Small molecule inhibitors for anti-nasopharyngeal carcinoma, methods for preparing the compounds, and their use.

Abstract

The small molecule inhibitor targeting EB virus antigen protein and / or pharmaceutical composition comprising the small molecule inhibitor can be used for treating diseases caused by EB virus infection, particularly nasopharyngeal cancer, including, but not limited to, cancer, infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. Further provided is an anti-nasopharyngeal cancer small molecule inhibitor and / or pharmaceutical composition comprising the small molecule inhibitor, which can be used for treating nasopharyngeal cancer.

Description

[Technical Field]

[0001] The present invention provides small molecule inhibitors for anti-nasopharyngeal cancer, methods for preparing compounds, and their use in the treatment and / or prevention of tumor diseases such as nasopharyngeal cancer. [Background technology]

[0002] Nasopharyngeal cancer is a common tumor in southern China, originating from poorly differentiated or undifferentiated epithelial cells of the nasopharynx mucosa, and is a highly malignant tumor. Nasopharyngeal cancer shows a clear ethnic tendency, with the majority of patients being Chinese or of Chinese descent. The incidence rate in China is highest in Guangdong Province, followed by Guangxi Zhuang Autonomous Region, Hunan Province, Fujian Province, and Jiangxi Province. Nasopharyngeal cancer can occur at any age, but the incidence rate has been observed to peak between the ages of 30 and 50.

[0003] Studies have confirmed a strong correlation between the development of nasopharyngeal cancer and Epstein-Barr virus (EBV) infection. EBV (Epstein-Barr virus, EBV) is a human herpesvirus (HHV-4) belonging to the subfamily Gamma-herpesviruses. EBV is a B-lymphotropic virus that infects a wide range of humans. Primary EBV infection occurs in oropharyngeal squamous epithelial cells, and then remains in a long-term latent infection state in B lymphocytes. Once EBV becomes activated from its latent state, it becomes the etiology associated with many diseases, including tumors. Studies have shown that, in addition to causing Burkitt lymphoma, EBV is associated with Hodgkin's disease, non-Hodgkin lymphoma, nasopharyngeal cancer, NK / T-cell lymphoma, leiomyosarcoma, and malignant epithelial tumors in areas such as the stomach, mammary gland, and lung. Therefore, EBV is classified as a Group I human oncogenic virus by the IARC (1997).

[0004] In all of the tumor cells mentioned above, EBNA1 (viral nuclear antigen 1) was detected when EBV infection was detected. Research has revealed that EBNA1 is a protein expressed by the EBV virus and is involved in important pathological processes such as viral DNA replication, maintenance of viral latent state and tumor induction through mutation, and induction of immune evasion by causing tumor cell migration.

[0005] In recent years, research targeting EBNA1 to develop targeted chemotherapy drugs for specific tumors has made considerable progress, laying the foundation for EBNA1 protein target evaluation, structure-based drug design, and small molecule activity evaluation. For example, two international patents filed by Messick TE et al. in 2015 and 2016, WO2016183534A1 and WO2015073864A1, disclose the structure of a compound having two alkyne-conjugated aromatic rings that inhibits the binding of EBNA1 to DNA, thereby inhibiting the replication of EBV-infected cells and exerting an antitumor effect. In 2019, this team reported detailed research showing that their VK series molecules effectively suppress EBNA1 activity and showed relatively good effects at both the cellular level and in a mouse nasopharyngeal cancer model, and that these molecules are currently in Phase I clinical trials [Sci.Transl.Med.2019,11,eaau5612.]. This result demonstrates that the EBNA1 protein can be used as a novel drug target in the development of drugs to treat diseases associated with EBV infection, including tumors.

[0006] The present invention aims to develop small molecule drugs for anti-nasopharyngeal carcinoma using a structure-based drug design method. The pharmaceutical small molecule compounds according to the present invention have low activity in selectively inhibiting the proliferation of EBV-positive tumor cell lines at the cellular level, and at the same time possess excellent drug ADMET (Absorption, distribution, metabolism, excretion, toxicity) It exhibits functionality and possesses superior pharmacological properties. Its growth inhibitory activity against other EBV-positive or negative tumors also indicates the broad potential applications of the small molecule according to the present invention. [Overview of the project] [Problems that the invention aims to solve]

[0007] The present invention provides a compound of general formula (I), or its enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and / or isotope-substituted derivative, which serves as an anti-nasopharyngeal carcinoma inhibitor. [ka]

[0008] The present invention further provides a pharmaceutical composition comprising at least one compound according to the present invention, or its enantiomer, diastereomer, tautomer, salt, crystalline form, solvate and / or isotope-substituted derivative. The present invention further provides a pharmaceutical composition comprising at least one compound according to the present invention, or its enantiomer, diastereomer, tautomer, salt, crystalline form, solvate and / or isotope-substituted derivative, and at least one pharmaceutically acceptable carrier, excipient, or diluent. The present invention further provides a method for treating and / or preventing diseases or disorders caused by EBNA1 activity. The present invention further provides use in the preparation of agents for treating and / or preventing diseases or disorders caused by EBNA1 activity. The present invention further provides a method for treating and / or preventing nasopharyngeal cancer. The present invention further provides use in the preparation of agents for treating and / or preventing nasopharyngeal cancer. The present invention further provides a method for treating and / or preventing EBV infection in the lysis and / or latency phase. The present invention further provides use as an agent for treating and / or preventing diseases caused by EBV infection in the lysis and / or latency phase. The present invention further provides use in the preparation of agents for treating and / or preventing other non-EBV infection-related diseases. The present invention further provides a method for preparing compounds of general formula (I) according to the present invention. [Means for solving the problem]

[0009] The present invention relates to a compound of general formula (I) or its enantiomers, diastereomers, tautomers, salts, crystalline forms, solvates and / or isotope-substituted derivatives.

Chemical Formula

[0010] The present invention further relates to pharmaceutical compositions comprising the compound of general formula (I) described above, or its enantiomer, diastereomer, tautomer, salt, crystalline form, solvate and / or isotope-substituted derivative.

[0011] The present invention further relates to pharmaceutical compositions comprising the compound of general formula (I) above, or its enantiomer, diastereomer, tautomer, salt, crystalline form, solvate and / or isotope-substituted derivative, and pharmaceutically acceptable carriers, excipients, or diluents.

[0012] The present invention further relates to a method for treating and / or preventing diseases or disorders caused by EBNA1 activity, the method comprising administering an effective amount of the compound of general formula (I) above, or its enantiomer, diastereomer, tautomer, salt, crystalline form, solvate and / or isotope-substituted derivative, or a pharmaceutical composition thereof, to a subject.

[0013] The present invention further relates to the use of compounds of general formula (I) above, or their enantiomers, diastereomers, tautomers, salts, crystalline forms, solvates and / or isotope-substituted derivatives, or as pharmaceutical compositions thereof, in the preparation of agents for treating and / or preventing diseases caused by EBNA1 activity.

[0014] The present invention further relates to a method for treating and / or preventing nasopharyngeal cancer, the method comprising administering to a subject an effective amount of a compound of general formula (I) above, or its enantiomer, diastereomer, tautomer, salt, crystalline form, solvate and / or isotope-substituted derivative, or a pharmaceutical composition thereof.

[0015] The present invention further relates to the use of compounds of general formula (I) above, or their enantiomers, diastereomers, tautomers, salts, crystalline forms, solvates and / or isotope-substituted derivatives, or as pharmaceutical compositions thereof, in the preparation of agents for treating and / or preventing nasopharyngeal cancer. [Effects of the Invention]

[0016] The present invention relates to a compound of the above general formula (I), or its enantiomer, diastereomer, tautomer, salt, crystalline form, solvate and / or isotope-substituted derivative, or a pharmaceutical thereof. composition It may be used for the treatment and / or prevention of diseases or disorders caused by EBNA1 activity. The diseases or disorders mentioned above are selected from at least one of the following: cancer, infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, etc. Cancers include, in particular, nasopharyngeal carcinoma, non-Hodgkin lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, B-cell lymphoma, Burkitt lymphoma, cutaneous reticular disease, reticular disease, diffuse large B-cell lymphoma, extranodal NK / T-cell lymphoma / intravascular lymphoma, follicular lymphoma, immunoblastic lymphoma, mucosa-associated lymphoid tissue lymphoma, B-cell chronic lymphocytic leukemia, mantle cell lymphoma, mediastinal large B-cell lymphoma, lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma of the lymph nodes, marginal zone lymphoma of the spleen, intravascular large B-cell lymphoma, primary exudative lymphoma, lymphomatoid granulomatosis, angioimmunoblastic lymphadenopathy, X-linked lymphoproliferative syndrome, post-transplant lymphoproliferative disorder, or Hodgkin lymphoma. [Modes for carrying out the invention]

[0017] In the detailed description of the present invention, many specific details are provided for illustrative purposes so that those skilled in the art can understand the embodiments described. However, those skilled in the art will understand that these specific details of embodiments do not limit the scope of protection of the present invention. Furthermore, those skilled in the art will readily understand that the specific order of the relevant descriptions and methods of implementation of the present invention is merely illustrative, and that changes in the relevant order are permitted, but that such changes will remain within the spirit and scope of the embodiments disclosed by the present invention.

[0018] All technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art unless otherwise defined. Even if a reference is made to a definition different from those provided herein, the definitions provided herein shall prevail.

[0019] The following terms are used throughout this specification and the claims in the sense that they are clearly associated herein, unless otherwise clearly indicated by the context.

[0020] The phrase "in one embodiment" as used herein does not necessarily refer to the same embodiment, but may refer to the same embodiment. Similarly, the phrase "in another embodiment" as used herein does not necessarily refer to a different embodiment, but may refer to a different embodiment. Therefore, multiple embodiments of the present invention can be easily combined without departing from the scope or spirit of the invention.

[0021] As used herein, the term “EBNA1 inhibitor” means EBNA1 activity This refers to compounds that inhibit this process.

[0022] As used herein, the term "EBV" refers to the Epstein-Barr virus.

[0023] As used herein, “effective dose,” “therapeutic dose,” or “pharmaceutical dose” of a compound means an amount of the compound sufficient to provide a beneficial effect to the subject to which the compound is administered.

[0024] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspension, diluent, excipient, thickener, solvent, or encapsulating material, which transports or delivers the compounds usable in the present invention within a subject's body, or transports or delivers the compounds usable in the present invention to a subject, thereby enabling the compounds usable in the present invention to exhibit a desired function.

[0025] As used herein, the term “alkyl” refers to a linear, branched, or cycloalkyl group having a specified number of carbon atoms (i.e., C1-8 means 1 to 8 carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Alkyl groups may be optionally substituted. Non-limiting examples of substituted alkyl groups include hydroxylmethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, and 3-carboxypropyl.

[0026] As used herein, the term "alkoxy" refers to the -O-alkyl group, where the alkyl group is as defined above. The alkoxy group may be optionally substituted. The term C3-C8 cycloalkoxy refers to a ring containing 3 to 8 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran). The C3-C8 cycloalkoxy group may be optionally substituted.

[0027] As used herein, the term “haloalkyl” refers to a group comprising a linear and branched saturated aliphatic hydrocarbon group having a specified number of carbon atoms and substituted with one or more halogens. Haloalkyls include fully haloalkyls in which all hydrogens of the alkyl group are substituted with halogens (e.g., -CF3, CF2CF3). Haloalkyls may be optionally substituted with one or more substituents other than halogens. Examples of haloalkyls include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.

[0028] As used herein, the term "halogen" refers to chlorine, bromine, fluorine, and iodine.

[0029] As used herein, the term “heteroaryl” means a ring group in which at least one ring member is a heteroatom selected from N, O, and S, preferably with a number of heteroatoms of 1, 2, 3, or 4. Examples include 5-10 membered oxygen-containing heteroaryls, 5-10 membered sulfur-containing heteroaryls, and 5-10 membered nitrogen-containing heteroaryls. Specific examples include, but are not limited to, thiophene, furan, pyrrolyl, pyrazolyl, imidazolyl, isothiazole, pyrazine, oxazolyl, triazolyl, thiazole, pyridine, pyrimidine, indole, quinoline, quinazoline, indazolyl, benzofuran, benzothiophene, benzoxazolyl, benzotriazolyl, and benzothiazole.

[0030] As used herein, the term “optionally substituted” means the substitution or non-substitution of any substituteable substituent.

[0031] Throughout this specification, substituents of compounds are disclosed in groups or ranges. Specifically, this specification includes individual subcombinations of members of such groups and ranges. For example, the term “C1-C8 alkyl” is intended to specifically disclose C1, C2, C3, C4, C5, C6, C7, C8, C1-C8, C1-C7, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C8, C2-C7, C2-C6, C2-C5, C2-C4, C2-C3, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C8, C4-C7, C4-C6, C4-C5, C5-C8, C5-C7, and C5-C6 alkyls individually. The term "C1-C6 alkyl" is intended to specifically disclose C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl groups individually. The term "C1-C4 alkyl" is intended to specifically disclose C1, C2, C3, C4, C1-C4, C1-C3, C1-C2, C2-C4, C2-C3, and C3-C4 alkyl groups individually.

[0032] Throughout this specification, the term "aryl" refers to phenyl, naphthyl, and anthracene, and the term "heteroaryl" refers to thiophene, furan, pyrrolyl, pyrazolyl, imidazolyl, isothiazole, pyrazine, oxazolyl, triazolyl, thiazole, pyridine, pyrimidine, indole, quinoline, quinazoline, indazolyl, benzofuran, benzothiophene, benzoxazolyl, benzotriazolyl, and benzothiazole.

[0033] The present invention relates to a compound of general formula (I), or its enantiomer, diastereomer, tautomer, salt, crystalline form, solvate, and / or isotope-substituted derivative. [ka] During the ceremony, R 1These are -H, -COOH, -C(=O)-OR 1a -C(=O)-NHR 1b -C(=O)-NR 1b R 1c Selected from, however, R 1a , R 1b , R 1c These are either the same or different and independently selected from hydrogen, optionally substituted C1-C4 linear alkyl, optionally substituted C3-C4 branched alkyl, optionally substituted C3-C4 cycloalkyl, optionally substituted halogenated C1-C4 linear alkyl, optionally substituted halogenated C3-C4 branched alkyl, and optionally substituted halogenated C3-C4 cycloalkyl. Or, R 1b These are selected from hydroxyl and C1-C4 alkoxy compounds. Or, R 1b and R 1c These, together with the atoms to which they are bonded, form a cyclic group, and the cyclic group is selected from optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted morpholinyl. Preferably, R 1 These are -H, -COOH, -C(=O)-OR 1a -C(=O)-NHR 1b -C(=O)-NR 1b R 1c Selected from, R 1a , R 1b , R 1c These are either the same or different and independently selected from hydrogen, optionally substituted C1-C4 linear alkyl, optionally substituted C3-C4 branched alkyl, optionally substituted halogenated C1-C4 linear alkyl, and optionally substituted halogenated C3-C4 branched alkyl. Or, R 1b These are selected from hydroxyl and C1-C4 alkoxy compounds. Or, R 1b and R 1ctogether with the atoms to which they are attached form a cyclic group, wherein the cyclic group is selected from optionally substituted pyrrolidinyl and optionally substituted piperidinyl, More preferably, R 1 is selected from -H, -COOH, -C(=O)-O-R 1a , -C(=O)-NHR 1b , -C(=O)-NR 1b R 1c , R 1a , R 1b , R 1c are the same or different, and are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl and butyl, or, R 1b is selected from hydroxyl, methoxy, ethoxy and propoxy, or, R 1b and R 1c together with the atoms to which they are attached form a cyclic group, wherein the cyclic group is selected from pyrrolidinyl, More preferably, R 1 is selected from -H, -COOH, -COOCH3, -COOCH2CH3, -CONHOH, -CONHCH3, -CON(CH3)2, -CON(c-C4H8), -CONHOCH3, R 2 is selected from the groups consisting of hydrogen, halogen, optionally substituted C1-C4 alkyl, optionally substituted pyrrolyl, optionally substituted indolyl, and optionally substituted phenyl, Preferably, R 2 is selected from hydrogen, chlorine, methyl, pyrrolyl, indolyl, phenyl, chlorophenyl, hydroxyphenyl, and hydroxylalkoxyphenyl, L 1 is

Chemical formula

Chemical formula

[0034] In other preferred embodiments, the present invention relates to the compound of general formula (I) above, or its enantiomer, diastereomer, tautomer, salt, crystalline form, solvate and / or isotopically substituted derivative, however, L 2 ga-(CH2) q -O-(CH2) p -When selected from, Preferably, L 2 The following are selected from ·-CH2-O-*, ·-O-CH2-*, -O-, and -CH2-O-CH2-. R 3 It is selected from aryl and heteroaryl compounds. Aryl is selected from phenyl. Heteroaryls are selected from thiophene, pyrazolyl, isothiazole, pyridine, pyrimidine, pyrazine, and quinoline. Aryl and heteroaryl groups are optionally substituted once or more similarly or differently with hydrogen, C1-C4 alkyl, or C1-C4 alkoxy. Preferably, the aryl, heteroaryl is optionally substituted with hydrogen, methyl, or methoxy once or more in the same or different manner. Preferably, R 3 These are selected from phenyl, thiophene, pyrazolyl, isothiazole, pyridine, pyrimidine, pyrazine, quinoline, methylpyridine, methoxypyridine, and methylpyrazolyl. More preferably, L 2 It is selected from ·-CH2-O-*, R 3 is selected from phenyl, thiophene, pyrazolyl, isothiazole, pyridine, pyrimidine, pyrazine, quinoline, methylpyridine, methoxypyridine, and methylpyrazolyl, and more preferably R 3 is selected from phenyl, pyridine, methylpyridine, and methoxypyridine, and more preferably R 3 It is selected from pyridine, methylpyridine, and methoxypyridine. More preferably, L 2 It is selected from ·-O-CH2-*, R 3is selected from phenyl, thiophene, pyrazolyl, isothiazole, pyridine, pyrimidine, pyrazine, quinoline, methylpyridine, methoxypyridine, and methylpyrazolyl, and more preferably R 3 is selected from phenyl, pyridine, methylpyridine, and methoxypyridine, and more preferably R 3 is selected from pyridine, methylpyridine, and methoxypyridine, and more preferably R 3 It was selected from pyridine. More preferably, L 2 is selected from -O-, R 3 is selected from phenyl, thiophene, pyrazolyl, isothiazole, pyridine, pyrimidine, pyrazine, quinoline, methylpyridine, methoxypyridine, and methylpyrazolyl, and more preferably R 3 is selected from phenyl, pyridine, methylpyridine, and methoxypyridine, and more preferably R 3 is selected from pyridine, methylpyridine, and methoxypyridine, and more preferably R 3 It was selected from pyridine. More preferably, L 2 It is selected from -CH2-O-CH2-, R 3 is selected from phenyl, thiophene, pyrazolyl, isothiazole, pyridine, pyrimidine, pyrazine, quinoline, methylpyridine, methoxypyridine, and methylpyrazolyl, and more preferably R 3 is selected from phenyl, pyridine, methylpyridine, and methoxypyridine, and more preferably R 3 is selected from pyridine, methylpyridine, and methoxypyridine, and more preferably R 3 It was selected from pyridine. Or, L 2 ga-(CH2) q -NH-(CH2) p -,·-NH-C(=O)-(CH2) p -*,·-(CH2) q When selected from -C(=O)-NH-* and -CH=CH-, Preferably, L 2The following are selected from ·-CH2-NH-*, ·-CH2-NH-CH2-*, ·-NH-CH2-*, ·-NH-C(=O)-*, ·-NH-C(=O)-CH2-*, ·-C(=O)-NH-*, ·-CH2-C(=O)-NH-*, and -CH=CH-, R 3 It is selected from aryl and heteroaryl compounds. Aryl is selected from phenyl. Heteroaryls are selected from pyridines. More preferably, L 2 It is selected from ·-CH2-NH-*, ·-CH2-NH-CH2-*, and ·-NH-CH2-*, R 3 is selected from phenyl, thiophene, pyrazolyl, isothiazole, pyridine, pyrimidine, pyrazine, quinoline, methylpyridine, methoxypyridine, and methylpyrazolyl, and more preferably R 3 It is selected from phenyl, pyridine, methylpyridine, and methoxypyridine. More preferably, L 2 It is selected from ·-CH2-NH-*, R 3 is selected from pyridine, methylpyridine, and methoxypyridine, and more preferably L 2 It is selected from ·-CH2-NH-*, R 3 It was selected from pyridine. More preferably, L 2 It is selected from ·-NH-C(=O)-* and ·-NH-C(=O)-CH2-*, R 3 is selected from phenyl, thiophene, pyrazolyl, isothiazole, pyridine, pyrimidine, pyrazine, quinoline, methylpyridine, methoxypyridine, and methylpyrazolyl, and more preferably R 3 is selected from phenyl, pyridine, methylpyridine, and methoxypyridine, and more preferably R 3 is selected from pyridine, methylpyridine, and methoxypyridine, and more preferably R 3 It was selected from pyridine. More preferably, L 2 It is selected from ·-C(=O)-NH-* and ·-CH2-C(=O)-NH-*, R 3is selected from phenyl, thiophene, pyrazolyl, isothiazole, pyridine, pyrimidine, pyrazine, quinoline, methylpyridine, methoxypyridine, and methylpyrazolyl, and more preferably R 3 is selected from phenyl, pyridine, methylpyridine, and methoxypyridine, and more preferably L 2 It is selected from ·-CH2-C(=O)-NH-*, R 3 is selected from phenyl, pyridine, methylpyridine, and methoxypyridine, and more preferably L 2 It is selected from ·-CH2-C(=O)-NH-*, R 3 It is selected from phenyl and pyridine. More preferably, L 2 It is selected from -CH=CH-, and R 3 is selected from phenyl, thiophene, pyrazolyl, isothiazole, pyridine, pyrimidine, pyrazine, quinoline, methylpyridine, methoxypyridine, and methylpyrazolyl, and more preferably R 3 is selected from phenyl, pyridine, methylpyridine, and methoxypyridine, and more preferably R 3 is selected from pyridine, methylpyridine, and methoxypyridine, and more preferably R 3 It was selected from pyridine. Or, L 2 When selected from -NH-C(=O)-NH- and ·-N(CH3)-C(=O)-NH-*, R 3 It is selected from aryl and heteroaryl compounds. Aryl is selected from phenyl. Heteroaryls are selected from pyridines. Aryl and heteroaryl groups are substituted once or more similarly or differently with hydrogen, fluorine, cyano, C1-C4 alkyl, or C1-C4 alkyl halides. Preferably, the aryl, heteroaryl is substituted once or more similarly or differently with hydrogen, fluorine, cyano, methyl, methoxy, or trifluoromethyl, preferably R 3It is selected from cyanophenyl, trifluoromethylphenyl, pyridine, fluoropyridine, methylpyridine, methoxypyridine, trifluoromethylpyridine, and trifluoromethoxypyridine. More preferably, L 2 It is selected from -NH-C(=O)-NH-, R 3 is selected from cyanophenyl, trifluoromethylphenyl, pyridine, fluoropyridine, methylpyridine, methoxypyridine, trifluoromethylpyridine, and trifluoromethoxypyridine, and more preferably R 3 It is selected from trifluoromethylphenyl, pyridine, fluoropyridine, and methylpyridine. More preferably, L 2 It is selected from ·-N(CH3)-C(=O)-NH-*, R 3 is selected from cyanophenyl, trifluoromethylphenyl, pyridine, fluoropyridine, methylpyridine, methoxypyridine, trifluoromethylpyridine, and trifluoromethoxypyridine, and more preferably R 3 is selected from cyanophenyl, trifluoromethylphenyl, pyridine, fluoropyridine, and methylpyridine, and more preferably R 3 It is selected from cyanophenyls. Or, L 2 ga-(CH2) n -When selected from, Preferably, L 2 It is selected from -CH2- and -CH2-CH2-. R 3 It is selected from aryl and heteroaryl compounds. Aryl is selected from phenyl. The heteroaryl is selected from pyridine and imidazolyl. More preferably, L 2 It is selected from -CH2-, R 3 is selected from phenyl, pyridine, and imidazolyl, and more preferably R 3 It was selected from imidazolyl, More preferably, L 2 It is selected from -CH2-CH2-, R3 is selected from phenyl, pyridine, and imidazolyl, and more preferably R 3 It is selected from pyridine.

[0035] In other preferred embodiments, the present invention relates to the compound of general formula (I) above, or its enantiomer, diastereomer, tautomer, salt, crystalline form, solvate and / or isotopically substituted derivative, however, L 1 When selected from oxy-azetidine, R 2 This is selected from hydrogen, halogens, optionally substituted C1-C4 alkyls, optionally substituted pyrrolyls, optionally substituted indoles, and optionally substituted phenyls. Preferably, R 2 It is selected from hydrogen, chlorine, methyl, pyrrolyl, indole, phenyl, and chlorophenyl. L 2 is, -(CH2) q -O-(CH2) p -,-(CH2) q -NH-(CH2) p -, -NH-C(=O)-NH-, ·-N(CH3)-C(=O)-NH-*, -CH=CH-, -(CH2) n -,·-NH-C(=O)-(CH2) p -*,·-(CH2) q Selected from -C(=O)-NH-*, R 3 These are selected from phenyl, thiophene, pyrazolyl, imidazolyl, isothiazole, pyridine, pyrimidine, pyrazine, quinoline, cyanophenyl, trifluoromethylphenyl, fluoropyridine, methylpyridine, methoxypyridine, and methylpyrazolyl. Comfortable, R 1 These are -H, -COOH, -C(=O)-OR 1a -C(=O)-NHR 1b -C(=O)-NR 1b R 1c Selected from, R 1a , R 1b , R 1cThese are either the same or different and independently selected from hydrogen, optionally substituted C1-C4 linear alkyl, optionally substituted C3-C4 branched alkyl, optionally substituted halogenated C1-C4 linear alkyl, and optionally substituted halogenated C3-C4 branched alkyl. Or, R 1b These are selected from hydroxyl and C1-C4 alkoxy compounds. Or, R 1b and R 1c These, together with the atoms to which they are bonded, form a cyclic group, and the cyclic group is selected from optionally substituted pyrrolidinyl and optionally substituted piperidinyl. Comfortable, R 1 These are -H, -COOH, -C(=O)-OR 1a -C(=O)-NHR 1b -C(=O)-NR 1b R 1c Selected from, R 1a , R 1b , R 1c These are either the same or different, and independently of each other, selected from hydrogen, methyl, ethyl, propyl, isopropyl, and butyl. Or, R 1b These are selected from hydroxyl, methoxy, ethoxy, and propoxy. Or, R 1b and R 1c These, together with the atoms to which they are bonded, form a cyclic group, and the cyclic group is selected from pyrrolidinyl. More preferably, R 1 It is selected from -H, -COOH, -COOCH3, -COOCH2CH3, -CONHOH, -CONHCH3, -CON(CH3)2, -CON(c-C4H8), -CONHOCH3, Comfortable, R 3 When is selected from phenyl, cyanophenyl, and trifluoromethylphenyl, L 2 is -NH-C(=O)-NH-, ·-N(CH3)-C(=O)-NH-*, ·-(CH2) q -C(=O)-NH-* is selected, R 2It is selected from pyrrolyl and chlorophenyl, R 1 It is selected from -H, -COOH, -COOCH3, and -CONHOH. Comfortable, R 3 When is selected from pyridine, fluoropyridine, methylpyridine, and methoxypyridine, L 2 is, -(CH2) q -O-(CH2) p -,-(CH2) q -NH-(CH2) p -, -NH-C(=O)-NH-, ·-N(CH3)-C(=O)-NH-*, -CH=CH-, -(CH2) n -,·-NH-C(=O)-(CH2) p -*,·-(CH2) q -C(=O)-NH-* is selected, R 2 R is selected from hydrogen, chlorine, methyl, pyrrolyl, indole, phenyl, and chlorophenyl. 1 It is selected from -H, -COOH, -COOCH3, -COOCH2CH3, -CONHOH, -CONHCH3, -CON(CH3)2, -CON(c-C4H8), -CONHOCH3, More preferably, L 2 When is selected from ·-CH2-O-*, ·-O-CH2-*, -O-, and -CH2-O-CH2-, R 3 R is selected from pyridine, methylpyridine, and methoxypyridine. 2 R is selected from pyrrolyl, phenyl, and chlorophenyl. 1 It is selected from -H, -COOH, -COOCH3, -COOCH2CH3, -CONHOH, -CONHCH3, -CON(CH3)2, and -CON(c-C4H8). More preferably, L 2 When selected from ·-CH2-NH-*, ·-CH2-NH-CH2-*, and ·-NH-CH2-*, R 3 R is selected from pyridine, methylpyridine, and methoxypyridine. 2 R is selected from pyrrolyl, phenyl, and chlorophenyl. 1is selected from -H, -COOH, -COOCH3, and -CONHOH, and more preferably R 3 It was selected from pyridine. More preferably, L 2 When R is selected from -NH-C(=O)-NH- and ·-N(CH3)-C(=O)-NH-*, 3 R is selected from pyridine, fluoropyridine, and methylpyridine. 2 R is selected from hydrogen, pyrrolyl, phenyl, and chlorophenyl. 1 It is selected from -H, -COOH, -COOCH3, -CONHOH, -CONHCH3, More preferably, L 2 When selected from -CH=CH-, R 3 R is selected from pyridine, methylpyridine, and methoxypyridine. 2 It is selected from pyrrolyl and phenyl, R 1 is selected from -H, -COOH, -COOCH3, and -CONHOH, and more preferably R 3 It was selected from pyridine. More preferably, L 2 When selected from -CH2- and -CH2-CH2-, R 3 R is selected from pyridine, methylpyridine, and methoxypyridine. 2 It is selected from pyrrolyl, R 1 is selected from -H, -COOH, and -COOCH3, and more preferably R 3 It was selected from pyridine. More preferably, L 2 When selected from ·-NH-C(=O)-* and ·-NH-C(=O)-CH2-*, R 3 R is selected from pyridine, methylpyridine, and methoxypyridine. 2 R is selected from hydrogen, chlorine, methyl, pyrrolyl, phenyl, and chlorophenyl. 1 is selected from -H, -COOH, -COOCH3, -CONHOH, -CONHCH3, -CONHOCH3, and more preferably R 3 It was selected from pyridine. More preferably, L2 When selected from ·-C(=O)-NH-* and ·-CH2-C(=O)-NH-*, R 3 R is selected from pyridine, methylpyridine, and methoxypyridine. 2 R is selected from hydrogen, indole, and phenyl. 1 is selected from -H, -COOH, -COOCH3, -CONHOH, -CONHCH3, and more preferably R 3 It was selected from pyridine. Or, L 1 When is chosen from ethinyl, R 2 This is selected from optionally substituted indole and optionally substituted phenyl. L 2 is, -(CH2) q -O-(CH2) p -, -NH-C(=O)-NH-, ·-N(CH3)-C(=O)-NH-*, ·-NH-C(=O)-(CH2) p -*,·-(CH2) q Selected from -C(=O)-NH-*, Preferably, R 2 It is selected from indole, phenyl, chlorophenyl, hydroxyphenyl, and hydroxyalkoxyphenyl. R 3 It is selected from pyridine, methylpyridine, and methoxypyridine. More preferably, L 2 When is selected from ·-CH2-O-*, ·-O-CH2-*, -O-, and -CH2-O-CH2-, R 3 It is selected from pyridine, R 2 It was selected from indole, R 1 It is selected from -H, -COOH, -COOCH3, and -CONHOH. More preferably, L 2 When R is selected from -NH-C(=O)-NH- and ·-N(CH3)-C(=O)-NH-*, 3 R is selected from pyridine, fluoropyridine, and methylpyridine. 2 R is selected from indole, phenyl, hydroxyphenyl, and hydroxyalkoxyphenyl.1 is selected from -H, -COOH, -COOCH3, and -CONHOH, and more preferably R 3 It was selected from pyridine. More preferably, L 2 When selected from ·-NH-C(=O)-* and ·-NH-C(=O)-CH2-*, R 3 R is selected from pyridine, methylpyridine, and methoxypyridine. 2 R is selected from phenyl. 1 is selected from -H, -COOH, and -COOCH3, and more preferably R 3 It was selected from pyridine. More preferably, L 2 When selected from ·-C(=O)-NH-* and ·-CH2-C(=O)-NH-*, R 3 R is selected from pyridine, methylpyridine, and methoxypyridine. 2 R is selected from indole and phenyl. 1 is selected from -H, -COOH, -COOCH3, and -CONHOH, and more preferably R 3 It is selected from pyridine.

[0036] In other preferred embodiments, the present invention relates to the compound of general formula (I) above, or its enantiomer, diastereomer, tautomer, salt, crystalline form, solvate and / or isotope-substituted derivative, wherein the compound is 3-(3-(4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3-(3-(4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)ethyl benzoate, N-hydroxyl-3-(3-(4-((pyridine-3-yloxy) Methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzamide, N-methyl-3-(3-(4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzamide, N,N-dimethyl-3-(3-(4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzamide, (3-(3-(4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1 -yl)-2-(1H-pyrrole-1-yl)phenyl)(pyrroridine-1-yl)methyl ketone, 3-((4-((1-(2-(1H-pyrrole-1-yl)phenyl)azetidine-3-yl)oxy)benzyl)oxy)pyridine, 3-(3-(4-((4-methylpyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-((4-methylpyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H- Pyrrole-1-yl)benzoic acid, 3-(3-(4-((5-methylpyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-((5-methylpyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3-(3-(4-(((6-methoxypyridine-3-yl)oxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate,3-(3-(4-(((6-methoxypyridine-3-yl)oxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3-(3-(4-((6-methylpyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(((6-methylpyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3-(3-(4-(((5- Methoxypyridine-3-yl)oxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(((5-Methoxypyridine-3-yl)oxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoate, 3-(3-(4-(3-(3-cyanophenyl)-1-methylurea)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(3-(3-cyanophenyl) -1-methylurea)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoate, 3-(3-(4-((pyridine-4-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-((pyridine-4-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoate, 2-(1H-pyrrole-1-yl)-3-(3-(4-((quinoline-3-yloxy)methyl)phenoxy )Azetidine-1-yl)methyl benzoate, 2-(1H-pyrrole-1-yl)-3-(3-(4-((quinoline-3-yloxy)methyl)phenoxy)azetidine-1-yl)benzoic acid, 2-(1H-pyrrole-1-yl)-3-(3-(4-(3-(3-(trifluoromethyl)phenyl)urea)phenoxy)azetidine-1-yl)methyl benzoate, 2-(1H-pyrrole-1-yl)-3-(3-(4-(3-(3-(trifluoromethyl)phenyl)urea)phenoxy)azetidine-1-yl)benzoic acid,N-hydroxyl-2-(1H-pyrrole-1-yl)-3-(3-(4-(3-(3-(trifluoromethyl)phenyl)urea)phenoxy)azetidine-1-yl)benzamide, 3-(3-(4-((pyrimidine-2-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(( Pyrimidine-2-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoate, 3-(3-(4-((pyridine-2-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-((pyridine-2-yloxy)methyl)phenoxy)azetidine -1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3-(3-(4-((pyrazine-2-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-((pyrazine-2-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3 -(3-(4-((pyrimidine-5-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-((pyrimidine-5-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoate, N-hydroxyl-3-(3-(4-((pyrimidine-5-, IlOxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzamide, 3-(3-(3-methyl-4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(3-methyl-4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3-(3-(2-methyl-4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(2-methyl-4-((pyridine-3-yloxy)methyl) Phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 6-(3-(4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-(3-(4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylic acid, N-hydroxyl-6-(3-(4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, 3'-chloro-6-(3-(4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-[1,1'-Biphenyl]-2-carboxylate methyl, 3-(3-(3-chloro-4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoate methyl, 3-(3-(3-chloro-4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoate methyl, 3-(3-(3-fluoro-4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoate methyl, 3-( 3-(3-fluoro-4-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3-(3-(3-((pyridine-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 6-((3-hydroxyl-4-(3-(pyridine-3-yl)urea)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylate methyl, 3-(3-(4-((pyridine-3-ylamino)methyl)phenoxy)azetidine-1-yl Methyl benzoate (1H-pyrrole-1-yl), 3-(3-(4-((pyridine-3-ylamino)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, N-hydroxyl-3-(3-(4-((pyridine-3-ylamino)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzamide, 3-(3-(4-(pyridine-3-ylmethoxy)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(pyridine -3-ylmethoxy)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, N-hydroxyl-3-(3-(4-(pyridine-3-ylmethoxy)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzamide, 3-(3-(4-(pyridine-3-yloxy)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(pyridine-3-yloxy)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid,3-(3-(4-(pyridine-4-yloxy)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(pyridine-4-yloxy)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3-(3-(4-((pyridine-3-ylmethoxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-((pyridine-3-ylmethoxy)methyl)phenoxy)azetidine-1 (E)-2-(1H-pyrrole-1-yl)benzoic acid, N-hydroxyl-3-(3-(4-((pyridine-3-ylmethoxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzamide, (E)-3-(3-(4-(2-(pyridine-3-yl)vinyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, (E)-3-(3-(4-(2-(pyridine-3-yl)vinyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1- (E)-N-hydroxyl-3-(3-(4-(2-(pyridine-3-yl)vinyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzamide, 3-(3-(4-(2-(pyridine-3-yl)ethyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(2-(pyridine-3-yl)ethyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoate, 2-(1H-pyrrole-1-yl )-3-(3-(4-((thiophen-2-yloxy)methyl)phenoxy)azetidine-1-yl)methyl benzoate, 2-(1H-pyrrole-1-yl)-3-(3-(4-((thiophen-2-yloxy)methyl)phenoxy)azetidine-1-yl)benzoic acid, 3-(3-(4-(nicotinamide)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(nicotinamide)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid,N-(4-((1-(3-(hydroxycarbamoyl)-2-(1H-pyrrole-1-yl)phenyl)azetidine-3-yl)oxy)phenyl)nicotinamide, 3-(3-(4-(((1-methyl-1H-pyrazole-3-yl)oxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(((1-methyl-1H-pyrazole-3-yl)oxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3 -(3-(4-((isothiazole-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-((isothiazole-3-yloxy)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(3-(pyridine-3-yl)urea)phenoxy (C)Azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, N-hydroxyl-3-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzamide, 3-(3-(4-(2-oxo-2-(phenylamino)ethyl)phenoxy)azetidine-1-yl)-2-(1H- Pyrrole-1-yl)benzoic acid, (E)-6-(3-(4-(2-(pyridine-3-yl)vinyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, (E)-6-(3-(4-(2-(pyridine-3-yl)vinyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylic acid, (E)-N-hydroxyl-6-(3-(4-(2-(pyridine-3-yl)vinyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide,3'-Chloro-6-(3-(4-(3-(3-(trifluoromethyl)phenyl)urea)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, 3'-Chloro-6-(3-(4-(3-(3-(trifluoromethyl)phenyl)urea)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate, 3'-Chloro-6-(3-(4-((pyridine-3-ylamino)methyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, 3'-Chloro-6-(3- (4-((pyridine-3-ylamino)methyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylic acid, 3'-chloro-N-hydroxyl-6-(3-(4-((pyridine-3-ylamino)methyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, 6-(3-(4-((pyridine-3-ylamino)methyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-(3-(4-((pyridine-3-ylamino)methyl)phenoxy)azetidine Zin-1-yl)-[1,1'-biphenyl]-2-carboxylic acid, N-hydroxyl-6-(3-(4-((pyridine-3-ylamino)methyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, 6-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl] -2-carboxylic acid, N-hydroxyl-6-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, N-methyl-6-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, 3'-chloro-6-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl,3'-Chloro-6-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylic acid, 3'-Chloro-N-hydroxyl-6-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, 6-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-(3-(4-(3-(pyridine-3-yl (Urea)Phenoxy)Azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylic acid, N-hydroxyl-6-(3-(4-(3-(pyridine-3-yl)urea)Phenoxy)Azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, N-methyl-6-(3-(4-(3-(pyridine-3-yl)urea)Phenoxy)Azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, 3-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)Phenoxy)Azetidine-1-yl ) Methyl benzoate, 3-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl)benzoic acid, N-hydroxyl-3-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl)benzamide, 2-(4-((1-phenylazetidine-3-yl)oxy)phenyl)-N-(pyridine-3-yl)acetamide, 2-(1H-indole-6-yl)-3-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl) Phenoxy)azetidine-1-yl)methyl benzoate, 2-(1H-indole-6-yl)-3-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl)benzoic acid, 6-(3-(4-(2-(pyridine-3-yl)acetylamide)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylic acid,N-hydroxyl-6-(3-(4-(2-(pyridine-3-yl)acetylamide)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, N-methyl-6-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, N-Methoxy-6-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, N-(4-((1-([1,1'-biphenyl]-2-yl)azetidine-3-yl)oxy)phenyl)-2-(pyridine-3-yl)acetamide, 3-(3-(4-(3-(5-fluoropyridine-3-yl)urea)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(3-(5-fluoropyridine-3-yl)urea)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl )benzoic acid, 3-(3-(4-(3-(5-methylpyridine-3-yl)urea)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(3-(5-methylpyridine-3-yl)urea)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3'-chloro-6-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, 3'-chloro-6-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-Biphenyl]-2-carboxylic acid, 3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)methyl benzoate, 3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)benzoic acid, 3-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)methyl benzoate, 3-(3-(4-(3-(pyridine-3 -yl)urea)phenoxy)azetidine-1-yl)benzoic acid, 3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3-(3-(3-fluoro-4-(2-(pyridine- 3-yl)acetylamino)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(3-fluoro-4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 2-methyl-3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)methyl benzoate, 2 -Methyl-3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)benzoic acid, 6-(3-(3-fluoro-4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-(3-(3-fluoro-4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-Biphenyl]-2-carboxylic acid, 2-chloro-3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)methyl benzoate, 2-chloro-3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)benzoic acid, 3-(3-(4-((1H-imidazole-1-yl)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-((1H-imidazole-1-yl)methyl)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3'-(2-hydroxylethoxy)-6-((4-(3-(pyridine-3-yl)urea)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-((4-(3-(pyridine-3-yl)urea)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-((4-( 3-(pyridine-3-yl)urea)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylic acid, N-hydroxyl-6-((4-(3-(pyridine-3-yl)urea)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxamide, 2-(1H-indole-6-yl)-3-((4-(3-(pyridine-3-yl)urea)phenyl)ethynyl)methyl benzoate, 2-(1H-indole-6-yl)-3-((4-(3-(pyridine-3-yl) (L)urea)phenyl)ethynyl)benzoic acid, 6-((4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-((4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylic acid, N-hydroxyl-6-((4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenyl)ethynyl)-[1,1'-Biphenyl]-2-Carboxamide, 2-(1H-Indole-6-yl)-3-((4-(2-Oxo-2-(Pyridine-3-ylamino)ethyl)phenyl)ethynyl)methyl benzoate, 2-(1H-Indole-6-yl)-3-((4-(2-Oxo-2-(Pyridine-3-ylamino)ethyl)phenyl)ethynyl)benzoic acid, 6-((4-(2-(Pyridine-3-yl) Selected from methyl acetamide group)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylate, 6-((4-(2-(pyridine-3-yl)acetamide group)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylic acid, and 3'-hydroxyl-6-((4-(3-(pyridine-3-yl)urea)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylate.

[0037] In another embodiment, the present invention further relates to pharmaceutical compositions comprising one or more compounds of the above general formula (I) according to the present invention, or enantiomers, diastereomers, tautomers, salts, crystalline forms, solvates and / or isotope-substituted derivatives thereof.

[0038] In another embodiment, the present invention further relates to pharmaceutical compositions comprising one or more compounds of the above general formula (I) according to the present invention, or enantiomers, diastereomers, tautomers, salts, crystalline forms, solvates and / or isotopically substituted derivatives thereof, and pharmaceutically acceptable carriers, excipients, or diluents.

[0039] In another embodiment, the present invention further relates to a method for treating and / or preventing diseases or disorders caused by EBNA1 activity, the method comprising administering an effective amount of the compound of general formula (I) or its enantiomer, diastereomer, tautomer, salt, crystalline form, solvate and / or isotopic derivative to a subject. All compounds of general formula (I) according to the present invention are EBNA1 at the cellular level. activity It shows excellent inhibitory effects against, and in particular, R 3 When pyridine or phenyl is selected, it exhibits superior inhibitory activity.

[0040] In another embodiment, the present invention further relates to the use of one or more compounds of the above general formula (I) according to the present invention, or their enantiomers, diastereomers, tautomers, salts, crystalline forms, solvates and / or isotopic derivatives, in the preparation of agents for treating and / or preventing diseases caused by EBNA1 activity, the use of which includes administering an effective amount of at least one compound according to the present invention, or its enantiomers, diastereomers, tautomers, salts, crystalline forms, solvates and / or isotopic derivatives, to a subject.

[0041] In another embodiment, the present invention further relates to a method for treating and / or preventing nasopharyngeal cancer, the method comprising administering an effective amount of at least one pharmaceutical composition according to the present invention to a subject.

[0042] In another embodiment, the present invention further relates to the use of one or more of the pharmaceutical compositions according to the present invention in the preparation of agents for treating and / or preventing nasopharyngeal cancer, the use of which includes administering at least one of the pharmaceutical compositions according to the present invention to a subject in an effective amount.

[0043] In preferred embodiments, the disease or disorder is cancer, infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis.

[0044] In a more preferred embodiment, the cancers here include nasopharyngeal carcinoma, non-Hodgkin lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, B-cell lymphoma, Burkitt lymphoma, cutaneous reticular disease, reticular disease, diffuse large B-cell lymphoma, extranodal NK / T-cell lymphoma / intravascular lymphoma, follicular lymphoma, immunoblastic lymphoma, and mucosa-associated lymphoid tissue. Lymphoma, B-cell chronic lymphocytic leukemia, mantle cell lymphoma, mediastinal large B-cell lymphoma, lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma of the lymph nodes, marginal zone lymphoma of the spleen, intravascular large B-cell lymphoma, primary exudative lymphoma, lymphomatoid granulomatosis, angioimmunoblastic lymphadenopathy, X-linked lymphoproliferative syndrome, post-transplant lymphoproliferative disorder, or Hodgkin lymphoma.

[0045] The examples and preparation examples provided by this invention further elucidate and illustrate the compounds and preparation methods described in this invention. It should be understood that the scope of the following preparation examples and examples is not in any way limited to the scope of this invention.

[0046] The following synthesis procedure describes a method for preparing derivatives of the general formula (I) of the present invention. The raw materials, reagents, catalysts, solvents, etc., used in the following synthesis procedure can be prepared by methods well known to those skilled in the field of organic chemistry, or commercially available materials can be used. All of the final derivatives of the present invention can be produced by the methods described in the procedure or similar methods, all of which are well known to those skilled in the field of organic chemistry. All variable elements applicable to these procedures are defined below or by the claims.

[0047] Preparation method Unless otherwise specified, all reagents were purchased from reagent companies and used directly without purification. Most reactions were carried out under anhydrous conditions with nitrogen protection. For information on the purification of reagents and solvents, see Purification of Laboratory Chemicals (WLFArmarego, Christina Li Lin Chai, Elsevier Inc. 2009). Unless otherwise specified, all solvents were redistilled before use. Tetrahydrofuran (THF) was treated with a sodium-benzophenone system, dichloromethane and N,N'-dimethylcarboxamide (DMF) with calcium hydride, and methanol was treated with magnesium waste and then redistilled. Triethylamine, diisopropylethylamine (DIPEA), and pyridine were treated with calcium hydride and redistilled. The reaction was monitored by thin-layer chromatography (TLC). The thin-layer silica gel plates used were GF254 (60-F250, 0.2 mm) and colored with UV (wavelength 254 nm) or iodine, or immersed in a phosphomolybdic acid and ninhydrin solution and then heated to develop color. High-performance column chromatography was performed using silica gel 60 (230-400 mesh ASTM), and typically, ethyl acetate and n-hexane or dichloromethane and methanol were used as eluents. 1 ¹H NMR was measured using a DRX-300, Bruker Avance-400, or Bruker Avance-500 nuclear magnetic resonance spectrometer, chemical shifts were positioned using residual peaks of the deuterated solvent, high-resolution mass spectrometry was performed using an ABI Q-star Elite mass spectrometer or a Thermo Q Exactive Focus mass spectrometer, and liquid-phase mass spectrometry was performed using an Agilent 6125.

[0048] General experimental procedure 1 [ka]

[0049] R 2 , R3 This refers to an aromatic ring or aromatic heterocycle; for a specific definition, please refer to the specification and claims. 4 For the definition, please refer to the specification and claims. X = OR 1a ,NHR 1b ,NR 1b R 1c For a specific definition of this, please refer to the specification and claims. 1 , Y 2 , Y 3 , Y 4 For the definition, please refer to the specification and claims.

[0050] N-Boc-3-hydroxylazetidine G1 (1.0 equivalent) was prepared and dissolved in dichloromethane. The mixture was protected with nitrogen gas, and triethylamine (1.5 equivalents) was added while cooling in an ice bath. Methanesulfonyl chloride (1.5 equivalents) was slowly added dropwise, and the mixture was allowed to react for 2 hours at room temperature. The solvent was removed by rotary evaporation under reduced pressure, and the mixture was diluted with a large amount of ethyl acetate and washed once with water. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a pale yellow, oily intermediate compound G2. G2 was dissolved in N,N-dimethylcarboxamide without further purification, and G3 (1.2 equivalents) and cesium carbonate (2.2 equivalents) were added. The mixture was then heated to 100°C under nitrogen gas protection and reacted for 14 hours. The mixture was cooled to room temperature, the reaction solution was diluted with a large amount of ethyl acetate, and washed twice with saturated aqueous solution of ammonium chloride and once with saturated aqueous solution of sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by silica gel column chromatography to obtain compound G4.

[0051] Compound G4 (1 equivalent) was dissolved in a solvent, sodium borohydride (3.0 equivalents) was added under nitrogen gas protection and ice bath cooling, and then a small amount of methanol was added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution, the organic phase was removed under reduced pressure, and the mixture was extracted with a large amount of ethyl acetate. ExtractedThe organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound G5. Compound G5 was dissolved in an appropriate amount of dichloromethane and treated with an excess of trifluoroacetic acid to remove the protection of Boc and obtain the trifluoroacetate salt of compound G6.

[0052] Intermediate G6 (1.0 equivalent), methyl 3-fluoro-2-nitrobenzoate G7 (1.0 equivalent), and cesium carbonate (2.5 equivalents) were prepared and dissolved in N,N-dimethylcarboxamide. The mixture was heated to 50°C under the protection of nitrogen gas and reacted for 2 hours. After the reaction mixture cooled to room temperature, it was diluted with a large amount of ethyl acetate, washed with saturated aqueous ammonium chloride solution, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by silica gel column chromatography to obtain compound G8.

[0053] In the nitro reduction operation, 1.0 equivalent of the nitro-substituted compound G8, awaiting reduction, was dissolved in a 1:1 methanol:dichloromethane mixture. While cooling in an ice bath, 5.0 equivalents of ammonium chloride were added, followed by 3.0 equivalents of reduced zinc powder. The mixture was allowed to return to room temperature and stirred for at least 2 hours, and monitored by thin-layer chromatography until the reaction was complete. The reaction mixture was filtered to remove solid insoluble matter, the filter cake was washed with ethyl acetate, the filtrate was diluted with a large amount of ethyl acetate and washed with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted twice more with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by silica gel column chromatography to obtain compound G9.

[0054] Compound G9 (1.0 equivalent) was dissolved in anhydrous chloroform, and appropriate amounts of dry silica gel, compound 2,5-dimethoxytetrahydrofuran (5.0 equivalents), and acetic anhydride (50.0 equivalents) were added, respectively. The reaction was refluxed under nitrogen gas protection for more than 2 hours and monitored by thin-layer chromatography until the reaction was complete. After cooling to room temperature, insoluble matter was removed by filtration, the filtrate was washed with saturated sodium bicarbonate aqueous solution, the aqueous phase was extracted twice more with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by silica gel column chromatography to obtain compound G10.

[0055] Compound G10 (1.0 equivalent), arylboronic acid compound (R 3 3.0 equivalents of B(OH)2, 0.3 equivalents of anhydrous copper acetate, and an appropriate amount of 40-60 mesh 4A molecular sieves were mixed and dissolved in dichloromethane. 5.0 equivalents of triethylamine were added, the oxygen environment was replaced, and the mixture was stirred at room temperature for 12 hours. Insoluble matter was filtered off, the filtrate was washed with saturated ammonium chloride aqueous solution, the aqueous phase was extracted twice more with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by silica gel column chromatography to obtain compound G11.

[0056] In the hydrolysis operation, compound G11 (1.0 equivalent) was dissolved in an appropriate amount of tetrahydrofuran, an aqueous lithium hydroxide solution (1.0 mole per liter, 3.0 equivalents) was added, and after purging with nitrogen gas, the mixture was stirred at room temperature for more than 4 hours and monitored by thin-layer chromatography until the reaction was complete. The organic phase was removed under reduced pressure, and dilute hydrochloric acid (1.0 mole per liter) was added dropwise to the residual aqueous phase to adjust the pH to 4, causing a large amount of white solid to precipitate in the system. The solid was then filtered, washed with water, and dried to obtain carboxylic acid compound G12.

[0057] Compound G12 (1.0 equivalent) was dissolved in an appropriate amount of anhydrous dichloromethane, and triethylamine (3.0 equivalents), nucleophile XH (1.2 equivalents), and HATU (1.5 equivalents) were added while cooling in an ice bath. The mixture was stirred for at least 4 hours under the protection of nitrogen gas and allowed to return to room temperature, and the reaction was monitored by thin-layer chromatography until completion. The reaction solution was diluted with a large amount of ethyl acetate, washed with saturated ammonium chloride aqueous solution, the aqueous phase was extracted twice more with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by silica gel column chromatography to obtain compound G13.

[0058] Compound G9 (1.0 equivalent) was dissolved in 1,4-dioxane-water, and hydroiodic acid (20.0 equivalents or more) was added while cooling in an ice bath. After stirring for 10 minutes, an aqueous solution of sodium nitrite (1.1 equivalents) was slowly added and the mixture was reacted for 1 hour. Then, an aqueous solution of potassium iodide (1.5 equivalents) was added while cooling in an ice bath, and the mixture was slowly heated to room temperature and reacted for 16 hours. A saturated sodium bicarbonate solution was added to adjust the pH to 7. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography to obtain compound G14.

[0059] Compound G14 and aromatic boronic acid (R 3 B(OH)2) (1.5 equivalents) was dissolved in tetrahydrofuran-water, and catalysts Pd(dppf)Cl2 (0.1 equivalents) and K2CO3 (3.0 equivalents) were added. The mixture was heated to 90°C and reacted for 16 hours. After the reaction was complete, the organic phase was removed under reduced pressure, the residue was diluted with a large amount of ethyl acetate, washed twice with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by silica gel column chromatography to obtain compound G15.

[0060] Compound G16 was prepared from compound G15, following the experimental procedure for preparing compound G11 from compound G10.

[0061] Compound G17 was prepared from compound G16 by referring to the hydrolysis experimental procedure for preparing compound G12 from compound G11.

[0062] Following the experimental procedure for preparing compound G13 from compound G12, compound G18 was prepared from compound G17.

[0063] General experimental procedure 2 [ka]

[0064] Compound G15 (1.0 equivalent) was dissolved in anhydrous dichloromethane, anhydrous sodium bicarbonate (5.0 equivalents) was added, and the Dessmartin oxidizing agent was added separately while cooling in an ice bath. The mixture was gradually returned to room temperature and stirred for more than 2 hours, and the reaction was monitored by thin-layer chromatography until completion. The reaction solution was diluted with a large amount of ethyl acetate, washed with saturated sodium bicarbonate aqueous solution, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by silica gel column chromatography to obtain compound G19.

[0065] Compound G19 is dissolved in anhydrous methanol, and an arylamine (R 3 Add 2.0 equivalents of -NH2 and stir overnight at room temperature. Cool again in an ice bath, add 2.0 equivalents of sodium borohydride, and stir at room temperature for at least 2 hours. Monitor by thin-layer chromatography until the reaction is complete. Quench the reaction under ice bath by adding an appropriate amount of saturated ammonium chloride aqueous solution, dilute with a large amount of ethyl acetate to extract the reaction solution, dry the organic phase over anhydrous sodium sulfate, filter and concentrate, and separate by silica gel column chromatography to obtain compound G20.

[0066] Compound G19 (1.0 equivalent) was dissolved in anhydrous tetrahydrofuran, potassium tert-butoxide (1.5 equivalents) was added, the temperature was lowered to -78°C, and aryl Wittig reagent (1.2 equivalents) in THF solution was added dropwise, stirring for a further 2 hours while maintaining the -78°C temperature. The reaction bottle was then transferred to an ice bath, and the temperature was gradually returned to 0°C while stirring for 2 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution, the reaction solution was diluted with a large amount of ethyl acetate and extracted. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by silica gel column chromatography to obtain compound G21.

[0067] Compound G21 was dissolved in methanol, an appropriate amount of palladium-carbon (0.2 equivalents) was added, and the hydrogen atmosphere was thoroughly replaced. The mixture was then stirred at room temperature for at least 2 hours, monitored by thin-layer chromatography until the reaction was complete, insoluble matter was removed by filtration, the filtrate was concentrated, and further purified by column chromatography to obtain compound G22.

[0068] 3-hydroxyazetidine hydrochloride (1.0 equivalent), methyl 3-fluoro-2-nitrobenzoate G7 (1.0 equivalent), and cesium carbonate (2.0 equivalents) were prepared and dissolved in N,N-dimethylcarboxamide. Under the protection of nitrogen gas, the mixture was heated to 50°C and reacted for 2 hours. After the reaction mixture cooled to room temperature, it was diluted with a large amount of ethyl acetate and washed three times with saturated aqueous solution of ammonium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by silica gel column chromatography to obtain compound G24. Compound G24 (1.0 equivalent) was dissolved in dichloromethane, imidazole (2.0 equivalents) was added, and after cooling in an ice bath, tert-butyldimethylchlorosilane (1.2 equivalents) was added. The mixture was returned to room temperature and stirred for 14 hours. The reaction was quenched with saturated ammonium chloride aqueous solution, diluted with a large amount of ethyl acetate, and the reaction solution was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Compound G25 was prepared from the crude product by following the nitro reduction experimental procedure used to prepare compound G9 from compound G8.

[0069] Referring to the experimental procedure for preparing compound G10 from compound G9, the tert-butyldimethylsilyl ether intermediate of compound G26 was prepared from compound G25. The tert-butyldimethylsilyl ether intermediate of compound G26 (1.0 equivalent) was dissolved in dichloromethane, and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 mole, 1.5 equivalents per liter) was added. The reaction was allowed to proceed at room temperature for at least 1 hour, and monitored by thin-layer chromatography until the reaction was complete. The solvent was removed under reduced pressure, the reaction mixture was diluted with a large amount of ethyl acetate, washed with saturated aqueous ammonium chloride solution, and the aqueous phase was extracted twice more with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by silica gel column chromatography to obtain compound G26(R 2 (When it is a pyrrole ring) was obtained.

[0070] Following the experimental procedure for preparing compound G14 from compound G9, compound G27 was prepared from compound G25.

[0071] Referring to the experimental procedure for preparing compound G15 from compound G14, a tert-butyldimethylsilyl ether intermediate of compound G26 was prepared from compound G27. The tert-butyldimethylsilyl ether protecting group of this intermediate was removed with tetrabutylammonium fluoride to obtain compound G26.

[0072] Following the experimental procedure for preparing compound G24 from compound G7, compound G28 was prepared from compounds G26 and G23.

[0073] Compound G29 was prepared from compound G28 by referring to the nitro reduction experimental procedure used to prepare compound G9 from compound G8.

[0074] Under ice bath cooling, N,N'-carbonyldiimidazole (CDI) (3.0 equivalents) is mixed with arylamine (R 3Adding 3.0 equivalents of anhydrous THF (-NH2) as a solvent, the mixture was allowed to return to room temperature under the protection of nitrogen gas and stirred for at least 2 hours. After adding 1.0 equivalent of compound G29, the reaction system was refluxed for 14 hours, cooled to room temperature, and the reaction was quenched by adding saturated aqueous ammonium chloride solution. The organic phase was removed under reduced pressure, and the reaction solution was extracted by dilution with a large amount of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and then separated by silica gel column chromatography to obtain compound G30.

[0075] Arylmethylcarboxylic acid (R 3 Dissolve 2.0 equivalents of -CH2CO2H in an appropriate amount of anhydrous N,N-dimethylcarboxamide, and add 3.0 equivalents of N,N-diisopropylethylamine, 1.0 equivalent of compound G29, and 1.5 equivalents of HATU while cooling in an ice bath. Stir for at least 4 hours under the protection of nitrogen gas and allowed to return to room temperature, and monitor by thin-layer chromatography until the reaction is complete. Dilute the reaction solution with a large amount of ethyl acetate, wash with saturated ammonium chloride aqueous solution, and extract the aqueous phase twice more with ethyl acetate. Combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate, and separate by silica gel column chromatography to obtain compound G31.

[0076] Following the experimental procedure for preparing compound G31 from compound G29, compound G32 was prepared from compound G29.

[0077] General experimental procedure 3 [ka]

[0078] Refer to the experimental procedure for preparing compound G30 from compound G29, using arylamine (R 3 Compound G34 was prepared from compound G33 and compound G33 (-NH2).

[0079] Refer to the experimental procedure for preparing compound G31 from compound G29, and arylmethylcarboxylic acid (R 3Compound G35 was prepared from compound G33 and compound G33 (-CH2CO2H).

[0080] Refer to the experimental procedure for preparing compound G31 from compound G29, using arylamine (R 3 Compound G37 was prepared from compound G36 and compound G36 (-NH2).

[0081] Compounds G34 (1.0 equivalent) and G38 (1.2 equivalents) were dissolved in anhydrous THF, triethylamine (2.0 equivalents) was added, and cuprous iodide (0.025 equivalents) and Pd(PPh3)2Cl2 (0.05 equivalents) were pre-mixed and added to the reaction system. The mixture was stirred at room temperature for 14 hours under the protection of nitrogen gas. The reaction solution was diluted with a large amount of ethyl acetate, washed with saturated ammonium chloride aqueous solution, and the aqueous phase was extracted twice more with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, and separated by silica gel column chromatography to obtain compound G39.

[0082] Example 1 [ka]

[0083] Compound 1 (9 milligrams, 50% yield) was synthesized following general experimental procedure 1. 1 H NMR(300MHz,CDCl3)δ8.37(dd,J=2.7,1.0Hz,1H),8.23(dd,J=4.1,1.9Hz,1H),7.41-7.09(m,6H),6.83-6 .55(m,5H),6.25(t,J=2.1Hz,2H),5.02(s,2H),4.93-4.78(m,1H),3.91-3.73(m,2H),3.71-3.31(m,5H). Mass spectrometry (mass to charge ratio) is C 27 H 25 N3NaO4 + [M+Na] + The theoretical value is 478.1737, and the measured value is 478.1738.

[0084] Example 1a Compound 1a (3.8 mg, 80% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ8.41-8.30(m,1H),8.28-8.15(m,1H),7.42-7.19(m,6H),6.86-6.63(m, 5H),6.37-6.05(m,2H),5.02(s,2H),4.89-4.79(m,1H),3.85-3.75(m,2H),3.69-3.60(m,2H). Mass spectrometry (mass to charge ratio) is C 26 H 23 N3NaO4 + [M+Na] + The theoretical value is 464.1581, and the measured value is 464.1582.

[0085] Example 1b Compound 1b (10.5 mg, 98% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ8.58-8.11(m,2H),7.44-7.05(m,5H),6.78-6.58(m,5H),6.24(t,J=2.1Hz,2H),5.02(s ,2H),4.90-4.77(m,1H),4.06(q,J=7.1Hz,2H),3.85-3.71(m,2H),3.71-3.57(m,2H),1.09(t,J=7.1Hz,3H). Mass spectrometry (mass to charge ratio) is C 28 H 28 N3O4 + [M+H] + The theoretical value is 470.2074, and the measured value is 470.2080.

[0086] Example 1c Compound 1c (6.5 mg, 96% yield) was synthesized following general experimental procedure 1. 1H NMR(500MHz,CDCl3)δ8.44-8.13(m,2H),7.40-7.27(m,3H),7.27-7.15(m,3H),6.81-6.63(m, 5H),6.43-6.29(m,2H),5.01(s,2H),4.89-4.75(m,1H),3.88-3.75(m,2H),3.69-3.61(m,2H). Mass spectrometry (mass to charge ratio) is C 26 H 25 N4O4 + [M+H] + The theoretical value is 457.1870, and the measured value is 457.1870.

[0087] Example 1d Compound 1d (6.6 mg, 64% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,CDCl3)δ8.47-8.08(m,2H),7.42-7.14(m,6H),6.75(t,J=2.1Hz,2H),6.72-6.66(m,2H),6.66-6. 58(m,1H),6.31(t,J=2.1Hz,2H),5.12-5.03(m,1H),5.01(s,2H),4.89-4.76(m,1H),2.61(d,J=4.9Hz,3H).13C NMR(126MHz,CDCl3)δ167.44,156.83,154.93,147.05,142.30,138.27,135.76,129.49,129.03,128.93,124.1 7,123.94,123.71,121.56,119.36,115.32,114.78,110.27,77.49,77.23,76.98,69.95,66.54,59.44,26.87. Mass spectrometry (mass to charge ratio) is C 27 H 27 N4O3 + [M+H] + The theoretical value is 455.2078, and the measured value is 455.2087.

[0088] Example 1e Compound 1e (13.8 mg, 33% yield) was synthesized following general experimental procedure 1. 1H NMR(300MHz,CDCl3)δ8.54-8.03(m,2H),7.41-7.07(m,5H),6.97-6.64(m,5H),6.64-6.53(m,1H),6.21(t,J= 2.0Hz,2H),5.01(s,2H),4.89-4.76(m,1H),4.07-3.86(m,1H),3.71-3.44(m,3H),2.82(s,3H),2.63(s,3H). Mass spectrometry (mass to charge ratio) is C 28 H 29 N4O3 + [M+H] + The theoretical value is 469.2234, and the measured value is 469.2229.

[0089] Example 1f Compound 1f (10.4 mg, 92% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,CDCl3)δ8.29(d,J=69.3Hz,2H),7.37-7.13(m,5H),6.92-6.73(m,3H),6.73-6.64(m,2H),6.64-6.51(m,1H),6.20(t,J= 2.1Hz,2H),5.00(s,2H),4.87-4.77(m,1H),3.79(s,2H),3.64-3.53(m,2H),3.43-3.12(m,2H),3.08-2.91(m,2H),1.77-1.57(m,4H). Mass spectrometry (mass to charge ratio) is C 30 H 31 N4O3 + [M+H] + The theoretical value is 495.2391, and the measured value is 495.2394.

[0090] Example 1g Following general experimental procedure 1, 1 g (4.3 mg, 48% yield) of the compound was synthesized. 1H NMR(400MHz,CDCl3)δ8.47-8.13(m,2H),7.38-7.19(m,5H),7.19-7.08(m,1H),6.89-6.79(m,3H),6.76-6.69(m,2H) ),6.65-6.55(m,1H),6.28(t,J=2.1Hz,2H),5.02(s,2H),4.91-4.81(m,1H),3.89-3.76(m,2H),3.69-3.57(m,2H). Mass spectrometry (mass to charge ratio) is C 25 H 24 N3O2 + [M+H] + The theoretical value is 398.1863, and the measured value is 398.1863.

[0091] Example 2 [ka]

[0092] Compound 2 (6 milligrams, 25% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,CDCl3)δ8.19(d,J=45.1Hz,2H),7.38-7.27(m,3H),7.15(dd,J=7.6,1.3Hz,1H),7.11(s,1H),6.77-6.63(m,5 H),6.26(t,J=2.1Hz,2H),5.08(s,2H),4.88-4.80(m,1H),3.86-3.77(m,2H),3.70-3.64(m,2H),3.62(s,3H),2.26(s,3H). Mass spectrometry (mass to charge ratio) is C 28 H 28 N3O4 + [M+H] + The theoretical value is 470.2074, and the measured value is 470.2076.

[0093] Example 2a Compound 2a (3 milligrams, 98% yield) was synthesized following general experimental procedure 1. 1H NMR(500MHz,CDCl3)δ8.13(d,J=47.0Hz,2H),7.38-7.21(m,4H),7.15(s,1H),6.81-6.73(m,2H),6.73-6 .64(m,3H),6.24(t,J=1.9Hz,2H),5.07(s,2H),4.89-4.78(m,1H),3.85-3.75(m,2H),3.73-3.59(m,2H). Mass spectrometry (mass to charge ratio) is C 27 H 26 N3O4 + [M+H] + The theoretical value is 456.1918, and the measured value is 456.1920.

[0094] Example 3 [ka]

[0095] Compound 3 (7 milligrams, 28% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ8.14(d,J=40.5Hz,2H),7.38-7.22(m,3H),7.21-7.11(m,1H),7.08(s,1H),6.77-6.61(m,5H),6 .26(t,J=2.1Hz,2H),5.00(s,2H),4.89-4.78(m,1H),3.85-3.75(m,2H),3.70-3.63(m,2H),3.62(s,3H),2.32(s,3H). Mass spectrometry (mass to charge ratio) is C 28 H 28 N3O4 + [M+H] + The theoretical value is 470.2074, and the measured value is 470.2084.

[0096] Example 3a Compound 3a (4.3 mg, 44% yield) was synthesized following general experimental procedure 1. 1H NMR(400MHz,CDCl3)δ8.26-7.91(m,2H),7.39-7.19(m,4H),7.13(s,1H),6.84-6.62(m,5H),6.34-6.1 6(m,2H),5.00(s,2H),4.88-4.78(m,1H),3.85-3.69(m,2H),3.65(dd,J=8.7,4.8Hz,2H),2.32(s,3H). Mass spectrometry (mass to charge ratio) is C 27 H 26 N3O4 + [M+H] + The theoretical value is 456.1918, and the measured value is 456.1920.

[0097] Example 4 [ka]

[0098] Compound 4 (11.4 mg, 44% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ7.90-7.78(m,1H),7.39-7.07(m,5H),6.76-6.60(m,6H),6.26(t,J=2.1Hz,2H ),4.95(s,2H),4.89-4.78(m,1H),3.89(s,3H),3.86-3.76(m,2H),3.69-3.63(m,2H),3.62(s,3H). Mass spectrometry (mass to charge ratio) is C 28 H 28 N3O5 + [M+H] + The theoretical value is 486.2023, and the measured value is 486.2028.

[0099] Example 4a Compound 4a (1.3 mg, 27% yield) was synthesized following general experimental procedure 1. 1H NMR(500MHz,CDCl3)δ8.11(s,1H),7.87-7.81(m,1H),7.37-7.18(m,5H),6.78-6.64(m,5H),6.30 -6.22(m,2H),4.95(s,2H),4.86-4.80(m,1H),3.89(s,3H),3.82-3.73(m,2H),3.69-3.61(m,2H). Mass spectrometry (mass to charge ratio) is C 27 H 26 N3O5 + [M+H] + The theoretical value is 472.1867, and the measured value is 472.1869.

[0100] Example 5 [ka]

[0101] Compound 5 (16 mg, 42% yield) was synthesized following general experimental procedure 1. 1 H NMR(300MHz,CDCl3)δ8.24(d,J=2.3Hz,1H),7.40-6.97(m,6H),6.76-6.60(m,5H),6.25(t,J=2 .1Hz,2H),4.98(s,2H),4.89-4.77(m,1H),3.86-3.73(m,2H),3.69-3.57(m,5H),2.49(s,3H). Mass spectrometry (mass to charge ratio) is C 28 H 28 N3O4 + [M+H] + The theoretical value is 470.2074, and the measured value is 470.2076.

[0102] Example 5a Compound 5a (8.1 mg, 83% yield) was synthesized following general experimental procedure 1. 1H NMR(400MHz,CDCl3)δ8.33-8.09(m,1H),7.38-7.16(m,5H),7.16-6.98(m,1H),6.85-6.59(m,5H),6. 34-6.11(m,2H),4.99(s,2H),4.88-4.76(m,1H),3.85-3.73(m,2H),3.73-3.56(m,2H),2.47(s,2H). Mass spectrometry (mass to charge ratio) is C 27 H 26 N3O4 + [M+H] + The theoretical value is 456.1918, and the measured value is 456.1917.

[0103] Example 6 [ka]

[0104] Compound 6 (17 milligrams, 44% yield) was synthesized following general experimental procedure 1. 1 H NMR(300MHz,CDCl3)δ8.12-7.85(m,2H),7.37-7.22(m,3H),7.20-7.10(m,1H),6.84-6.64(m,6H ),6.25(t,J=2.1Hz,2H),5.00(s,2H),4.89-4.79(m,1H),3.88-3.74(m,5H),3.71-3.57(m,5H). Mass spectrometry (mass to charge ratio) is C 28 H 27 N3NaO5 + [M+Na] + The theoretical value is 508.1843, and the measured value is 508.1845.

[0105] Example 6a Compound 6a (3.6 mg, 52% yield) was synthesized following general experimental procedure 1. 1H NMR(400MHz,CDCl3)δ7.97(s,2H),7.38-7.19(m,5H),6.88-6.64(m,5H),6.26(t,J =2.0Hz,2H),5.00(s,2H),4.90-4.77(m,1H),3.88-3.72(m,5H),3.71-3.60(m,2H). Mass spectrometry (mass to charge ratio) is C 27 H 26 N3O5 + [M+H] + The theoretical value is 472.1867, and the measured value is 472.1873.

[0106] Example 7 [ka]

[0107] Compound 7 (19 milligrams, 68% yield) was synthesized following general experimental procedure 1. 1 H NMR(300MHz,CDCl3)δ7.66(t,J=1.9Hz,1H),7.48(dt,J=8.1,1.8Hz,1H),7.30(t,J=8.1Hz,2H),7.24-7.15(m,3H),6.83-6.74(m,2H),6.7 4-6.66(m,3H),6.31-6.21(m,3H),4.92-4.79(m,1H),3.83(dd,J=8.7,6.2Hz,2H),3.67(dd,J=8.8,4.8Hz,2H),3.61(s,3H),3.28(s,3H). High resolution mass spectrometry (mass to charge ratio) 30 H 27 N5O4Na + [M+Na] + The theoretical value is 544.1961, and the measured value is 544.1956.

[0108] Example 7a Compound 7a (2 milligrams, 30% yield) was synthesized following general experimental procedure 1. 1H NMR(300MHz,MeOH-d4)δ7.82-7.77(m,1H),7.62-7.56(m,1H),7.40(d,J=7.7Hz,1H),7.35-7.30(m,1H),7.29(s,1H),7.29-7.21(m,2H),7.0 3-6.96(m,1H),6.84(d,J=9.0Hz,2H),6.78-6.66(m,3H),6.16(s,2H), 4.81-4.75(m,1H),3.88-3.79(m,2H),3.56-3.48(m,3H),3.26(s,3H). Mass spectrometry (mass to charge ratio) is C 29 H 25 N5O4Na + [M+Na] + The theoretical value is 530.1804, and the measured value is 530.1802.

[0109] Example 8 [ka]

[0110] Compound 8 (4 milligrams, 16% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ8.76-8.22(m,2H),7.36-7.22(m,4H),7.16(dd,J=7.7,1.4Hz,1H),6.90(s,1H),6.76-6.6 3(m,5H),6.26(t,J=2.1Hz,2H),5.02(s,2H),4.90-4.79(m,2H),3.81(dd,J=9.1,6.2Hz,2H),3.70-3.55(m,5H). Mass spectrometry (mass to charge ratio) is C 27 H 26 N3O4 + [M+H] + The theoretical value is 456.1918, and the measured value is 456.1918.

[0111] Example 8a Compound 8a (3.2 mg, 94% yield) was synthesized following general experimental procedure 1. 1H NMR(500MHz,CDCl3)δ8.59-8.15(m,2H),7.42-7.11(m,5H),6.89(s,1H),6.79-6.55(m,5H) ,6.29-6.06(m,2H),5.02(s,2H),4.87-4.75(m,1H),3.84-3.69(m,2H),3.68-3.52(m,2H). Mass spectrometry (mass to charge ratio) is C 26 H 24 N3O4 + [M+H] + The theoretical value is 442.1761, and the measured value is 442.1760.

[0112] Example 9 [ka]

[0113] Compound 9 (18 milligrams, 27% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ8.80-8.64(m,1H),8.11-7.97(m,1H),7.77-7.64(m,1H),7.62-7.43(m,3H),7.39(d,J=8.6Hz,2H),7.35-7.22(m,1H),7. 22-7.07(m,1H),6.81-6.61(m,5H),6.26(t,J=2.1Hz,2H),5.11(s,2H) ,4.90-4.80(m,1H),3.86-3.77(m,2H),3.71-3.64(m,2H),3.62(s,3H). Mass spectrometry (mass to charge ratio) is C 31 H 28 N3O4 + [M+H] + The theoretical value is 506.2074, and the measured value is 506.2078.

[0114] Example 9a Compound 9a (8.1 mg, 84% yield) was synthesized following general experimental procedure 1. 1H NMR(300MHz,CDCl3)δ8.88-8.42(m,1H),8.13-7.89(m,1H),7.88-7.65(m,1H),7.65-7.45(m,3H),7.45-7.24(m,3H),7.24-7.07 (m,1H),6.87-6.53(m,5H),6.35-6.10(m,2H),5.12(s,2H),4.85(dd,J=10.6,5.7Hz,1H),3.84-3.69(m,2H),3.71-3.52(m,2H). Mass spectrometry (mass to charge ratio) is C 30 H 26 N3O4 + [M+H] + The theoretical value is 492.1918, and the measured value is 492.1919.

[0115] Example 10 [ka]

[0116] Compound 10 (11 milligrams, 44% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,CDCl3)δ7.54-7.44(m,2H),7.32(d,J=5.5Hz,1H),7.23(d,J=7.7Hz,1H),7.17-7.06(m,4H),6.69(q,J=2.2Hz,2H),6.65(dd,J =8.3,1.4Hz,1H),6.60-6.54(m,2H),6.23(t,J=2.1Hz,2H),4.70(p,J=5.3Hz,1H),3.75(dd,J=8.6,6.1Hz,2H),3.58(dd,J=8.9,4.7Hz,5H). Mass spectrometry (mass to charge ratio) is C 29 H 25 F3N4O4Na + [M+Na] + The theoretical value is 573.1726, and the measured value is 573.1722.

[0117] Example 10a Compound 10a (4.6 mg, 72% yield) was synthesized following general experimental procedure 2. 1H NMR(400MHz,MeOH-d4)δ7.87(d,J=2.0Hz,1H),7.57(dd,J=8.2,2.1Hz,1H),7.44(t,J=8.0Hz,1H),7.33-7.25(m,4H),7.03(dd,J=7. 6,1.3Hz,1H),6.73-6.66(m,5H),6.18(t,J=2.1Hz,2H),4.82-4.79(m,1H),3.80(dd,J=8.7,6.0Hz,2H),3.51(dd,J=8.9,4.3Hz,2H). Mass spectrometry (mass to charge ratio) is C 28 H 23 F3N4O4Na + [M+Na] + The theoretical value is 559.1569, and the measured value is 559.1565.

[0118] Example 10b Compound 10b (2.5 mg, 14.4% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,MeOH-d4)δ7.98-7.79(m,1H),7.59(dd,J=8.3,2.1Hz,1H),7.46(t,J=8.0Hz,1H),7.38-7.24(m, 4H),6.90-6.62(m,6H),6.21(t,J=2.2Hz,2H),3.83(dd,J=8.7,6.1Hz,2H),3.51(td,J=10.5,9.6,4.0Hz,2H). Mass spectrometry (mass to charge ratio) is C 28 H 24 F3N5NaO4 + [M+Na] + The theoretical value is 574.16726, and the measured value is 574.16748.

[0119] Example 11 [ka]

[0120] Compound 11 (8.7 mg, 30% yield) was synthesized following general experimental procedure 1. 1H NMR(300MHz,CDCl3)δ8.62-8.42(m,2H),7.39(d,J=8.6Hz,2H),7.33-7.26(m,1H),7.19-7.07(m,1H),6.94(t,J=4.7Hz,1H), 6.75-6.57(m,5H),6.31-6.14(m,2H),5.36(s,2H),4.88-4.76(m,1H),3.84-3.73(m,2H),3.67-3.57(m,5H), mass spectrometry (mass to charge ratio) is C 26 H 25 N4O4 + [M+H] + The theoretical value is 457.1870, and the measured value is 457.1877.

[0121] Example 11a Compound 11a (5.4 mg, 93% yield) was synthesized following general experimental procedure 1. 1 H NMR(300MHz,CDCl3)δ8.52(d,J=4.7Hz,2H),7.39(d,J=8.6Hz,2H),7.32-7.18(m,1H),7.08-6.99(m,1H),6.94(t,J=4.8 Hz,1H),6.76-6.54(m,5H),6.23(t,J=2.1Hz,2H),5.36(s,2H),4.87-4.77(m,1H),3.82-3.68(m,2H),3.68-3.55(m,2H). Mass spectrometry (mass to charge ratio) is C 25 H 23 N4O4 + [M+H] + The theoretical value is 443.1714, and the measured value is 443.1714.

[0122] Example 12 [ka]

[0123] Compound 12 (5.8 mg, 83% yield) was synthesized following general experimental procedure 1. 1H NMR(300MHz,CDCl3)δ8.25-8.09(m,1H),7.65-7.51(m,1H),7.43-7.22(m,3H),7.21-7.07(m,1H),6.94-6.83(m,1H) ),6.83-6.61(m,6H),6.25(t,J=2.1Hz,2H),5.29(s,2H),4.89-4.78(m,1H),3.87-3.73(m,2H),3.70-3.57(m,5H). Mass spectrometry (mass to charge ratio) is C 27 H 26 N3O4 + [M+H] + The theoretical value is 456.1918, and the measured value is 456.1917.

[0124] Example 12a Compound 12a (19.7 mg, 24% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,CDCl3)δ8.23-8.09(m,1H),7.63-7.51(m,1H),7.40-7.19(m,4H),6.93-6.83(m,1H),6.77(d,J=8.4Hz, 1H),6.74-6.62(m,5H),6.21(t,J=2.1Hz,2H),5.24(s,2H),4.86-4.77(m,1H),3.82-3.72(m,2H),3.68-3.58(m,2H). Mass spectrometry (mass to charge ratio) is C 26 H 24 N3O4 + [M+H] + The theoretical value is 442.1761, and the measured value is 442.1766.

[0125] Example 13 [ka]

[0126] Compound 13 (6 mg, 33% yield) was synthesized following general experimental procedure 1. 1H NMR(400MHz,CDCl3)δ8.25(s,1H),8.20-8.06(m,2H),7.40-7.33(m,2H),7.33-7.27(m,1H),7.19-7.08(m,1H),6.76-6 .63(m,5H),6.25(t,J=2.1Hz,2H),5.31(s,2H),4.88-4.81(m,1H),3.86-3.75(m,2H),3.69-3.63(m,2H),3.62(s,3H). Mass spectrometry (mass to charge ratio) is C 26 H 25 N4O4 + [M+H] + The theoretical value is 457.1870, and the measured value is 457.1872.

[0127] Example 13a Compound 13a (4 mg, 9% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,CDCl3)δ8.23(s,1H),8.16-8.03(m,2H),7.40-7.26(m,4H),6.75-6.64(m,5H), 6.25(t,J=2.1Hz,2H),5.29(s,2H),4.86-4.78(m,1H),3.80-3.74(m,2H),3.68-3.61(m,2H). Mass spectrometry (mass to charge ratio) is C 25 H 23 N4O4 + [M+H] + The theoretical value is 443.1714, and the measured value is 443.1708.

[0128] Example 14 [ka]

[0129] Compound 14 (3 milligrams, 17% yield) was synthesized following general experimental procedure 1. 1H NMR(500MHz,CDCl3)δ8.86(s,1H),8.45(s,2H),7.32(t,J=8.3Hz,3H),7.16(dd,J=7.7,1.3Hz,1H),6.76-6.66(m ,5H),6.26(t,J=2.1Hz,2H),5.08(s,2H),4.88-4.81(m,1H),3.86-3.78(m,2H),3.69-3.63(m,2H),3.62(s,3H). High resolution mass spectrometry (mass to charge ratio) 26 H 25 N4O4 + [M+H] + The theoretical value is 457.1870, and the measured value is 457.1873.

[0130] Example 14a Compound 14a (1.4 mg, 48% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ8.84(s,1H),8.46(s,2H),7.42-7.15(m,4H),6.86-6.59(m,5H) ,6.24(s,2H),5.08(s,2H),4.89-4.78(m,1H),3.83-3.72(m,2H),3.69-3.57(m,2H). High resolution mass spectrometry (mass to charge ratio) 25 H 23 N4O4 + [M+H] + The theoretical value is 443.1714, and the measured value is 443.1716.

[0131] Example 14b Compound 14b (1.7 mg, 20% yield) was synthesized following general experimental procedure 1. 1 H NMR(300MHz,CDCl3)δ8.85(s,1H),8.45(s,2H),7.45-7.28(m,4H),6.87-6.58(m,5H),6.4 1(t,J=1.9Hz,2H),5.08(s,2H),4.93-4.78(m,1H),3.89-3.75(m,2H),3.75-3.59(m,2H). Mass spectrometry (mass to charge ratio) is C 25 H 23 N5NaO4 +[M+Na] + The theoretical value is 480.16423, and the measured value is 480.16483.

[0132] Example 15 [ka]

[0133] Compound 15 (5 milligrams, 10.5% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,CDCl3)δ8.49-8.15(m,2H),7.31-7.24(m,4H),7.15(dd,J=7.7,1 .3Hz,1H),6.71(t,J=2.1Hz,2H),6.68(dd,J=8.2,1.3Hz,1H),6.61(d,J=2.4H z,1H),6.51(dd,J=8.3,2.6Hz,1H),6.25(t,J=2.1Hz,2H),5.00(s,2H),4.88- 4.78(m,1H),3.85-3.75(m,2H),3.67-3.63(m,2H),3.61(s,3H),2.33(s,3H). Mass spectrometry (mass to charge ratio) is C 28 H 28 N3O4 + [M+H] + The theoretical value is 470.20743, and the measured value is 470.20764.

[0134] Example 15a Compound 15a (2 milligrams, 34.36% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,CDCl3)δ8.37(s,1H),8.24(s,1H),7.34-7.24(m,5H),6.75(t,J=2.1Hz,2H),6.71(dd,J=8.0,1.4Hz,1H),6.61(d,J=2.4Hz,1 H),6.50(dd,J=8.3,2.5Hz,1H),6.27(t,J=2.0Hz,2H),5.00(s,2H),4.88-4.78(m,1H),3.86-3.74(m,2H),3.68-3.57(m,2H),2.33(s,3H). Mass spectrometry (mass to charge ratio) is C27 H 26 N3O4 + [M+H] + The theoretical value is 456.19178, and the measured value is 456.19189.

[0135] Example 16 [ka]

[0136] Compound 16 (5 mg, 6.43% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,CDCl3)δ8.38(s,1H),8.24(s,1H),7.32-7.28(m,1H),7.28-7.21( m,2H),7.21-7.19(m,1H),7.17-7.13(m,2H),6.71(t,J=2.1Hz,2H),6.69(dd,J= 8.2,1.3Hz,1H),6.44(d,J=8.3Hz,1H),6.26(t,J=2.1Hz,2H),4.99(s,2H),4.8 9-4.79(m,1H),3.85-3.77(m,2H),3.68-3.64(m,2H),3.62(s,3H),2.19(s,3H). Mass spectrometry (mass to charge ratio) is C 28 H 28 N3O4 + [M+H] + The theoretical value is 470.20743, and the measured value is 470.2076.

[0137] Example 16a Compound 16a (4 mg, 58.90% yield) was synthesized following general experimental procedure 1. 1H NMR(500MHz,CDCl3)δ8.34(s,1H),8.21(s,1H),7.32-7.27(m,2H),7.25- 7.21(m,2H),7.20-7.18(m,1H),7.17-7.12(m,1H),6.76-6.71(m,2H),6. 69(d,J=7.8Hz,1H),6.43(d,J=8.3Hz,1H),6.27-6.22(m,2H),4.98(s,2H) ),4.87-4.80(m,1H),3.81-3.74(m,2H),3.67-3.63(m,2H),2.19(s,3H). Mass spectrometry (mass to charge ratio) is C 27 H 26 N3O4 + [M+H] + The theoretical value is 456.19178, and the measured value is 456.19193.

[0138] Example 17 [ka]

[0139] Compound 17 (31 milligrams, 35.2% yield) was synthesized following general experimental procedure 1. 1 H NMR(300MHz,CDCl3)δ8.37(s,1H),8.25(s,1H),7.46-7.13(m,11H),6.74-6.59(m,3H) ,5.02(s,2H),4.74(ddd,J=6.2,4.8,1.4Hz,1H),3.77-3.63(m,2H),3.57-3.42(m,5H). Mass spectrometry (mass to charge ratio) is C 29 H 27 N2O4 + [M+H] + The theoretical value is 467.19653, and the measured value is 467.19669.

[0140] Example 17a Compound 17a (25 mg, 85% yield) was synthesized following general experimental procedure 1. 1H NMR(500MHz,MeOH-d4)δ8.31-8.15(m,1H),8.15-8.00(m,1H),7.52-7.39(m,1H),7.39-7.17(m,9H),7.1 7-7.00(m,1H),6.78-6.61(m,3H),5.05(s,2H),4.79-4.68(m,1H),3.78-3.63(m,2H),3.41-3.32(m,2H). Mass spectrometry (mass to charge ratio) is C 28 H 25 N2O4 + [M+H] + The theoretical value is 453.2, and the measured value is 453.2.

[0141] Example 17b Compound 17b (6.7 mg, 79% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,MeOH-d4)δ8.28-8.16(m,1H),8.12-8.05(m,1H),7.49-7.39(m,1H),7.38-7.23(m,9H),6.85(d,J=7 .4Hz,1H),6.74-6.63(m,3H),5.05(s,2H),4.78-4.72(m,1H),4.58(s,1H),3.78-3.64(m,2H),3.41-3.35(m,2H). Mass spectrometry (mass to charge ratio) is C 28 H 26 N3O4 + [M+H] + The theoretical value is 468.2, and the measured value is 468.2.

[0142] Example 18 [ka]

[0143] Compound 18 (15 milligrams, 19.0% yield) was synthesized following general experimental procedure 1. 1H NMR(400MHz,CDCl3)δ8.39(s,1H),8.25(d,J=4.5Hz,1H),7.44-7.12(m,11H),6.76-6.65(m, 3H),5.04(s,2H),4.79(p,J=5.4Hz,1H),3.81(s,1H),3.71(s,2H),3.57(s,3H),3.50(s,1H). Mass spectrometry (mass to charge ratio) is C 29 H 26 ClN2O4 + [M+H] + The theoretical value is 501.15756, and the measured value is 501.15768.

[0144] Example 19 [ka]

[0145] Compound 19 (5 mg, 4.21% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,CDCl3)δ8.39(s,1H),8.26(s,1H),7.39(d,J=8.5Hz,1H),7.32-7.28(m,1H),7 .26-7.22(m,2H),7.16(dd,J=7.6,1.2Hz,1H),6.78(d,J=2.5Hz,1H),6.71(t,J=2.1Hz,2H), 6.68(dd,J=8.2,1.2Hz,1H),6.62(dd,J=8.5,2.5Hz,1H),6.26(t,J=2.1Hz,2H),5.12(s,2H) ),4.85-4.77(m,1H),3.81(dd,J=8.9,6.3Hz,2H),3.64(dd,J=9.1,4.8Hz,2H),3.62(s,3H). Mass spectrometry (mass to charge ratio) is C 27 H 25 ClN3O4 + [M+H] + The theoretical value is 490.15281, and the measured value is 490.15295.

[0146] Example 19a Compound 19a (3 mg, 44.12% yield) was synthesized following general experimental procedure 1.1 H NMR(300MHz,CDCl3)δ8.35(s,1H),8.23(s,1H),7.39(d,J=8.5Hz,1H),7.33-7.20(m,4H),6.80- 6.58(m,5H),6.25(s,2H),5.11(s,2H),4.88-4.74(m,1H),3.83-3.72(m,2H),3.65-3.58(m,2H). Mass spectrometry (mass to charge ratio) is C 26 H 23 ClN3O4 + [M+H] + The theoretical value is 476.13716, and the measured value is 476.13736.

[0147] Example 20 [ka]

[0148] Compound 20 (5 mg, 4.92% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ8.43(s,1H),8.30(s,1H),7.39-7.28(m,4H),7.18(dd,J=7.6,1.1Hz,1H),6.74-6.67(m,3H),6.56-6.45(m, 2H),6.28(t,J=2.0Hz,2H),5.09(s,2H),4.88-4.80(m,1H),3.83(dd,J=8.9,6.3Hz,2H),3.67(dd,J=9.0,4.8Hz,2H),3.64(s,3H). Mass spectrometry (mass to charge ratio) is C 27 H 25 FN3O4 + [M+H] + The theoretical value is 474.18236, and the measured value is 474.18250.

[0149] Example 20a Compound 20a (1.5 mg, 30.92% yield) was synthesized following general experimental procedure 1. 1H NMR(500MHz,CDCl3)δ8.65-7.97(m,2H),7.37-7.27(m,4H),7.23-7.13(m,1H),6.72(s,2H),6.66-6.59(m,1H) ,6.51-6.41(m,2H),6.25-6.13(m,2H),5.06(s,2H),4.83-4.73(m,1H),3.79-3.72(m,2H),3.65-3.57(m,2H). Mass spectrometry (mass to charge ratio) is C 26 H 23 FN3O4 + [M+H] + The theoretical value is 460.16671, and the measured value is 460.16672.

[0150] Example 21 [ka]

[0151] Compound 21 (3 milligrams, 9.59% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,CDCl3)δ8.52-8.33(m,1H),8.33-8.18(m,1H),7.32-7.27(m,2H),7.26-7.22(m, 2H),7.15(dd,J=7.7,1.3Hz,1H),7.01(d,J=7.6Hz,1H),6.79-6.77(m,1H),6.70(t,J=2.1Hz, 2H),6.68(dd,J=8.2,1.3Hz,1H),6.64(dd,J=8.1,2.3Hz,1H),6.25(t,J=2.1Hz,2H),5.06(s, 2H),4.88-4.81(m,1H),3.80(dd,J=9.1,6.2Hz,2H),3.65(dd,J=9.1,4.8Hz,2H),3.61(s,3H). Mass spectrometry (mass to charge ratio) is C 27 H 26 N3O4 + [M+H] + The theoretical value is 456.19178, and the measured value is 456.19480.

[0152] Example 22 [ka]

[0153] Compound 22 (30 milligrams, 43.05% yield) was synthesized following general experimental procedure 3. 1 H NMR(500MHz,DMSO)δ10.31(s,1H),9.55(s,1H),8.55(s,1H),8.41(s,1H),8.18(d ,J=4.3Hz,1H),8.03(d,J=8.4Hz,1H),7.92(d,J=7.5Hz,1H),7.78(d,J=7.8Hz,1H ),7.72(d,J=7.8Hz,1H),7.51(t,J=7.8Hz,1H),7.45(dt,J=14.2,6.9Hz,3H),7.3 0(d,J=6.7Hz,3H),6.66(d,J=1.6Hz,1H),6.62(d,J=8.4Hz,1H),3.51(s,3H)ppm. Mass spectrometry (mass to charge ratio) is C 28 H 21 O4N3 + [M+H] + The theoretical value is 464.2, and the measured value is 464.2.

[0154] Example 23 [ka]

[0155] Compound 23 (39 milligrams, 31% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,MeOH-d4)δ7.93-7.85(m,1H),7.76-7.67(m,1H),7.36-7.23(m,3H),7.13-6.94(m,3H),6.82- 6.66(m,5H),6.20(t,J=2.1Hz,2H),4.87-4.79(m,1H),4.26(s,2H),3.89-3.80(m,2H),3.58-3.46(m,5H). Mass spectrometry (mass to charge ratio) is C 27 H 27 N4O3 + [M+H] +The theoretical value is 455.20777, and the measured value is 455.20776.

[0156] Example 23a Compound 23a (4.4 mg, 80% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,MeOH-d4)δ8.01-7.62(m,2H),7.31-6.91(m,5H),6.89-6.63(m,5H),6.54(dd,J=8.2,1.2 Hz,1H),6.12(t,J=2.1Hz,2H),4.84-4.73(m,1H),4.25(s,2H),3.81-3.65(m,2H),3.51-3.35(m,2H). Mass spectrometry (mass to charge ratio) is C 26 H 25 N4O3 + [M+H] + The theoretical value is 441.19212, and the measured value is 441.19196.

[0157] Example 23b Compound 23b (3 milligrams, 27% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ8.12-7.85(m,2H),7.43-7.30(m,2H),7.27-7.17(m,2H),7.12-7.00(m,1H),6.93-6.80(m, 1H),6.80-6.57(m,5H),6.44-6.31(m,2H),4.88-4.77(m,1H),4.27(s,2H),3.85-3.74(m,2H),3.70-3.61(m,2H). Mass spectrometry (mass to charge ratio) is C 26 H 26 N5O3 + [M+H] + The theoretical value is 456.20302, and the measured value is 456.20313.

[0158] Example 24 [ka]

[0159] Compound 24 (40 milligrams, 39.85% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,CDCl3)δ8.66(d,J=1.8Hz,1H),8.58(dd,J=4.8,1.3Hz,1H),7.78-7. 72(m,1H),7.34-7.27(m,2H),7.15(dd,J=7.6,1.1Hz,1H),6.89-6.84(m,2H),6.7 0(t,J=2.1Hz,2H),6.69-6.66(m,1H),6.65-6.62(m,2H),6.25(t,J=2.1Hz,2H),5 .02(s,2H),4.80-4.74(m,1H),3.81-3.74(m,2H),3.66-3.62(m,2H),3.61(s,3H). Mass spectrometry (mass to charge ratio) is C 27 H 26 N3O4 + [M+H] + The theoretical value is 456.19178, and the measured value is 456.19189.

[0160] Example 24a Compound 24a (6 mg, 51.59% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,CDCl3)δ8.62(s,1H),8.59-8.49(m,1H),7.81(d,J=7.8Hz,1H), 7.35(dd,J=7.7,5.0Hz,1H),7.33-7.27(m,1H),7.26-7.20(m,1H),6.88-6.8 1(m,2H),6.74(s,2H),6.68(d,J=7.1Hz,1H),6.66-6.60(m,2H),6.26-6.20( m,2H),5.01(s,2H),4.79-4.73(m,1H),3.81-3.71(m,2H),3.66-3.59(m,2H). Mass spectrometry (mass to charge ratio) is C 26 H 24 N3O4 + [M+H] + The theoretical value is 442.17613, and the measured value is 442.17578.

[0161] Example 24b Compound 24b (10 mg, 53.83% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,MeOH-d4 / CDCl3)δ8.58(d,J=1.2Hz,1H),8.47(dd,J=4.8,1.2Hz,1H),7.94- 7.85(m,1H),7.43(dd,J=7.8,5.0Hz,1H),7.29(t,J=7.9Hz,1H),6.94-6.87(m,2H),6.86 -6.82(m,1H),6.75(t,J=2.1Hz,2H),6.69(dd,J=8.2,0.9Hz,1H),6.67-6.62(m,2H),6.1 9(t,J=2.1Hz,2H),5.06(s,2H),4.79-4.75(m,1H),3.82-3.74(m,2H),3.60-3.50(m,2H). Mass spectrometry (mass to charge ratio) is C 26 H 25 N4O4 + [M+H] + The theoretical value is 457.18703, and the measured value is 457.18719.

[0162] Example 25 [ka]

[0163] Compound 25 (8 milligrams, 52% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ8.39-8.36(m,1H),8.36-8.33(m,1H),7.32(t,J=7.9Hz,1H),7.27-7.21(m,2H),7.18(dd,J=7.7,1.3Hz,1H),7.00-6.9 6(m,2H),6.77-6.68(m,5H),6.28(t,J=2.1Hz,2H),4.88-4.80(m,1H),3.82(dd,J=9.0,6.3Hz,2H),3.68(dd,J=9.1,4.8Hz,2H),3.64(s,3H). Mass spectrometry (mass to charge ratio) is C 26 H 24 N3O4 + [M+H] +The theoretical value is 442.17613, and the measured value is 442.17535.

[0164] Example 25a Compound 25a (6 mg, 51.64% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ8.31-8.28(m,1H),8.28-8.24(m,1H),7.32-7.28(m,1H),7.27-7.23(m,2H),7.22-7.16(m,1H),6.98-6.91( m,2H),6.74(t,J=2.0Hz,2H),6.71-6.65(m,3H),6.23(t,J=2.0Hz,2H),4.84-4.75(m,1H),3.81-3.72(m,2H),3.66-3.61(m,2H). Mass spectrometry (mass to charge ratio) is C 25 H 22 N3O4 + [M+H] + The theoretical value is 428.16048, and the measured value is 428.1606.

[0165] Example 26 [ka]

[0166] Compound 26 (7 mg, 48% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ8.50-8.45(m,2H),7.33(t,J=7.9Hz,1H),7.20-7.17(m,1H),7.03-7.00(m,2H),6.84-6.80(m, 2H),6.77-6.71(m,5H),6.28(t,J=2.1Hz,2H),4.89-4.81(m,1H),3.87-3.81(m,2H),3.72-3.67(m,2H),3.64(s,3H). Mass spectrometry (mass to charge ratio) is C 26 H 24 N3O4 + [M+H] + The theoretical value is 442.17613, and the measured value is 442.17609.

[0167] Example 26a Compound 26a (7 mg, 72.30% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,MeOH-d4-CDCl3)δ8.33(d,J=6.2Hz,2H),7.37-7.34(m,1H),7.28(t,J=7.9Hz,1H),7.16(d,J=7.6Hz,1H),7.00-6.95(m,2H), 6.83-6.79(m,2H),6.74-6.71(m,3H),6.69-6.65(m,1H),6.20(t,J=1.9Hz,2H),4.87-4.75(m,1H),3.81-3.71(m,2H),3.65-3.58(m,2H). Mass spectrometry (mass to charge ratio) is C 25 H 22 N3O4 + [M+H] + The theoretical value is 428.16048, and the measured value is 428.16049.

[0168] Example 27 [ka]

[0169] Compound 27 (11.4 mg, 18.3% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ8.71-8.37(m,2H),7.73(d,J=7.8Hz,1H),7.40-7.22(m,4H),7.16(d,J=7.6Hz,1H),6.77-6.60(m,5H), 6.26(t,J=2.2Hz,2H),4.84(q,J=5.5Hz,1H),4.55(s,2H),4.50(s,2H),3.81(dd,J=8.6,6.2Hz,2H),3.64(d,J=17.0Hz,5H). Mass spectrometry (mass to charge ratio) is C 28 H 28 N3O4 + [M+H] + The theoretical value is 470.20743, and the measured value is 470.20859.

[0170] Example 27a Compound 27a (10.3 mg, yield 17.11%) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ8.64-8.44(m,2H),7.78(d,J=8.0Hz,1H),7.41-7.19(m,4H),6.76(t,J=2.2Hz,2H),6.72-6.64(m,3H),6. 25(t,J=2.2Hz,2H),4.84(p,J=5.5Hz,1H),4.54(s,2H),4.50(s,2H),3.79(dd,J=8.6,6.2Hz,2H),3.65(dd,J=8.7,4.9Hz,2H). Mass spectrometry (mass to charge ratio) is C 27 H 26 N3O4 + [M+H] + The theoretical value is 456.19178, and the measured value is 456.19113.

[0171] Example 27b Compound 27b (28 milligrams, 64.72% yield) was synthesized following general experimental procedure 1. 1 H NMR(300MHz,CDCl3)δ8.64-8.33(m,2H),7.71(d,J=7.6Hz,1H),7.27(t,J=9.7Hz,4H),6.82-6.54(m,5H),6.33(s,2H) ),5.30(s,2H),4.90-4.72(m,1H),4.53(s,2H),4.49(s,2H),3.78(q,J=7.2,6.7Hz,2H),3.64(dd,J=8.5,4.6Hz,2H). Mass spectrometry (mass to charge ratio) is C 27 H 26 N4NaO4 + [M+Na] + The theoretical value is 493.18463, and the measured value is 493.18463.

[0172] Example 28 [ka]

[0173] Compound 28 (12 milligrams, 56.78% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,CDCl3)δ8.72(d,J=2.2Hz,1H),8.49(dd,J=4.8,1.6Hz,1H),7.82(dt,J=8 .0,1.8Hz,1H),7.48-7.43(m,2H),7.35-7.29(m,2H),7.18(dd,J=7.7,1.4Hz,1H),7.12 (d,J=16.4Hz,1H),6.95(d,J=16.4Hz,1H),6.75-6.70(m,5H),6.28(t,J=2.1Hz,2H),4. 93-4.85(m,1H),3.84(dd,J=9.2,6.2Hz,2H),3.69(dd,J=9.2,4.8Hz,2H),3.64(s,3H). Mass spectrometry (mass to charge ratio) is C 28 H 26 N3O3 + [M+H] + The theoretical value is 452.19687, and the measured value is 452.19684.

[0174] Example 28a Compound 28a (5 mg, 57.34% yield) was synthesized following general experimental procedure 2. 1 H NMR(300MHz,CDCl3)δ8.61(s,1H),8.42(d,J=4.1Hz,1H),7.87-7.78(m,1H ),7.44(d,J=8.7Hz,2H),7.35-7.27(m,2H),7.26-7.20(m,1H),7.11(d,J=1 6.4Hz,1H),6.91(d,J=16.4Hz,1H),6.79-6.74(m,2H),6.73-6.64(m,3H),6 .32-6.21(m,2H),4.90-4.81(m,1H),3.86-3.73(m,2H),3.71-3.60(m,2H). Mass spectrometry (mass to charge ratio) is C 27 H 24 N3O3 + [M+H] + The theoretical value is 438.18122, and the measured value is 438.18134.

[0175] Example 28b Compound 28b (7 mg, 57.34% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,MeOH-d4 / CDCl3)δ8.63(d,J=1.6Hz,1H),8.36(dd,J=4.8,1.1Hz,1H),8.03(dt,J =8.0,1.7Hz,1H),7.53-7.47(m,2H),7.41(dd,J=8.0,4.9Hz,1H),7.34-7.29(m,1H),7.24(d, J=16.4Hz,1H),7.04(d,J=16.4Hz,1H),6.85(dd,J=7.5,1.2Hz,1H),6.77-6.70(m,5H),6.20( t,J=2.1Hz,2H),4.91-4.88(m,1H),3.84(dd,J=8.9,6.2Hz,2H),3.54(dd,J=9.0,4.3Hz,2H). Mass spectrometry (mass to charge ratio) is C 27 H 25 N4O3 + [M+H] + The theoretical value is 453.19212, and the measured value is 453.19217.

[0176] Example 29 [ka]

[0177] Compound 29 (2.5 mg, 49.78% yield) was synthesized following general experimental procedure 2. 1H NMR(500MHz,CDCl3)δ8.47-8.42(m,1H),8.42-8.37(m,1H),7.45-7.40(m,1H),7.29(t,J=7.9Hz ,1H),7.20(dd,J=7.7,4.8Hz,1H),7.15(dd,J=7.6,1.2Hz,1H),7.04-6.98(m,2H),6.71(t,J=2. 1Hz,2H),6.68(dd,J=8.2,1.2Hz,1H),6.60(d,J=8.6Hz,2H),6.25(t,J=2.1Hz,2H),4.84-4.76( m,1H),3.79(dd,J=8.9,6.3Hz,2H),3.65(dd,J=9.0,4.9Hz,2H),3.61(s,3H),2.91-2.81(m,4H). Mass spectrometry (mass to charge ratio) is C 28 H 28 N3O3 + [M+H] + The theoretical value is 454.21252, and the measured value is 454.21262.

[0178] Example 29a Refer to General Experimental Procedure 2, and the compound 29a (5.5 milligrams, yield 56.76%) was synthesized. 1 H NMR(500MHz,MeOH-d4)δ8.30(d,J=4.0Hz,1H),8.26(s,1H),7.46-7.36(m,1H),7.32-7.26(m,1H),7.21-7.15(m,1H),7.15-7.10(m,1H),6.98-6. 90(m,2H),6.69-6.58(m,3H),6.57-6.49(m,2H),6.19-6.12(m,2H),4.7 7-4.69(m,1H),3.72-3.68(m,2H),3.58-3.54(m,2H),2.87-2.74(m,4H). Mass spectrometry (mass to charge ratio) is C 27 H 26 N3O3 + [M+H] + The theoretical value is 440.19687, and the measured value is 440.19690.

[0179] Example 30 [ka]

[0180] Compound 30 (7 mg, 6.37% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,CDCl3)δ7.33-7.27(m,3H),7.15(dd,J=7.7,1.3Hz,1H),6.72-6.67(m,6H),6.56(dd,J=5.8,1.5H z,1H),6.27-6.24(m,3H),4.98(s,2H),4.88-4.81(m,1H),3.82-3.79(m,2H),3.67-3.63(m,2H),3.62(s,3H). Mass spectrometry (mass to charge ratio) is C 26 H 25 N2O4S + [M+H] + The theoretical value is 461.15295, and the measured value is 461.15305.

[0181] Example 30a: Compound 30a (6 mg, 61.89% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ7.36-7.29(m,3H),7.23-7.17(m,1H),6.74-6.66(m,6H),6.60-6.55(m,1H),6. 29-6.26(m,1H),6.22(s,2H),5.00(s,2H),4.89-4.80(m,1H),3.82-3.73(m,2H),3.69-3.60(m,2H). Mass spectrometry (mass to charge ratio) is C 25 H 23 N2O4S + [M+H] + The theoretical value is 447.13730, and the measured value is 447.13751.

[0182] Example 31 [ka]

[0183] Compound 31 (103 mg, 79.90% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,CDCl3)δ9.07(s,1H),8.75(d,J=4.8Hz,1H),8.19(d,J=7.9Hz,1H ),8.09(s,1H),7.51(d,J=8.4Hz,2H),7.42(dd,J=8.0,4.9Hz,1H),7.29(dd,J =14.2,6.2Hz,1H),7.15(d,J=7.6Hz,1H),6.70(d,J=8.8Hz,5H),6.25(t,J=2. 2Hz, 2H), 4.83 (p, J = 5.5Hz, 1H), 3.81 (t, J = 7.4Hz, 2H), 3.64 (d, J = 17.3Hz, 5H). Mass spectrometry (mass to charge ratio) is C 27 H 24 N4NaO4 + [M+Na] + The theoretical value is 491.16898, and the measured value is 491.16910.

[0184] Example 31a Compound 31a (81 milligrams, 92.78% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,DMSO-d6)δ10.35(s,1H),9.08(s,1H),8.74(d,J=4.8Hz,1H),8.27(d,J=8.0Hz,1H),7.64(d,J=8.4Hz,2H),7.55(d,J=6.9 Hz,1H),7.27(d,J=7.9Hz,1H),6.93(d,J=7.4Hz,1H),6.85-6.60(m,5H),6.11(s,2H),4.89(s,1H),3.78(t,J=7.4Hz,2H),3.42(s,2H). Mass spectrometry (mass to charge ratio) is C 26 H 23 N4O4 + [M+H] + The theoretical value is 455.17138, while the measured value is 455.17120.

[0185] Example 31b Compound 31b (3.4 mg, 17.69% yield) was synthesized following general experimental procedure 2. 1H NMR(400MHz,MeOH-d4)δ9.07(d,J=2.2Hz,1H),8.72(dd,J=5.0,1.6Hz,1H),7.59(dd,J=8.0,5.5Hz,3H),7.40-7.25(m,1H),6. 85(dd,J=7.5,1.3Hz,1H),6.81-6.68(m,5H),6.22(t,J=2.1Hz,2H),3.85(dd,J=8.8,6.1Hz,2H),3.54(dd,J=8.9,4.4Hz,2H). Mass spectrometry (mass to charge ratio) is C 26 H 23 N5NaO4 + [M+Na] + The theoretical value is 492.16423, and the measured value is 492.16479.

[0186] Example 32 [ka]

[0187] Compound 32 (11 milligrams, 23.99% yield) was synthesized following general experimental procedure 1. 1 H NMR(400MHz,CDCl3)δ7.39-7.35(m,2H),7.34-7.29(m,1H),7.19-7.13(m,2H),6.75-6.66(m,5H),6.27(t,J=2.1Hz,2H),5.65(d, J=2.3Hz,1H),5.11(s,2H),4.90-4.82(m,1H),3.82(dd,J=9.1,6.2Hz,2H),3.78(s,3H),3.67(dd,J=9.2,4.9Hz,2H),3.64(s,3H). Mass spectrometry (mass to charge ratio) is C 26 H 27 N4O4 + [M+H] + The theoretical value is 459.20268, and the measured value is 459.20270.

[0188] Example 32a Compound 32a (6 mg, 61.89% yield) was synthesized following general experimental procedure 1. 1H NMR(500MHz,CDCl3)δ7.35-7.27(m,3H),7.26-7.21(m,1H),7.12(d,J=2.2Hz,1H),6.73-6.65(m,5H),6.22(t,J=2. 0Hz,2H), 5.62(d,J=2.3Hz,1H),5.07(s,2H),4.87-4.78(m,1H),3.80-3.75(m,2H),3.74(s,3H),3.65-3.61(m,2H). Mass spectrometry (mass to charge ratio) is C 25 H 25 N4O4 + [M+H] + The theoretical value is 445.18703, and the measured value is 445.18728.

[0189] Example 33 [ka]

[0190] Compound 33 (23 milligrams, 27.14% yield) was synthesized following general experimental procedure 1. 1 H NMR(500MHz,CDCl3)δ8.44(d,J=4.7Hz,1H),7.38-7.34(m,2H),7.29(t,J=7.9Hz,1H),7.15(dd,J=7.6,1.3Hz,1H),6.72-6.67(m,5H) ),6.61(d,J=4.7Hz,1H),6.25(t,J=2.1Hz,2H),5.33(s,2H),4.87-4.81(m,1H),3.83-3.78(m,2H),3.67-3.64(m,2H),3.61(s,3H). Mass spectrometry (mass to charge ratio) is C 25 H 24 N3O4S + [M+H] + The theoretical value is 462.14820, and the measured value is 462.14835.

[0191] Example 33a Compound 33a (10 mg, 68.76% yield) was synthesized following general experimental procedure 1. 1H NMR(500MHz,CDCl3 / MeOH-d4)δ8.46-8.37(m,1H),7.35-7.29(m,2H),7.25-7.19(m,1H),7.16-7.05(m,1H),6.74-6.6 3(m,4H),6.63-6.52(m,2H),6.23-6.12(m,2H),5.26(s,2H),4.83-4.73(m,1H),3.77-3.67(m,2H),3.62-3.54(m,2H). Mass spectrometry (mass to charge ratio) is C 24 H 22 N3O4S + [M+H] + The theoretical value is 448.13255, and the measured value is 448.13272.

[0192] Example 34 [ka]

[0193] Compound 34 (40 mg, 75.16% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,CDCl3)δ8.39(s,1H),8.30(d,J=4.8Hz,1H),8.06(d,J=8.4Hz,1H),7.27(s,14H),7.17(dd,J=7.7,1.4Hz,1 H),6.88(s,1H),6.77-6.64(m,8H),6.26(t,J=2.1Hz,2H),4.82(t,J=5.5Hz,1H),3.86-3.78(m,2H),3.68-3.59(m,6H). Mass spectrometry (mass to charge ratio) is C 27 H 26 N5O4 + [M+H] + The theoretical value is 484.19793, and the measured value is 484.19885.

[0194] Example 34a Compound 34a (25 mg, 85.82% yield) was synthesized following general experimental procedure 2. 1H NMR(500MHz,MeOH-d4)δ10.15(d,J=2.6Hz,1H),9.72(dd,J=4.8,1.5Hz,1H), 9.55(ddd,J=8.4,2.7,1.4Hz,1H),8.96-8.89(m,1H),8.88-8.78(m,3H),8.52 (dd,J=7.6,1.3Hz,1H),8.30(t,J=2.1Hz,2H),8.28-8.20(m,3H),7.71(t,J=2 .1Hz,2H),6.39-6.27(m,1H),5.42-5.26(m,2H),5.05(dd,J=8.9,4.4Hz,2H). Mass spectrometry (mass to charge ratio) is C 26 H 24 N5O4 + [M+H] + The theoretical value is 470.18228, and the measured value is 470.18253.

[0195] Example 34b Compound 34b (20 mg, 76% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,MeOH-d4)δ8.60(d,J=2.4Hz,1H),8.16(dd,J=4.8,1.3Hz,1H),8.00(d,J=8.4Hz,1H),7.48-7.22(m,4H),6.87(d,J=7.5Hz,1H), 6.77(t,J=2.1Hz,2H),6.76-6.59(m,3H),6.18(t,J=2.2Hz,2H),4.84-4.78(m,1H),3.80(dd,J=8.7,6.1Hz,2H),3.50(dd,J=8.9,4.4Hz,2H). Mass spectrometry (mass to charge ratio) is C 26 H 25 N6O4 + [M+H] + The theoretical value is 485.2, and the measured value is 485.2.

[0196] Example 35 [ka]

[0197] Compound 35 (25 mg, 18% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,CDCl3)δ7.42(d,J=7.8Hz,2H),7.35-7.03(m,7H),6.77-6.60(m,5H),6.26 (t,J=2.1Hz,2H),4.90-4.79(m,1H),3.87-3.75(m,2H),3.71-3.64(m,4H),3.62(s,3H). Mass spectrometry (mass to charge ratio) is C 29 H 28 N3O4 + [M+H] + The theoretical value is 482.20, and the measured value is 482.20.

[0198] Example 35a Compound 35a (3.5 mg, 25% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,CDCl3)δ7.41(d,J=7.9Hz,2H),7.35-7.04(m,7H),6.81-6.61(m,5 H),6.30-6.17(m,2H),4.87-4.78(m,1H),3.84-3.74(m,2H),3.70-3.60(m,4H). Mass spectrometry (mass to charge ratio) is C 28 H 26 N3O4 + [M+H] + The theoretical value is 468.19, and the measured value is 468.20.

[0199] Example 36 [ka]

[0200] Compound 36 (28 milligrams, 66% yield) was synthesized following general experimental procedure 2. 1H NMR(500MHz,CDCl3)δ8.84-8.28(m,2H),7.79(d,J=8.0Hz,1H),7.44-7.23(m,9H),7.22-7.16(m,1H),7.07(d,J= 16.4Hz, 1H), 6.91 (d, J = 16.4Hz, 1H), 6.72-6.60 (m, 3H), 4.80-4.69 (m, 1H), 3.75-3.67 (m, 2H), 3.55-3.46 (m, 5H). Mass spectrometry (mass to charge ratio) is C 30 H 27 N2O3 + [M+H] + The theoretical value is 463.20, and the measured value is 463.20.

[0201] Example 36a Compound 36a (24 mg, 90% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,MeOH-d4)δ8.89-8.40(m,2H),8.40-8.28(m,1H),7.74-7.61(m,1H),7.58-7.48(m,2H),7.46-7.25 (m,7H),7.12(t,J=12.2Hz,2H),6.75(t,J=9.1Hz,3H),4.82-4.76(m,1H),3.81-3.71(m,2H),3.45-3.36(m,2H). Mass spectrometry (mass to charge ratio) is C 29 H 25 N2O3 + [M+H] + The theoretical value is 449.18597, and the measured value is 449.20.

[0202] Example 36b Compound 36b (10 mg, 59% yield) was synthesized following general experimental procedure 2. 1H NMR(400MHz,MeOH-d4)δ8.62(s,1H),8.36(d,J=4.0Hz,1H),8.02(d,J=7.9Hz,1H),7.48(d,J=8.5Hz,2H),7.43-7.17(m,8H) ,7.03(d,J=16.4Hz,1H),6.87(d,J=7.3Hz,1H),6.76-6.64(m,3H),4.83-4.73(m,1H),3.79-3.68(m,2H),3.43-3.36(m,2H). Mass spectrometry (mass to charge ratio) is C 29 H 26 N3O3 + [M+H] + The theoretical value is 464.19687, and the measured value is 464.20.

[0203] Example 37 [ka]

[0204] Compound 37 (27 milligrams, 56% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,CDCl3)δ7.56(d,J=10.6Hz,2H),7.37(t,J=7.8Hz,1H),7.34-7.27(m,5H),7.23(dd,J=7.7,1.2Hz,1H),7.21 -7.15(m,3H),6.84(s,1H),6.70-6.62(m,3H),6.58(s,1H),4.73(t,J=5.6Hz,1H),3.79-3.66(m,2H),3.58-3.46(m,5H). Mass spectrometry (mass to charge ratio) is C 31 H 24 ClF3N3O4 - [MH] - The theoretical value is 594.1, and the measured value is 594.2.

[0205] Example 37a Compound 37a (2.3 mg, 34% yield) was synthesized following general experimental procedure 2. 1H NMR(500MHz,MeOH-d4)δ7.88(d,J=2.2Hz,1H),7.58(dd,J=8.1,2.0Hz,1H),7.45(t,J=7.9Hz,1H),7.35-7.24(m,8H),7.12(d ,J=7.5Hz,1H),6.74(d,J=8.6Hz,1H),6.72-6.67(m,2H),4.80-4.76(m,1H),3.83-3.70(m,2H),3.42(dd,J=14.5,8.8Hz,2H). Mass spectrometry (mass to charge ratio) is C 30 H 22 ClF3N3O4 - [MH] - The theoretical value is 580.1, and the measured value is 580.2.

[0206] Example 38 [ka]

[0207] Compound 38 (23 milligrams, 55% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,CDCl3)δ8.14-7.89(m,2H),7.37-7.14(m,8H),7.12-7.03(m,1H),6.90-6.82(m, 1H),6.71-6.61(m,3H),4.81-4.70(m,1H),4.25(s,2H),3.83-3.63(m,2H),3.62-3.45(m,5H). Mass spectrometry (mass to charge ratio) is C 29 H 27 ClN3O3 + [M+H] + The theoretical value is 500.2, and the measured value is 500.2.

[0208] Example 38a Compound 38a (16 mg, 96% yield) was synthesized following general experimental procedure 2. 1H NMR(400MHz,MeOH-d4)δ7.95-7.87(m,1H),7.87-7.79(m,1H),7.49-7.12(m,10H),6.8 1-6.66(m,3H),4.83-4.75(m,1H),4.31(s,2H),3.84-3.69(m,2H),3.46-3.35(m,2H). Mass spectrometry (mass to charge ratio) is C 28 H 25 ClN3O3 + [M+H] + The theoretical value is 486.2, and the measured value is 486.1.

[0209] Example 38b Compound 38b (7.3 mg, 85% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,MeOH-d4)δ7.96-7.79(m,1H),7.79-7.61(m,1H),7.43-7.18(m,7H),7.14-7.02(m,1H),7.02-6.91(m ,1H),6.91-6.82(m,1H),6.76-6.61(m,3H),4.82-4.70(m,1H),4.25(s,2H),3.88-3.65(m,2H),3.48-3.27(m,2H). Mass spectrometry (mass to charge ratio) is C 28 H 26 ClN4O3 + [M+H] + The theoretical value is 501.2, and the measured value is 501.1.

[0210] Example 39 [ka]

[0211] Compound 39 (23 milligrams, 63% yield) was synthesized following general experimental procedure 2. 1H NMR(400MHz,CDCl3)δ8.08-8.01(m,1H),8.01-7.92(m,1H),7.41-7.15(m,11H),7.10-7.02(m,1H),6.90 -6.81(m,1H),6.71-6.58(m,2H),4.77-4.68(m,1H),4.25(s,2H),3.73-3.66(m,2H),3.55-3.42(m,5H). Mass spectrometry (mass to charge ratio) is C 29 H 28 N3O3 + [M+H] + The theoretical value is 466.2, and the measured value is 466.2.

[0212] Example 39a Compound 39a (1.6 mg, 32% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,MeOH-d4)δ7.92-7.81(m,1H),7.79-7.68(m,1H),7.38-7.14(m,9H),7.12-7.01(m ,2H),6.73-6.60(m,3H),4.76-4.66(m,1H),4.25(s,2H),3.73-3.66(m,2H),3.38-3.33(m,2H). Mass spectrometry (mass to charge ratio) is C 28 H 26 N3O3 + [M+H] + The theoretical value is 452.2, and the measured value is 452.2.

[0213] Example 39b Compound 39b (2.2 mg, 37% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,MeOH-d4)δ7.92-7.82(m,1H),7.77-7.66(m,1H),7.41-7.18(m,8H),7.16-7.09(m,1H),7.03-6.95(m ,1H),6.89-6.82(m,1H),6.74-6.60(m,3H),4.77-4.70(m,1H),4.25(s,2H),3.76-3.67(m,2H),3.40-3.34(m,2H). Mass spectrometry (mass to charge ratio) is C 28 H 27N4O3 + [M+H] + The theoretical value is 467.2, and the measured value is 467.2.

[0214] Example 40 [ka]

[0215] Compound 40 (65 mg, 59% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,CDCl3)δ8.46-8.37(m,1H),8.37-8.29(m,1H),8.17-8.06(m,1H),7.44-7. 06(m,10H),6.75-6.62(m,3H),4.80-4.68(m,1H),3.77-3.61(m,4H),3.55-3.45(m,5H). Mass spectrometry (mass to charge ratio) is C 30 H 28 N3O4 + [M+H] + The theoretical value is 494.2, and the measured value is 494.2.

[0216] Example 40a Compound 40a (5 mg, 51% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,MeOH-d4)δ8.76-8.63(m,1H),8.32-8.15(m,1H),8.14-8.02(m,1H),7.44-7.18(m,9H),7.1 5-7.07(m,1H),6.76-6.62(m,3H),4.77-4.70(m,1H),3.76-3.65(m,2H),3.62(s,2H),3.39-3.33(m,2H). Mass spectrometry (mass to charge ratio) is C 29 H 26 N3O4 + [M+H] + The theoretical value is 480.2, and the measured value is 480.2.

[0217] Example 40b Compound 40b (3.2 mg, 46% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,MeOH-d4)δ8.75-8.63(m,1H),8.27-8.17(m,1H),8.13-8.03(m,1H),7.43-7.15(m,9H),6.8 8-6.79(m,1H),6.72-6.59(m,3H),4.79-4.69(m,1H),3.75-3.66(m,2H),3.59(s,2H),3.40-3.31(m,2H). Mass spectrometry (mass to charge ratio) is C 29 H 27 N4O4 + [M+H] + The theoretical value is 495.2, and the measured value is 495.2.

[0218] Example 40c Refer to General Experimental Procedure 2, Compound 40c (7.3 mg, yield 44%) synthesized . 1 H NMR(400MHz,CDCl3)δ8.49-8.41(m,1H),8.30(d,J=4.0Hz,1H),8.16(d,J=8.3Hz,1H),7.93-7.84(m,1H),7.42-7.21(m,6H),7.16-7.08(m,2H),7.0 8-7.01(m,1H),6.71-6.55(m,3H),5.17-5.06(m,1H),4.79-4.67(m,1H), 3.76-3.67(m,2H),3.62(s,2H),3.51-3.44(m,2H),2.57(d,J=4.9Hz,3H). Mass spectrometry (mass to charge ratio) is C 30 H 29 N4O3 + [M+H] + The theoretical value is 493.2, and the measured value is 493.1.

[0219] Example 41 [ka]

[0220] Compound 41 (50 milligrams, 48.31% yield) was synthesized following general experimental procedure 2.1 H NMR(400MHz,CDCl3)δ8.38(d,J=2.4Hz,1H),8.28(dd,J=4.8,1.3Hz,1H),8.15-8.04(m,1H),7.36-7.30(m,4H),7.27-7.19(m,4H),6.89-6. 81(m,1H),6.73-6.62(m,3H),4.78-4.71(m,1H),3.83-3.75(m,1H),3 .74-3.65(m,1H),3.59(s,3H),3.58-3.53(m,1H),3.52-3.44(m,1H). Mass spectrometry (mass to charge ratio) is C 29 H 26 ClN4O4 + [M+H] + The theoretical value is 529.16371, and the measured value is 529.16412.

[0221] Example 41a Compound 41a (3 milligrams, 30.82% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,MeOH-d4)δ8.64-8.58(m,1H),8.19(d,J=3.6Hz,1H),8.04-7.98(m,1H),7.40-7.30(m,7H),7.29-7.24(m, 1H),7.17-7.13(m,1H),6.79-6.75(m,1H),6.74-6.69(m,2H),4.82-4.79(m,1H),3.83-3.72(m,2H),3.48-3.41(m,2H). Mass spectrometry (mass to charge ratio) is C 28 H 24 ClN4O4 + [M+H] + The theoretical value is 515.14806, and the measured value is 515.14850.

[0222] Example 41b Compound 41b (11 milligrams, 42.49% yield) was synthesized following general experimental procedure 2. 1H NMR(500MHz,MeOH-d4)δ8.58(d,J=2.4Hz,1H),8.16(dd,J=4.8,1.1Hz,1H),8.02-7.95(m,1H),7.40-7.26(m,8H), 6.89-6.84(m,1H),6.76-6.71(m,1H),6.71-6.66(m,2H),4.82-4.76(m,1H),3.86-3.71(m,2H),3.49-3.36(m,2H). Mass spectrometry (mass to charge ratio) is C 28 H 25 ClN5O4 + [M+H] + The theoretical value is 530.15896, and the measured value is 530.15936.

[0223] Example 42 [ka]

[0224] Compound 42 (50 milligrams, 47.32% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,MeOH-d4)δ8.85-8.76(m,1H),8.42-8.33(m,1H),8.25-8.16(m,1H),7.66-7.41(m,9H),7.35-7.23(m ,1H),7.03-6.93(m,1H),6.92-6.84(m,2H),5.00-4.91(m,1H),3.99-3.91(m,2H),3.68(s,3H),3.64-3.57(m,2H). Mass spectrometry (mass to charge ratio) is C 29 H 27 N4O4 + [M+H] + The theoretical value is 495.20268, and the measured value is 495.20291.

[0225] Example 42a Compound 42a (4.2 mg, 36.02% yield) was synthesized following general experimental procedure 2. 1H NMR(500MHz,MeOH-d4)δ8.59(d,J=2.2Hz,1H),8.17(dd,J=4.8,1.4Hz,1H),8.01-7.97(m,1H),7.38-7.31(m,4H),7.31-7.26(m, 5H),7.11(dd,J=7.6,1.0Hz,1H),6.75-6.71(m,1H),6.69-6.64(m,2H),4.76-4.71(m,1H),3.73-3.69(m,2H),3.39-3.36(m,2H). Mass spectrometry (mass to charge ratio) is C 28 H 25 N4O4 + [M+H] + The theoretical value is 481.18703, and the measured value is 481.18729.

[0226] Example 42b Compound 42b (7.5 mg, 35.09% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,MeOH-d4)δ8.61(d,J=2.0Hz,1H),8.22-8.16(m,1H),8.04-7.96(m,1H),7.41-7.34(m,6H),7.33-7.28(m,3H), 6.88(dd,J=7.5,0.9Hz,1H),6.75-6.71(m,1H),6.71-6.66(m,2H),4.81-4.73(m,1H),3.79-3.71(m,2H),3.42-3.38(m,2H). Mass spectrometry (mass to charge ratio) is C 28 H 26 N5O4 + [M+H] + The theoretical value is 496.19793, and the measured value is 496.19809.

[0227] Example 42c Compound 42c (20 mg, 64.91% yield) was synthesized following general experimental procedure 2. 1H NMR(500MHz,CDCl3)δ8.54(s,1H),8.44(d,J=2.4Hz,1H),8.19(dd,J=4.7,1.1Hz,1H ),8.15-8.09(m,1H),7.72(s,1H),7.36-7.18(m,7H),7.02(dd,J=7.5,0.9Hz,1H),6 .78-6.72(m,2H),6.61(dd,J=8.3,0.8Hz,1H),6.46-6.39(m,2H),5.42(q,J=4.8Hz, 1H),4.67-4.60(m,1H),3.66-3.59(m,2H),3.38-3.32(m,2H),2.59(d,J=4.9Hz,3H). Mass spectrometry (mass to charge ratio) is C 29 H 28 N5O3 + [M+H] + The theoretical value is 494.21867, and the measured value is 494.21881.

[0228] Example 43 [ka]

[0229] Compound 43 (60 mg, 56% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,CDCl3)δ8.49-8.39(m,1H),8.36-8.29(m,1H),8.18-7.98(m,1H),7.49-7.40(m,1H),7.39-7.20(m,6H),7.17-7.11(m ,1H),6.84(d,J=8.6Hz,2H),6.70-6.62(m,1H),5.15-5.05(m,1H),4.44-4.32(m,2H),3.99-3.91(m,2H),3.90(s,3H),3.72(s,2H). Mass spectrometry (mass to charge ratio) is C 24 H 24 N3O4 + [M+H] + The theoretical value is 418.2, and the measured value is 418.1.

[0230] Example 43a Compound 43a (30 mg, 68% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,MeOH-d4)δ8.78-8.67(m,1H),8.30-8.20(m,1H),8.16-8.07(m,1H),7.45-7.22(m,5H),7.17-7.08(m ,1H),6.91-6.80(m,2H),6.79-6.69(m,1H),5.19-5.07(m,1H),4.40-4.31(m,2H),3.90-3.79(m,2H),3.67(s,2H). Mass spectrometry (mass to charge ratio) is C 23 H 22 N3O4 + [M+H] + The theoretical value is 404.2, and the measured value is 404.1.

[0231] Example 43b Compound 43b (2.3 mg, 27% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,MeOH-d4)δ8.77-8.66(m,1H),8.28-8.19(m,1H),8.15-8.04(m,1H),7.43-7.19(m,4H),7.11-7.02(m,1H),6 .89-6.79(m,3H),6.71-6.61(m,1H),5.17-5.10(m,1H),4.57(s,1H),4.40-4.29(m,2H),3.90-3.77(m,2H),3.66(s,2H). Mass spectrometry (mass to charge ratio) is C 23 H 23 N4O4 + [M+H] + The theoretical value is 419.2, and the measured value is 419.1.

[0232] Example 43c Compound 43c (10.5 mg, 6.8% yield) was synthesized following general experimental procedure 2. 1H NMR(400MHz,MeOH-d4)δ8.73(s,1H),8.24(d,J=4.2Hz,1H),8.15-8.06(m,1H),7.41-7.32(m,1H),7.29(d,J=8.7Hz,2H),7.22-7.13(m ,2H),6.88-6.78(m,2H),6.77-6.68(m,1H),6.54-6.45(m,2H),5.12-5.03(m,1H),4.33-4.21(m,2H),3.81-3.72(m,2H),3.65(s,2H). Mass spectrometry (mass to charge ratio) is C 22 H 22 N3O2 + [M+H] + The theoretical value is 360.2, and the measured value is 360.0.

[0233] Example 44 [ka]

[0234] Compound 44 (15 mg, 36% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,CDCl3)δ8.64-8.53(m,1H),8.41-8.33(m,1H),8.33-8.22(m,1H),8.14-8.03(m,1H),7.70-7.56(m,2H),7.32-6.99(m, 8H),6.70-6.62(m,1H),6.62-6.56(m,2H),6.56-6.48(m,1H),4.71-4.59(m,1H),3.75-3.61(m,2H),3.59(s,2H),3.55-3.39(m,5H). Mass spectrometry (mass to charge ratio) is C 32 H 29 N4O4 + [M+H] + The theoretical value is 533.2, and the measured value is 533.2.

[0235] Example 44a Compound 44a (3 mg, 25% yield) was synthesized following general experimental procedure 2. 1H NMR(400MHz,MeOH-d4)δ8.73-8.64(m,1H),8.27-8.20(m,1H),8.12-8.04(m,1H),7.55-7.46(m,1H),7.42-7.30(m,2H),7.27-7.13(m ,4H),7.06-6.96(m,2H),6.73-6.52(m,3H),6.48-6.38(m,1H),4.73-4.66(m,1H),3.76-3.62(m,2H),3.60(s,2H),3.39-3.34(m,2H). Mass spectrometry (mass to charge ratio) is C 31 H 27 N4O4 + [M+H] + The theoretical value is 519.2, and the measured value is 519.2.

[0236] Example 45 [ka]

[0237] Refer to General Experimental Procedure 2, Compound 45 (Yield 75.86%) They were synthesized. 1 H NMR(500MHz,CDCl3)δ8.60-8.54(m,2H),7.75-7.69(m,1H),7.38-7.26(m,9H),7.20(dd,J=7.6,1.0Hz,1H),7.07-7.03 (br,1H),6.68-6.64(m,1H),6.61-6.55(m,2H),4.73-4.64(m,1H),3.70-3.64(m,4H),3.51(s,3H),3.49-3.45(m,2H). Mass spectrometry (mass to charge ratio) is C 30 H 28 N3O4 + [M+H] + The theoretical value is 494.20743, and the measured value is 494.20764.

[0238] Example 45a Compound 45a (30 mg, 77.19% yield) was synthesized following general experimental procedure 2. 1H NMR(500MHz,MeOH-d4)δ8.51(d,J=1.6Hz,1H),8.44(dd,J=4.9,1.3Hz,1H),7.84(dt,J=7.9,1.9Hz,1H),7.46-7.37(m,3H),7.37-7.25(m, 6H),7.11(dd,J=7.6,1.0Hz,1H),6.73(dd,J=8.2,1.0Hz,1H),6.68-6.60(m,2H),4.74-4.70(m,1H),3.73-3.67(m,4H),3.38-3.34(m,2H). Mass spectrometry (mass to charge ratio) is C 29 H 26 N3O4 + [M+H] + The theoretical value is 480.19178, and the measured value is 480.19202.

[0239] Example 45b Compound 45b (8.1 mg, 47.39% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,MeOH-d4)δ8.57-8.49(m,1H),8.49-8.41(m,1H),7.89-7.83(m,1H),7.46-7.27(m,9H),6.91-6 .85(m,1H),6.75-6.70(m,1H),6.70-6.63(m,2H),4.79-4.72(m,1H),3.79-3.70(m,4H),3.41-3.37(m,2H). Mass spectrometry (mass to charge ratio) is C 29 H 27 N4O4 + [M+H] + The theoretical value is 495.20268, and the measured value is 495.20288.

[0240] Example 45c Compound 45c (10.3 mg, 50% yield) was synthesized following general experimental procedure 2. 1H NMR(400MHz,MeOH-d4)δ8.51(s,1H),8.44(d,J=4.1Hz,1H),7.88-7.81(m,1H),7.79-7.71(m,1H),7.46-7.22(m,9H),6.85 (dd,J=7.5,1.0Hz,1H),6.71-6.61(m,3H),4.77-4.69(m,1H),3.78-3.67(m,4H),3.41-3.33(m,2H),2.52(d,J=3.9Hz,3H). Mass spectrometry (mass to charge ratio) is C 30 H 29 N4O3 + [M+H] + The theoretical value is 493.2, and the measured value is 493.0.

[0241] Example 45d Compound 45d (7.3 mg, 34% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,MeOH-d4)δ8.51(d,J=1.7Hz,1H),8.44(dd,J=4.9,1.4Hz,1H),7.84(dt,J=7.9,1.8Hz,1H),7.47-7.23(m,9H),6.85(dd,J=7 .5,0.9Hz,1H),6.74-6.68(m,1H),6.68-6.62(m,2H),4.78-4.70(m,1H),3.79-3.73(m,2H),3.71(s,2H),3.42-3.37(m,2H),3.28(s,3H). Mass spectrometry (mass to charge ratio) is C 30 H 29 N4O4 + [M+H] + The theoretical value is 509.2, and the measured value is 509.2.

[0242] Example 45e Compound 45e (9.2 mg, 50% yield) was synthesized following general experimental procedure 2. 11H NMR (400 MHz, CDCl3) δ 8.63-8.46 (m, 2H), 7.73 (d, J=7.8 Hz, 1H), 7.49-7.20 (m, 10H), 7.19-7.09 (m, 1H), 6.94-6.85 (m, 1H), 6.66-6.54 (m, 3H), 4.81-4.71 (m, 1H), 3.92-3.79 (m, 2H), 3.67 (s, 2H), 3.57-3.46 (m, 2H). Mass spectrometry (mass-to-charge ratio) for C 28 H 26 N3O2 + [M+H] + , the theoretical value is 436.2, and the measured value is 436.1.

[0243] Example 46 [Chemical Formula]

[0244] Referring to General Experimental Procedure 2, Compound 46 (41 mg, 59% yield) was synthesized. 1 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 8.15 (d, J=2.6 Hz, 1H), 7.94 (dt, J=11.7, 2.3 Hz, 1H), 7.37-7.29 (m, 3H), 7.01 (dd, J=7.6, 1.1 Hz, 1H), 6.80 (dd, J=8.3, 1.0 Hz, 1H), 6.74-6.69 (m, 4H), 6.14 (t, J=2.1 Hz, 2H), 4.93-4.79 (m, 1H), 3.81 (dd, J=8.7, 6.3 Hz, 2H), 3.48 (s, 3H), 3.45 (dd, J=9.0, 4.1 Hz, 2H) ppm. Mass spectrometry (mass-to-charge ratio) for C 27 H 24 FN5O4 + [M+H] + , the theoretical value is 502.2, and the measured value is 502.1.

[0245] Example 46a: Referring to General Experimental Procedure 2, Compound 46a (11 mg, 79% yield) was synthesized. 1H NMR(500MHz,DMSO-d6)δ10.06(s,1H),9.58(s,1H),8.39(s,1H),8.11(s,1H), 7.92(d,J=11.8Hz,1H),7.33(d,J=8.9Hz,2H),7.22(t,J=7.6Hz,1H),6.92(d,J =7.5Hz,1H),6.72(t,J=1.9Hz,2H),6.67(d,J=8.9Hz,2H),6.59(d,J=6.5Hz,1 H),6.05(s,2H),4.83(s,1H),3.71(t,J=7.1Hz,2H),3.37(d,J=6.8Hz,2H)ppm. Mass spectrometry (mass to charge ratio) is C 26 H 22 FN5O4 + [M+H] + The theoretical value is 488.17286, and the measured value is 488.17319.

[0246] Example 47 [ka]

[0247] Compound 47 (54 milligrams, 78% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,DMSO-d6)δ8.71(s,1H),8.61(s,1H),8.36(s,1H),8.00(s,1H),7.75(s,1H) ),7.34(dd,J=15.3,8.5Hz,3H),7.01(dd,J=7.6,1.2Hz,1H),6.80(dd,J=8.3,1.2Hz,1H) ,6.73(t,J=2.1Hz,2H),6.69(d,J=9.0Hz,2H),6.14(t,J=2.1Hz,2H),4.93-4.79(m,1H) ,3.81(dd,J=8.8,6.3Hz,2H),3.48(s,3H),3.45(dd,J=8.9,4.2Hz,2H),2.26(s,3H)ppm. Mass spectrometry (mass to charge ratio) is C 28 H 27 N5O4 + [M+H] + The theoretical value is 498.2, and the measured value is 498.1.

[0248] Example 47a Compound 47a (11 milligrams, 75% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,DMSO-d6)δ9.56(s,1H),9.40(s,1H),8.41(s,1H),7.98(s,1H),7.72 (s,1H),7.32(d,J=9.0Hz,2H),7.21(t,J=7.7Hz,1H),6.90(d,J=7.6Hz,1H),6.72 (t,J=2.0Hz,2H),6.67(d,J=9.0Hz,2H),6.57(d,J=7.7Hz,1H),6.06(s,2H),4.83 (d,J=4.6Hz,1H),3.69(t,J=7.3Hz,2H),3.38(d,J=11.6Hz,2H),2.25(s,3H)ppm. Mass spectrometry (mass to charge ratio) is C 27 H 25 N5O4 + [M+H] + The theoretical value is 484.19793, and the measured value is 484.19809.

[0249] Example 48 [ka]

[0250] Compound 48 (1.3 mg, 2% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,CDCl3)δ8.66-8.44(m,2H),7.78-7.68(m,1H),7.40-7.06(m,9H),6 .73-6.55(m,3H),4.79-4.67(m,1H),3.83-3.60(m,4H),3.51(d,J=47.9Hz,5H). Mass spectrometry (mass to charge ratio) is C 30 H 27 ClN3O4 + [M+H] + The theoretical value is 528.2, and the measured value is 528.1.

[0251] Example 48a Compound 48a (2 milligrams, 20% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,MeOH-d4)δ8.57-8.48(m,1H),8.48-8.40(m,1H),7.85(d,J=7.8Hz,1H),7.47-7.26(m,7H),7.26-7.19(m, 1H),7.19-7.11(m,1H),6.80-6.72(m,1H),6.72-6.65(m,2H),4.81-4.74(m,1H),3.85-3.68(m,4H),3.47-3.34(m,2H). Mass spectrometry (mass to charge ratio) is C 29 H 25 ClN3O4 + [M+H] + The theoretical value is 514.2, and the measured value is 514.1.

[0252] Example 49 [ka]

[0253] Compound 49 (6.6 mg, 13% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,CDCl3)δ8.64-8.44(m,2H),7.81-7.70(m,1H),7.53-7.19(m,6H),7.17-7.06(m,1H),6.81 -6.70(m,2H),6.68-6.61(m,1H),5.09-5.00(m,1H),4.38-4.28(m,2H),3.97-3.84(m,5H),3.70(s,2H). Mass spectrometry (mass to charge ratio) is C 24 H 24 N3O4 + [M+H] + The theoretical value is 418.2, and the measured value is 418.1.

[0254] Example 49a Compound 49a (3.2 mg, 66% yield) was synthesized following general experimental procedure 2. 1H NMR(500MHz,MeOH-d4)δ8.53(s,1H),8.45(d,J=3.9Hz,1H),7.86(d,J=7.9Hz,1H),7.52-7.35(m,4H),7.28(t,J=7.9Hz,1H) ,7.13(s,1H),6.88-6.79(m,2H),6.78-6.69(m,1H),5.15-5.07(m,1H),4.39-4.28(m,2H),3.87-3.80(m,2H),3.73(s,2H). Mass spectrometry (mass to charge ratio) is C 23 H 22 N3O4 + [M+H] + The theoretical value is 404.2, and the measured value is 404.1.

[0255] Example 50 [ka]

[0256] Compound 50 (80 milligrams, 57.04% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,MeOH-d4)δ8.61(d,J=2.6Hz,1H),8.18(dd,J=4.8,1.4Hz,1H),8 .01(ddd,J=8.4,2.6,1.4Hz,1H),7.43-7.35(m,4H),7.30(t,J=7.9Hz,1H),7 .13(dd,J=2.5,1.6Hz,1H),6.91-6.81(m,2H),6.76(ddd,J=8.1,2.6,1.1Hz, 1H), 5.13 (ddd, J=6.1, 4.1, 1.9Hz, 1H), 4.40-4.29 (m, 2H), 3.92-3.78 (m, 6H). Mass spectrometry (mass to charge ratio) is C 23 H 23 N4O4 + [M+H] + The theoretical value is 419.17138, and the measured value is 419.17139.

[0257] Example 50a Compound 50a (17 mg, 70.36% yield) was synthesized following general experimental procedure 2. 1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),9.45(s,1H),8.65(s,1H),8.25-8.05(m,1H),8.01-7.86(m,1H),7.43(d,J=8.5Hz,2H),7.34-7.22(m,3H) ),7.04(s,1H),6.85(d,J=8.6Hz,2H),6.69(d,J=7.0Hz,1H),5.12(h,J=4.3Hz,1H),4.34(dd,J=8.4,6.1Hz,2H),3.80(dd,J=8.4,4.0Hz,2H). Mass spectrometry (mass to charge ratio) is C 22 H 21 N4O4 + [M+H] + The theoretical value is 405.15573, and the measured value is 405.15573.

[0258] Example 51 [ka]

[0259] Compound 51 (55 milligrams, 75.31% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,CDCl3)δ8.61-8.54(m,2H),7.76-7.69(m,1H),7.35-7.30(m,3 H),7.29-7.27(m,1H),7.14(dd,J=7.6,1.1Hz,1H),7.01(br,1H),6.69(t,J =2.1Hz,2H),6.67(d,J=7.3Hz,1H),6.63(d,J=9.0Hz,2H),6.24(t,J=2.1Hz ,2H),4.82-4.75(m,1H),3.80-3.74(m,2H),3.70(s,2H),3.65-3.57(m,5H). Mass spectrometry (mass to charge ratio) is C 28 H 27 N4O4 + [M+H] + The theoretical value is 483.20268, and the measured value is 483.20282.

[0260] Example 51a Compound 51a (15 mg, 61.80% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,MeOH-d4)δ8.54(d,J=1.6Hz,1H),8.46(dd,J=4.9,1.3Hz,1H),7 .90-7.84(m,1H),7.48-7.41(m,3H),7.33(t,J=7.9Hz,1H),7.09(dd,J=7.6, 1.1Hz,1H),6.77(dd,J=8.2,1.1Hz,1H),6.74-6.66(m,4H),6.20(t,J=2.1Hz ,2H),4.82-4.79(m,1H),3.86-3.78(m,2H),3.74(s,2H),3.57-3.51(m,2H). Mass spectrometry (mass to charge ratio) is C 27 H 25 N4O4 + [M+H] + The theoretical value is 469.18703, and the measured value is 469.18716.

[0261] Example 52 [ka]

[0262] Compound 52 (65 milligrams, 82.55% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,CDCl3)δ8.61(M,2H),8.03(t,J=9.0Hz,1H),7.81-7.69(m,1H),7.39-7.29(m,2H),7.20(br,1H),7.19-7.15(m,1H),6.75-6.66 (m,3H),6.52-6.47(m,1H),6.46-6.42(m,1H),6.26(t,J=2.0Hz,2H),4.83-4.75(m,1H),3.83-3.77(m,2H),3.76(s,2H),3.66-3.59(m,5H). Mass spectrometry (mass to charge ratio) is C 28 H 26 FN4O4 + [M+H] + The theoretical value is 501.19326, and the measured value is 501.19354.

[0263] Example 52a With reference to General Experimental Procedure 2, Compound 52a (20 milligrams, yield 51.44%) was synthesized. 1 1H NMR (400 MHz, MeOH-d4) δ 8.56 (s, 1H), 8.47 (d, J=4.3 Hz, 1H), 7.94-7.84 (m, 1H), 7.63-7.53 (m, 1H), 7.46 (dd, J=7.8, 4.9 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.08 (dd, J=7.6, 1.3 Hz, 1H), 6.77 (dd, J=8.2, 1.2 Hz, 1H), 6.72 (t, J=2.1 Hz, 2H), 6.63 (dd, J=12.0, 2.7 Hz, 1H), 6.58-6.52 (m, 1H), 6.20 (t, J=2.1 Hz, 2H), 5.09-5.01 (m, 1H), 3.88-3.79 (m, 4H), 3.55-3.49 (m, 2H). Mass spectrometry (mass-to-charge ratio): C 27 H 24 FN4O4 + [M+H] + , theoretical value: 487.17761, measured value: 487.17767.

[0264] Example 53

Chemical Formula

[0265] With reference to General Experimental Procedure 2, Compound 53 (90 milligrams, yield 65.15%) was synthesized. 1 1H NMR (500 MHz, CDCl3) δ 8.61-8.53 (m, 2H), 7.78-7.67 (m, 1H), 7.40-7.35 (m, 2H), 7.35-7.29 (m, 2H), 7.15 (t, J=7.9 Hz, 1H), 7.09 (br, 1H), 6.78-6.74 (m, 2H), 6.70 (d, J=7.5 Hz, 1H), 5.05-4.93 (m, 1H), 4.37-4.29 (m, 2H), 3.92-3.85 (m, 5H), 3.71 (s, 2H), 2.34 (s, 3H). Mass spectrometry (mass-to-charge ratio): C 25 H 26 N3O4 +[M+H] + The theoretical value is 432.19178, and the measured value is 432.19177.

[0266] Example 53a Compound 53a (12 mg, 72.96% yield) was synthesized following general experimental procedure 2. 1 H NMR(400MHz,MeOH-d4)δ8.55(d,J=1.3Hz,1H),8.50-8.42(m,1H),7.92-7.86(m,1H),7.52-7.42(m,3H),7.31-7.26(m,1H),7.17(t,J= 7.9Hz,1H),6.90-6.84(m,2H),6.83-6.77(m,1H),5.08-5.05(m,1H),4.43-4.35(m,2H),3.89-3.82(m,2H),3.76(s,2H),2.36(s,3H). Mass spectrometry (mass to charge ratio) is C 24 H 22 N3O4 - [MH] - The theoretical value is 416.16158, and the measured value is 416.16177.

[0267] Example 54 [ka]

[0268] Compound 54 (45 mg, 73.64% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,CDCl3)δ8.62-8.54(m,2H),7.99(t,J=9.0Hz,1H),7.75-7.68(m,1H),7.38-7.26(m,7H),7.21(d,J=6.7Hz,1H),7.13(br,1H),6.70- 6.62(m,1H),6.43(dd,J=12.2,2.7Hz,1H),6.40-6.34(m,1H),4.69-4.64 (m,1H),3.73(s,2H),3.70-3.63(m,2H),3.51(s,3H),3.47-3.42(m,2H). Mass spectrometry (mass to charge ratio) is C 30 H 27FN3O4 + [M+H] + The theoretical value is 512.19801, and the measured value is 512.19824.

[0269] Example 54a Compound 54a (6 mg, 41.13% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,MeOH-d4)δ8.52(d,J=1.8Hz,1H),8.44(dd,J=4.9,1.3Hz,1H),7.87 -7.83(m,1H),7.53(t,J=8.9Hz,1H),7.45-7.40(m,1H),7.37-7.26(m,6H),7.14- 7.08(m,1H),6.77-6.71(m,1H),6.57(dd,J=12.1,2.7Hz,1H),6.53-6.46(m,1H) ,4.76-4.75(m,1H),3.77(s,2H),3.72(dd,J=8.9,6.2Hz,2H),3.38-3.35(m,2H). Mass spectrometry (mass to charge ratio) is C 29 H 25 FN3O4 + [M+H] + The theoretical value is 498.18236, and the measured value is 498.18250.

[0270] Example 55 [ka]

[0271] Compound 55 (80 milligrams, 73.64% yield) was synthesized following general experimental procedure 2. 1H NMR(500MHz,CDCl3)δ8.57(d,J=2.7Hz,2H),7.77-7.71(m,1H),7.41-7.36(m,2H),7.34-7.29(m,2H),7.20-7.11(m,2H),6.76 -6.72(m,2H),6.66(dd,J=7.7,1.9Hz,1H),5.00-4.95(m,1H),4.57-4.49(m,2H),4.05-4.01(m,2H),3.91(s,3H),3.70(s,2H). Mass spectrometry (mass to charge ratio) is C 24 H 23 ClN3O4 + [M+H] + The theoretical value is 452.13716, and the measured value is 452.13699.

[0272] Example 55a Compound 55a (11 mg, 70.95% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,MeOH-d4)δ8.54(d,J=1.7Hz,1H),8.46(dd,J=4.9,1.3Hz,1H),7.91-7.86(m,1H),7.50-7.43(m,3H),7.22(t,J=7.9Hz,1H),7.11 (dd,J=7.6,1.4Hz,1H),6.87-6.81(m,2H),6.78(dd,J=8.2,1.3Hz,1H),5.06-5.03(m,1H),4.56-4.52(m,2H),4.02-3.96(m,2H),3.74(s,2H). Mass spectrometry (mass to charge ratio) is C 23 H 21 ClN3O4 + [M+H] + The theoretical value is 438.1, and the measured value is 438.0.

[0273] Example 56 [ka]

[0274] Compound 56 (12 milligrams, 26.49% yield) was synthesized following general experimental procedure 2. 1H NMR(500MHz,CDCl3)δ7.59(s,1H),7.29(t,J=7.9Hz,1H),7.19-6.94(m,5H),6.70(t,J=2.1Hz,2H),6.69-6.65(m,3H),6.2 4(t,J=2.1Hz,2H),5.03(s,2H),4.85-4.77(m,1H),3.79(dd,J=9.1,6.2Hz,2H),3.64(dd,J=9.1,4.8Hz,2H),3.61(s,3H). Mass spectrometry (mass to charge ratio) is C 25 H 25 N4O3 + [M+H] + The theoretical value is 429.2, and the measured value is 429.2.

[0275] Example 56a Compound 56a (2 milligrams, 20.68% yield) was synthesized following general experimental procedure 2. 1 H NMR(500MHz,MeOH-d4)δ7.96(s,1H),7.27(t,J=7.9Hz,1H),7.23-7.19(m,2H),7.19-7.16(m,1H),7.10-7.06(m,1H),7.00-6.95(m,1H),6. 76-6.71(m,4H),6.69-6.66(m,1H),6.15(t,J=2.0Hz,2H),5.17(s,2H),4.87-4.85(m,1H),3.82-3.76(m,2H),3.49(dd,J=8.9,4.4Hz,2H). Mass spectrometry (mass to charge ratio) is C 24 H 23 N4O3 + [M+H] + The theoretical value is 415.2, and the measured value is 415.2.

[0276] Example 57 [ka]

[0277] Compound 57 (120 mg, 71.0% yield) was synthesized following general experimental procedure 3. 1H NMR(400MHz,MeOD)δ8.60(s,1H),8.24-8.15(m,1H),8.00(d,J=9.3Hz,1H),7.72(dd,J=7.8,3.5Hz,2H),7.46(t,J=7.8Hz,1H),7.42-7.31(m,4 H),7.11(d,J=8.7Hz,2H),7.03(dd,J=8.3,1.9Hz,1H),6.96(s,1H),6.88(d,J=7.6Hz,1H),4.12-4.02(m,2H),3.92-3.83(m,2H),3.58(s,3H). Mass spectrometry (mass to charge ratio) is C 30 H 26 N3O5 + [M+H] + The theoretical value is 508.19, and the measured value is 508.20.

[0278] Example 58 [ka]

[0279] Compound 58 (50 milligrams, 52.80% yield) was synthesized following general experimental procedure 3. 1 H NMR(500MHz,MeOH-d4)δ8.60(d,J=2.4Hz,1H),8.19(dd,J=4.8,1.2Hz,1H),8.01(ddd,J=8.4,2.6,1.4Hz,1H),7 .73(d,J=7.8Hz,2H),7.48-7.41(m,4H),7.39-7.35(m,3H),7.34-7.30(m,2H),7.09-7.04(m,2H),3.55(s,3H). Mass spectrometry (mass to charge ratio) is C 28 H 22 N3O3 + [M+H] + The theoretical value is 448.16557, and the measured value is 448.16568.

[0280] Example 58a Compound 58a (1.4 mg, 14.45% yield) was synthesized following general experimental procedure 3. 1H NMR (400MHz, MeOH-d4) δ8.62-8.56(m,1H),8.22-8.16(m,1H),8.05-7.99(m,1H),7.75-7.62(m,3H),7.43-7.36(m,8H),7.10-7.06(m,2H). Mass spectrometry (mass to charge ratio) is C 27 H 18 N3O3 - [MH] - The theoretical value is 432.13537, and the measured value is 432.13550.

[0281] Example 58b Compound 58b (3.7 mg, 43.94% yield) was synthesized following general experimental procedure 3. 1 H NMR(500MHz,MeOH-d4)δ8.61(s,1H),8.19(d,J=4.5Hz,1H),8.01(d,J=8.9Hz,1H),7.70-7.65(m,1H),7.47-7.36(m,10H),7.12-7.05(m,2H). Mass spectrometry (mass to charge ratio) is C 27 H 19 N4O3 - [MH] - The theoretical value is 447.14626, and the measured value is 447.14661.

[0282] Example 59 [ka]

[0283] Compound 59 (40 mg, 41.15% yield) was synthesized following general experimental procedure 3. 1H NMR(500MHz,MeOH-d4)δ8.58(d,J=2.4Hz,1H),8.18(dd,J=4.8,1.4Hz,1H),7. 99(ddd,J=8.4,2.6,1.4Hz,1H),7.71(dd,J=7.7,1.3Hz,1H),7.65(dd,J=7.8,1 .3Hz,1H),7.60(dd,J=8.1,0.5Hz,1H),7.44-7.39(m,2H),7.38-7.33(m,1H),7 .32-7.27(m,3H),7.01-6.95(m,3H),6.52(dd,J=3.1,0.9Hz,1H),3.49(s,3H). Mass spectrometry (mass to charge ratio) is C 30 H 23 N4O3 + [M+H] + The theoretical value is 487.17647, and the measured value is 487.17667.

[0284] Example 59a Compound 59a (5.5 mg, 80.90% yield) was synthesized following general experimental procedure 3. 1 H NMR(400MHz,MeOH-d4)δ8.63-8.58(m,1H),8.21-8.17(m,1H),8.05-7.99(m,1H),7.67-7 .59(m,3H),7.53-7.49(m,1H),7.42-7.28(m,6H),7.01-6.98(m,2H),6.53-6.50(m,1H). Mass spectrometry (mass to charge ratio) is C 29 H 21 N4O3 + [M+H] + The theoretical value is 473.16082, and the measured value is 473.16101.

[0285] Example 60 [ka]

[0286] Compound 60 (55 mg, 48.51% yield) was synthesized following general experimental procedure 3. 1H NMR(500MHz,MeOH-d4)δ8.71(d,J=2.3Hz,1H),8.25(dd,J=4.8,1.3Hz,1H),8.10(ddd,J=8.4,2.5,1.5Hz,1H),7.77- 7.72(m,2H),7.48-7.36(m,5H),7.33-7.29(m,2H),7.28-7.24(m,2H),7.13-7.08(m,2H),3.69(s,2H),3.54(s,3H). Mass spectrometry (mass to charge ratio) is C 29 H 23 N2O3 + [M+H] + The theoretical value is 447.17032, and the measured value is 447.17050.

[0287] Example 60a Compound 60a (7.1 mg, 81.45% yield) was synthesized following general experimental procedure 3. 1 H NMR(400MHz,MeOH-d4)δ8.74(d,J=2.3Hz,1H),8.30-8.24(m,1H),8.16-8.09(m,1H),7.78(dd,J=7.7,1.0H z,1H),7.73(dd,J=7.7,1.1Hz,1H),7.49-7.36(m,7H),7.32-7.24(m,2H),7.16-7.09(m,2H),3.72(s,2H). Mass spectrometry (mass to charge ratio) is C 28 H 21 N2O3 + [M+H] + The theoretical value is 433.15467, and the measured value is 433.15485.

[0288] Example 60b Compound 60b (4 milligrams, 15.84% yield) was synthesized following general experimental procedure 3. 1 H NMR(400MHz,MeOH-d4)δ8.74(d,J=1.7Hz,1H),8.30-8.25(m,1H),8.15-8.09(m,1H),7.75- 7.68(m,1H),7.50-7.38(m,8H),7.29(d,J=8.1Hz,2H),7.15(d,J=8.1Hz,2H),3.72(s,2H). Mass spectrometry (mass to charge ratio) is C28 H 20 N3O3 - [MH] - The theoretical value is 446.15102, and the measured value is 446.15088.

[0289] Example 61 [ka]

[0290] Compound 61 (65 milligrams, 61.43% yield) was synthesized following general experimental procedure 3. 1 H NMR(500MHz,MeOH-d4)δ8.74-8.64(m,1H),8.29-8.21(m,1H),8.13-8.04(m,1H),7 .75-7.70(m,1H),7.67(dd,J=7.8,1.3Hz,1H),7.61-7.57(m,1H),7.45-7.41(m,2H ),7.40-7.34(m,1H),7.29(d,J=3.1Hz,1H),7.21-7.16(m,2H),7.04-7.00(m,2H), 6.97(dd,J=8.1,1.5Hz,1H),6.50(dd,J=3.1,0.9Hz,1H),3.66(s,2H),3.49(s,3H). Mass spectrometry (mass to charge ratio) is C 31 H 24 N3O3 + [M+H] + The theoretical value is 486.18122, and the measured value is 486.18149.

[0291] Example 61a Compound 61a (15 mg, 38.62% yield) was synthesized following general experimental procedure 3. 1H NMR(500MHz,MeOH-d4)δ8.69(d,J=2.2Hz,1H),8.24(dd,J=4.8,1.4Hz,1H), 8.11-8.04(m,1H),7.72-7.66(m,2H),7.58(d,J=8.1Hz,1H),7.47-7.44(m, 1H),7.43-7.35(m,2H),7.28-7.24(m,1H),7.21-7.16(m,2H),7.05(dd,J=8 .1,1.5Hz,1H),7.03-6.98(m,2H),6.49(dd,J=3.1,0.8Hz,1H),3.66(s,2H). Mass spectrometry (mass to charge ratio) is C 30 H 20 N3O3 - [MH] - The theoretical value is 470.15102, and the measured value is 470.15100.

[0292] Example 62 [ka]

[0293] Compound 62 (60 milligrams, 52.92% yield) was synthesized following general experimental procedure 3. 1 H NMR(500MHz,CDCl3)δ8.59-8.56(m,1H),8.54(s,1H),7.79(dd,J=7.8,1.3Hz,1H),7 .74-7.68(m,2H),7.44-7.29(m,10H),7.10-7.03(m,2H),3.70(s,2H),3.58(s,3H). Mass spectrometry (mass to charge ratio) is C 29 H 23 N2O3 + [M+H] + The theoretical value is 447.17032, and the measured value is 447.17038.

[0294] Example 62a Compound 62a (45 mg, 84.47% yield) was synthesized following general experimental procedure 3. 1H NMR(500MHz,DMSO-d6)δ10.37(s,1H),8.49(d,J=1.4Hz,1H),8.44(dd,J=4.7,1. 3Hz, 1H), 7.76-7.66 (m, 3H), 7.59-7.28 (m, 9H), 7.12-7.04 (m, 2H), 3.69 (s, 2H). Mass spectrometry (mass to charge ratio) is C 28 H 21 N2O3 + [M+H] + The theoretical value is 433.15467, and the measured value is 433.15475.

[0295] Example 63 [ka]

[0296] Compound 63 (68 milligrams, 71.38% yield) was synthesized following general experimental procedure 3. 1 H NMR(400MHz,DMSO)δ9.49(s,1H),9.06(s,1H),8.97(s,1H),8.45(d,J=152.9Hz,1H),7.92(d, J=8.4Hz,1H),7.75(dd,J=7.7,1.1Hz,1H),7.68(dd,J=7.8,1.1Hz,1H),7.49(t,J=7.8Hz,1H) ,7.44(d,J=8.7Hz,2H),7.34(dt,J=16.0,7.2Hz,1H),7.23(t,J=7.8Hz,1H),7.15(d,J=8.6Hz ,2H),6.80(dd,J=8.1,2.0Hz,1H),6.77-6.71(m,1H),6.68(d,J=7.6Hz,1H),3.53(s,3H)ppm. Mass spectrometry (mass to charge ratio) is C 28 H 21 O4N3 + [M+H] + The theoretical value is 464.2, and the measured value is 464.2.

[0297] Example 64: Measurement of C666-1 cell activity To evaluate the inhibitory effect of the small molecule compound according to the present invention on EBNA1 at the cellular level, cytotoxicity experiments were conducted. The small molecule compound according to the present invention can selectively kill EB virus-positive cell lines (C666-1 cells), and its killing power is clearly superior to that of EB virus-negative cell lines (HONE1 cells and HK1 cells).

[0298] As explained in the background information of this invention, nasopharyngeal carcinoma is a disease highly correlated with latent EBV infection. Latent EBV expresses only a limited number of proteins to maintain genome replication, and among these, the EBNA1 protein is a particularly essential functional protein. Studies have shown that inhibiting EBNA1 leads to... Nasopharyngeal cancer cells It has been confirmed that it can reduce the proliferation of or kill the corresponding nasopharyngeal cancer cells. Therefore, by selecting EB virus-positive nasopharyngeal cancer tumor cells (C666-1 cells) for experimental purposes, the effects of the small molecule compound according to the present invention can be verified.

[0299] During the test, 100 microliters of different cell lines were inoculated into a clear 96-well plate, with C666-1 being 5 × 10⁶ per well. 3 Cells were inoculated. After culturing the cells in a 5% carbon dioxide incubator at 37°C for 24 hours, 10 microliters of a compound with a concentration range of 1 mmol / L to 7.8 mmol / L was added to each well (8 spots, 2-fold dilution, final concentration 100-0.78 mmol / L), and the cells were treated in a carbon dioxide incubator at 37°C for 72 hours. Cell activity was evaluated using the redox indicator resazurin. 10 microliters of 600 mmol / L of resazurin were added to each well and incubated at 37°C for 3 hours. Then, using a Tecan microplate reader, the cells were excited at a wavelength of 560 nanometers, and the emitted fluorescence signal was detected at a wavelength of 590 nanometers. Inhibition curves were fitted using software, and the half-effect concentration (EC2) was determined. 50 The EC of EB virus-positive and EB virus-negative cell lines was calculated.50 The selectivity of compound activity was evaluated by comparing these factors.

[0300] [Table 1] TIFF0007939654000075.tif179129TIFF0007939654000076.tif180129TIFF0007939654000077.tif184131TIFF0007939654000078.tif179130TIFF000 7939654000079.tif181130TIFF0007939654000080.tif165130TIFF0007939654000081.tif165131TIFF0007939654000082.tif177129TIFF0007939654 000083.tif172131TIFF0007939654000084.tif163130TIFF0007939654000085.tif171128TIFF0007939654000086.tif176131TIFF0007939654000087. tif180130TIFF0007939654000088.tif172132TIFF0007939654000089.tif174128TIFF0007939654000090.tif177130TIFF0007939654000091.tif89130

[0301] The data in the table above shows that the compounds according to the present invention can effectively inhibit the proliferative activity of C666-1 cells and that this is dose-dependent.

[0302] Although this technology has been described with reference to certain exemplary embodiments, it should be understood that the invention should not be unduly limited to such specific embodiments. In practice, as will be apparent to those skilled in the art, other embodiments and variations of the invention can be designed without departing from the true spirit and scope of the invention. The appended claims are intended to be construed as encompassing all such embodiments and equivalent variations.

Claims

1. Compounds represented by general formula (I), or their enantiomers, diastereomers, tautomers, salts, solvates, and / or isotope-substituted derivatives. 【Chemistry 1】 During the ceremony, R １ is -H, -COOH, -C(=O)-OR １ａ , -C(=O)-NHR １ｂ , -C(=O)-NR １ｂ R １ｃ Selected from, however, R １ａ , R １ｂ , R １ｃ These are either the same or different and independently selected from hydrogen, optionally substituted C1-C4 linear alkyl, optionally substituted C3-C4 branched alkyl, optionally substituted C3-C4 cycloalkyl, optionally substituted halogenated C1-C4 linear alkyl, optionally substituted halogenated C3-C4 branched alkyl, and optionally substituted halogenated C3-C4 cycloalkyl. or, R １ｂ is selected from hydroxyl and C1-C4 alkoxy, Or, R １ｂ and R １ｃ These, together with the atoms to which they are bonded, form a cyclic group, and the cyclic group is selected from optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted morpholinyl. R ２ teeth, A group selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, optionally substituted pyrrolyl, optionally substituted indole, and optionally substituted phenyl, L １ teeth, 【Chemistry 2】 Selected from the ethinyl group, however, 【Transformation 3】 is, L １ The symbol represents the connection point that connects to the A ring on the right side of the compound of general formula (I), However, the asterisk * represents L １ The symbol represents the connection point that connects to the B ring on the left side of the compound of general formula (I), L ２ is ・-NH-C(=O)-NH-*, ・-N(CH ３ )-C(=O)-NH-*, .-NH-C(=O)-(CH ２ ) ｐ -*,・- (CH ２ ) ｑ Selected from the group -C(=O)-NH-*, However, the dot is L ２ The symbol represents the connection point that connects to the B ring on the right side of the compound of general formula (I). However, the asterisk * represents L ２ The left side of the compound of general formula (I) is R ３ This represents a connection point that connects to, p and q are independently either 1 or 2. R ３ is an arbitrarily substituted heteroaryl, The aforementioned heteroaryl is selected from thienyl, imidazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl, and quinolinyl. The heteroaryl is optionally substituted once or more similarly or differently with hydrogen, fluorine, chlorine, cyano, C1-C4 alkyl, C1-C4 alkyl halogen, C1-C4 alkoxy, or C1-C4 alkoxy halogen. R ４ The element is selected from hydrogen, halogen, C1-C4 linear alkyl, and hydroxyl.

2. L ２ is・-NH-C(=O)-(CH ２ ) ｐ -*,・- (CH ２ ) ｑ -C(=O)-NH-*, -NH-C(=O)-NH-, -N(CH ３ When selected from )-C(=O)-NH-*, R ３ This is selected from thienyl, imidazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl, quinolinyl, fluoropyridyl, methylpyridyl, and methoxypyridyl. The compound according to claim 1, or its enantiomer, diastereomer, tautomer, salt, solvate and / or isotope-substituted derivative.

3. L １ When selected from oxy-azetidine, R ２ This is selected from hydrogen, halogen, optionally substituted C1-C4 alkyl, optionally substituted pyrrolyl, optionally substituted indole, and optionally substituted phenyl. L ２ is -NH-C(=O)-NH-, -N(CH ３ )-C(=O)-NH-*, .-NH-C(=O)-(CH ２ ) ｐ -*,・- (CH ２ ) ｑ -C(=O)-NH-* are selected, R ３ This is selected from thienyl, imidazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl, quinolinyl, fluoropyridyl, methylpyridyl, and methoxypyridyl. The compound according to claim 1, or its enantiomer, diastereomer, tautomer, salt, solvate and / or isotope-substituted derivative.

4. L １ When is chosen from ethinyl, R ２ This is selected from optionally substituted indole and optionally substituted phenyl. L ２ is -NH-C(=O)-NH-, -N(CH ３ )-C(=O)-NH-*, .-NH-C(=O)-(CH ２ ) ｐ -*,・- (CH ２ ) ｑ -C(=O)-NH-* are selected, R ３ It is selected from pyridyl, methylpyridyl, and methoxypyridyl. The compound according to claim 1, or its enantiomer, diastereomer, tautomer, salt, solvate and / or isotope-substituted derivative.

5. 6-((3-hydroxyl-4-(3-(pyridine-3-yl)urea)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylate methyl, 3-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoate methyl, 3-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoate, N-hydroxyl-3-(3-(4-(3-(pyridine-3-yl)urea) Phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzamide, 6-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate, N-hydroxyl-6-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl) (Tyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, N-methyl-6-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, 3'-chloro-6-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, 3'-chloro-6-(3-(4-(3-(pyridine-3-yl)urea) Phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylic acid, 3'-chloro-N-hydroxyl-6-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, 6-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylic acid, N-hydroxyl-6-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, N-methyl-6-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, 3-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl)methyl benzoate, 3-(3-(4-(2- Oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl)benzoic acid, N-hydroxyl-3-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl)benzamide, 2-(4-((1-phenylazetidine-3-yl)oxy)phenyl)-N-(pyridine-3-yl)acetamide, 2-(1H-indole-6-yl)-3-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl ) Methyl benzoate, 2-(1H-indole-6-yl)-3-(3-(4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenoxy)azetidine-1-yl)benzoic acid, 6-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate, N-hydroxyl-6- (3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, N-methyl-6-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, N-methoxy-6-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxamide, N-(4-((1-([1,1'-Biphenyl]-2-yl)azetidine-3-yl)oxy)phenyl)-2-(pyridine-3-yl)acetamide, 3-(3-(4-(3-(5-fluoropyridine-3-yl)urea)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(3-(5-fluoropyridine-3-yl)urea)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 3-(3-(4-(3-(5-methylpyridine-3-yl)urea)phenoxy)azetidine Methyl azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoate, 3-(3-(4-(3-(5-methylpyridine-3-yl)urea)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoate, 3'-chloro-6-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylate, 3'-chloro-6-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylic acid, 3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)methyl benzoate, 3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)benzoic acid, 3-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)methyl benzoate, 3-(3-(4-(3-(pyridine-3-yl)urea)phenoxy)azetidine-1-yl)benzoic acid, 3-(3-(4-(2-(pyridine-3- (Iyl)acetylamino)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)benzoate, 3-(3-(3-fluoro-4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-2-(1H-pyrrole-1-yl)methyl benzoate, 3-(3-(3-fluoro-4-(2-(pyridine-3-yl)acetylamino)phenoxy C) Azethidine-1-yl)-2-(1H-pyrrole-1-yl)benzoic acid, 2-methyl-3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy) azethidine-1-yl) methyl benzoate, 2-methyl-3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy) azethidine-1-yl) benzoic acid, 6-(3-(3-fluoro-4-(2-(pyridine-3-yl)acetylamino)phenoxy) azethidine-1-yl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-(3-(3- Fluoro-4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)-[1,1'-biphenyl]-2-carboxylic acid, 2-chloro-3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)methyl benzoate, 2-chloro-3-(3-(4-(2-(pyridine-3-yl)acetylamino)phenoxy)azetidine-1-yl)benzoic acid, 3'-(2-hydroxylethoxy)-6-((4-(3-(pyridine-3-yl)urea)phenyl)ethynyl)-[1,1'-biphenyl]-2-methyl carboxylate, 6-((4-(3-(pyridine-3-yl)urea)phenyl)ethynyl)-[1,1'-biphenyl]-2-methyl carboxylate, 6-((4-(3-(pyridine-3-yl)urea)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylic acid, N-hydroxyl-6-((4-(3-(pyridine-3-yl)urea)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxamide, 2-(1H-indole-6-yl)-3-((4-(3-(P Lysine-3-yl)urea)phenyl)ethynyl)methyl benzoate, 2-(1H-indole-6-yl)-3-((4-(3-(pyridine-3-yl)urea)phenyl)ethynyl)benzoic acid, 6-((4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-((4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylate, N-hydroxyl-6 -((4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxamide, 2-(1H-indole-6-yl)-3-((4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenyl)ethynyl)methyl benzoate, 2-(1H-indole-6-yl)-3-((4-(2-oxo-2-(pyridine-3-ylamino)ethyl)phenyl)ethynyl)benzoic acid, 6-((4-(2-(pyridine-3-yl)acetylamino) A compound selected from phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylate methyl, 6-((4-(2-(pyridine-3-yl)acetylamino)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylate, 3'-hydroxyl-6-((4-(3-(pyridine-3-yl)urea)phenyl)ethynyl)-[1,1'-biphenyl]-2-carboxylate methyl, or an enantiomer, diastereomer, tautomer, salt, solvate and / or isotope-substituted derivative thereof.

6. A pharmaceutical composition comprising a compound represented by general formula (I) as described in any one of claims 1 to 5, or an enantiomer, diastereomer, tautomer, salt, solvate and / or isotope-substituted derivative thereof, and optionally further comprising a pharmaceutically acceptable carrier, excipient, or diluent.

7. The pharmaceutical composition according to claim 6, for use in the treatment and / or prevention of diseases or disorders caused by EBNA1 activity.

8. The pharmaceutical composition according to claim 6, for use in the treatment and / or prevention of nasopharyngeal cancer.

9. The pharmaceutical composition according to claim 7, wherein the disease or disorder caused by the EBNA1 activity is cancer, infectious mononucleosis, chronic fatigue syndrome, multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis.

10. The aforementioned cancers include nasopharyngeal carcinoma, non-Hodgkin lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, hepatosplenic T-cell lymphoma, B-cell lymphoma, Burkitt lymphoma, cutaneous reticular disease, reticular disease, diffuse large B-cell lymphoma, extranodal NK / T-cell lymphoma / intravascular lymphoma, follicular lymphoma, immunoblastic lymphoma, mucosa-associated lymphoid tissue lymphoma, and B-cell chronic lymphocytic leukemia. The pharmaceutical composition according to claim 9, wherein the disease is a hematopoietic disease, mantle cell lymphoma, mediastinal large B-cell lymphoma, lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma of the lymph node, marginal zone lymphoma of the spleen, intravascular large B-cell lymphoma, primary exudative lymphoma, lymphomatoid granulomatosis, angioimmunoblastic lymphadenopathy, X-linked lymphoproliferative syndrome, post-transplant lymphoproliferative disorder, or Hodgkin lymphoma.

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