.45(s,3H),2.22-2.09(m,2H),2.04(quint,J=5.6Hz,2H),1.94-1.86(m ,1H),1.73-1.67(m,1H),1.65(s,3H),1.57(s,3H),1.45(s,3H); HRMS(ESI)m / z calcd forC 23 H 29 O6[M+H] + 401.1959, found 401.1966.

[0162] Example 15, Preparation of Compound 15:

[0163]

[0164] Compound 15 was prepared by a similar method to compound 10, using hydroxymethylcyclopropane instead of isopentenol (5b). Compound 15 was obtained as a colorless oil. 1 H NMR(400MHz, CDCl3) δ9.03(brs,1H),7.63(s,1H),6.59(d,J=10.0Hz,1H),5.64(d,J=1 0.0Hz,1H),5.14-5.09(m,1H),3.92(d,J=10.8Hz,1H),3.87(d,J=10.8Hz,1H),2.49(s, 3H),2.23-2.07(m,2H),1.87-1.79(m,1H),1.75-1.69(m,1H),1.66(s,3H),1.58(s,3H ),1.41(s,3H),1.34-1.24(m,1H),0.62-0.57(m,2H),0.34-0.30(m,2H); HRMS(ESI)m / z calcd for C 24 H 29 O5[M+H] + 397.2015, found 397.2017.

[0165] Example 16, Preparation of Compound 16:

[0166]

[0167] a) To a solution of compound 3e (0.2 g, 0.54 mmol) in ACN (5 mL), ethyl bromoacetate (6a, 135 mg, 0.69 mmol) and anhydrous potassium carbonate (0.15 g, 1.08 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give compound 6b (0.21 g, 85% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.46 (s, 1H), 6.57 (d, J = 10.0Hz, 1H), 5.63 (d, J = 10.0Hz, 1H), 5.11-5. 08(m,1H),4.74(d,J=16.0Hz,1H),4.70(d,J=16.0Hz,1H),4.41(q,J=7.2Hz,2H),4.25(q,J =7.2Hz,2H),2.50(s,3H),2.20-2.04(m,2H),1.85-1.78(m,1H),1.72-1.67(m,1H),1.65(s ,3H),1.57(s,3H),1.40(s,3H),1.39(t,J=7.2Hz,3H),1.30(t,J=7.2Hz,3H); HRMS(ESI)m / z calcd for C 26 H 33 O7[M+H] + 457.2221, found 457.2222.

[0168] b) At room temperature, 1M sodium hydroxide solution (2 mL) was added to an ethanol (5 mL) solution of compound 6b (0.20 g, 4.4 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (20 mL) was added for dilution. The pH was adjusted to 1-2 with 1M hydrochloric acid solution, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated sodium chloride solution (20 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give compound 16 (0.14 g, yield 81%) as a white solid: mp: 135-138 °C; 1H NMR (400MHz, CDCl3) δ11.19(brs,1H),7.63(s,1H),6.60(d,J=10.0Hz,1H),5.69(d,J=10.0Hz,1H),5.08(t,J=7.2Hz,1H),4.78(d,J=16.8Hz,1H),4 .70(d,J=16.8Hz,1H),2.50(s,3H),2.19-2.08(m,2H),1.91-1.83(m,1H) ,1.74-1.66(m,1H),1.63(s,3H),1.56(s,3H),1.44(s,3H); HRMS(ESI)m / z calcd for C 22 H 25 O7[M+H] + 401.1600, found 401.1605.

[0169] Example 17, Preparation of Compound 17:

[0170]

[0171] Compound 17 was prepared by a similar method to compound 10, with N-hydroxyethylpiperidine replacing isopentenol (5b). Compound 17 was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.40(s,1H),6.52(d,J=10.0Hz,1H),5.60(d,J=10.0Hz,1H),5.06-5.02(t ,J=7.2Hz,1H),4.51-4.46(m,1H),4.31-4.27(m,1H),3.95(d,J=12.0Hz,1H),3.78(d,J=12.0Hz ,1H),3.60-3.47(m,2H),3.02(t,J=12.8Hz,2H),2.36(s,3H),2.32-2.18(m,2H),2.13-2.04(m, 2H),2.00-1.77(m,5H),1.71-1.65(m,1H),1.59(s,3H),1.50(s,3H),1.44(s,3H); HRMS(ESI)m / z calcd for C 27 H 36 NO5[M+H] + 454.2593, found 454.2597.

[0172] Example 18, Preparation of Compound 18:

[0173]

[0174] Compound 18 was prepared by a similar method to compound 10, with N-hydroxyethylmorpholine used instead of isopentenol (5b). Compound 18 was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ11.72(brs,1H),7.33(s,1H),6.56(d,J=10.0Hz,1H),5 .60(d,J=10.0Hz,1H),5.06-5.03(t,J=7.2Hz,1H),4.33-4.19(m,2H),3.99-3 .96(m,4H),3.41-3.15(m,6H),2.42(s,3H),2.15-2.04(m,2H),1.92-1.84(m, 1H),1.72-1.64(m,1H),1.59(s,3H),1.52(s,3H),1.43(s,3H); HRMS(ESI)m / z calcd forC 26 H 34 NO6[M+H] + 456.2386, found 456.2390.

[0175] Example 19, Preparation of Compound 19:

[0176]

[0177] a) Under nitrogen protection, anhydrous cesium carbonate (1.0 g, 3.0 mmol), palladium acetate (23 mg, 0.1 mmol), and BINAP (62 mg, 0.1 mmol) were added sequentially to a mixed solution of 1,4-dioxane (5 mL) of compounds 4a (0.5 g, 1.0 mmol) and 7a (0.17 g, 2.0 mmol). The reaction was carried out at 80 °C for 5 hours. After the reaction was complete, the system was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give compound 7b (0.33 g, 75% yield) as a colorless oil. 1H NMR (400MHz, CDCl3) δ7.46 (s, 1H), 6.57 (d, J = 9.6Hz, 1H), 5.61 (d, J = 9.6Hz, 1H) ,5.15-5.10(m,1H),4.42(q,J=7.2Hz,2H),3.81(brs,4H),3.64(brs,2H),2.68 (brs,2H),2.51(s,3H),2.25-2.07(m,2H),1.95-1.88(m,1H),1.73-1.69(m,1H ),1.67(s,3H),1.59(s,3H),1.41(t,J=7.2Hz,3H),1.41(s,3H); HRMS(ESI)m / z calcd for C 26 H 34 NO5[M+H] + 440.2437, found 440.2436.

[0178] b) Compound 19 was prepared by a similar method to compound 2, using compound 7b instead of compound 2f. Compound 19 was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ9.84(brs,1H),7.62(s,1H),6.59(d,J=9.6Hz,1H),5.63(d,J=9.6Hz,1H),5.13(t,J=7.2Hz,1H),3.85(brs,4H),3.65(brs, 2H),2.69(brs,2H),2.53(s,3H),2.25-2.08(m,2H),1.96-1.89(m,1H), 1.77-1.66(m,1H),1.66(s,3H),1.59(s,3H),1.42(s,3H); HRMS(ESI)m / z calcd for C 24 H 30 NO5[M+H] + 412.2124, found 412.2125.

[0179] Example 20, Preparation of Compound 20:

[0180]

[0181] Compound 20 was prepared by a similar method to compound 19, except that 4,4-difluoropiperidine was used instead of compound 7a. Compound 20 was obtained as a colorless oil. 1H NMR (400MHz, CDCl3) δ8.99(brs,1H),7.64(s,1H),6.59(d,J=9.6Hz,1H),5.65(d,J=9.6Hz,1H),5.16-5.11(m,1H),3.56(brs,2H),2.96 (brs,2H),2.51(s,3H),2.25-2.08(m,6H),1.92-1.84(m,1H),1.77-1.68(m,1H),1.68(s,3H),1.60(s,3H),1.41(s,3H); HRMS(ESI)m / z calcd for C 25 H 30 F2NO4[M+H] + 446.2143, found 446.2143.

[0182] Example 21, Preparation of Compound 21:

[0183]

[0184] Compound 21 was prepared by a similar method to compound 19, except that compound 7a was replaced with 3,3-difluoropyrrolidine. Compound 21 was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ8.96(brs,1H),7.65(s,1H),6.62(d,J=10.0Hz,1H),5.60(d,J=10.0Hz,1H),5.16-5.11(m,1H),3.45-3.41(m ,4H),2.51(s,3H),2.25-2.08(m,2H),1.92-1.84(m,3H),1.77-1.68(m,1H),1.68(s,3H),1.60(s,3H),1.41(s,3H); HRMS(ESI)m / z calcd for C 24 H 28 F2NO4[M+H] + 432.1981, found 432.1977.

[0185] Example 22, Preparation of Compound 22:

[0186]

[0187] Compound 22 was prepared by a similar method to compound 19, except that 1-(2-pyrimidinyl)piperazine was used instead of compound 7a. Compound 22 was obtained as a white solid: mp = 135-138 °C; 1H NMR(400MHz, CDCl3) δ8.39(d,J=4.8Hz,2H),7.60(s,1H),6.58(d,J=10.0Hz,1H),6 .53(t,J=4.8Hz,1H),5.61(d,J=10.0Hz,1H),5.07(m,1H),4.63(brs,2H),3.53(brs ,2H),3.26(brs,2H),2.94(brs,2H),2.56(s,3H),2.17-1.99(m,2H),1.86-1.79(m, 1H),1.69-1.61(m,1H),1.63(s,3H),1.52(s,3H),1.38(s,3H); HRMS(ESI)m / zcalcd for C 28 H 33 N4O4[M+H] + 489.2502, found 489.2502.

[0188] Example 23, Preparation of Compound 23:

[0189]

[0190] Compound 23 was prepared by a similar method to compound 19, with 4-fluoroaniline replacing compound 7a. Compound 23 was obtained as a pale yellow solid: mp = 145-146 °C; 1 H NMR (400MHz, DMSO-d6) δ13.31(brs,1H),7.83(s,1H),7.16(s,1H),6.91(dd,J=8.8and 8.4Hz,2H),6.85(d,J=10.0Hz,1H),6.59(brs,2H),5.75(d,J=10.0Hz,1H),4.96(t,J=7.2Hz,1H),2.2 3(s,3H),1.93-1.83(m,2H),1.63-1.56(m,2H),1.56(s,3H),1.40(s,3H),1.24(s,3H); HRMS(ESI)m / z calcd for C 26 H 27 FNO4[M+H] + 436.1924, found 436.1928.

[0191] Example 24, Preparation of Compound 24:

[0192]

[0193] Compound 24 was prepared by a similar method to compound 19, with 4-trifluoromethoxyaniline replacing compound 7a. Compound 24 was obtained as a pale yellow solid: mp = 151-153 °C; 1 H NMR (400MHz, CDCl3) δ7.69(s,1H),7.68(brs,1H),7.06(d,J=8.4Hz,2H),6.71(d,J=8.4Hz,2H),6.63(d,J=10.0Hz,1H),5.67(d,J=10.0 Hz,1H),5.01(t,J=7.2Hz,1H),2.32(s,3H),2.10-1.90(m,2H),1.71-1.67(m,2H),1.62(s,3H),1.46(s,3H),1.37(s,3H); HRMS(ESI)m / z calcd for C 27 H 27 F3NO5[M+H] + 502.1841, found 502.1846.

[0194] Example 25, Preparation of Compound 25:

[0195]

[0196] Compound 25 was prepared by a similar method to compound 19, except that m-aminobenzonitrile was used instead of compound 7a. Compound 25 was obtained as a pale yellow solid: mp = 146-147 °C; 1 H NMR (400MHz, CDCl3) δ7.69(s,3H),7.29-7.25(m,1H),7.12-7.10(m,1H),6.91-6.89(m,2H),6.63(d,J=10.0Hz,1H),5.67(d,J=10.0 Hz,1H),5.01-4.97(m,1H),2.34(s,3H),2.07-1.89(m,2H),1.69-1.65(m,2H),1.62(s,3H),1.45(s,3H),1.35(s,3H); HRMS(ESI)m / z calcd for C 27 H 27 N₂O₄[M+H] + 443.1971, found 443.1972.

[0197] Example 26, Preparation of Compound 26:

[0198]

[0199] Compound 26 was prepared by a similar method to compound 19, with 3-methylaniline replacing compound 7a. Compound 26 was obtained as a pale yellow solid: mp = 133-135℃; 1 H NMR (400MHz, CDCl3) δ7.70(s,1H),7.47(brs,1H),7.12-7.08(m,1H),6.71(d,J=7.6Hz,1H),6.63(d,J=10.0Hz,1H),6.60-6.58(m,2H),5.67(d,J=1 0.Hz,1H),5.05-5.02(m,1H),2.30(s,3H),2.28(s,3H),2.14-1.97(m,2H) ,1.74-1.67(m,2H),1.63(s,3H),1.49(s,3H),1.39(s,3H); HRMS(ESI)m / z calcd for C 27 H 30 NO4[M+H] + 432.2175, found 432.2178.

[0200] Example 27, Preparation of Compound 27:

[0201]

[0202] Compound 27 was prepared by a similar method to compound 19, with 3-methoxyaniline replacing compound 7a. Compound 27 was obtained as a pale yellow solid: mp = 139-142℃; 1 H NMR (400MHz, CDCl3) δ7.91(brs,1H),7.69(s,1H),7.11(t,J=8.0Hz,1H),6.63(d,J=9.6Hz,1H),6.44(dd,J=8.0and 2.0Hz,1H),6.38(dd,J=8.0and 2.0Hz,1H),6.30(t,J=2.0Hz,1H),5.66(d,J=9.6Hz,1H),5.05-5.01(m,1H),3.75(s,3H),2.33(s ,3H),2.13-1.93(m,2H),1.76-1.68(m,2H),1.63(s,3H),1.49(s,3H),1.38(s,3H); HRMS(ESI)m / z calcd for C 27 H 30 NO5[M+H] + 448.2124, found 448.2124.

[0203] Example 28, Preparation of Compound 28:

[0204]

[0205] Compound 28 was prepared by a similar method to compound 19, with 4-aminopyridine replacing compound 7a. Compound 28 was obtained as a white solid: mp = 159-162 °C; 1 H NMR (400MHz, CDCl3) δ10.02(brs,1H),8.46(d,J=7.2Hz,2H),7.60(s,1H),6.99(d,J=7.2Hz,2H),6.61(d,J=10.0Hz,1H),5.66(d,J=10 .0Hz,1H),5.05-5.01(m,1H),2.30(s,3H),2.12-1.92(m,2H),1.77-1.69(m,2H),1.61(s,3H),1.50(s,3H),1.29(s,3H); HRMS(ESI)m / z calcd for C 25 H 27 N₂O₄[M+H] + 419.1965, found 419.1953.

[0206] Example 29, Preparation of Compound 29:

[0207]

[0208] Compound 29 was prepared by a similar method to compound 19, except that 4-fluorobenzylamine was used instead of compound 7a. Compound 29 was obtained as a pale yellow solid: mp = 149-152 °C; 1 H NMR(400MHz, CDCl3)δ8.62(brs,1H),7.52(s,1H),7.31(dd,J=8.8and 5.6Hz,2H),6.98(t,J=8.8Hz,2H),6.55(d,J=9.6Hz,1H),5.63(d,J=9.6Hz,1H),5.08(t,J=7.2Hz,2H),4.35(s,2H),2.47(s ,3H),2.15-2.00(m,2H),1.81-1.74(m,1H),1.71-1.61(m,1H),1.66(s,3H),1.56(s,3H),1.34(s,3H); HRMS(ESI)m / zcalcd for C 27 H 29 FNO4[M+H] + 450.2075, found 450.2062.

[0209] Example 30, Preparation of Compound 30:

[0210]

[0211] Compound 30 was prepared by a similar method to compound 19, with 4-trifluoromethylbenzylamine used instead of compound 7a. Compound 30 was obtained as a pale yellow solid: mp = 151-152 °C; 1 H NMR (400MHz, CDCl3) δ8.17(brs,1H),7.60(s,1H),7.57(d,J=8.0Hz,2H),7.47(d,J=8.0Hz,2H),6.58(d,J=10.0Hz,1H),5.64(d,J=10.0Hz,1H) ,5.07(t,J=7.2Hz,1H),4.45(s,2H),2.50(s,3H),2.15-1.98(m,2H),1.81-1.63(m,2H),1.66(s,3H),1.55(s,3H),1.32(s,3H); HRMS(ESI)m / z calcd for C 28 H 29 F3NO4[M+H] + 500.2043, found 500.2055.

[0212] Example 31, Preparation of Compound 31:

[0213]

[0214] Compound 31 was prepared by a similar method to compound 19, with 4-trifluoromethoxybenzylamine replacing compound 7a. Compound 31 was obtained as a pale yellow solid: mp = 153-154 °C; 1 H NMR (400MHz, CDCl3) δ8.59 (brs, 1H), 7.54 (s, 1H), 7.38 (d, J = 8.0Hz, 2H), 7.1 6(d,J=8.0Hz,2H),6.56(d,J=10.0Hz,1H),5.63(d,J=10.0Hz,1H),5.08(t,J= 7.2Hz,1H),4.39(s,2H),2.48(s,3H),2.17-1.99(m,2H),1.81-1.73(m,1H),1 .71-1.62(m,1H),1.66(s,3H),1.56(s,3H),1.32(s,3H); HRMS(ESI)m / zcalcd for C 28 H 29 F3NO5[M+H]+ 516.1992, found 516.1979.

[0215] Example 32, Preparation of Compound 32:

[0216]

[0217] Compound 32 was prepared by a similar method to compound 19, using benzylamine instead of compound 7a. Compound 32 was obtained as a pale yellow solid: mp = 149-151℃; 1 H NMR (400MHz, CDCl3) δ8.44(brs,1H),7.53(s,1H),7.37-7.24(m,5H),6.55(d,J=10.0Hz,1H),5.63(d,J=10.0Hz,1H),5.11-5.07(m,1H), 4.40(s,2H),2.47(s,3H),2.17-1.99(m,2H),1.83-1.75(m,1H),1.72-1.61(m,1H),1.66(s,3H),1.57(s,3H),1.34(s,3H); HRMS(ESI)m / z calcd for C 27 H 30 NO4[M+H] + 432.2169, found 432.2184.

[0218] Example 33, Preparation of Compound 33:

[0219]

[0220] Compound 33 was prepared by a similar method to compound 19, with 4-methylbenzylamine replacing compound 7a. Compound 33 was obtained as a pale yellow solid: mp = 142-145℃; 1 H NMR (400MHz, CDCl3) δ7.49 (s, 1H), 7.24 (d, J = 8.0Hz, 2H), 7.15 (brs, 1H), 7.11 ( d,J=8.0Hz,2H),6.54(d,J=10.0Hz,1H),5.62(d,J=10.0Hz,1H),5.11-5.07(m,1 H),4.35(s,2H),2.45(s,3H),2.32(s,3H),2.15-2.03(m,2H),1.83-1.75(m,1H) ,1.71-1.63(m,1H),1.66(s,3H),1.56(s,3H),1.36(s,3H); HRMS(ESI)m / zcalcd for C 28 H32 NO4[M+H] + 446.2331, found 446.2334.

[0221] Example 34, Preparation of Compound 34:

[0222]

[0223] Compound 34 was prepared by a similar method to compound 19, except that 4-methoxybenzylamine was used instead of compound 7a. Compound 34 was obtained as a pale yellow solid: mp = 145-147 °C; 1 H NMR (400MHz, CDCl3) δ7.51 (s, 1H), 7.26 (d, J = 8.4Hz, 2H), 6.83 (d, J = 8.4Hz, 2H) ,6.55(d,J=10.0Hz,1H),6.16(brs,1H),5.63(d,J=10.0Hz,1H),5.10-5.07(m,1 H),4.32(s,2H),3.78(s,3H),2.46(s,3H),2.16-2.01(m,2H),1.83-1.75(m,1H) ,1.71-1.65(m,1H),1.65(s,3H),1.56(s,3H),1.35(s,3H); HRMS(ESI)m / zcalcd for C 28 H 32 NO5[M+H] + 462.2280, found 462.2283.

[0224] Example 35, Preparation of Compound 35:

[0225]

[0226] Compound 35 was prepared by a similar method to compound 19, except that 2-furanylamine was used instead of compound 7a. Compound 35 was obtained as a pale yellow oil. 1H NMR (400MHz, CDCl3) δ7.59(s,1H),7.31(dd,J=1.6and 0.8Hz,1H),6.57(brs,1H),6.57(d,J=10.0Hz,1H),6.25(dd,J=3.2and 1.6Hz,1H),6.14(dd,J=3.2and0.8Hz,1H),5.63(d,J=10.0Hz,1H),5.13-5.08(m,1H),4.36(s,2H),2.49(s,3H) ,2.20-2.04(m,2H),1.85-1.77(m,1H),1.73-1.67(m,1H),1.67(s,3H),1.58(s,3H),1.35(s,3H); HRMS(ESI)m / z calcd for C 25 H 28 NO5[M+H] + 422.1967, found 422.1969.

[0227] Example 36, Preparation of Compound 36:

[0228]

[0229] Compound 36 was prepared by a similar method to compound 10, except that 4-fluorobenzyl alcohol was used instead of isopentenol (5b). Compound 36 was obtained as a pale yellow solid: mp = 153-155 °C; 1 H NMR (400MHz, CDCl3) δ9.84 (brs, 1H), 7.66 (s, 1H), 7.47 (dd, J = 8.4and 5.6Hz,2H),7.07(t,J=8.4Hz,2H),6.63(d,J=10.0Hz,1H),5.69(d,J=10.0Hz,1H),5.14-5.11(m,1H),5.05(s,2H),2.36(s ,3H),2.27-2.11(m,2H),1.91-1.83(m,1H),1.79-1.72(m,1H),1.67(s,3H),1.57(s,3H),1.47(s,3H); HRMS(ESI)m / zcalcd for C 27 H 28 FO5[M+H] + 451.1921, found 451.1923.

[0230] Example 37, Preparation of Compound 37:

[0231]

[0232] Compound 37 was prepared by a similar method to compound 10, except that p-fluorophenylethanol was used instead of isopentenol (5b). Compound 37 was obtained as a pale yellow solid: mp = 152-155 °C; 1 H NMR (400MHz, CDCl3) δ11.70(brs,1H),7.65(s,1H),7.29(dd,J=8.4and 5.6Hz,2H),7.00(t,J=8.4Hz,2H),6.59(d,J=10.0Hz,1H),5.66(d,J=10.0Hz,1H),5.12-5.09(m,1H),4.25(t,J=6.8Hz,2H),3.10(t,J= 6.8Hz,2H),2.34(s,3H),2.21-2.06(m,2H),1.84-1.76(m,1H),1.73-1.65(m,1H),1.67(s,3H),1.56(s,3H),1.41(s,3H); HRMS(ESI)m / z calcd for C 28 H 30 FO5[M+H] + 465.2072, found 465.2068.

[0233] Example 38, Preparation of Compound 38:

[0234]

[0235] Compound 38 was prepared by a similar method to compound 10, but with 4-chlorobenzyl alcohol instead of isopentenol (5b). Compound 38 was obtained as a pale yellow solid: mp = 150-153 °C; 1 H NMR (400MHz, CDCl3) δ12.11(brs,1H),7.66(s,1H),7.43(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),6.62(d,J=10.0Hz,1H),5.69(d,J=10.0Hz,1H),5.14- 5.10(m,1H),5.05(s,2H),2.37(s,3H),2.24-2.10(m,2H),1.89-1.81(m,1H ),1.78-1.70(m,1H),1.67(s,3H),1.57(s,3H),1.46(s,3H); HRMS(ESI)m / z calcd forC 27 H 28 ClO5[M+H] + 467.1620, found 467.1615.

[0236] Example 39, Preparation of Compound 39:

[0237]

[0238] Compound 39 was prepared by a similar method to compound 10, except that 4-trifluoromethylbenzyl alcohol was used instead of isopentenol (5b). Compound 39 was obtained as a pale yellow solid: mp = 161-163 °C; 1 H NMR (400MHz, CDCl3) δ12.18(brs,1H),7.67(s,1H),7.66(d,J=8.4Hz,2H),7.64 (d,J=8.4Hz,2H),6.63(d,J=9.6Hz,1H),5.70(d,J=9.6Hz,1H),5.16(d,J=12.0H z,1H),5.12(d,J=12.0Hz,1H),5.11(t,J=7.6Hz,1H),2.41(s,3H),2.24-2.08( m,2H),1.86-1.69(m,2H),1.66(s,3H),1.55(s,3H),1.45(s,3H); HRMS(ESI)m / z calcd for C 28 H 28 F3O5[M+H] + 501.1883, found 501.1898.

[0239] Example 40, Preparation of Compound 40:

[0240]

[0241] Compound 40 was prepared by a similar method to compound 10, except that 4-trifluoromethylphenylethanol was used instead of isopentenol (5b). Compound 40 was obtained as a pale yellow solid: mp = 165-166 °C; 1 H NMR (400MHz, CDCl3) δ11.88(brs,1H),7.65(s,1H),7.58(d,J=8.0Hz,2H),7.4 7(d,J=8.0Hz,2H),6.59(d,J=10.0Hz,1H),5.66(d,J=10.0Hz,1H),5.11-5.08 (m,1H),4.34-4.26(m,2H),3.19(t,J=6.4Hz,2H),2.34(s,3H),2.20-2.04(m, 2H),1.81-1.64(m,2H),1.67(s,3H),1.55(s,3H),1.39(s,3H); HRMS(ESI)m / z calcd for C 29 H30 F3O5[M+H] + 515.2040, found 515.2051.

[0242] Example 41, Preparation of Compound 41:

[0243]

[0244] Compound 41 was prepared by a similar method to compound 10, except that 4-(hydroxymethyl)benzonitrile was used instead of isopentenol (5b). Compound 41 was obtained as a pale yellow solid: mp = 161-163 °C; 1 H NMR (400MHz, CDCl3) δ12.02(brs,1H),7.68(d,J=8.0Hz,2H),7.65(s,1H),7.62(d,J=8.0Hz,2H),6.61(d,J=10.0Hz,1H),5.68(d,J=10.0Hz,1 H),5.13(s,2H),5.09-5.05(m,1H),2.40(s,3H),2.19-2.04(m,2H),1.80-1.68(m,2H),1.65(s,3H),1.53(s,3H),1.41(s,3H); HRMS(ESI)m / z calcd forC 28 H 28 NO5[M+H] + 458.1962, found 458.1981.

[0245] Example 42, Preparation of Compound 42:

[0246]

[0247] Compound 42 was prepared by a similar method to compound 10, with 4-methylbenzyl alcohol used instead of isopentenol (5b). Compound 42 was obtained as a pale yellow solid: mp = 145-148℃; 1H NMR (400MHz, CDCl3) δ11.89(brs,1H),7.67(s,1H),7.38(d,J=8.0Hz,1H),7.20(d,J=8. 0Hz,1H),6.64(d,J=10.0Hz,1H),5.70(d,J=10.0Hz,1H),5.17-5.12(m,1H),5.08(d,J= 11.6Hz,1H),5.05(d,J=11.6Hz,1H),2.38(s,3H),2.36(s,3H),2.30-2.14(m,2H),1.94 -1.86(m,1H),1.81-1.73(m,1H),1.68(s,3H),1.60(s,3H),1.49(s,3H); HRMS(ESI)m / z calcd for C 28 H 31 O5[M+H] + 447.2166, found 447.2180.

[0248] Example 43, Preparation of Compound 43:

[0249]

[0250] Compound 43 was prepared by a similar method to compound 10, except that 4-methoxybenzyl alcohol was used instead of isopentenol (5b). Compound 43 was obtained as a pale yellow solid: mp = 153-156 °C; 1 H NMR (400MHz, CDCl3) δ11.24(brs,1H),7.66(s,1H),7.40(d,J=8.4Hz,2H),6.90(d,J=8. 4Hz,2H),6.63(d,J=10.0Hz,1H),5.69(d,J=10.0Hz,1H),5.16-5.12(m,1H),5.04(d,J= 10.8Hz,1H),5.01(d,J=10.8Hz,1H),3.83(s,3H),2.33(s,3H),2.29-2.13(m,2H),1.94 -1.86(m,1H),1.80-1.73(m,1H),1.67(s,3H),1.58(s,3H),1.48(s,3H); HRMS(ESI)m / z calcd for C 28 H 31 O6[M+H] + 463.2115, found 463.2130.

[0251] Example 44, Preparation of Compound 44:

[0252]

[0253] Compound 44 was prepared by a similar method to compound 10, with 4-tert-butylbenzyl alcohol used instead of isopentenol (5b). Compound 44 was obtained as a pale yellow solid: mp = 158-160 °C; 1 H NMR (400MHz, CDCl3) δ12.26(brs,1H),7.68(s,1H),7.46(d,J=8.4Hz,2H),7.43(d,J=8. 4Hz,2H),6.64(d,J=10.0Hz,1H),5.71(d,J=10.0Hz,1H),5.17-5.13(m,1H),5.09(d,J= 10.4Hz,1H),5.06(d,J=10.4Hz,1H),2.40(s,3H),2.31-2.14(m,2H),1.94-1.87(m,1H) ,1.81-1.74(m,1H),1.69(s,3H),1.60(s,3H),1.49(s,3H),1.36(s,9H); HRMS(ESI)m / z calcd for C 31 H 37 O5[M+H] + 489.2636, found 489.2648.

[0254] Example 45, Preparation of Compound 45:

[0255]

[0256] Compound 45 was prepared by a similar method to compound 10, except that 4-pyridinemethanol was used instead of isopentenol (5b). Compound 45 was obtained as a pale yellow solid: mp = 155-158 °C; 1 H NMR (400MHz, CDCl3) δ12.21 (brs, 1H), 8.46 (d, J = 7.2Hz, 2H), 7.60 (s, 1H), 6.99 (d,J=7.2Hz,2H),6.61(d,J=10.0Hz,1H),5.66(d,J=10.0Hz,1H),5.05-5.01(m ,1H),5.09(d,J=10.4Hz,1H),5.06(d,J=10.4Hz,1H),2.30(s,3H),2.12-1.92( m,2H),1.77-1.69(m,2H),1.61(s,3H),1.50(s,3H),1.29(s,3H); HRMS(ESI)m / z calcd for C 26 H 28NO5[M+H] + 434.1962, found 434.1951.

[0257] Example 46, Preparation of Compound 46:

[0258]

[0259] Compound 46 was prepared by a similar method to compound 10, except that 2-naphthalenol was substituted for isopentenol (5b). Compound 46 was obtained as a pale yellow solid: mp = 171-174 °C; 1 H NMR(400MHz, CDCl3)δ11.88(brs,1H),7.95(s,1H),7.90-7.85(m,3H),7.69-7.67(m,2H ),7.53-7.49(m,2H),6.65(d,J=10.0Hz,1H),5.72(d,J=10.0Hz,1H),5.29(d,J=11.6Hz, 1H),5.26(d,J=11.6Hz,1H),5.15(t,J=7.2Hz,1H),2.43(s,3H),2.32-2.16(m,2H),1.9 5-1.88(m,1H),1.83-1.75(m,1H),1.69(s,3H),1.59(s,3H),1.51(s,3H); HRMS(ESI)m / z calcd for C 31 H 31 O5[M+H] + 483.2166, found 483.2181.

[0260] Example 47, Preparation of Compound 47:

[0261]

[0262] Compound 47 was prepared by a similar method to compound 10, except that isopentenol (5b) was replaced with biphenyl-4-methanol. Compound 47 was obtained as a pale yellow solid: mp = 175-178 °C; 1H NMR(400MHz, CDCl3)δ12.28(brs,1H),7.70(s,1H),7.66-7.60(m,6H),7.5 0-7.46(m,2H),7.40-7.36(m,1H),6.66(d,J=10.0Hz,1H),5.72(d,J=10.0H z,1H),5.19-5.17(m,3H),2.44(s,3H),2.31-2.16(m,2H),1.96-1.88(m,1H ),1.84-1.76(m,1H),1.70(s,3H),1.62(s,3H),1.51(s,3H); HRMS(ESI)m / z calcd forC 33 H 33 O5[M+H] + 509.2323, found 509.2328.

[0263] Example 48, Preparation of Compound 48:

[0264]

[0265] Compound 48 was prepared by a similar method to compound 10, except that 2-benzyloxyethanol was used instead of isopentenol (5b). Compound 48 was obtained as a pale yellow solid: mp = 174-176 °C; 1 H NMR(400MHz, CDCl3)δ9.71(brs,1H),7.63(s,1H),7.38-7.25(m,5H),6.59(d,J =10.0Hz,1H),5.65(d,J=10.0Hz,1H),5.12-5.08(m,1H),4.65(s,2H),4.32-4. 24(m,2H),3.82(t,J=4.8Hz,2H),2.48(s,3H),2.22-2.07(m,2H),1.87-1.79(m ,1H),1.74-1.68(m,1H),1.66(s,3H),1.57(s,3H),1.41(s,3H); HRMS(ESI)m / z calcd for C 29 H 33 O6[M+H] + 477.2277, found 477.2279.

[0266] Example 49, Preparation of Compound 49:

[0267]

[0268] a) Under nitrogen protection, anhydrous sodium carbonate (0.32 g, 3.0 mmol) and tetrakis(triphenylphosphine)palladium (56 mg, 0.05 mmol) were added sequentially to a mixed solution of 1,4-dioxane (5 mL) of compounds 4a (0.5 g, 1.0 mmol) and 8a (0.28 g, 2.0 mmol). The reaction was carried out at 80 °C for 5 hours. After the reaction was complete, the system was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give compound 8b (0.38 g, 85% yield) as a colorless oil. 1 HNMR (400MHz, CDCl3) δ7.54 (s, 1H), 7.21 (dd, J = 8.4and 5.6Hz,2H),7.10(dd,J=8.8and8.4Hz,2H),6.62(d,J=10.0Hz,1H),5.62(d,J=10.0Hz,1H),5.03-4.99(m,1H),4.44(q,J=7.2Hz,2H ),2.29(s,3H),2.02-1.82(m,2H),1.63(s,3H),1.63-1.57(m,2H),1.49(s,3H),1.43(t,J=7.2Hz,3H),1.28(s,3H); HRMS(ESI)m / z calcd for C 28 H 30 FO4[M+H] + 449.2128, found 449.2129.

[0269] b) Compound 49 was prepared by a similar method to compound 2, with compound 8b replacing compound 2f. Compound 49 was obtained as a pale yellow solid: mp = 144-146℃; 1 H NMR (400MHz, CDCl3) δ10.46(brs,1H),7.72(s,1H),7.24-7.20(m,2H),7.14-7.09(m,2H),6.64(d,J=10.0Hz,1H),5.64(d,J=10.0H z,1H),5.04-5.00(m,1H),2.31(s,3H),2.03-1.84(m,2H),1.64(s,3H),1.64-1.58(m,2H),1.50(s,3H),1.29(s,3H); HRMS(ESI)m / z calcd for C 26 H 26 FO4[M+H] + 421.1815, found 421.1814.

[0270] Example 50, Preparation of Compound 50:

[0271]

[0272] Compound 50 was prepared by a similar method to compound 49, except that 3-fluoro-4-methoxyphenylboronic acid was used instead of 4-fluorophenylboronic acid (8a). Compound 50 was obtained as a pale yellow solid: mp = 154-156 °C; 1 H NMR (400MHz, CDCl3) δ8.43(brs,1H),7.70(s,1H),7.04-6.99(m,2H),6.96-6.94(m,1H),6.64(d,J=9.6Hz,1H),5.64(d,J=9.6Hz,1H),5 .04-5.00(m,1H),3.95(s,3H),2.33(s,3H),2.04-1.86(m,2H),1.63(s,3H),1.63-1.59(m,2H),1.50(s,3H),1.30(s,3H); HRMS(ESI)m / z calcd for C 27 H 28 FO5[M+H] + 451.1921, found 451.1926.

[0273] Example 51, Preparation of Compound 51:

[0274]

[0275] Compound 51 was prepared by a similar method to compound 49, except that 4-trifluoromethoxyphenylboronic acid was used instead of 4-fluorophenylboronic acid (8a). Compound 51 was obtained as a pale yellow solid: mp = 163-165 °C; 1 H NMR (400MHz, CDCl3) δ11.62(brs,1H),7.72(s,1H),7.30-7.26(m,4H),6.65(d,J=10.0Hz,1H),5.65(d,J=10.0Hz,1H),5.01 (t,J=7.2Hz,1H),2.32(s,3H),2.03-1.83(m,2H),1.67-1.55(m,2H),1.63(s,3H),1.48(s,3H),1.30(s,3H); HRMS(ESI)m / z calcd for C 27 H 26 F3O5[M+H] + 487.1727, found 487.1751.

[0276] Example 52, Preparation of Compound 52:

[0277]

[0278] Compound 52 was prepared by a similar method to compound 49, except that 4-trifluoromethylphenylboronic acid was used instead of 4-fluorophenylboronic acid (8a). Compound 52 was obtained as a pale yellow solid: mp = 161-162 °C; 1 H NMR (400MHz, CDCl3) δ8.87(brs,1H),7.72(s,1H),7.69(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),6.65(d,J=10.0Hz,1H),5.65(d,J=10. 0Hz,1H),5.03-4.98(m,1H),2.30(s,3H),2.01-1.82(m,2H),1.63(s,3H),1.63-1.57(m,2H),1.47(s,3H),1.29(s,3H); HRMS(ESI)m / z calcd for C 27 H 26 F3O4[M+H] + 471.1783, found 471.1786.

[0279] Example 53, Preparation of Compound 53:

[0280]

[0281] Compound 53 was prepared by a similar method to compound 49, except that 4-tert-butylphenylboronic acid was used instead of 4-fluorophenylboronic acid (8a). Compound 53 was obtained as a pale yellow solid: mp = 163-164 °C; 1 H NMR (400MHz, CDCl3) δ10.98(brs,1H),7.72(s,1H),7.42(d,J=8.0Hz,2H),7.18(d,J=8.0Hz,2H),6.65(d,J=9.6Hz,1H),5.63(d,J=9.6Hz,1H) ,5.02(t,J=7.2Hz,1H),2.34(s,3H),2.03-1.84(m,2H),1.68-1.58(m,2H),1.63(s,3H),1.47(s,3H),1.38(s,9H),1.31(s,3H); HRMS(ESI)m / z calcd forC 30 H 35 O4[M+H] + 459.2530, found 459.2538.

[0282] Example 54, Preparation of Compound 54:

[0283]

[0284] Compound 54 was prepared by a similar method to compound 49, except that 3-hydroxymethylphenylboronic acid was used instead of 4-fluorophenylboronic acid (8a). Compound 54 was obtained as a pale yellow solid: mp = 159-163 °C; 1 H NMR(400MHz, CDCl3)δ7.70(s,1H),7.46-7.42(m,1H),7.38-7.36(m,1H),7.31(brs ,1H),7.24-7.21(m,1H),7.10-7.04(m,3H),7.04-7.00(m,1H),6.70(d,J=10.0Hz,1 H),6.68(brs,1H),5.69(d,J=10.0Hz,1H),4.78(s,2H),2.66-2.58(m,1H),2.51-2. 44(m,1H),2.34(s,3H),2.10(s,3H),1.88-1.74(m,2H),1.37(s,3H); HRMS(ESI)m / z calcd for C 30 H 29 O5[M+H] + 469.2010, found 469.2011.

[0285] Example 55, Preparation of Compound 55:

[0286]

[0287] Compound 55 was prepared by a similar method to compound 49, except that pyridine-4-boronic acid was used instead of 4-fluorophenylboronic acid (8a). Compound 55 was obtained as a pale yellow solid: mp = 171-173 °C; 1 H NMR (400MHz, CDCl3) δ12.20(brs,1H),7.96(d,J=7.2Hz,2H),7.70(s,1H),7.36(d,J=7.2Hz,2H),6.70(d,J=10.0Hz,1H ),5.69(d,J=10.0Hz,1H),2.43-2.35(m,2H),2.34(s,3H),2.10(s,3H),1.88-1.74(m,2H),1.37(s,3H); HRMS(ESI)m / z calcd for C 25 H 26 NO4[M+H] +404.1856, found 404.1860.

[0288] Example 56, Preparation of Compound 56:

[0289]

[0290] Compound 56 was prepared by a similar method to compound 49, except that 4-N-(methylsulfonamide)phenylboronic acid was used instead of 4-fluorophenylboronic acid (8a). Compound 56 was obtained as a pale yellow solid: mp = 171-173 °C; 1 H NMR (400MHz, CDCl3) δ12.31(brs,1H),7.86(d,J=7.2Hz,2H),7.69(s,1H),7.22(d,J=7.2Hz,2H),6.65(d,J=10.0Hz,1H ),5.62(d,J=10.0Hz,1H),2.32-2.25(m,2H),2.23(s,3H),2.11(s,3H),1.89-1.74(m,2H),1.39(s,3H); HRMS(ESI)m / z calcd for C 27 H 30 NO6S[M+H] + 496.1788, found 496.1790.

[0291] Example 57, Preparation of Compound 57:

[0292]

[0293] Compound 57 was prepared by a similar method to compound 49, except that 4-carboxyphenylboronic acid was used instead of 4-fluorophenylboronic acid (8a). Compound 57 was obtained as a pale yellow solid: mp = 170-173 °C; 1 H NMR (400MHz, CDCl3) δ12.30(brs,1H),7.76(d,J=7.2Hz,2H),7.59(s,1H),7.33(d,J=7.2Hz,2H),6.54(d,J=10.0Hz,1H ),5.32(d,J=10.0Hz,1H),2.42-2.38(m,2H),2.20(s,3H),2.10(s,3H),1.91-1.76(m,2H),1.35(s,3H); HRMS(ESI)m / z calcd for C 27 H 27 O6[M+H] + 447.1802, found 447.1812.

[0294] Example 58, Preparation of Compound 58:

[0295]

[0296] Compound 58 was prepared by a similar method to compound 49, except that 5-pyrimidineboronic acid was used instead of 4-fluorophenylboronic acid (8a). Compound 58 was obtained as a pale yellow solid: mp = 165-168 °C; 1 H NMR (400MHz, CDCl3) δ12.68(brs,1H),9.31(s,1H),8.82(s,2H),7.65(s,1H),6.66(d,J=10.0Hz,1H),5.67(d,J=10.0Hz,1H),4 .99(t,J=7.2Hz,1H),2.40(s,3H),2.05-1.82(m,2H),1.70-1.56(m,2H),1.60(s,3H),1.48(s,3H),1.33(s,3H); HRMS(ESI)m / z calcd for C 24 H 25 N₂O₄[M+H] + 405.1809, found 405.1815.

[0297] Example 59, Preparation of Compound 59:

[0298]

[0299] a) At 0 °C, triethylamine (2.02 g, 20 mmol) and N,N'-carbonyldiimidazole (71 mg, 0.41 mmol) were added sequentially to a mixed solution of compound 9a (2.15 g, 10.0 mmol) and N-methyl-N-methoxyamine hydrochloride (0.73 g, 12.0 mmol) in dichloromethane (20 mL). After the addition was complete, the reaction was maintained at this temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1, v / v) to give compound 9b (2.3 g, 90% yield) as a colorless oil. 1 HNMR(400MHz, CDCl3)δ7.45-7.42(m,2H),7.19-7.15(m,2H),3.73(s,2H),3.63(s,3H),3.19(s,3H); HRMS(ESI)m / z calcd for C 10 H 13 BrNO2[M+H] + 258.0130, found 258.0127.

[0300] b) Under nitrogen protection, methyl magnesium bromide (1M tetrahydrofuran solution, 10.7 mL, 10.7 mmol) was slowly added dropwise to a tetrahydrofuran (20 mL) solution of compound 9b (2.3 g, 8.9 mmol) at 0 °C. After the addition was complete, the reaction was maintained at this temperature for 2 hours. Once the reaction was complete, a saturated ammonium chloride solution (50 mL) was slowly added dropwise to quench the reaction mixture, and the mixture was stirred for 10 minutes. The resulting mixture was extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with a saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give compound 9c (1.55 g, 82% yield) as a colorless oil. 1 H NMR(500MHz, CDCl3)δ7.48-7.48(m,2H),7.09-7.06(m,2H),3.66(s,2H),2.17(s,3H); HRMS(ESI)m / z calcd for C9H 10 BrO[M+H] + 212.9915, found 212.9912.

[0301] c) Ethoxyformylmethylenetriphenylphosphine (3.1 g, 8.8 mmol) was added to a toluene (20 mL) solution of compound 9c (1.55 g, 7.3 mmol), and the mixture was reacted at 90 °C for 5 hours. After the reaction was complete, the system was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give compound 9d (1.36 g, 66% yield) as a pale yellow oil. 1 H NMR (500MHz, CDCl3) δ7.45-7.38(m,2H),7.14-7.03(m,2H),5.79-5.64(m,1H),4.21-4.12(m,2H),3.96(s,0. 36H),3.38(s,1.71H),2.11(d,J=1.2Hz,2.47H),1.78(d,J=1.4Hz,0.47H),1.31-1.25(m,3H); HRMS(ESI)m / z calcd for C 13 H 16 BrO2[M+H] + 283.0334, found 283.0330.

[0302] d) Under nitrogen protection, DIBAL-H (1M tetrahydrofuran solution, 5.8 mL, 5.8 mmol) was slowly added dropwise to a toluene (20 mL) solution of compound 9d (1.36 g, 4.8 mmol) at -78 °C. After the addition was complete, the reaction was maintained at this temperature for 2 hours. Once the reaction was complete, a saturated ammonium chloride solution (50 mL) was slowly added dropwise to quench the reaction mixture, and the mixture was stirred for 30 minutes. The resulting mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (20 mL × 3). After separation of the filtrate, the organic phase was retained and washed with a saturated sodium chloride solution (50 mL). After drying with anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1, v / v) to give compound 9e (0.89 g, yield 77%) as a colorless oil. 1 H NMR (500MHz, CDCl3) δ7.42-7.39(m,2H),7.07-7.03(m,2H),5.60-5.45(m,1H),4.2 7-4.18(m,2H),3.37-3.27(m,2H),1.66-1.60(m,3H),1.48(brs,1H); HRMS(ESI)m / z calcd for C 11 H 14 BrO[M+H] + 241.0228, found241.0225.

[0303] e) At room temperature, DCC (1.5 g, 7.4 mmol) was added in portions to a solution of compound 9e (0.89 g, 3.7 mmol) in dichloromethane (20 mL). After the addition was complete, the reaction was allowed to proceed for 2 hours. Once the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give compound 9f (0.79 g, 90% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ10.09(d,J=7.8Hz,0.28H),10.00(d,J=7.9Hz,0.71H),7.47-7.43(m,2H),7.08-7.02(m,2H),6.06-6.03(m,0.2 7H),5.88-5.84(m,0.72H),3.86(s,0.61H),3.45(s,1.60H),2.12(d,J=1.3Hz,2.28H),1.88(d,J=1.3Hz,0.87H); HRMS(ESI)m / zcalcd for C 11 H 12 BrO[M+H] + 239.0072, found 239.0073.

[0304] f) Compound 9g was prepared by a similar method to compound 1h, with compound 9f replacing compound 1g. Compound 9g was obtained as a yellow solid: mp = 152-155℃; 1 H NMR (400MHz, CDCl3) δ12.30(s,1H),10.05(s,1H),7.26(d,J=8.0Hz,2H),7.04(d,J=8.0Hz,2H),6.87(d,J=10.0Hz,1H),6. 29(s,1H),5.79(d,J=10.0Hz,1H),3.01(d,J=14.0Hz,1H),2.85(d,J=14.0Hz,1H),2.15(s,3H),1.40(s,3H); HRMS(ESI)m / z calcd for C 19 H 18 ClO4[M+H] + 345.0894, found 345.0891.

[0305] Compound 9h was prepared by a similar method to compound 1i, with compound 9g used instead of compound 1h. Compound 9h was obtained as a yellow oil: HRMS(ESI) m / z calcd for C 21 H 22 BrO5[M+H] + 433.0645, found 433.0655.

[0306] h) Compound 9i was prepared by a similar method to compound 1j, with compound 9h used instead of compound 1i. Compound 9i was obtained as a colorless oil: HRMS(ESI) m / z calcd for C 25 H 26 BrO6[M+H] + 501.0907, found 501.0911.

[0307] i) Compound 9j was prepared by a similar method to compound 1k, with compound 9i replacing compound 1j. Compound 9j was obtained as a colorless oil: HRMS(ESI) m / z calcd for C 23 H 22 BrO5[M+H] + 457.0645, found 457.0662.

[0308] (j) Compound 59 was prepared by a similar method to compound 1, with compound 9j replacing compound 1k. Compound 59 was obtained as a pale yellow solid: mp = 152-155℃;1 H NMR (400MHz, CDCl3) δ13.07(brs,1H),7.82(d,J=7.6Hz,2H),7.60(s,1H),7.10(d,J=7.6Hz,2H),6.88(d,J=10.0Hz, 1H), 5.98 (d, J = 10.0Hz, 1H), 3.04 (d, J = 12.0Hz, 1H), 2.79 (d, J = 12.0Hz, 1H), 2.33 (s, 3H), 1.32 (s, 3H); HRMS (ESI) m / z calcd for C 21 H 18 BrO5[M+H] + 429.0332, found 429.0339.

[0309] Example 60, Preparation of Compound 60:

[0310]

[0311] Compound 60 was prepared by a similar method to compound 59, except that p-methoxyphenylacetic acid was used instead of p-bromophenylacetic acid (9a). Compound 60 was obtained as a pale yellow solid: mp = 161-162 °C; 1 H NMR (400MHz, CDCl3) δ12.91(brs,1H),7.61(s,1H),7.13(d,J=7.6Hz,2H),6.95-6.72(m,3H),5.96(d,J=10.0Hz, 1H),3.81(s,3H),3.03(d,J=12.0Hz,1H),2.78(d,J=12.0Hz,1H),2.13(s,3H),1.22(s,3H); HRMS(ESI)m / zcalcd for C 22 H 21 O6[M+H] + 381.1333, found 381.1321.

[0312] Example 61, Preparation of Compound 61:

[0313]

[0314] Compound 61 was prepared by a similar method to compound 59, except that 2-methylhydrocinnamic acid was used instead of p-bromophenylacetic acid (9a). Compound 61 was obtained as a pale yellow solid: mp = 171-173 °C; 1H NMR (400MHz, CDCl3) δ10.18(brs,1H),7.66(s,1H),7.16-7.08(m,4H),6.67(d,J=10.0Hz,1H),5.74(d,J=10 .0Hz,1H),2.84-2.69(m,2H),2.47(s,3H),2.28(s,3H),2.09-1.95(m,2H),1.53(s,3H); HRMS(ESI)m / zcalcd for C 23 H 23 O5[M+H] + 379.1545, found 379.1546.

[0315] Example 62, Preparation of Compound 62:

[0316]

[0317] Compound 62 was prepared by a similar method to compound 59, except that 3-(4-methoxyphenyl)propionic acid was used instead of p-bromophenylacetic acid (9a). Compound 62 was obtained as a pale yellow solid: mp = 173-175 °C; 1 H NMR (400MHz, CDCl3) δ7.65(s,1H),7.08(d,J=8.4Hz,2H),6.82(d,J=8.4Hz,2H),6.64(d,J=9.6Hz,1H),5.69( d,J=9.6Hz,1H),3.78(s,3H),2.80-2.64(m,2H),2.46(s,3H),2.14-1.97(m,2H),1.50(s,3H); HRMS(ESI)m / z calcd for C 23 H 23 O6[M+H] + 395.1495, found 395.1496.

[0318] Example 63, Preparation of Compound 63:

[0319]

[0320] Compound 63 was prepared by a similar method to compound 59, except that 3-(4-bromophenyl)propionic acid was used instead of p-bromophenylacetic acid (9a). Compound 63 was obtained as a pale yellow solid: mp = 170-173 °C; 1H NMR (400MHz, CDCl3) δ10.20(brs,1H),7.82(d,J=7.6Hz,2H),7.63(s,1H),7.09(d,J=7.6Hz,2H),6.88(d,J=10.0Hz ,1H),5.98(d,J=10.0Hz,1H),2.81-2.65(m,2H),2.43(s,3H),2.13-1.96(m,2H),1.51(s,3H); HRMS(ESI)m / zcalcd for C 22 H 20 BrO5[M+H] + 443.0489, found 443.0498.

[0321] Example 64, Preparation of Compound 64:

[0322]

[0323] Compound 64 was prepared by a similar method to compound 59, except that 4'-methyl-biphenyl-4-propionic acid was used instead of p-bromophenylacetic acid (9a). Compound 64 was obtained as a pale yellow solid: mp = 170-173 °C; 1 H NMR (400MHz, CDCl3) δ10.05(brs,1H),7.62-7.60(m,2H),7.33-7.28(m,4H),7.15(d,J=7.6Hz,2H),6.88(d,J=10 .0Hz,1H),5.98(d,J=10.0Hz,1H),2.93-2.68(m,2H),2.41(s,3H),2.15-1.98(m,2H),1.50(s,3H); HRMS(ESI)m / z calcd for C 29 H 27 O5[M+H] + 455.1853, found 455.1869.

[0324] Example 65, Preparation of Compound 65:

[0325]

[0326] Compound 65 was prepared by a similar method to compound 59, except that 3-(4-(trifluoromethoxy)phenyl)propionic acid was used instead of p-bromophenylacetic acid (9a). Compound 65 was obtained as a pale yellow solid: mp = 166-167 °C; 1H NMR (400MHz, CDCl3) δ13.07(brs,1H),7.61(s,1H),7.13(d,J=7.2Hz,2H),7.05-6.88(m,3H),5.83(d ,J=10.0Hz,1H),2.78-2.62(m,2H),2.39(s,3H),2.10-1.95(m,2H),1.49(s,3H); HRMS(ESI)m / zcalcd for C 23 H 20 F3O6[M+H] + 449.1206, found 449.1218.

[0327] Example 66, Preparation of Compound 66:

[0328]

[0329] a) At 0°C, trifluoromethanesulfonic anhydride (2.07 g, 7.4 mmol) was slowly added to a mixed solution of compound 10j (2.0 g, 4.9 mmol) and triethylamine (1.49 g, 14.8 mmol) in dichloromethane (10 mL). The reaction solution was reacted at 0°C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1, v / v) to give compound 11a (2.45 g, 93% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.53(s,1H),7.15-7.08(m,4H),6.67(d,J=10.0Hz,1H),5.80(d,J=10.0Hz,1H),4.46(q,J=7.2Hz,2H),2.85(td,J=13.2and 4.8Hz,1H),2.75(td,J=13.2and 4.8Hz,1H),2.57(s,3H),2.31(s,3H),2.11(td,J=13.2and 4.8Hz,1H),1.94(td,J=13.2and 4.8Hz,1H),1.98-1.90(m,1H),1.52(s,3H),1.44(q,J=7.2Hz,3H); HRMS(ESI)m / z calcd for C 26 H 26 F3O7S[M+H] + 539.1346, found 539.1355.

[0330] b) Under nitrogen protection, anhydrous cesium carbonate (362 mg, 1.11 mmol), palladium acetate (9 mg, 0.04 mmol), and BINAP (25 mg, 0.25 mmol) were added sequentially to a mixed solution of 1,4-dioxane (5 mL) of compounds 11a (0.2 g, 0.37 mmol) and 7a (65 mg, 0.74 mmol). The reaction was carried out at 80 °C for 5 hours. After the reaction was complete, the system was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give compound 11b (0.3 g, 80% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.50 (s, 1H), 7.15-7.08 (m, 4H), 6.65 (d, J = 10.0Hz, 1H), 5.70 (d, J =10.0Hz,1H),4.43(q,J=7.2Hz,2H),3.83(brs,4H),3.67(brs,2H),2.86(td,J=13.2and 4.8Hz,1H),2.76(td,J=13.2and 4.8Hz,1H),2.70(brs,2H),2.54(s,3H),2.33(s,3H),2.16(td,J=13.2and 4.8Hz,1H),1.94(td,J=13.2and 4.8Hz,1H),1.48(s,3H),1.43(t,J=7.2Hz,3H); HRMS(ESI)m / z calcd for C 29 H 34 NO5[M+H] + 476.2431, found 476.2440.

[0331] c) At room temperature, 1M sodium hydroxide solution (2 mL) was added to an ethanol (5 mL) solution of compound 11b (0.3 g, 0.63 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, it was diluted with water (20 mL). The pH was adjusted to 2-3 with 1M hydrochloric acid solution, and then extracted with ethyl acetate (20 mL). The organic layer was washed with saturated sodium chloride solution (20 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give compound 66 (0.25 g, yield 88%) as a white solid: mp: 145-148 °C; 1H NMR (400MHz, CDCl3) δ9.79 (brs, 1H), 7.65 (s, 1H), 7.16-7.08 (m, 4H), 6.67 (d, J = 10. 0Hz,1H),5.72(d,J=10.0Hz,1H),3.87(brs,4H),3.69(brs,2H),2.86(td,J=13.2and 4.8Hz,1H),2.77(td,J=13.2and 4.8Hz,1H),2.71(brs,2H),2.55(s,3H),2.33(s,3H),2.17(td,J=13.2and 4.8Hz,1H),1.95(td,J=13.2and 4.8Hz,1H),1.49(s,3H); HRMS(ESI)m / z calcd for C 27 H 30 NO5[M+H] + 448.2118, found 448.2120.

[0332] Example 67, Preparation of Compound 67:

[0333]

[0334] Compound 67 was prepared by a similar method to compound 66, except that 4,4-difluoropiperidine was used instead of morpholine (7a). Compound 67 was obtained as a pale yellow solid: mp = 153-157 °C; 1 H NMR (400MHz, CDCl3) δ7.67 (s, 1H), 7.16-7.09 (m, 4H), 6.67 (d, J = 10.0Hz, 1H), 5.73 ( d,J=10.0Hz,1H),3.64(brs,1H),3.57(brs,1H),2.98(brs,1H),2.86(td,J=13.2and 4.8Hz,1H),2.74(td,J=13.2and 4.8Hz,1H),2.53(s,3H),2.34(s,3H),2.17-2.06(m,5H),1.94(td,J=13.2and 4.8Hz,1H),1.46(s,3H); HRMS(ESI)m / z calcd for C 28 H 30 F2NO4[M+H] + 482.2137, found 482.2145.

[0335] Example 68, Preparation of Compound 68:

[0336]

[0337] Compound 68 was prepared by a similar method to compound 66, except that 1-(2-pyrimidinyl)piperazine was used instead of morpholine (7a). Compound 68 was obtained as a pale yellow solid: mp = 166-167 °C; 1 H NMR (400MHz, CDCl3) δ8.92(brs,1H),8.37(d,J=4.8Hz,2H),7.62(s,1H),7.12-7.05(m,4H),6.64(d,J=10.0Hz,1H),6.49(t,J=4.8 Hz,1H),5.68(d,J=10.0Hz,1H),4.67(brs,2H),3.64(brs,1H),3.53(brs,1H),3.28(brs,2H),2.96(brs,2H),2.78(td,J=13.2and 4.8Hz,1H),2.68(td,J=13.2and 4.8Hz,1H),2.58(s,3H),2.22(s,3H),2.05(td,J=13.2and 4.8Hz,1H),1.90(td,J=13.2and4.8Hz,1H),1.44(s,3H); HRMS(ESI)m / z calcd for C 31 H 33 N4O4[M+H] + 525.2496, found 525.2493.

[0338] Example 69, Preparation of Compound 69:

[0339]

[0340] Compound 69 was prepared by a similar method to compound 66, with 4-methoxybenzylamine used instead of morpholine (7a). Compound 69 was obtained as a pale yellow solid: mp = 156-157 °C; 1 H NMR (400MHz, CDCl3) δ8.41(brs,1H),7.49(s,1H),7.28(d,J=8.4Hz,2H),7.13-7.07(m,4H),6.82(d,J=8.4Hz,2H),6.60(d,J=10.0Hz,1H),5.70(d,J= 10.0Hz,1H),4.36(s,2H),3.76(s,3H),2.82-2.66(m,2H),2.45(s,3H),2.2 6(s,3H),2.07-2.00(m,1H),1.96-1.88(m,1H),1.42(s,3H); HRMS(ESI)m / z calcd forC31 H 32 NO5[M+H] + 498.2275, found 498.2280.

[0341] Example 70, Preparation of Compound 70:

[0342]

[0343] Compound 70 was prepared by a similar method to compound 49, with compound 11a replacing compound 4a. Compound 70 was obtained as a pale yellow solid: mp = 176-178℃; 1 H NMR (400MHz, CDCl3) δ10.03(brs,1H),7.75(s,1H),7.43-7.38(m,1H),7.12-7.00(m,7H),6.71(d,J=10.0Hz,1H),5.72(d,J= 10.0Hz,1H),2.68-2.60(m,1H),2.53-2.45(m,1H),2.35(s,3H),2.13(s,3H),1.89-1.76(m,2H),1.37(s,3H); HRMS(ESI)m / z calcd for C 29 H 26 FO4[M+H] + 457.1810, found 457.1803.

[0344] Example 71, Preparation of Compound 71:

[0345]

[0346] Compound 71 was prepared by a similar method to compound 49, with compound 11a replacing compound 4a and 3-hydroxymethylphenylboronic acid replacing 4-fluorophenylboronic acid (8a). Compound 71 was obtained as a pale yellow solid: mp = 173-176℃; 1H NMR(400MHz, CDCl3)δ7.70(s,1H),7.46-7.42(m,1H),7.38-7.36(m,1H),7.31(brs ,1H),7.24-7.21(m,1H),7.10-7.04(m,3H),7.04-7.00(m,1H),6.70(d,J=10.0Hz,1 H),6.68(brs,1H),5.69(d,J=10.0Hz,1H),4.78(s,2H),2.66-2.58(m,1H),2.51-2. 44(m,1H),2.34(s,3H),2.10(s,3H),1.88-1.74(m,2H),1.37(s,3H); HRMS(ESI)m / z calcd for C 30 H 29 O5[M+H] + 469.2010, found 469.2011.

[0347] Example 72, Preparation of Compound 72:

[0348]

[0349] Compound 72 was prepared by a similar method to compound 49, with compound 11a replacing compound 4a and 4-trifluoromethylphenylboronic acid replacing 4-fluorophenylboronic acid (8a). Compound 72 was obtained as a pale yellow solid: mp = 177-179℃; 1 H NMR (400MHz, CDCl3) δ7.74(s,3H),7.70(d,J=8.0Hz,2H),7.41(d,J=8.0Hz,2H),7.09-7.06(m,3H),7.03-6.99(m,1H),6.72(d,J=10.0Hz,1H) ,5.72(d,J=10.0Hz,1H),2.65-2.58(m,1H),2.49-2.41(m,1H),2.33(s,3H),2.07(s,3H),1.88-1.77(m,2H),1.36(s,3H); HRMS(ESI)m / zcalcd for C 30 H 26 F3O4[M+H] + 507.1778, found 507.1780.

[0350] Example 73, Preparation of Compound 73:

[0351]

[0352] Compound 73 was prepared by a similar method to compound 66, with 4-trifluoromethoxyaniline replacing morpholine (7a). Compound 73 was obtained as a pale yellow solid: mp = 162-165℃; 1 H NMR (400MHz, CDCl3) δ7.72(s,1H),7.08-7.06(m,5H),6.99-6.97(m,1H),6.74-6.68(m,3H),5.74(d,J=1 0.0Hz,1H),2.73-2.57(m,2H),2.35(s,3H),2.13(s,3H),1.97-1.90(m,2H),1.45(s,3H); HRMS(ESI)m / z calcd forC 30 H 27 F3NO5[M+H] + 538.1836, found 538.1851.

[0353] Example 74, Preparation of Compound 74:

[0354]

[0355] Compound 74 was prepared by a similar method to compound 66, with 4-methylaniline used instead of morpholine (7a). Compound 74 was obtained as a pale yellow solid: mp = 155-156 °C; 1 H NMR (400MHz, CDCl3) δ13.07(brs,1H),7.72(s,1H),7.09-7.05(m,5H),7.00-6.97(m,1H),6.75-6.68(m,3H),5.74(d,J =10.0Hz,1H),2.73-2.57(m,2H),2.35(s,3H),2.13(s,3H),1.97-1.90(m,2H),1.86(s,3H),1.45(s,3H); HRMS(ESI)m / z calcd for C 30 H 30 NO4[M+H] + 468.2169, found 468.2181.

[0356] Example 75, Preparation of Compound 75:

[0357]

[0358] a) At room temperature, potassium carbonate (1.66 g, 12.0 mmol) was added to a 10 mL solution of compound 3d (1.0 g, 2.4 mmol) in acetonitrile. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give compound 12a (0.35 g, 43% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.58(d,J=2.0Hz,1H),6.71(d,J=2.0Hz,1H),6.59(d,J=1 0.0Hz,1H),5.61(d,J=10.0Hz,1H),5.17(d,J=5.6Hz,1H),5.15(d,J=5.6Hz,1H ),5.15-5.10(m,1H),3.64(s,3H),2.47(s,3H),2.23-2.10(m,2H),1.87-1.80( m,1H),1.75-1.70(m,1H),1.68(s,3H),1.60(s,3H),1.42(s,3H); HRMS(ESI)m / z calcd for C 21 H 27 O4[M+H] + 343.1909, found 343.1914.

[0359] b) At room temperature, 1M sodium hydroxide solution (2 mL) was added to an ethanol (5 mL) solution of compound 12a (0.35 g, 1.02 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, it was diluted with water (20 mL). The pH was adjusted to 1-2 with 1M hydrochloric acid solution, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated sodium chloride solution (20 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give compound 75 (0.23 g, 77% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ7.52(d,J=2.0Hz,1H),6.69(d,J=2.0Hz,1H),6.60(d,J=10.0Hz,1H),5.60(d,J=10.0Hz,1H),5.59(s,1H),5 .12-5.08(m,1H),2.40(s,3H),2.21-2.05(m,2H),1.83-1.72(m,2H),1.67(s,3H),1.58(s,3H),1.43(s,3H); HRMS(ESI)m / zcalcd for C 19 H23 O3[M+H] + 299.1647, found 299.1653.

[0360] Example 76, Preparation of Compound 76:

[0361]

[0362] a) At room temperature, bromoacetonitrile (13a, 0.26 g, 2.2 mmol) and anhydrous potassium carbonate (0.99 g, 7.2 mmol) were added to a 10 mL solution of compound 3c (0.5 g, 1.44 mmol) in ACN. The reaction mixture was heated to 80 °C and reacted for 12 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1, v / v) to give compound 13b (0.37 g, 70% yield) as a pale yellow oil. 1 H NMR (500MHz, CDCl3) δ7.38 (s, 1H), 6.53 (d, J = 10.0Hz, 1H), 5.67 (d, J = 10.0Hz, 1H), 5.18 (d, J = 8.8Hz, 1H), 5.17 (d, J = 8.8Hz, 1H), 5.12-5.08 (m, 1H), 3.61(s,3H),2.44(s,3H),2.19-2.06(m,2H),1.86-1.79(m,1H),1.74-1.68(m,1H),1.66(s,3H),1.57(s,3H),1.41(s,3H); HRMS(ESI)m / zcalcdfor C 22 H 26 NO4[M+H] + 368.1862, found 368.1859.

[0363] b) At room temperature, p-toluenesulfonic acid (17 mg, 0.1 mmol) was added to an ethanol (10 mL) solution of compound 13b (0.37 g, 1.0 mmol). The reaction solution was heated to 50 °C and reacted for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature. The solution was diluted with ethyl acetate (30 mL), and the resulting mixture was washed successively with saturated sodium bicarbonate aqueous solution (20 mL), water (20 mL), and saturated sodium chloride solution (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1, v / v) to give compound 76 (0.14 g, 65% yield) as a pale yellow oil. 1H NMR (500MHz, CDCl3) δ7.36(s,1H),6.54(d,J=10.0Hz,1H),5.88(brs,1H),5.67(d,J=10.0Hz,1H),5.09(t,J=7.2 Hz,1H),2.37(s,3H),2.20-2.02(m,2H),1.85-1.69(m,2H),1.66(s,3H),1.56(s,3H),1.45(s,3H); HRMS(ESI)m / z calcd for C 20 H 22 NO3[M+H] + 324.1600, found 324.1604.

[0364] Example 77, Preparation of Compound 77:

[0365]

[0366] Compound 77 was prepared by a similar method to compound 76, using bromotrifluoroethane instead of bromoacetonitrile (13a). Compound 77 was obtained as a pale yellow oil. 1 H NMR(500MHz, CDCl3)δ8.00(s,1H),6.84(d,J=10.0Hz,1H),5.88(d,J=10.0Hz,1H),5.21(t,J=7.2Hz,1H), 2.38(s,3H),2.21-2.02(m,2H),1.85-1.69(m,2H),1.68(s,3H),1.66(s,3H),1.44(s,3H); HRMS(ESI)m / z calcd for C 20 H 22 F3O3[M+H] + 367.1516, found 367.1531.

[0367] Example 78, Preparation of Compound 78:

[0368]

[0369] Compound 78 was prepared by a similar method to compound 76, except that bromonitromethane was used instead of bromoacetonitrile (13a). Compound 78 was obtained as a pale yellow oil. 1H NMR (500MHz, CDCl3) δ7.62(s,1H),6.55(d,J=10.0Hz,1H),6.07(brs,1H),5.70(d,J=10.0Hz,1H),5.08(t,J=7.2 Hz,1H),2.40(s,3H),2.18-2.04(m,2H),1.86-1.71(m,2H),1.64(s,3H),1.56(s,3H),1.46(s,3H); HRMS(ESI)m / z calcd forC 19 H 22 NO5[M+H] + 344.1498, found 344.1496.

[0370] Example 79, Preparation of Compound 79:

[0371]

[0372] a) At room temperature, ammonium chloride (14a, 0.14g, 2.6mmol) and HATU (0.99g, 2.6mmol) were added sequentially to a DMF (5mL) solution of compound 11 (0.5g, 1.3mmol) and DIPEA (0.34g, 2.6mmol). After addition, the reaction was allowed to proceed at room temperature for 12 hours. Once the reaction was complete, the reaction solution was diluted with ethyl acetate (20mL), and the product solution was washed sequentially with water (20mL x 2) and saturated sodium chloride solution (20mL). The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give compound 14b (0.38g, 75% yield) as a pale yellow oil: HRMS(ESI)m / zcalcd for C 22 H 28 NO5[M+H] + 386.1967, found 386.1973.

[0373] b) At room temperature, p-toluenesulfonic acid (17 mg, 0.1 mmol) was added to an ethanol (5 mL) solution of compound 14b (0.38 g, 1.0 mmol). The reaction solution was heated to 50 °C and reacted for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature. The solution was diluted with ethyl acetate (30 mL), and the resulting mixture was washed successively with saturated sodium bicarbonate aqueous solution (20 mL), water (20 mL), and saturated sodium chloride solution (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give compound 79 (0.19 g, yield 55%) as a pale yellow solid: mp = 135-138 °C;1 HNMR(500MHz, CDCl3)δ7.48(s,1H),6.57(d,J=10.0Hz,1H),6.50(brs,1H),6.30(brs,1H),5.91(brs,1H),5.63(d,J=10.0Hz,1H),5 .08(t,J=6.8Hz,1H),2.39(s,3H),2.19-2.04(m,2H),1.83-1.69(m,2H),1.65(s,3H),1.55(s,3H),1.43(s,3H); HRMS(ESI)m / zcalcd forC 20 H 24 NO4[M+H] + 342.1705, found 342.1708.

[0374] Example 80, Preparation of Compound 80:

[0375]

[0376] a) Lithium borohydride (0.32 g, 14.4 mmol) was added to a tetrahydrofuran (30 mL) solution of compound 3d (3.0 g, 7.2 mmol), and the mixture was heated to 60 °C for 1 hour. After the reaction was complete, it was quenched with a saturated ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give compound 15a (2.17 g, 81% yield) as a colorless oil. 1 HNMR(500MHz, CDCl3)δ6.59(s,1H),6.54(d,J=10.0Hz,1H),5.60(d,J=10.0Hz,1H),5.15-5.09(m,3H),4.72(s,2H),3.62(s,3H ),2.43(s,3H),2.22-2.06(m,2H),1.85-1.78(m,1H),1.73-1.68(m,1H),1.66(s,3H),1.58(s,3H),1.40(s,3H); HRMS(ESI)m / z calcd for C 22 H 29 O5[M+H] + 373.2015, found 373.2019.

[0377] b) To a solution of compound 15a (2.17 g, 5.8 mmol) in dichloromethane (20 mL), Dys-Martin oxidant (4.9 g, 11.6 mmol) was added in portions, and the reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was complete, it was quenched with saturated sodium thiosulfate solution (100 mL) and stirred for 30 minutes. Extraction was performed with ethyl acetate (50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1, v / v) to give compound 15b (1.61 g, 75% yield) as a colorless oil. 1 H NMR (500MHz, CDCl3) δ9.77(s,1H),7.51(s,1H),6.60(d,J=10.0Hz,1H),5.67(d,J=10.0Hz,1H),5.21(d,J=6.0Hz,1H),5.19(d,J=6.0Hz,1H),5.12-5 .08(m,1H),3.62(s,3H),2.49(s,3H),2.20-2.07(m,2H),1.87-1.79(m,1H ),1.74-1.68(m,1H),1.66(s,3H),1.57(s,3H),1.42(s,3H); HRMS(ESI)m / z calcd for C 22 H 27 O5[M+H] + 371.1858, found 371.1860.

[0378] c) At room temperature, p-toluenesulfonic acid (76 mg, 0.44 mmol) was added to an ethanol (20 mL) solution of compound 15b (1.61 g, 4.4 mmol). The reaction solution was heated to 50 °C and reacted for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature. The solution was diluted with ethyl acetate (100 mL), and the resulting mixture was washed successively with saturated sodium bicarbonate aqueous solution (50 mL), water (50 mL), and saturated sodium chloride solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1, v / v) to give compound 80 (1.20 g, yield 84%) as a pale yellow oil. 1H NMR (500MHz, CDCl3) δ9.72(s,1H),7.51(s,1H),6.60(d,J=10.0Hz,1H),5.97(s,1H),5.67(d,J=10.0Hz,1H),5.09(t,J =7.6Hz,1H),2.42(s,3H),2.19-2.07(m,2H),1.85-1.69(m,2H),1.66(s,3H),1.56(s,3H),1.45(s,3H); HRMS(ESI)m / z calcd for C 20 H 23 O4[M+H] + 327.1596, found 327.1594.

[0379] Example 81, Preparation of Compound 81:

[0380]

[0381] Compound 81 was prepared by a similar method to compound 79, using 4,4-difluoropiperidine instead of ammonium chloride (14a). Compound 81 was obtained as a pale yellow oil. 1 H NMR (500MHz, CDCl3) δ7.37(s,1H),6.59(d,J=9.6Hz,1H),5.84(s,1H),5.64(d,J=9.6Hz,1H),5.10-5.06(m,1H),3.96(b rs,4H),2.38(s,3H),2.16-2.06(m,6H),1.83-1.69(m,2H),1.66(s,3H),1.56(s,3H),1.43(s,3H); HRMS(ESI)m / zcalcd for C 25 H 30 F2NO4[M+H] + 446.2143, found 446.2145.

[0382] Example 82, Preparation of Compound 82:

[0383]

[0384] Compound 82 was prepared by a similar method to compound 79, using morpholine instead of ammonium chloride (14a). Compound 82 was obtained as a pale yellow oil. 1H NMR (500MHz, CDCl3) δ8.69(brs,1H),7.51(s,1H),6.78(d,J=10.0Hz,1H),5.74(d,J=10.0Hz,1H),5.09-5.05(m,1H),3.73(brs,4H) ,3.66-3.64(m,4H),2.26(s,3H),2.15-2.01(m,2H),1.77-1.62(m,2H),1.60(s,3H),1.52(s,3H),1.36(s,3H); HRMS(ESI)m / zcalcd for C 24 H 30 NO5[M+H] + 412.2124, found 412.2126.

[0385] Example 83, Preparation of Compound 83:

[0386]

[0387] Compound 83 was prepared by a similar method to compound 79, using n-hexylamine instead of ammonium chloride (14a). Compound 83 was obtained as a pale yellow oil. 1 H NMR (500MHz, CDCl3) δ7.41 (s, 1H), 6.58 (s, 1H), 6.57 (d, J = 10.0Hz, 1H), 5.85 (s, 1 H),5.62(d,J=10.0Hz,1H),5.09-5.06(t,J=7.2Hz,1H),3.46(q,J=6.8Hz,2H),2. 39(s,3H),2.19-2.04(m,2H),1.82-1.70(m,2H),1.68-1.60(m,2H),1.65(s,3H), 1.55(s,3H),1.42(s,3H),1.40-1.31(m,6H),0.89(t,J=6.8Hz,3H); HRMS(ESI)m / z calcdfor C 26 H 36 NO4[M+H] + 426.2644, found 426.2646.

[0388] Example 84, Preparation of Compound 84:

[0389]

[0390] Compound 84 was prepared by a similar method to compound 79, using phenylhydrazine instead of ammonium chloride (14a). Compound 84 was obtained as a pale yellow oil. 1H NMR (500MHz, CDCl3) δ8.35(brs,1H),7.50(s,1H),7.25-7.20(m,2H),6.93-6.88(m,3H),6.55(d,J=10.0Hz,1H),5.91(s,1H),5.62(d,J= 10.0Hz,1H),5.11-5.06(m,1H),2.41(s,3H),2.20-2.06(m,2H),1.83-1.69(m,2H),1.66(s,3H),1.56(s,3H),1.43(s,3H); HRMS(ESI)m / z calcd for C 26 H 29 N₂O₄[M+H] + 433.2127, found 433.2129.

[0391] Example 85, Preparation of Compound 85:

[0392]

[0393] Compound 85 was prepared by a similar method to compound 79, using 4-fluorophenylethylamine instead of ammonium chloride (14a). Compound 85 was obtained as a pale yellow oil. 1 H NMR (500MHz, CDCl3) δ7.42 (s, 1H), 7.21 (dd, J = 5.6and 8.4Hz,2H),7.01(t,J=8.4Hz,2H),6.64(t,J=6.0Hz,1H),6.57(d,J=10.0Hz,1H),5.88(s,1H),5.63(d,J=10.0Hz,1H),5.08(t,J=7.2Hz,1H),3.7 2-3.67(m,2H),2.94-2.91(m,2H),2.35(s,3H),2.18-2.06(m,2H),1.83- 1.70(m,2H),1.66(s,3H),1.56(s,3H),1.43(s,3H); HRMS(ESI)m / zcalcd for C 28 H 31 FNO4[M+H] + 464.2237, found 464.2239.

[0394] Example 86, Preparation of Compound 86:

[0395]

[0396] Compound 86 was prepared by a similar method to compound 79, using diethylamine instead of ammonium chloride (14a). Compound 86 was obtained as a pale yellow oil. 1 H NMR(500MHz, CDCl3)δ7.35(s,1H),6.59(d,J=10.0Hz,1H),5.82(s,1H),5.61(d,J=10.0Hz,1H),5.10-5.06(m,1H),3.61(brs, 4H),2.38(s,3H),2.19-2.04(m,2H),1.82-1.70(m,2H),1.65(s,3H),1.56(s,3H),1.42(s,3H),1.31(brs,6H); HRMS(ESI)m / z calcd for C 24 H 32 NO4[M+H] + 398.2331, found 398.2329.

[0397] Example 87, Preparation of Compound 87:

[0398]

[0399] Compound 87 was prepared by a similar method to compound 79, using 4-fluoroaniline instead of ammonium chloride (14a). Compound 87 was obtained as a pale yellow oil. 1 H NMR (500MHz, CDCl3) δ8.22 (s, 1H), 7.67 (dd, J = 8.4and 5.2Hz,2H),7.55(s,1H),7.07(t,J=8.4Hz,2H),6.60(d,J=10.0Hz,1H),5.85(s,1H),5.65(d,J=10.0Hz,1H),5.10(t,J =7.2Hz,1H),2.44(s,3H),2.21-2.06(m,2H),1.85-1.71(m,2H),1.67(s,3H),1.57(s,3H),1.45(s,3H); HRMS(ESI)m / z calcd for C 26 H 27 FNO4[M+H] + 436.1924, found 436.1928.

[0400] Example 88, Preparation of Compound 88:

[0401]

[0402] Compound 88 was prepared by a similar method to compound 79, using cyclopropylamine instead of ammonium chloride (14a). Compound 88 was obtained as a pale yellow oil. 1 H NMR (500MHz, CDCl3) δ7.42(s,1H),6.65(brs,1H),6.57(d,J=10.0Hz,1H),5.83(brs,1H),5.61(d,J=10.0Hz,1H),5.08(t,J=7.2Hz,1H),2.94-2.87(m ,1H),2.37(s,3H),2.17-2.03(m,2H),1.81-1.70(m,2H),1.65(s,3H),1.5 5(s,3H),1.42(s,3H),0.91-0.86(m,2H),0.71-0.67(m,2H); HRMS(ESI)m / z calcd for C 23 H 28 NO4[M+H] + 382.2018, found 382.2016.

[0403] Example 89, Preparation of Compound 89:

[0404]

[0405] Compound 89 was prepared by a similar method to compound 79, using furfurylamine instead of ammonium chloride (14a). Compound 89 was obtained as a pale yellow oil. 1 H NMR (500MHz, CDCl3) δ7.45(s,1H),7.39(s,1H),6.89(t,J=5.6Hz,1H),6.57(d,J =10.0Hz,1H),6.35-6.34(m,1H),6.32-6.31(m,1H),5.88(s,1H),5.62(d,J=10. 0Hz,1H),5.10-5.06(m,1H),4.67(s,1H),4.66(s,1H),2.38(s,3H),2.19-2.04( m,2H),1.82-1.70(m,2H),1.65(s,3H),1.55(s,3H),1.42(s,3H); HRMS(ESI)m / z calcd forC 25 H 28 NO5[M+H] + 422.1967, found 422.1969.

[0406] Example 90, Preparation of Compound 90:

[0407]

[0408] Compound 90 was prepared by a similar method to compound 79, using 5-methoxytryptamine instead of ammonium chloride (14a). Compound 90 was obtained as a pale yellow oil. 1 H NMR (500MHz, CDCl3) δ8.30(brs,1H),7.42(s,1H),7.27(d,J=10.8Hz,1H),7.09-7.07(m,2H),6.87(dd,J=8.8and 2.4Hz,1H),6.75(t,J=6.0Hz,1H),6.56(d,J=10.0Hz,1H),5.87(s,1H),5.62(d,J=10.0Hz,1H),5.08(t,J=7.2Hz,1H),3.83-3.80(m,2H),3 .79(s,3H),3.08(t,J=6.8Hz,2H),2.29(s,3H),2.18-2.05(m,2H),1.83-1.70(m,2H),1.66(s,3H),1.56(s,3H),1.42(s,3H); HRMS(ESI)m / z calcd forC 31 H 35 N₂O₅[M+H] + 515.2546, found 515.2543.

[0409] Example 91, Preparation of Compound 91:

[0410]

[0411] a) Hydroxylamine hydrochloride (0.95 g, 13.6 mmol) and triethylamine (1.37 g, 13.6 mmol) were added sequentially to an ethanol (10 mL) solution of compound 13b (1.0 g, 2.7 mmol), and the mixture was heated to 80 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain crude compound 16a, which can be used directly in the next step; HRMS(ESI) m / z calcd for C 22 H 29 N₂O₅[M+H] + 401.2071, found 401.2075.

[0412] b) Acetic anhydride (0.38 g, 3.8 mmol) was slowly added to a solution of compound 16a (1.0 g, 2.5 mmol) and triethylamine (0.51 g, 5.0 mmol) in dichloromethane (10 mL), and the mixture was reacted at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain crude compound 16b, which can be used directly in the next step; HRMS(ESI) m / z calcd for C 24 H 31 N₂O₆[M+H] + 443.2177, found 443.2189.

[0413] c) Compound 16b (1.0 g, 2.3 mmol) was dissolved in pyridine (5 mL) and heated to 120 °C for 5 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give compound 16c (0.61 g, yield 62%) as a colorless oil. 1 H NMR (500MHz, CDCl3) δ7.43 (s, 1H), 6.60 (d, J = 9.6Hz, 1H), 5.65 (d, J = 9.6Hz, 1H), 5.18 (d, J = 6.0Hz, 1H), 5.16 (d, J = 6.0Hz, 1H), 5.13-5.09 (m, 1H), 3. 62(s,3H),2.67(s,3H),2.51(s,3H),2.22-2.07(m,2H),1.87-1.79(m,1H) ,1.74-1.70(m,1H),1.66(s,3H),1.58(s,3H),1.42(s,3H); HRMS(ESI)m / z calcd forC 24 H 29 N₂O₅[M+H] + 425.2076, found 425.2077.

[0414] d) At room temperature, p-toluenesulfonic acid (25 mg, 0.14 mmol) was added to a 5 mL ethanol solution of compound 16c (0.61 g, 1.4 mmol). The reaction solution was heated to 50 °C and reacted for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature. The solution was diluted with ethyl acetate (30 mL), and the resulting mixture was washed successively with saturated sodium bicarbonate aqueous solution (20 mL), water (20 mL), and saturated sodium chloride solution (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give compound 91 (0.47 g, 88% yield) as a colorless oil. 1HNMR(500MHz, CDCl3)δ7.42(s,1H),6.60(d,J=10.0Hz,1H),5.78(s,1H),5.64(d,J=10.0Hz,1H),5.09(t,J=7.2Hz,1H) ,2.67(s,3H),2.46(s,3H),2.19-2.07(m,2H),1.82-1.72(m,2H),1.66(s,3H),1.57(s,3H),1.44(s,3H); HRMS(ESI)m / z calcd for C 22 H 25 N₂O₄[M+H] + 381.1814, found 381.1814.

[0415] Example 92, Preparation of Compound 92:

[0416]

[0417] Compound 92 was prepared by a similar method to compound 91, reacting compound 16a with trifluoroacetic anhydride instead of acetic anhydride. Compound 92 was obtained as a colorless oil. 1 H NMR (500MHz, CDCl3) δ7.54(s,1H),6.59(d,J=10.0Hz,1H),5.85(s,1H),5.66(d,J=10.0Hz,1H),5.12-5.07(m,1H ),2.45(s,3H),2.20-2.05(m,2H),1.85-1.71(m,2H),1.67(s,3H),1.57(s,3H),1.45(s,3H); HRMS(ESI)m / zcalcd for C 22 H 24 F3N2O4[M+H] + 437.1688, found 437.1690.

[0418] II. Pharmacological Experiments

[0419] The inhibitory activity of SARS-CoV-2 3CL protease (3CLpro) was detected using the 2019-nCoV Mpro / 3CLpro Inhibitor Screening Kit P0315M (Beyotime Biotechnology Co., Ltd., Shanghai, China). This kit is based on fluorescence resonance energy transfer (FRET) technology and uses the MCA-AVLQSGFR-Lys(Dnp)-Lys-NH2 substrate. The positive control ebselen and the test compound were dissolved in 0.5% DMSO / water at concentrations of 10 μM and 50 μM, respectively. In a black 96-well plate, the reaction mixture contained 92 μL of detection buffer, 5 μL of the test compound solution, 1 μL of SARS-CoV-2 3CLpro, and 2 μL of substrate. After incubation at 37°C for 10 min, the relative fluorescence units (RFU) were detected using a microplate reader (DU-730; Beckman Coulter, Brea, CA, USA) at an excitation wavelength of 325 nm and an emission wavelength of 393 nm. Three replicate experiments were conducted, and the inhibition rate of the test compound was calculated. Some results are shown below:

[0420]

[0421] in conclusion:

[0422] The compounds involved in this invention have novel structures and exhibit certain inhibitory activity against SARS-CoV-2 3CLpro. These compounds use sesamol as a starting material, which is simple, readily available, and the synthetic route is relatively simple and efficient, making them suitable for industrial production. In summary, the compounds involved in this invention are simple to synthesize, low in cost, and possess good inhibitory activity against SARS-CoV-2 3CLpro, facilitating the subsequent development of SARS-CoV-2 inhibitors.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: R 1 Selected from: hydrogen, nitro, cyano, carboxyl, aldehyde, halogenated C 1-16 Alkyl, C 1-16 alkoxycarbonyl, carbamoyl, C 1-16 Alkylaminocarbonyl, (C 1-16 alkyl)2-aminocarbonyl, C 1-16 alkyl carbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 1-16 Alkyl)2-morpholinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, halopyrrolidinylcarbonyl, piperidinylcarbonyl, halopiperidinylcarbonyl, C 1-16 alkylpiperazinylcarbonyl, piperidinyl C 1-16 Alkoxycarbonyl, morpholinyl C 1-16 alkoxycarbonyl, C 1-16 Alkylpiperazine C 1-16 alkoxycarbonyl, oxadiazole, C 1-16 Alkyl oxadiazole group, halogenated C 1-16 Alkyl oxadiazolyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-substituted C 1-16 alkylaminocarbonyl, heteroaryl substituted C 1-16 Alkylaminocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl; the above aryl groups are selected from phenyl, naphthyl, and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyrroleyl, quinolinyl, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, amino, (C 1-16 alkyl)2amino, C 1-16 Alkyl, Halogenated C 1-16 Alkyl, C 1-16 Alkoxy, halogenated C 1-16 Alkoxy; R 2 Selected from: hydrogen, hydroxyl, C 1-16 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-16 Alkoxy C 1-16 Alkoxy, hydroxy C 1-16 Alkoxy, carboxyl C 1-16 Alkoxy, C 1-16 alkoxycarbonyl C 1-16 Alkoxy, piperidinyl carbonyl C 1-16 Alkoxy, halopiperidinyl carbonyl C 1-16 Alkoxy, Morpholinyl Carbonyl C 1-16 Alkoxy, piperidinyl C 1-16 Alkoxy, Morpholinyl C 1-16 Alkoxy, C 1-16 Alkylpiperazine C 1-16 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-16 alkoxy and aryl substituted C 1-16 Alkoxy C 1-16 alkoxy- and heteroaryl-substituted C 1-16 alkoxy and aryl substituted C 1-16 alkylamino and heteroaryl substituted C 1-16 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrrolyl, quinolinyl, pyrimidinyl, pyridyl, indolyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-16 alkoxycarbonyl, amino, (C 1-16 alkyl)2-amino, hydroxy C 1-16 Alkyl, C 1-16 Alkyl, Halogenated C 1-16 Alkyl, C 1-16 Alkoxy, halogenated C 1-16 Alkoxy, C 1-16 alkylsulfonyl, C 1-16 alkylsulfonylamino; R 3 Selected from: C 1-21 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-16 alkyl and heteroaryl substituted C 1-16 Alkyl; the above aryl group is selected from phenyl, naphthyl, and biphenyl; the above heteroaryl group is selected from furanyl, thiophene, pyrrolyl, quinolinyl, pyrimidinyl, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, and C. 1-16 alkoxycarbonyl, amino, (C 1-16 alkyl)2amino, C 1-16 Alkyl, Halogenated C 1-16 Alkyl, C 1-16 Alkoxy, halogenated C 1-16 Alkoxy; R 4 Selected from: hydrogen, C 1-16 alkyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 1 Selected from: hydrogen, nitro, cyano, carboxyl, aldehyde, halogenated C 1-8 Alkyl, C 1-8 alkoxycarbonyl, carbamoyl, C 1-8 Alkylaminocarbonyl, (C 1-8 alkyl)2-aminocarbonyl, C 1-8 alkyl carbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 1-8 Alkyl)2-morpholinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, halopyrrolidinylcarbonyl, piperidinylcarbonyl, halopiperidinylcarbonyl, C 1-8 alkylpiperazinylcarbonyl, piperidinyl C 1-8 Alkoxycarbonyl, morpholinyl C 1-8 alkoxycarbonyl, C 1-8 Alkylpiperazine C 1-8 alkoxycarbonyl, oxadiazole, C 1-8 Alkyl oxadiazole group, halogenated C 1-8 Alkyl oxadiazolyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-substituted C 1-8 alkylaminocarbonyl, heteroaryl substituted C 1-8 Alkylaminocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl; the above aryl groups are selected from phenyl, naphthyl, and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, amino, (C 1-8 alkyl)2amino, C 1-8 Alkyl, Halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 Alkoxy; R 2 Selected from: hydrogen, hydroxyl, C 1-8 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-8 Alkoxy C 1-8 Alkoxy, hydroxy C 1-8 Alkoxy, carboxyl C 1-8 Alkoxy, C 1-8 alkoxycarbonyl C 1-8 Alkoxy, piperidinyl carbonyl C 1-8 Alkoxy, halopiperidinyl carbonyl C 1-8 Alkoxy, Morpholinyl Carbonyl C 1-8 Alkoxy, piperidinyl C 1-8 Alkoxy, Morpholinyl C 1-8 Alkoxy, C 1-8 Alkylpiperazine C 1-8 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-8 alkoxy and aryl substituted C 1-8 Alkoxy C 1-8 alkoxy- and heteroaryl-substituted C 1-8 alkoxy and aryl substituted C 1-8 alkylamino and heteroaryl substituted C 1-8 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrimidinyl, pyridyl, indolyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-8 alkoxycarbonyl, amino, (C 1-8 alkyl)2-amino, hydroxy C 1-8 Alkyl, C 1-8 Alkyl, Halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 Alkoxy, C 1-8 alkylsulfonyl, C 1-8 alkylsulfonylamino; R 3 Selected from: C 1-11 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-8 alkyl and heteroaryl substituted C 1-8 Alkyl; the above aryl group is selected from phenyl, naphthyl, and biphenyl; the above heteroaryl group is selected from furanyl, thiophene, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, and C. 1-8 alkoxycarbonyl, amino, (C 1-8 alkyl)2amino, C 1-8 Alkyl, Halogenated C 1-8 Alkyl, C 1-8 Alkoxy, halogenated C 1-8 Alkoxy; R 4 Selected from: hydrogen, C 1-8 alkyl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that, R 1 Selected from: hydrogen, nitro, cyano, carboxyl, aldehyde, C 1-4 alkoxycarbonyl, carbamoyl, C 1-6 Alkylaminocarbonyl, (C 1-4 alkyl)2-aminocarbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 1-4 Alkyl)2-morpholinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, halopyrrolidinylcarbonyl, piperidinylcarbonyl, halopiperidinylcarbonyl, C 1-4 alkylpiperazinylcarbonyl, piperidinyl C 1-4 Alkoxycarbonyl, morpholinyl C 1-4 alkoxycarbonyl, C 1-4 Alkylpiperazine C 1-4 alkoxycarbonyl, oxadiazole, C 1-4 Alkyl oxadiazole group, halogenated C 1-4 Alkyl oxadiazolyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-substituted C 1-4 alkylaminocarbonyl, heteroaryl substituted C 1-4 Alkylaminocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl; the above aryl groups are selected from phenyl, naphthyl, and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy; R 2 Selected from: hydrogen, hydroxyl, C 1-5 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-4 Alkoxy C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, carboxyl C 1-4 Alkoxy, C 1-4 alkoxycarbonyl C 1-4 Alkoxy, piperidinyl carbonyl C 1-4 Alkoxy, halopiperidinyl carbonyl C 1-4 Alkoxy, Morpholinyl Carbonyl C 1-4 Alkoxy, piperidinyl C 1-4 Alkoxy, Morpholinyl C 1-4 Alkoxy, C 1-4 Alkylpiperazine C 1-4 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 Alkoxy C 1-4 alkoxy- and heteroaryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 alkylamino and heteroaryl substituted C 1-4 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrimidinyl, pyridinyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, carboxyl, C 1-4 alkoxycarbonyl, (C 1-4 alkyl)2-amino, hydroxy C 1-4 Alkyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino; R 3 Selected from: C 1-6 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-4 alkyl and heteroaryl substituted C 1-4 Alkyl; the above aryl group is selected from phenyl, biphenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy; R 4 Selected from: hydrogen, C 1-4 alkyl.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in Formula IA. R 5 Selected from: hydrogen, hydroxyl, C 1-5 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-4 Alkoxy C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, carboxyl C 1-4 Alkoxy, C 1-4 alkoxycarbonyl C 1-4 Alkoxy, piperidinyl carbonyl C 1-4 Alkoxy, halopiperidinyl carbonyl C 1-4 Alkoxy, Morpholinyl Carbonyl C 1-4 Alkoxy, piperidinyl C 1-4 Alkoxy, Morpholinyl C 1-4 Alkoxy, C 1-4 Alkylpiperazine C 1-4 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 Alkoxy C 1-4 alkoxy- and heteroaryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 alkylamino and heteroaryl substituted C 1-4 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrimidinyl, pyridinyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, carboxyl, C 1-4 alkoxycarbonyl, (C 1-4 alkyl)2-amino, hydroxy C 1-4 Alkyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino; R 6 Selected from: C 1-6 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-4 alkyl and heteroaryl substituted C 1-4 Alkyl; the above aryl group is selected from phenyl, biphenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy; R 7 Selected from: hydrogen, C 1-4 alkyl.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in Formula IB. R 6a Selected from: C 1-6 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-4 alkyl and heteroaryl substituted C 1-4 Alkyl; the above aryl group is selected from phenyl, biphenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy; R 7a Selected from: hydrogen, C 1-4 alkyl.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in formula IC. R 6b Selected from: aryl, heteroaryl; the above aryl group is selected from phenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, carboxyl, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl group.

7. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in Formula ID. R 5c Selected from: hydrogen, hydroxyl, C 1-5 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-4 Alkoxy C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, carboxyl C 1-4 Alkoxy, C 1-4 alkoxycarbonyl C 1-4 Alkoxy, piperidinyl carbonyl C 1-4 Alkoxy, halopiperidinyl carbonyl C 1-4 Alkoxy, Morpholinyl Carbonyl C 1-4 Alkoxy, piperidinyl C 1-4 Alkoxy, Morpholinyl C 1-4 Alkoxy, C 1-4 Alkylpiperazine C 1-4 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 Alkoxy C 1-4 alkoxy- and heteroaryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 alkylamino and heteroaryl substituted C 1-4 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrimidinyl, pyridinyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, carboxyl, C 1-4 alkoxycarbonyl, (C 1-4 alkyl)2-amino, hydroxy C 1-4 Alkyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino; R 6c Selected from: C 1-6 Straight-chain or branched saturated or unsaturated alkyl, aryl-substituted C 1-4 alkyl and heteroaryl substituted C 1-4 Alkyl; the above aryl group is selected from phenyl, biphenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl group.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in Formula IE. R 5d Selected from: hydrogen, hydroxyl, C 1-5 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-4 Alkoxy C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, carboxyl C 1-4 Alkoxy, C 1-4 alkoxycarbonyl C 1-4 Alkoxy, piperidinyl C 1-4 Alkoxy, Morpholinyl C 1-4 Alkoxy, C 1-4 Alkylpiperazine C 1-4 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 Alkoxy C 1-4 alkoxy- and heteroaryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 alkylamino and heteroaryl substituted C 1-4 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrimidinyl, pyridinyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, carboxyl, C 1-4 alkoxycarbonyl, (C 1-4 alkyl)2-amino, hydroxy C 1-4 Alkyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylsulfonyl, C 1-4 Alkylsulfonylamino.

9. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in formula IF. R 5e Selected from: hydroxyl, morpholino, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-4 alkoxy- and heteroaryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 alkylamino and heteroaryl substituted C 1-4 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, pyrazolyl, pyrimidinyl, pyridinyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-4 alkoxycarbonyl, hydroxy C 1-4 Alkyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylsulfonylamino; R 8e Selected from: hydrogen, halogen, cyano, nitro, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl group.

10. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in formula IG. R 6f Selected from: C 1-6 Straight-chain or branched saturated or unsaturated alkyl, aryl-substituted C 1-4 alkyl and heteroaryl substituted C 1-4 Alkyl; the above aryl group is selected from phenyl, biphenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl group.

11. The compound or its pharmaceutically acceptable salt according to any one of claims 1-3, characterized in that, The compound is shown in formula IH. R 9 Selected from: hydrogen, nitro, cyano, carboxyl, aldehyde, C 1-4 alkoxycarbonyl, carbamoyl, C 1-6 Alkylaminocarbonyl, (C 1-4 alkyl)2-aminocarbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 1-4 Alkyl)2-morpholinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, halopyrrolidinylcarbonyl, piperidinylcarbonyl, halopiperidinylcarbonyl, C 1-4 alkylpiperazinylcarbonyl, oxadiazolyl, C 1-4 Alkyl oxadiazole group, halogenated C 1-4 Alkyl oxadiazolyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-substituted C 1-4 alkylaminocarbonyl, heteroaryl substituted C 1-4 Alkylaminocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl; the above aryl groups are selected from phenyl, naphthyl, and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy; R 10 Selected from: hydrogen, hydroxyl, C 1-5 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-4 Alkoxy C 1-4 Alkoxy, hydroxy C 1-4 Alkoxy, carboxyl C 1-4 Alkoxy, C 1-4 alkoxycarbonyl C 1-4 Alkoxy, piperidinyl carbonyl C 1-4 Alkoxy, halopiperidinyl carbonyl C 1-4 Alkoxy, Morpholinyl Carbonyl C 1-4 Alkoxy, piperidinyl C 1-4 Alkoxy, Morpholinyl C 1-4 Alkoxy, C 1-4 Alkylpiperazine C 1-4 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 Alkoxy C 1-4 alkoxy- and heteroaryl-substituted C 1-4 alkoxy and aryl substituted C 1-4 alkylamino and heteroaryl substituted C 1-4 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrimidinyl, pyridinyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, carboxyl, C 1-4 alkoxycarbonyl, (C 1-4 alkyl)2-amino, hydroxy C 1-4 Alkyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-4 alkylsulfonyl, C 1-4 alkylsulfonylamino; R 11 Selected from: C 1-6 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-4 alkyl and heteroaryl substituted C 1-4 Alkyl; the above aryl group is selected from phenyl, biphenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl group.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in Formula II. R 9a Selected from: hydrogen, nitro, cyano, carboxyl, aldehyde, C 1-4 alkoxycarbonyl, carbamoyl, C 1-6 Alkylaminocarbonyl, (C 1-4 alkyl)2-aminocarbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 1-4 Alkyl)2-morpholinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, halopyrrolidinylcarbonyl, piperidinylcarbonyl, halopiperidinylcarbonyl, C 1-4 alkylpiperazinylcarbonyl, oxadiazolyl, C 1-4 Alkyl oxadiazole group, halogenated C 1-4 Alkyl oxadiazolyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-substituted C 1-4 alkylaminocarbonyl, heteroaryl substituted C 1-4 Alkylaminocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl; the above aryl groups are selected from phenyl, naphthyl, and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy; R 11a Selected from: C 1-6 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-4 alkyl and heteroaryl substituted C 1-4 Alkyl; the above aryl group is selected from phenyl, biphenyl; the above heteroaryl group is selected from thienyl, benzothienyl; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 alkoxycarbonyl, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl group.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is shown in Formula IJ. R 9b Selected from: hydrogen, nitro, cyano, carboxyl, aldehyde, C 1-4 alkoxycarbonyl, carbamoyl, C 1-6 Alkylaminocarbonyl, (C 1-4 alkyl)2-aminocarbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 1-4 Alkyl)2-morpholinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, halopyrrolidinylcarbonyl, piperidinylcarbonyl, halopiperidinylcarbonyl, C 1-4 alkylpiperazinylcarbonyl, oxadiazolyl, C 1-4 Alkyl oxadiazole group, halogenated C 1-4 Alkyl oxadiazolyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-substituted C 1-4 alkylaminocarbonyl, heteroaryl substituted C 1-4 Alkylaminocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl; the above aryl groups are selected from phenyl, naphthyl, and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl group.

14. The compound or its pharmaceutically acceptable salt according to any one of claims 1-13, characterized in that, The compound is selected from 15. A pharmaceutical composition, characterized in that... The compound containing a pharmaceutically effective amount of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

16. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-13 in the preparation of an anti-SARS-CoV-2 drug.

17. The method for preparing the compound or its pharmaceutically acceptable salt according to any one of claims 1-13, in, R 1 Selected from: hydrogen, nitro, cyano, carboxyl, aldehyde, halogenated C 1-16 Alkyl, C 1-16 alkoxycarbonyl, carbamoyl, C 1-16 Alkylaminocarbonyl, (C 1-16 alkyl)2-aminocarbonyl, C 1-16 alkyl carbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 1-16 Alkyl)2-morpholinylcarbonyl, morpholinylcarbonyl, pyrrolidinylcarbonyl, halopyrrolidinylcarbonyl, piperidinylcarbonyl, halopiperidinylcarbonyl, C 1-16 alkylpiperazinylcarbonyl, piperidinyl C 1-16 Alkoxycarbonyl, morpholinyl C 1-16 alkoxycarbonyl, C 1-16 Alkylpiperazine C 1-16 alkoxycarbonyl, oxadiazole, C 1-16 Alkyl oxadiazole group, halogenated C 1-16 Alkyl oxadiazolyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-substituted C 1-16 alkylaminocarbonyl, heteroaryl substituted C 1-16 Alkylaminocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl, arylhydrazinocarbonyl, heteroarylhydrazinocarbonyl; the above aryl groups are selected from phenyl, naphthyl, and biphenyl; the above heteroaryl groups are selected from furanyl, thiophene, pyrroleyl, quinolinyl, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, amino, (C 1-16 alkyl)2amino, C 1-16 Alkyl, Halogenated C 1-16 Alkyl, C 1-16 Alkoxy, halogenated C 1-16 Alkoxy; R 2 Selected from: hydrogen, hydroxyl, C 1-16 Straight-chain or branched saturated or unsaturated alkoxy groups, C 1-16 Alkoxy C 1-16 Alkoxy, hydroxy C 1-16 Alkoxy, carboxyl C 1-16 Alkoxy, C 1-16 alkoxycarbonyl C 1-16 Alkoxy, piperidinyl carbonyl C 1-16 Alkoxy, halopiperidinyl carbonyl C 1-16 Alkoxy, Morpholinyl Carbonyl C 1-16 Alkoxy, piperidinyl C 1-16 Alkoxy, Morpholinyl C 1-16 Alkoxy, C 1-16 Alkylpiperazine C 1-16 Alkoxy, morpholino, pyrrolyl, halopyrrolyl, piperidinyl, halopiperidinyl, pyrimidinylpiperazinyl, aryl, heteroaryl, aryl-substituted C 1-16 alkoxy and aryl substituted C 1-16 Alkoxy C 1-16 alkoxy- and heteroaryl-substituted C 1-16 alkoxy and aryl substituted C 1-16 alkylamino and heteroaryl substituted C 1-16 Alkylamino, arylamino, heteroarylamino; the aryl group is selected from phenyl, naphthyl, biphenyl; the heteroaryl group is selected from furanyl, thiophene, pyrrolyl, quinolinyl, pyrimidinyl, pyridyl, indolyl, benzofuranyl, benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-16 alkoxycarbonyl, amino, (C 1-16 alkyl)2-amino, hydroxy C 1-16 Alkyl, C 1-16 Alkyl, Halogenated C 1-16 Alkyl, C 1-16 Alkoxy, halogenated C 1-16 Alkoxy, C 1-16 alkylsulfonyl, C 1-16 alkylsulfonylamino; R 3 Selected from: C 1-21 Straight-chain or branched saturated or unsaturated alkyl, aryl, heteroaryl, aryl-substituted C 1-16 alkyl and heteroaryl substituted C 1-16 Alkyl; the above aryl group is selected from phenyl, naphthyl, and biphenyl; the above heteroaryl group is selected from furanyl, thiophene, pyrrolyl, quinolinyl, pyrimidinyl, pyridyl, indolyl, benzofuranyl, and benzothiophene; these aryl and heteroaryl groups may have one or more substituents, which are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, and C. 1-16 alkoxycarbonyl, amino, (C 1-16 alkyl)2amino, C 1-16 Alkyl, Halogenated C 1-16 Alkyl, C 1-16 Alkoxy, halogenated C 1-16 Alkoxy; R 4 Selected from: hydrogen, C 1-16 alkyl; Step 1: Protect the phenolic hydroxyl group of sesamol A with MOM protecting group to obtain intermediate B; Step 2: Intermediate B undergoes a methylation reaction to obtain intermediate C; Step 3: Intermediate C undergoes a formylation reaction to obtain intermediate D; Step 4: Remove the MOM protecting group from intermediate D to obtain intermediate E; Step 5: Remove the methylene protecting group from intermediate E to obtain intermediate F; Step 6: Intermediate F and G undergo a cascaded Knoevenagel-electrocyclization reaction to obtain intermediate H; Step 7: Protect the phenolic hydroxyl group of intermediate H with a MOM protecting group to obtain intermediate I; Step 8: Intermediate I and J undergo a cascade of nucleophilic substitution-condensation reaction to obtain intermediate K; Step 9: Remove the MOM protecting group from intermediate K to obtain intermediate L; Step 10: Intermediate L undergoes a nucleophilic substitution reaction with trifluoromethanesulfonic anhydride to obtain intermediate M; Step 11: Intermediate M is used to prepare the target compound represented by general formula (Ⅰ) via a metal-catalyzed coupling reaction.

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