Acyl sulfonamide compound and use thereof in medicine

Abstract

The present invention provides a compound or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof, having good prospects in the treatment of hyperproliferative diseases, particularly cancer, more particularly cancer associated with KAT6A and / or KAT6B.

Description

Acylsulfonamide compounds and their applications in medicine Technical Field

[0001] The present invention relates to the field of medicine, and in particular to acylsulfonamide compounds and their application in medicine. Background Art

[0002] Lysine acetyltransferases (KATs) are a class of enzymes that catalyze the transfer of an acetyl group from acetyl-CoA to the ε-amino group of lysine in protein substrates. Lysine acetylation can influence protein function, playing a crucial role in regulating chromosome structure, gene transcriptional regulation, DNA binding ability, enzyme activity and stability, protein-protein interactions, and intracellular localization.

[0003] KATs are divided into several subfamilies, of which the MYST (MOZ, YBF2 / SAS3, SAS2, TIP60) is the largest, including KAT5 (TIP60), KAT6A (MOZ; MYST3), KAT6B (MORF; MYST4), KAT7 (HBO; MYST2), and KAT8 (MOF; MYST1). KAT6A / B, as key members of the MYST family, play crucial roles in development, stem cell maintenance in the hematopoiesis and immune systems, tumorigenesis and progression, and drug resistance.

[0004] Summary of the Invention

[0005] The present invention provides a novel acylsulfonamide compound, which has ideal inhibitory activity against KAT6A and / or KAT6B and has good drug development prospects.

[0006] Specifically,

[0007] In one aspect, the present invention provides a compound having a structure as shown in Formula I or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs;

[0008] Ring A is a 5-membered or 6-membered heteroaromatic ring;

[0009] Ring B is phenyl or a 5-6 membered heteroaryl group;

[0010] Each R 1 Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, R 1a R 1b N-、C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, R 1a R 1b NC(=O)-、R 1a R 1b NS(=O)2-or R 1c O(C=O)-; each R 1a 、R 1b and R 1c Independently selected from: hydrogen, deuterium, C 1-6 Alkyl; wherein R 1 C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, R 1a R 1b NC(=O)-、R 1a R 1b NS(=O)2-or R 1c O(C=O)- are each independently optionally substituted with one or more R 1d Replacement; each R 1d Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, -NH2, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkylamino-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkylamino-C(=O)-, NH2-(C=O)-, C 1-6 Alkylamino-S(=O)2-, NH2-S(=O)2- or C 1-6 Alkyl O(C=O)-; wherein R 1d C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkylamino-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkylamino-C(=O)-, C 1-6 Alkylamino-S(=O)2- or C 1-6 Alkyl O (C = O) - each independently optionally substituted by one or more selected from deuterium, halogen, cyano, nitro, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, (C 1-6 alkyl)2N(C=O)-, C 1-6 Alkyl NH(C=O)-, NH2-(C=O)-, C 1-6 Alkyl (C=O)-, C 3-6 substituted with a cycloalkyl or phenyl substituent; optionally, two R 1The atoms to which they are connected, together form a 5-8 membered monocyclic ring, a 6-10 membered bridged ring, a 6-10 membered spirocyclic ring or a 6-10 membered condensed ring; wherein said 5-8 membered monocyclic ring, 6-10 membered bridged ring, 6-10 membered spirocyclic ring or 6-10 membered condensed ring are each independently optionally substituted by one or more R 1e Replacement; each R 1e Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, -NH2, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkylamino-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkylamino-C(=O)-, NH2-(C=O)-, C 1-6 Alkylamino-S(=O)2-, NH2-S(=O)2- or C 1-6 Alkyl O(C=O)-; wherein R 1e C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkylamino-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkylamino-C(=O)-, C 1-6 Alkylamino-S(=O)2-, or C 1-6Alkyl O(C=O)- is each independently optionally substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, hydroxyl, and amino;

[0011] R 2 Selected from: -OR 2a 、-NR 2b R 2c , 5-6 membered heteroaryl, 4-6 membered heterocyclic group; wherein the 5-6 membered heteroaryl, 4-6 membered heterocyclic group are each independently optionally substituted by one or more selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkynyl, C 2-6 Hydroxyalkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, -NH(C 1-6 alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl) substituent;

[0012] R 2a 、R 2b and R 2c Each independently selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups are each independently optionally substituted by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, amino, -NH(C 1-6 alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl) substituent;

[0013] R 3 Selected from: deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, -NH2, -NH(C1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl);

[0014] R 4a and R 4b Each independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-6 Halogenated cycloalkyl;

[0015] X 1 Select N or CR X1 ;X 2 Select N or CR X2 ; R X1 and R X2 Each independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-6 Halogenated cycloalkyl;

[0016] n is 0, 1, 2, 3, 4 or 5;

[0017] m is 0, 1, 2, or 3;

[0018] t is 0, 1, 2, or 3.

[0019] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug and at least one pharmaceutically acceptable carrier.

[0020] In another aspect, the present invention provides a compound of the present invention or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite thereof, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof, for use in treating a disease or condition mediated by KAT6A and / or KAT6B.

[0021] In another aspect, the present invention provides use of the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug in the preparation of a medicament for treating a disease or condition mediated by KAT6A and / or KAT6B.

[0022] In another aspect, the present invention provides a method for treating a disease or condition mediated by KAT6A and / or KAT6B, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug.

[0023] In some embodiments, the disease or condition is cancer.

[0024] Another aspect of the present invention relates to methods for preparing, separating and purifying compounds represented by formula I, II-1, II-2, III-1, III-2, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, V and VI.

[0025] Any embodiment of any aspect of the present invention can be combined with other embodiments, as long as they do not conflict. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as they do not conflict.

[0026] The foregoing description only summarizes certain aspects of the present invention, but is not intended to be limiting. These and other aspects will be described in more detail and fully below. All references in this specification are incorporated herein by reference in their entirety.

[0027] BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG1 shows the tumor growth curves of five groups of mice in the in vivo pharmacodynamic study of the subcutaneously transplanted mouse model of human breast cancer ZR-75-1 cells in Test Example 10.

[0029] FIG2 is a curve showing the weight change of five groups of mice in the in vivo pharmacodynamic study of the subcutaneously transplanted mouse model of human breast cancer ZR-75-1 cells in Test Example 10.

[0030] FIG3 is a tumor growth curve of the test animals in the anti-tumor efficacy study of the test substance in Test Example 11 on the human pancreatic cancer PDX animal model.

[0031] FIG4 is a weight change curve of the test animals in the anti-tumor efficacy study of the test substance in Test Example 11 on the human pancreatic cancer PDX animal model.

[0032] FIG5 is a tumor growth curve of the test animals in the anti-tumor efficacy study of the test substance in Test Example 12 on the human colon cancer PDX animal model.

[0033] FIG6 is a curve showing the weight change of the test animals in the anti-tumor efficacy study of the test substance in Test Example 12 on a human colon cancer PDX animal model. DETAILED DESCRIPTION

[0034] To make the objectives, technical solutions, and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the following examples. The specific embodiments described herein are intended only to illustrate the present invention and are not intended to limit the present invention in any way. In addition, in the following description, descriptions of known structures and technologies are omitted to avoid unnecessary confusion about the concepts of the present disclosure. Such structures and technologies are also described in many publications.

[0035] definition

[0036] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0037] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0038] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0039] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, the chemical elements are referred to in accordance with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0040] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., more than one component may be contemplated for use or use in implementing the described embodiments.

[0041] The term "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from a disease (e.g., a disease described herein) (referred to as a patient) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0042] The term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers, for example, to a primate (e.g., human, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0043] The term "patient" refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0044] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0045] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0046] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0047] The term "diastereoisomer" refers to stereoisomers that have two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0048] The terms "racemate," "racemate," or "racemic mixture" refer to an equimolar mixture of two enantiomers devoid of optical activity.

[0049] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions performed by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0050] The term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0051] The term "geometric isomers" is also called "cis-trans isomers", which are isomers caused by the inability of double bonds (including olefin double bonds, C=N double bonds and N=N double bonds) or single bonds of ring carbon atoms to rotate freely.

[0052] The stereochemical definitions and conventions used herein generally follow those of SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0053] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0054] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, such as a racemate or a mixture of diastereoisomers (depending on the number of asymmetric carbon atoms). Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in the cis or trans configuration.

[0055] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0056] Any racemate of the resulting final product or intermediate can be resolved into its optical antipodes by methods familiar to those skilled in the art using known methods, such as by separation of its diastereomeric salts obtained. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).

[0057] The term "nitrogen oxide" refers to when a compound contains several amine functional groups, where one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. Available oxidants such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) can be used to treat the corresponding amine to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), where, for example, an amine compound is reacted with meta-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0058] The term "metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting a compound of the invention with a mammal for a sufficient period of time.

[0059] The term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other ingredients of the formulation and / or the mammal to be treated therewith. Preferably, the "pharmaceutically acceptable" herein means approved by federal regulatory agencies or national governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeia for use in animals, particularly humans.

[0060] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts include salts formed by compounds with acids, including but not limited to inorganic acid salts (such as hydrochlorides, hydrobromides, phosphates, sulfates, nitrates, perchlorates) and organic acid salts (such as acetates, glycolates, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, sulfosalicylate), or these salts can be obtained by other methods described in the literature, such as ion exchange methods. Further pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts also include salts formed between compounds and bases, including but not limited to inorganic base salts (such as alkali metal salts, alkaline earth metal salts, ammonium salts and N+(C1-4 alkyl)4 salts), alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The present invention also contemplates quaternary ammonium salts formed by compounds containing any N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter-balancing ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates. Organic base salts (e.g., primary, secondary, and tertiary amine salts, substituted amine salts (including naturally occurring substituted amines, cyclic amines, basic ion exchange resins)), certain organic amine salts include, for example, isopropylamine salts, benzathine salts, cholinate salts, diethanolamine salts, diethylamine salts, lysine salts, meglumine salts, piperazine salts, and tromethamine salts.

[0061] Pharmaceutically acceptable acid addition salts can be formed by the action of the compounds of this invention with inorganic or organic acids, and pharmaceutically acceptable base addition salts can be formed by the action of the compounds of this invention with inorganic or organic bases. Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from the parent compound, alkaline or acidic moieties. Generally speaking, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or a mixture thereof. Generally, in appropriate cases, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Additional lists of suitable salts can be found, for example, in “Remington's Pharmaceutical Sciences,” 20th edition, Mack Publishing Company, Easton, Pa., (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0062] The term "solvate" refers to an association complex formed by one or more solvent molecules and the compound of the present invention. The solvent can be water, acetic acid, diethyl ether, isopropyl ether, petroleum ether, ethyl formate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl tert-butyl ether (MTBE), n-heptane, a mixed solvent of ethanol and water in a volume ratio of 10:90 to 90:10, acetone, methyl isobutyl ketone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, n-butanol, tert-butanol , sec-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, n-hexane, cyclohexane, n-heptane, a mixed solvent of n-heptane and ethyl acetate in a volume ratio of 1:5 to 5:1, isopropyl alcohol, methanol, butanone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, n-propanol, isopropyl alcohol, 2-acetone, 4-methyl-2-pentanone, pyridine, tetrahydrofuran, methyl ethyl ketone, toluene, xylene, cumene or a mixture thereof, etc.

[0063] The term "hydrate" refers to an association of one or more water molecules with a compound of the present invention.

[0064] In addition, the compounds disclosed herein, including their salts, can also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed herein can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include both solvated and unsolvated forms.

[0065] The term "ester" is represented by the formula -OC(O)R or -C(O)OR, wherein R can be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl group as described herein.

[0066] The term "isotopically labeled compound" means a compound of the present invention that is labeled with an isotope. It is identical to those compounds described herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that may also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0067] Compounds of the present invention containing the aforementioned isotopic labels and / or other isotopic labels of other atoms and pharmaceutically acceptable salts of the compounds are all within the scope of the present invention. Isotope-labeled compounds of the present invention, such as radioisotope-labeled compounds, such as 3 H and 14 C is incorporated into the compounds of the present invention for drug and / or substrate tissue distribution analysis. Due to ease of preparation and detection, tritiated, i.e., 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred. In addition, isotopes with larger mass numbers, such as deuterium, 2 H substitutions may offer therapeutic advantages of greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances.

[0068] In addition, the substitution of heavier isotopes, particularly deuterium (i.e., 2H or D), can provide certain therapeutic advantages, which are due to the higher metabolic stability. For example, an increase in in vivo half-life or a reduction in dosage requirements or an improvement in therapeutic index are achieved. It should be understood that deuterium in the present invention is considered a substituent of the compounds of formula I to VI. The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. Where a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, eg D2O, acetone-d6, DMSO-d6.

[0069] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound shown in Formula I in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylating the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following literature: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345.

[0070] Unless otherwise expressly stated, the descriptions used in the present invention of "each...independently is" and "...each independently is" and "...independently is" can be interchanged and should be understood in a broad sense. They can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0071] The terms "optional," "optionally," or "arbitrarily" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted with" means that the substitution may or may not occur.

[0072] When the term "each independently" is used in combination with "optionally", for example, "each independently arbitrarily replaced by..." means that the specific options are either replaced by... or not replaced by... without affecting each other.

[0073] The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0074] The term "comprising" is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended, and does not exclude additional, unrecited elements or ingredients from the drug (or, in the case of a method, a step). The phrase "consisting of excludes any element, step, or ingredient not specified in the drug (or, in the case of a method, a step). The phrase "consisting essentially of refers to the specified materials and those materials that do not materially affect the basic and novel characteristics of the drug (or, in the case of a method, a step).

[0075] In various parts of this specification, substituents of compounds disclosed herein are disclosed in terms of group types or ranges. It is specifically noted that the present invention includes every independent subcombination of the individual members of these group types and ranges. For example, the term "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl as disclosed independently.

[0076] In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0077] The term "heteroatom" refers to O, S, N, P, and Si, including any oxidation state of S, N, and P; primary, secondary, and tertiary amines and quaternary ammonium salts; or a form in which the hydrogen on the nitrogen atom in a heterocyclic ring is substituted, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl), or NRT (such as NRT in N-substituted pyrrolidinyl, where RT is a substituent on N). Among the compounds involved in the present invention, when containing multiple heteroatoms, the compounds composed thereof conform to the covalent and compositional rules of organic compounds, that is, compounds containing multiple heteroatoms should exclude compounds that do not conform to the covalent and compositional rules of organic compounds.

[0078] The term "alkyl" or "alkyl group" refers to a saturated, straight-chain or branched hydrocarbon group containing carbon atoms. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, i.e., C 1-6 Alkyl; In another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., C1-4 Alkyl; In another embodiment, the alkyl group contains 1-3 carbon atoms, ie, C 1-3 Alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0079] The term "alkylene" refers to a saturated, straight-chain or branched divalent hydrocarbon group containing carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms, i.e., C1-C6 alkylene; in another embodiment, the alkylene group contains 1 to 4 carbon atoms, i.e., C1-C4 alkylene; in another embodiment, the alkylene group contains 1 to 3 carbon atoms, i.e., C1-C3 alkylene.

[0080] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing carbon atoms, wherein at least one site of unsaturation is present, i.e., a carbon-carbon sp2 double bond, including "cis" and "tans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2-6 carbon atoms, i.e., C2-C6 alkenyl; in another embodiment, the alkenyl group contains 2-4 carbon atoms, i.e., C2-C4 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), allyl (CH3CH=CH-), CH2=C(CH3)-, CH2=CH-CH=CH-, and the like.

[0081] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing carbon atoms, wherein at least one site of unsaturation, i.e., a carbon-carbon triple bond, sp, is present. In one embodiment, the alkynyl group contains 2-6 carbon atoms, i.e., a C2-C6 alkynyl; in another embodiment, the alkynyl group contains 2-4 carbon atoms, i.e., a C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), CH≡C-CH2-, CH≡CC≡C-, and the like.

[0082] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as defined herein. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms, i.e., C 1-6 In another embodiment, the alkoxy group contains 1-4 carbon atoms, ie, C 1-4 In another embodiment, the alkoxy group contains 1-3 carbon atoms, ie, C 1-3 Alkoxy.

[0083] The term "alkylamino" refers to an alkyl group attached to the rest of the molecule via a nitrogen atom, wherein the alkyl group has the meaning as defined herein. The alkylamino group includes N-alkylamino and N,N-dialkylamino groups, i.e., one alkyl group attached to the nitrogen atom and two alkyl groups attached to the nitrogen atom; in some embodiments, the alkylamino group is (C 1-6 In some embodiments, the alkylamino group is (C 1-6 In one embodiment, the alkylamino group contains 1 to 6 carbon atoms, i.e., C 1-6 In another embodiment, the alkylamino group contains 1-4 carbon atoms, i.e., C 1-4 In another embodiment, the alkylamino group contains 1-3 carbon atoms, i.e., C 1-3 Alkylamino. When the number of carbon atoms is used before the alkylamino group, such as C 1-6 Alkylamino groups can be understood as when there are two alkyl groups on nitrogen, the number of carbon atoms of the two alkyl groups is the limited number of carbon atoms, for example, 1-6; when there is only one alkyl group on nitrogen, the number of carbon atoms of this alkyl group is the limited number of carbon atoms, for example, 1-6.

[0084] The term "cycloalkyl" refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring system containing carbon atoms. Saturated or partially unsaturated cycloalkyl groups can be fully saturated or contain one or more degrees of unsaturation, but cannot have an aromatic ring. In one embodiment, the cycloalkyl group contains 3 to 8 carbon atoms, such as C 3-8 In one embodiment, the cycloalkyl group contains 3 to 6 carbon atoms, such as C 3-6 Saturated or partially unsaturated cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like. In one embodiment, the saturated or partially unsaturated cycloalkyl is selected from the group consisting of: saturated monocyclic cycloalkyl, saturated bicyclic cycloalkyl, saturated tricyclic cycloalkyl, partially unsaturated monocyclic cycloalkyl, partially unsaturated bicyclic cycloalkyl, and partially unsaturated tricyclic cycloalkyl. 4-7 Cycloalkyl refers to a cycloalkyl group with 4 to 7 ring atoms. C3-6 cycloalkyl refers to a cycloalkyl group with 3 to 6 ring atoms. In some embodiments, cycloalkyl groups include carbon spiro rings, carbon fused rings, and carbon bridged rings. For example, but not limited to,

[0085] The term "heterocyclyl" or "heterocycle" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic ring system containing carbon atoms and heteroatoms. The heteroatoms have the meanings as described herein. A saturated or partially unsaturated heterocyclyl group may be fully saturated or contain one or more degrees of unsaturation, but may not contain an aromatic ring. In one embodiment, the heterocyclyl group is a 3-8 membered ring, such as a 3-8 membered saturated or partially unsaturated heterocyclyl group (2-8 carbon atoms and 1-3 heteroatoms selected from N, O, P, and S, where S or P is optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, and PO2). In one embodiment, the heterocyclyl group is a 3-6 membered ring, such as a 3-6 membered saturated or partially unsaturated heterocyclyl group (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, and S, where S or P is optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, and PO2). In one embodiment, the saturated or partially unsaturated heterocyclyl is selected from the group consisting of a saturated monocyclic heterocyclyl, a saturated bicyclic heterocyclyl, a saturated tricyclic heterocyclyl, a partially unsaturated monocyclic heterocyclyl, a partially unsaturated bicyclic heterocyclyl, and a partially unsaturated tricyclic heterocyclyl. A bicyclic heterocyclyl represents a heterocyclyl of a bicyclic ring system. A monocyclic heterocyclyl represents a heterocyclyl of a monocyclic ring system, such as, but not limited to, an oxirane, an aziridine, an azetidinyl, an oxetanyl, a tetrahydrofuranyl, a dioxolyl, a pyrrolidinyl, a pyrrolidonyl, an imidazolidinyl, a pyrazolidinyl, a pyrrolinyl, a tetrahydropyranyl, a piperidinyl, a morpholinyl, a dithianyl, a thiomorpholinyl, a piperazinyl, or a trithianyl. A 5-6 membered heterocyclyl represents a heterocyclyl having 5-6 ring atoms. 4-7 membered heterocyclyl refers to a heterocyclyl with 4-7 ring atoms. 3-6 membered heterocyclyl refers to a heterocyclyl with 3-6 ring atoms. In some embodiments, cycloalkyl includes heterospiro ring, heterofused ring, heterobridged ring. For example, but not limited to,

[0086] The monocycle described in the present invention represents a monocyclic alkyl group, a monoheterocyclic group or a monoheteroaryl group; for example, a 5-8 membered monocycle or a 5-7 membered monocycle.

[0087] The "bridged ring" of the present invention refers to a polycyclic group in which any two rings in the system share two atoms that are not directly connected, which may contain one or more double bonds. Optionally, it contains one or more heteroatoms. The heteroatoms have the meanings as described in the present invention. In some embodiments, the bridged ring is a 6-10 membered bridged ring, and in other embodiments, the bridged ring is a 6-8 membered bridged ring. Polycyclic bridged cycloalkyl groups can be divided into bicyclic, tricyclic, tetracyclic and other types according to the number of constituent rings, preferably bicyclic, tricyclic and tetracyclic, and more preferably bicyclic and tricyclic.

[0088] The "fused ring" of the present invention refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Optionally, it contains more than one heteroatom. The heteroatom has the meaning as described in the present invention. In some embodiments, the fused ring is a 6-10 membered fused ring. In other embodiments, the fused ring is a 6-8 membered fused ring. According to the number of constituent rings, polycyclic fused cycloalkyl groups such as bicyclic, tricyclic, and tetracyclic can be divided, preferably bicyclic and tricyclic, more preferably 3 / 4 membered, 3 / 5 membered, 3 / 6 membered, 4 / 4 membered, 4 / 5 membered, 4 / 6 membered, 5 / 4 membered, 5 / 5 membered, 5 / 6 membered, 6 / 3 membered, 6 / 4 membered, 6 / 5 membered, and 6 / 6 membered bicyclic fused rings.

[0089] " Spirocycle " of the present invention refers to a polycyclic group in which one atom (called spiro atom) is shared between the monocycles in the system, and it may contain one or more double bonds. Optionally, it contains more than one heteroatom. The heteroatom has the meaning as described in the present invention. In certain embodiments, the spirocycle is a 6-10 membered spirocycle. In other embodiments, the spirocycle is a 6-8 membered spirocycle. According to the number of shared spiro atoms between the rings, spiroalkyl is divided into single spiroalkyl, double spiroalkyl and polyspiroalkyl, preferably single spiroalkyl and double spiroalkyl. More preferably, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl.

[0090] The term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic, bicyclic and tricyclic aromatic system containing heteroatoms. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". The heteroatoms have the definition described in the present invention. In some embodiments, the heteroaryl group is a heteroaryl group composed of 5 to 10 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-10 membered heteroaryl group; the heteroaryl group is a heteroaryl group composed of 5 to 8 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-8 membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group composed of 5 to 7 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a 5-7 membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-6-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-6-membered heteroaryl group; In some embodiments, the heteroaryl group is a 5-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-membered heteroaryl group; In some embodiments, the heteroaryl group is a 6-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 6-membered heteroaryl group. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl), thiadiazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives.

[0091] The term "aryl" or "aromatic ring" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic ring system. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring." A 6- to 10-membered aryl group refers to an aromatic group containing 6-10 ring atoms. Examples include, but are not limited to, phenyl and naphthyl.

[0092] The term "hydrogen" means 1 H; "deuterium" refers to 2 H.

[0093] The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0094] The term "amino" when used alone refers to -NH2; when used in conjunction with other groups, the hydrogen on it is replaced by other groups.

[0095] The term "hydroxyl" refers to -OH;

[0096] The term "cyano" refers to -CN;

[0097] The term "nitro" refers to -NO2;

[0098] The term "carboxyl" refers to HO(C=O)-;

[0099] The term "O=" refers to oxo, that is, when the substituent is O=", O is connected to the substituted group through a double bond.

[0100] When two groups are used together, it means that the group written first is connected to the rest of the molecule through the group written second, such as C 2-6 Alkenyloxy represents C 2-6 The alkenyl group is connected to the rest of the molecule through -O-. 2-6 Alkynyloxy represents C 2-6 The alkynyl group is linked to the rest of the molecule through -O-. 3-6 Cycloalkyloxy represents C 3-6 Cycloalkyl is connected to the rest of the molecule through -O-, 3-8 membered heterocyclyloxy means 3-8 membered heterocyclyl is connected to the rest of the molecule through -O-, C 6-10 Aryloxy represents C 6-10 Aryl is linked to the rest of the molecule through -O-, and 5- to 10-membered heteroaryloxy means that 5- to 10-membered heteroaryl is linked to the rest of the molecule through -O-.

[0101] The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" as used herein are not mutually exclusive and refer to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues.

[0102] As used herein, the terms "cancer" and "cancerous" refer to or describe the physiological condition in a subject that is typically characterized by unregulated cell growth and / or proliferation. Some cancers are composed of cells that divide rapidly, while other cancers are composed of cells that divide more slowly than normal cells. Examples of types of cancer may include glioma, glioblastoma, astrocytoma, multiforme cell tumor, bannayan-Zonana syndrome, Cowden disease, cerebellar dysplastic ganglioneuroma (Lhermitte-Duclos disease), breast cancer, colon cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, bone cancer, colon cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma and thyroid cancer, lymphoblastic T-cell leukemia, chronic myeloid leukemia, long-term lymphocytic leukemia, hairy cell leukemia, acute lymphocytic leukemia, acute myeloid leukemia, Chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin lymphoma, non-Hodgkin malignant lymphoma, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulvar cancer, uterine / cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, oral cancer, cancer, gastrointestinal stromal tumor (GIST), neuroendocrine cancer, testicular cancer and virus-related cancers.

[0103] As described herein, the substituent R is connected to the central ring by a bond to form a ring system (as shown below) and represents the substituent R at any substitutable or any reasonable position on the ring A. For example, formula f represents any possible substitutable position on the ring A, as shown in formulas f1-f4:

[0104] As described herein, a substituent is connected to a central ring by a bond to form a ring system, such as (R x ) n , representing n substituents R x Substitution can be made at any substitutable position on the ring. For example, formula a represents a benzene ring which can be substituted by n R x replace.

[0105] The term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is a substituent described above or a substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position, i.e., each substitution is independent of the others. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible.

[0106] Description of the compounds of the present invention

[0107] The present invention provides a compound or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, which plays a positive role in treating diseases or conditions mediated by KAT6A and / or KAT6B.

[0108] Specifically, the present invention provides a compound having a structure represented by Formula I or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs;

[0109] Among them, ring A, ring B, R 1 、R 2 、R 3 、R 4a 、R 4b 、X 1 、X 2 , n, m and t have the definitions described in the present invention.

[0110] In some embodiments, Ring A is a 5- or 6-membered heteroaryl ring.

[0111] In some embodiments, Ring A is a 5-membered heteroaromatic ring, wherein the heteroatom is selected from O, S, or N.

[0112] In some embodiments, Ring A is a 5-membered heteroaryl ring, and the heteroatom is O.

[0113] In some embodiments, Ring A is a 5-membered heteroaromatic ring having two heteroatoms selected from O and / or N.

[0114] In some embodiments, Ring A is a furan ring.

[0115] In some embodiments, Ring B is phenyl or a 5-6 membered heteroaryl.

[0116] In some embodiments, Ring B is phenyl or a 6-membered heteroaryl.

[0117] In some embodiments, each R 1 Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, R 1a R 1b N-、C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, R 1a R 1b NC(=O)-、R 1a R 1b NS(=O)2-or R 1c O(C=O)-; each R 1a 、R 1b and R 1c Independently selected from: hydrogen, deuterium, C 1-6 Alkyl; wherein R 1 C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, R 1a R 1b NC(=O)-、R 1a R 1b NS(=O)2-or R 1cO(C=O)- are each independently optionally substituted with one or more R 1d Replacement; each R 1d Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, -NH2, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkylamino-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkylamino-C(=O)-, NH2-(C=O)-, C 1-6 Alkylamino-S(=O)2-, NH2-S(=O)2- or C 1-6 Alkyl O(C=O)-; wherein R 1d C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkylamino-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkylamino-C(=O)-, C 1-6 Alkylamino-S(=O)2- or C 1-6 Alkyl O (C = O) - each independently optionally substituted by one or more selected from deuterium, halogen, cyano, nitro, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy, (C 1-6 alkyl)2N(C=O)-, C 1-6 Alkyl NH(C=O)-, NH2-(C=O)-, C 1-6 Alkyl (C=O)-, C 3-6 substituted with a cycloalkyl or phenyl substituent; optionally, two R 1 The atoms to which they are connected, together form a 5-8 membered monocyclic ring, a 6-10 membered bridged ring, a 6-10 membered spirocyclic ring or a 6-10 membered condensed ring; wherein said 5-8 membered monocyclic ring, 6-10 membered bridged ring, 6-10 membered spirocyclic ring or 6-10 membered condensed ring are each independently optionally substituted by one or more R 1e Replacement; each R 1e Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, -NH2, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkylamino-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkylamino-C(=O)-, NH2-(C=O)-, C 1-6 Alkylamino-S(=O)2-, NH2-S(=O)2- or C 1-6 Alkyl O(C=O)-; wherein R 1e C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkylamino-, C 1-6 Alkyl-C(=O)-, C 1-6Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkylamino-C(=O)-, C 1-6 Alkylamino-S(=O)2-, or C 1-6 The alkyl O(C=O)- groups are each independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, hydroxyl, and amino.

[0118] In some embodiments, each R 1 Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, R 1a R 1b N-、C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, R 1a R 1b NC(=O)-、R 1a R 1b NS(=O)2-or R 1c O(C=O)-; each R 1a 、R 1b and R 1c Independently selected from: hydrogen, deuterium, C 1-4 Alkyl; wherein R 1 C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-4 Alkyl-C(=O)-, C 1-4Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, R 1a R 1b NC(=O)-、R 1a R 1b NS(=O)2-or R 1c O(C=O)- are each independently optionally substituted with one or more R 1d Replacement; each R 1d Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, -NH2, carboxyl, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-4 Alkylamino-, C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, C 1-4 Alkylamino-C(=O)-, NH2-(C=O)-, C 1-4 Alkylamino-S(=O)2-, NH2-S(=O)2- or C 1-4 Alkyl O(C=O)-; wherein R 1d C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-4 Alkylamino-, C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, C 1-4 Alkylamino-C(=O)-, C 1-4Alkylamino-S(=O)2- or C 1-4 Alkyl O (C = O) - each independently optionally substituted by one or more selected from deuterium, halogen, cyano, nitro, hydroxyl, oxo, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 substituted with a haloalkoxy, (CH3)2N(C=O)-, CH3NH(C=O)-, NH2-(C=O)-, CH3(C=O)-, cyclopropyl or phenyl group; optionally, two R 1 The atoms to which they are connected, together form a 5-7 membered monocyclic ring, a 6-8 membered bridged ring, a 6-8 membered spirocyclic ring or a 6-8 membered condensed ring; wherein the 5-7 membered monocyclic ring, the 6-8 membered bridged ring, the 6-8 membered spirocyclic ring or the 6-8 membered condensed ring are each independently optionally substituted by one or more R 1e Replacement; each R 1e Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, -NH2, carboxyl, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-4 Alkylamino-, C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, C 1-4 Alkylamino-C(=O)-, NH2-(C=O)-, C 1-4 Alkylamino-S(=O)2-, NH2-S(=O)2- or C 1-4 Alkyl O(C=O)-; wherein R 1e C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-10 Aryl, C 6-10Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-4 Alkylamino-, C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, C 1-4 Alkylamino-C(=O)-, C 1-4 Alkylamino-S(=O)2- or C 1-4 The alkyl O(C=O)- groups are each independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, hydroxyl, and amino.

[0119] In some embodiments, each R 1 Independently selected from: deuterium, fluorine, chlorine, bromine, cyano, nitro, hydroxyl, amino, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-4 Alkylamino-, C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, C 1-4 Alkylamino-C(=O)-, NH2-(C=O)-, C 1-4 Alkylamino-S(=O)2-, NH2-S(=O)2-, C 1-4 Alkyl O(C=O)-, C 3-6 Cycloalkyl C 1-2 Alkylene, C 3-6 Cycloalkyl C 1-2 Alkyleneoxy, 3-6 membered heterocyclic group C 1-2 Alkylene, 3-6 membered heterocyclic group C 1-2 Alkyleneoxy, C 6-10 Aryl C 1-2 Alkylene, C 6-10 Aryl C 1-2 Alkyleneoxy, 5-10 membered heteroaryl C 1-2 Alkylene or 5-10 membered heteroaryl C 1-2 Alkyleneoxy; wherein R 1 C1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-4 Alkylamino-, C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, C 1-4 Alkylamino-C(=O)-, C 1-4 Alkylamino-S(=O)2-, C 1-4 Alkyl O(C=O)-, C 3-6 Cycloalkyl C 1-2 Alkylene, C 3-6 Cycloalkyl C 1-2 Alkyleneoxy, 3-6 membered heterocyclic group C 1-2 Alkylene, 3-6 membered heterocyclic group C 1-2 Alkyleneoxy, C 6-10 Aryl C 1-2 Alkylene, C 6-10 Aryl C 1-2 Alkyleneoxy, 5-10 membered heteroaryl C 1-2 Alkylene, 5-10 membered heteroaryl C 1-2 Each alkyleneoxy group is independently optionally substituted by one or more substituents selected from: deuterium, fluorine, chlorine, bromine, cyano, hydroxy, oxo, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoromethoxy, (CH3)2N(C=O)-, CH3NH(C=O)-, NH2-(C=O)-, CH3(C=O)-, CH3-O(C=O)-, cyclopropyl or phenyl; optionally, two R 1 The atoms to which they are connected, together form a 5-7 membered monocyclic ring, a 6-8 membered bridged ring, a 6-8 membered spirocyclic ring or a 6-8 membered condensed ring; wherein the 5-7 membered monocyclic ring, the 6-8 membered bridged ring, the 6-8 membered spirocyclic ring or the 6-8 membered condensed ring are each independently optionally substituted by one or more R 1e Replacement; each R 1e Substituted with substituents independently selected from: deuterium, fluorine, chlorine, bromine, cyano, nitro, hydroxy, amino, carboxyl, oxo, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, (CH3)2N(C=O)-, CH3NH(C=O)-, CH3(C=O)-, cyclopropyl or phenyl.

[0120] In some embodiments, each R 1 Independently selected from: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 6-10 Aryl C 1-2 Alkyleneoxy, 5-10 membered heteroaryl C 1-2 Alkylene; wherein R 1 C 1-4 Alkyl, C 3-6 The cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl or 5-10 membered heteroaryloxy groups are each independently optionally substituted by one or more substituents selected from: methyl, ethyl, trifluoromethyl, trifluoromethoxy, (CH3)2N(C=O)-, CH3NH(C=O)-, NH2-(C=O)-, CH3-O(C=O)- or phenyl; optionally, two R 1 The atoms to which they are attached, together form a 5-7 membered monocyclic ring; wherein said 5-7 membered monocyclic ring is optionally substituted by one or more R 1e Replacement; each R 1e Independently selected from: methyl, ethyl.

[0121] In some embodiments, each R 1 Independently selected from: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, 5-10 membered heteroaryl; wherein, R 1 C 1-4 Alkyl, C 3-6 The cycloalkyl group and the 5-10 membered heteroaryl group are each independently optionally substituted with one or more methyl groups or trifluoromethyl groups.

[0122] In some embodiments, each R 1 Independently selected from: deuterium, fluorine, chlorine, bromine, cyano, nitro, hydroxy, amino, carboxyl, ethynyl, methyl, ethyl, -CHF2, -CH2F, trifluoromethyl, 2,2,2-trifluoroethyl, propyl, isopropyl, 2-fluoro-prop-2-yl, 2-hydroxy-prop-2-yl tert-Butyl, butyl-2-yl, 1-hydroxy-2-methyl-prop-2-yl 2-(1,1,1-Trifluoro-methyl)-propan-2-yl Prop-1-en-2-yl Methoxy, ethoxy, trifluoromethoxy, cyclopropyl, 1-methylcyclopropyl 1-Trifluoromethylcyclopropyl 1-Cyanocyclopropyl 1-Fluorocyclopropyl Cyclobutyloxy, cyclopentyl, oxetanyl, pyrazolylmethylene (preferably ), benzyloxy, phenylethyleneoxy, (CH3)2N(C=O)-CH2-, (1-methyl-1H-pyrazol-4-yl)methyleneoxy 1-Ethyl-1H-pyrazole-4-oxy 3,5-Dimethylisoxazol-4-yl Pyrrolidin-1-yl, 2-(N,N-dimethylaminoacyl)-pyrrolidin-1-yl 2-(N-methylaminoacyl)-pyrrolidin-1-yl 2-Aminoacyl-pyrrolidin-1-yl 2-Phenyl-pyrrolidin-1-yl 2-Acetyl-pyrrolidin-1-yl 2-Cyclopropyl-pyrrolidin-1-yl CH3(C=O)-, 5-methyl-pyrazin-2-yl 6-Methyl-pyridin-3-yl Hydroxy(pyridin-3-yl)methyl 2H-1,2,3-triazol-2-yl 1,3-Dimethyl-1H-pyrazol-4-yl 4-Azaspiro[2.4]heptan-4-yl or 1H-pyrazol-1-yl Proline methyl ester-1-yl 1-methoxy-4-(tert-pentyl)phenyl-2-yl 2-Cyano-2-propan-1 2-Methyl-2-propionic acid methyl ester Bicyclo[1,1,1]pentane Optionally, two R 1 The atoms to which they are attached, and ring B together form the following group:

[0123] In some embodiments, each R 1 Independently selected from: bromo, methoxy, tert-butyl, ethynyl, trifluoromethoxy, trifluoromethyl, Phenylethyleneoxy, Cyclopropyl, Isopropyl, (CH3)2N(C=O)-CH2-, Optionally, two R 1 The atoms to which they are attached, and ring B together form the following group:

[0124] In some embodiments, each R 1 Independently selected from: bromo, ethyl, methoxy, tert-butyl, trifluoromethoxy, trifluoromethyl, Cyclopropyl.

[0125] In some embodiments, R 2 Selected from: -OR 2a 、-NR 2b R 2c , 5-6 membered heteroaryl, 4-6 membered heterocyclic group; wherein the 5-6 membered heteroaryl, 4-6 membered heterocyclic group are each independently optionally substituted by one or more selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkynyl, C 2-6 Hydroxyalkynyl (e.g. ), C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, -NH(C 1-6 alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl) substituent;

[0126] In some embodiments, R 2 Selected from: 5-6 membered heteroaryl, 4-6 membered heterocyclic group; the 5-6 membered heteroaryl, 4-6 membered heterocyclic group are each independently optionally substituted by one or more selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, -NH(C 1-4 alkyl) or -N(C 1-4 Alkyl)(C 1-4 alkyl) substituent.

[0127] In some embodiments, R 2 Selected from: 5-6 membered heteroaryl, 4-6 membered heterocyclic group; the 5-6 membered heteroaryl, 4-6 membered heterocyclic group are each independently optionally substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, amino or hydroxymethyl.

[0128] In some embodiments, R 2 Selected from: pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl or azetidinyl; wherein the pyrazolyl, oxazolyl, isoxazolyl, triazole (including 1,2,3-triazole, 1,2,4-triazole, 1,3,4-triazole) pyridinyl, pyrazinyl, pyrimidinyl or azetidinyl are each independently optionally substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl or hydroxymethyl.

[0129] In some embodiments, R 2a 、R 2b and R 2c Each independently selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups are each independently optionally substituted by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, amino, -NH(C 1-6 alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl) substituent.

[0130] In some embodiments, R 2a 、R 2b and R 2c Each independently selected from: hydrogen, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; wherein the C 1-4 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups are each independently optionally substituted by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C3-6 Halogenated cycloalkyl, amino, -NH(C 1-4 alkyl) or -N(C 1-4 Alkyl)(C 1-4 alkyl) substituent.

[0131] In some embodiments, R 2a 、R 2b and R 2c are each independently selected from: hydrogen, deuterium or methyl.

[0132] In some embodiments, R 3 Selected from: deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl).

[0133] In some embodiments, R 3 Selected from: deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)(C 1-4 alkyl).

[0134] In some embodiments, R 3 Selected from: deuterium, fluorine, chlorine, bromine, methyl, ethyl or trifluoromethyl.

[0135] In some embodiments, R 4a and R 4b Each independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-6 Halogenated cycloalkyl.

[0136] In some embodiments, R 4a and R 4bEach independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-6 Halogenated cycloalkyl.

[0137] In some embodiments, R 4a and R 4b are each independently selected from: hydrogen or deuterium.

[0138] In some embodiments, X 1 Select N or CR X1 ;X 2 Select N or CR X2 ; R X1 and R X2 Each independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-6 Halogenated cycloalkyl.

[0139] In some embodiments, X 1 Select N or CR X1 , X 2 CR X2 or X 1 CR X1 , X 2 Select N or CR X2 ; R X1 and R X2 Each independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 Alkyl or C 1-4 Alkoxy.

[0140] In some embodiments, X 1 CR X1 , X 2 CR X2 ; R X1 and R X2 Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, ethyl, methoxy, and ethoxy.

[0141] In some embodiments, n is 0, 1, 2, 3, 4, or 5.

[0142] In some embodiments, n is 0, 1, 2, or 3.

[0143] In some embodiments, m is 0, 1, 2, or 3.

[0144] In some embodiments, m is 0 or 1.

[0145] In some embodiments, m is 0.

[0146] In some embodiments, t is 0, 1, 2, or 3.

[0147] In some embodiments, t is 0 or 1.

[0148] In some embodiments, the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, the compound has the structure shown in Formula II-1 or II-2;

[0149] Among them, ring B, R 1 、R 2 、R 3 、R 4a 、R 4b 、X 1 、X 2 , n, m and t have the definitions described in the present invention;

[0150] Each X 3 Independently selected from: CH2, O, NH or S; X 4 and X 5 are each independently selected from: CH or N.

[0151] In some embodiments, the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, the compound has the structure shown in formula III-1 or III-2

[0152] in,

[0153] Among them, ring B, R 1 、R 3 、R 4a 、R 4b 、X 1 、X 2 , n, m and t have the definitions described in the present invention;

[0154] Each X 3Independently selected from: CH2, O, NH or S;

[0155] X 4 、X 5 、X 6 、X 7 and X 8 are each independently selected from: CH or N;

[0156] Each R 5 Independently selected from: deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, -NH(C 1-6 alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl); preferably, each R 5 Independently selected from: deuterium, halogen, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, -NH(C 1-4 alkyl) or -N(C 1-4 Alkyl)(C 1-4 alkyl); preferably, each R 5 Independently selected from: deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, amino or hydroxymethyl;

[0157] Each p is independently 0, 1 or 2.

[0158] In some embodiments, the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, the compound has the structure shown in Formula IV-1, IV-2 or IV-3;

[0159] Among them, ring A, ring B, R 1 、R 2 、R 3 、R 4a 、R 4b 、X 1 、X 2, n, m and t have the definitions described in the present invention.

[0160] In some embodiments, the compounds described in the present invention have the structure shown in Formula IV-1 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs.

[0161] In some embodiments, the compounds described in the present invention have the structure shown in Formula IV-2 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs.

[0162] In some embodiments, the compounds described in the present invention have the structure shown in Formula IV-3 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs.

[0163] In some embodiments, the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, the compound has the structure shown in Formula IV-4, IV-5 or IV-6;

[0164] Among them, ring A, ring B, R 1 、R 2 、R 3 、R 4a 、R 4b 、X 1 、X 2 , n, m and t have the definitions described in the present invention.

[0165] In some embodiments, the compounds described in the present invention have the structure shown in Formula IV-4 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs.

[0166] In some embodiments, the compounds described in the present invention have the structure shown in Formula IV-5 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs.

[0167] In some embodiments, the compounds described in the present invention have the structure shown in Formula IV-6 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs.

[0168] In some embodiments, the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, the compound has the structure shown in Formula V;

[0169] Among them, R 1 、R 3 、R 4a 、R 4b 、X 1 、X 2 , n, m and t have the definitions described in the present invention.

[0170] In some embodiments, the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, the compound has the structure shown in Formula VI;

[0171] Among them, R 1 、R 3 、R 4a 、R 4b 、X 1 、X 2 , n, m and t have the definitions described in the present invention;

[0172] R 1f Selected from: C 1-6 Alkyl, C 6-10 Aryl C 1-2 Alkylene, 5-10 membered heteroaryl C 1-2 Alkylene or C 3-6 Cycloalkyl;

[0173] n1 is 0, 1, 2, 3 or 4.

[0174] In some embodiments, R 1f Selected from: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, pyrazolylmethylenyl, pyrazolylethylene.

[0175] In some embodiments, n1 is 0, 1, or 2.

[0176] In some embodiments, the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof has the structure shown below;

[0177] Pharmaceutical compositions and methods of administration

[0178] The present invention relates to a pharmaceutical composition comprising the compound of the present invention or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; and a pharmaceutically acceptable carrier.

[0179] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and diluents. Other components may also include excipients such as excipients, binders, and fillers, as well as additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, or lipid-lowering agents. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0180] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that can be used to prepare or use a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, 2013, pp. 1049-1070).

[0181] The present invention also relates to pharmaceutical compositions comprising as active ingredients a compound of formula I, II-1, II-2, III-1, III-2, IV-1, IV-2, IV-3, V, VI or a pharmaceutically acceptable salt thereof, which can be used, in particular, for the treatment of neoplastic diseases, in particular cancer, as described herein. The compositions can be formulated for non-parenteral administration, such as nasal, oral, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, or in particular for oral administration, for example in the form of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard and soft capsules or hydroxypropylmethylcellulose (HPMC) capsules (coated where applicable), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration to mammals, in particular humans, for example in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. These compositions may contain the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.

[0182] The compounds of formula I, II-1, II-2, III-1, III-2, IV-1, IV-2, IV-3, V, VI or pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert inorganic or organic excipients for the production of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or orally disintegrating tablets. Fillers such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or its derivatives, binders such as cellulose, starch, polyvinyl pyrrolidone or its derivatives, glidants such as talc, stearic acid or its salts, and flow agents such as fumed silica can be used as such excipients for the formulation and manufacture of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or orally disintegrating tablets. Suitable excipients for soft capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.

[0183] Suitable excipients for the production of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, sucrose, invert sugar, glucose and the like.

[0184] Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants and the like.

[0185] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically valuable substances.

[0186] The dosage can vary within wide limits and, of course, will be adapted to the individual requirements in each particular case. In general, in the case of oral administration, a daily dosage of about 1 to 1000 mg of a compound of formula I per person should be appropriate, although the above lower or upper limits may also be exceeded if necessary.

[0187] The compounds of formula I, II-1, II-2, III-1, III-2, IV-1, IV-2, IV-3, V, VI can also be used in combination with one or more other pharmacologically active compounds that are also effective against the same disease, preferably using a different mode of action, or that reduce or prevent possible undesirable side effects of the compounds of formula I, II-1, II-2, III-1, III-2, IV-1, IV-2, IV-3, V, VI. The combination partners can be administered simultaneously in such treatment, for example by incorporating them into a single pharmaceutical formulation, or sequentially by administering two or more different dosage forms, each containing one or more combination partners.

[0188] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that will elicit a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement of symptoms, alleviation of symptoms, slowing or delaying disease progression, or prevention of disease, etc.). In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective in at least partially alleviating, inhibiting, preventing, and / or ameliorating a disease or condition mediated by KAT6A and / or KAT6B.

[0189] The term "treatment" or "treating" as used herein in the context of treating a disease or disorder generally relates to treatment and therapy for humans or animals (e.g., in veterinary applications), wherein some desired therapeutic effects are obtained, e.g., suppressing the progression of a disease or disorder, and including reducing the rate of progression, stopping the rate of progression, alleviating the symptoms of a disease or disorder, improving a disease or disorder, and curing a disease or disorder. Also included are treatments (i.e., preventions) as preventive measures. For example, a patient who has not yet developed the disease or disorder but is at risk of developing the disease or disorder is covered by the term "treatment." For example, treatment includes prevention of cancer, reducing the incidence of cancer, alleviating cancer symptoms, etc.

[0190] In some embodiments, the present invention provides compounds I, II-1, II-2, III-1, III-2, IV-1, IV-2, IV-3, V, VI, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds, or prodrugs thereof, for use in treating diseases or conditions mediated by KAT6A and / or KAT6B.

[0191] In some embodiments, the present invention provides use of compound I, II-1, II-2, III-1, III-2, IV-1, IV-2, IV-3, V, VI, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds, or prodrugs, or pharmaceutical compositions thereof, in the preparation of a medicament for treating a disease or condition mediated by KAT6A and / or KAT6B thereof.

[0192] In some embodiments, the present invention provides a method of treating a disease or condition mediated by KAT6A and / or KAT6B, comprising administering to a subject in need thereof a therapeutically effective amount of compound I, II-1, II-2, III-1, III-2, IV-1, IV-2, IV-3, V, VI, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition thereof.

[0193] In some embodiments, the disease or condition is cancer.

[0194] In some embodiments, the cancer is selected from the group consisting of: glioma, glioblastoma, astrocytoma, multiforme cell tumor, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, bone cancer, colon cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma and thyroid cancer, lymphoblastic T-cell leukemia, chronic myeloid leukemia, long-term lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, leukemia, and leukemia. Baxterous leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin lymphoma, non-Hodgkin malignant lymphoma, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulvar cancer, uterine / cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, oral cancer, cancer, gastrointestinal stromal tumor (GIST), neuroendocrine cancer, testicular cancer, and virus-related cancers.

[0195] Synthesis method

[0196] Compounds of formula I, II-1, II-2, III-1, III-2, IV-1, IV-2, IV-3, V, VI can be synthesized by the methods given below, by the methods given below in the experimental section, or by analogous methods. The schemes described herein are not intended to present an exhaustive list of methods for preparing compounds of formula I, II-1, II-2, III-1, III-2, IV-1, IV-2, IV-3, V, VI; rather, other techniques known to skilled chemists can also be used for compound synthesis.

[0197] The structures of the compounds were determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR and / or 19 F-NMR). 1 H-NMR, 13 C-NMR, 19 F-NMR chemical shifts (δ) are given in parts per million (ppm). 1 H-NMR, 13 C-NMR, 19 F-NMR measurements were performed using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer. The solvents used were deuterated chloroform (CDCl₃), deuterated methanol (CD₃OD or MeOH-d₄), or deuterated dimethyl sulfoxide (DMSO-d₆). TMS (0 ppm) or chloroform (7.25 ppm) was used as the reference standard. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), and brs (broadened singlet). Coupling constants, J, are expressed in Hertz (Hz).

[0198] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260 mass spectrometer. HPLC analysis was performed using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100 x 3.0 mm column).

[0199] TLC silica gel plates used were Qingdao GF254 silica gel plates, with a diameter of 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative thin layer chromatography. Column chromatography generally used Qingdao 200-300 mesh silica gel as a carrier.

[0200] The starting materials in the examples of the present invention are all known and commercially available, or can be synthesized using or according to literature data reported in the art.

[0201] Unless otherwise specified, all reactions of the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperatures are all degrees Celsius.

[0202] It will be appreciated by those skilled in the art of organic synthesis that optimal reaction conditions may vary with the specific reactant or solvent used, but these conditions may be determined by conventional optimization procedures. In some cases, the order of the following reaction scheme and / or reaction steps may be changed to promote reaction or to avoid forming unwanted by-products. In addition, the functional groups present in each position of the molecule must be compatible with the proposed reagent and reaction. This limitation of substituents compatible with reaction conditions is apparent to those skilled in the art, and then alternative methods must be used. In addition, in some reactions mentioned herein, it may be necessary or desirable to protect any sensitive group in the compound, and it is assumed that such a blocking group (PG) is in the appropriate position if necessary. Conventional blocking groups can be used according to standard practices well known in the art (for explanation, see Greene TW, Wuts PGM, Protective Groups in Organic Synthesis [blocking group in organic synthesis], 5th edition, publisher: John Wiley & Sons (John Wiley & Sons), 2014). Blocking groups can be removed at any convenient stage in the synthesis using conventional techniques well known in the art, or blocking groups can be removed in subsequent reaction steps or aftertreatment.

[0203] The following abbreviations are used throughout this invention:

[0204] LCMS: Liquid chromatography-mass spectrometry

[0205] M, mol / L: moles per liter

[0206] mL: milliliters

[0207] g: grams

[0208] mmol: millimole

[0209] DMAP: 4-dimethylaminopyridine

[0210] EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0211] The following examples are provided to assist in understanding the present invention. However, it should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the present invention in any way. The actual scope of the present invention is set forth in the claims. It should be understood that any modifications and variations may be made without departing from the spirit of the present invention.

[0212] Example 1. Synthesis of Compound 001

[0213] Synthesis route

[0214] Experimental procedures

[0215] 1) Preparation of intermediate 1-2

[0216] At room temperature, 1-1 (8 g, 34.63 mmol) and N,N-dimethylformamide (50 mL) were added to a single-necked flask, and M1 (4.91 mL, 41.55 mmol) and potassium carbonate (9.57 g, 69.25 mmol) were added under stirring. The reaction was carried out at 100 degrees Celsius for 18 hours. 500 mL of water was added to the reaction solution, and the mixture was extracted once with 500 mL of ethyl acetate. The organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 10:1) to obtain intermediate 1-2 (8 g). LC-MS: m / z: 319.0 (M+H) + .

[0217] 2) Preparation of Intermediate 1-3

[0218] At room temperature, 1-2 (6 g, 18.80 mmol) and chlorobenzene (50 mL) were added to a single-necked flask, and polyphosphoric acid (0.13 mL, 3.38 mmol) was added under stirring. The reaction was allowed to react at 130°C for 18 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 1-3 (1.5 g). LC-MS: m / z: 256.0 (M+H) + .

[0219] 3) Preparation of Intermediates 1-4

[0220] At room temperature, 1-3 (1 g, 3.92 mmol), M2 (1.89 g, 5.88 mmol), and 1,4-dioxane (10 mL) were added to a single-necked flask, stirred, and tetrakis(triphenylphosphine)palladium (0.45 g, 0.39 mmol) was added under a nitrogen atmosphere. The reaction was allowed to proceed at 80 degrees Celsius for 18 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) to obtain intermediate 1-4 (540 mg). LC-MS: m / z: 207.0 (M+H) + .

[0221] 4) Preparation of Intermediate 1-5

[0222] At room temperature, 1-4 (200 mg, 0.97 mmol) and acetonitrile (4 mL) were added to a single-necked flask, and M3 (155.94 mg, 1.07 mmol) and cesium carbonate (474.03 mg, 1.45 mmol) were added under stirring. The reaction was carried out at 80 degrees Celsius for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 5:1) to obtain intermediate 1-5 (220 mg). LC-MS: m / z: 257.2 (M+H) + .

[0223] 5) Preparation of Intermediate 1-6

[0224] At room temperature, 1-5 (260 mg, 1.01 mmol), methanol (4 mL) and water (11 mL) were added to a single-necked flask, and sodium hydroxide (284.09 mg, 7.10 mmol) was added under stirring. The reaction was allowed to react at 50 degrees Celsius for 2 hours. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 2 with 2 mol / L hydrochloric acid, and extracted with 10 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 1-6 (220 mg). LC-MS: m / z: 243.0 (M+H) + .

[0225] 6) Preparation of Compound 001

[0226] To a single-necked flask at room temperature, 1-6 (80 mg, 0.33 mmol) and dichloromethane (3 mL) were added. DMAP (80.70 mg, 0.66 mmol), EDCI (94.97 mg, 0.50 mmol), and M4 (61.83 mg, 0.33 mmol) were added under stirring. The reaction was allowed to react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (formic acid / acetonitrile / water system) to obtain compound 001 (30 mg). 1H NMR (400MHz, CDCl3) δ9.84(s,1H),8.13(dd,J=7.9,1.7Hz,1H),7.90(d,J=7.9Hz,1H),7.72(d,J=2.3Hz,1H),7.56–7.48(m,2H),7.3 4(d,J=1.6Hz,1H),7.08(m,2H),6.91(m,1H),6.62(d,J=2.3Hz,1H),6.26(m,1H),5.53(s,2H),3.79(s,3H); LC-MS:m / z:412.2(M+H) + .

[0227] Example 2. Synthesis of Compound 002

[0228] Synthesis route

[0229] Experimental procedures

[0230] 1) Preparation of intermediate 2-2

[0231] At room temperature, 2-1 (4.0 g, 16.06 mmol), 2-bromo-1,1-diethoxyethane (M5, 3.80 g, 19.27 mmol), potassium carbonate (3.33 g, 24.05 mmol), and N,N-dimethylformamide (150.0 mL) were added to a single-necked flask. The reaction was allowed to proceed at 120 degrees Celsius for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 2-2 (2.0 g). LC-MS: m / z: 387.0 (M+Na) + .

[0232] 2) Preparation of intermediate 2-3

[0233] At room temperature, 2-2 (2.0 g, 5.48 mmol), polyphosphoric acid (1.74 g, 21.22 mmol), and toluene (100 mL) were added to a single-necked flask. The reaction was allowed to proceed at 100°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 2-3 (200.0 mg). 1 H NMR (400MHz, DMSO-d6) δ8.36 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 3.94 (s, 3H).

[0234] 3) Preparation of Intermediate 2-4

[0235] At room temperature, 2-3 (200.0 mg, 0.73 mmol), M2 (352.8 mg, 1.10 mmol), tetrakistriphenylphosphine palladium (84.6 mg, 0.07 mmol) and 1,4-dioxane (20 mL) were added to a single-necked bottle. The reaction was carried out at 100 degrees Celsius for 18 hours. The reaction solution was added with saturated potassium fluoride solution (100 mL) and stirred for 1 hour to quench the reaction. The mixture was extracted with ethyl acetate (100 mL * 3), the organic phases were combined, dried with sodium sulfate, filtered, and the solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 3:1) to obtain intermediate 2-4 (150 mg). 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=2.4Hz,1H),7.60(d,J=10.4Hz,1H),7.28(d,J=2.4Hz,1H),5.46(t,J=5.6Hz,1H),4.80 (d, J=5.6Hz, 2H), 3.93 (s, 3H).

[0236] 4) Preparation of Intermediate 2-5

[0237] At room temperature, 2-4 (150.0 mg, 0.67 mmol), M3 (146.7 mg, 1.00 mmol), cesium carbonate (872.0 mg, 2.68 mmol) and 1,4-dioxane (20 mL) were added to a single-necked flask. The reaction was allowed to proceed at 70 degrees Celsius for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 2-5 (100.0 mg). LC-MS: m / z: 275.0 (M+H) + .

[0238] 5) Preparation of Intermediate 2-6

[0239] At room temperature, 2-5 (100.0 mg, 0.36 mmol), sodium hydroxide (43.8 mg, 1.09 mmol), water (2 mL), and methanol (6 mL) were added to a single-necked flask. The reaction was allowed to react at 50°C for 2 hours. The reaction solution was adjusted to pH 2 with hydrochloric acid (4N), filtered, and the filter cake was dried under reduced pressure to obtain intermediate 2-6 (30.0 mg). LC-MS: m / z: 261.0 (M+H) + .

[0240] 6) Preparation of Compound 002

[0241] At room temperature, 2-6 (25.00 mg, 0.10 mmol), dichloromethane (2.0 mL), and M4 (27.00 mg, 0.14 mmol) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (27.63 mg, 0.14 mmol) and 4-dimethylaminopyridine (35.21 mg, 0.29 mmol) were added sequentially under stirring. The reaction was allowed to react at room temperature for 18 hours, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain compound 002 (3.40 mg, 0.01 mmol). 1 H NMR (400MHz, DMSO-d6) δ12.49 (s, 1H), 8.16 (d, J = 2.4Hz, 1H), 7.92 (dd, J = 8.0, 1. 6Hz,1H),7.88(d,J=2.4Hz,1H),7.67(t,J=8.0Hz,1H),7.53(d,J=10.4Hz,1H),7. 43(d,J=1.6Hz,1H),7.24(d,J=8.4Hz,1H),7.15(t,J=7.6Hz,1H),6.86(d,J=2.4 Hz, 1H), 6.26 (t, J = 2.0Hz, 1H), 5.64 (s, 2H), 3.87 (s, 3H); LC-MS: m / z: 430.2 (M+H) + .

[0242] Example 3. Synthesis of Compound 004

[0243] Synthesis route

[0244] Experimental procedures

[0245] 1) Preparation of intermediate 4-2

[0246] At room temperature, 4-1 (500.0 mg, 1.96 mmol), sodium hydroxide (235.23 mg, 5.88 mmol), water (5 mL), and methanol (15 mL) were added to a single-necked flask. The reaction was allowed to react at 50°C for 2 hours. The reaction solution was adjusted to pH 2 with hydrochloric acid (4N), filtered, and the filter cake was dried under reduced pressure to obtain intermediate 4-2 (300.0 mg). LC-MS: m / z: 241.0 (M+H) + .

[0247] 2) Preparation of intermediate 4-3

[0248] At room temperature, 4-2 (300.00 mg, 1.24 mmol), dichloromethane (20.0 mL), and M4 (256.30 mg, 1.37 mmol) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (357.89 mg, 1.87 mmol) and 4-dimethylaminopyridine (456.16 mg, 3.73 mmol) were added sequentially under stirring. The reaction was allowed to react at room temperature for 18 hours, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 4-3 (200.0 mg). 1 H NMR (400MHz, DMSO-d6) δ12.47(s,1H),8.28(d,J=2.4Hz,1H),7.94(dd,J=8.0,2.0Hz,1H),7.69(m, 1H),7.64–7.53(m,2H),7.30–7.22(m,1H),7.21–7.15(m,1H),7.03(d,J=2.4Hz,1H),3.88(s,3H).

[0249] 3) Preparation of intermediate 4-4

[0250] At room temperature, 4-3 (180.0 mg, 0.44 mmol), M2 (140.88 mg, 0.44 mmol), tetrakistriphenylphosphine palladium (50.70 mg, 0.04 mmol) and 1,4-dioxane (20 mL) were added to a single-necked bottle. The reaction was carried out at 100 degrees Celsius for 18 hours. The reaction solution was quenched with saturated potassium fluoride solution (20 mL) and stirred for one hour, extracted once with ethyl acetate (50 mL), and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1 to 10: 1) to obtain compound 4-4 (200.0 mg). LC-MS: m / z: 362.0 (M+H) + .

[0251] 4) Preparation of intermediate 4-5

[0252] To a single-necked flask at room temperature were added 4-4 (200.0 mg, 0.33 mmol), thionyl chloride (179.26 mg, 1.33 mmol), dichloromethane (10 mL), and N,N-dimethylformamide (0.1 mL). The reaction was allowed to react at room temperature for 1 hour. The reaction solution was distilled under reduced pressure to afford crude product 4-5 (125.34 mg). The crude product was used directly in the next step without purification.

[0253] 5) Preparation of Compound 004

[0254] To a single-necked flask at room temperature were added 4-5 (125.34 mg, 0.33 mmol), M6 (47.40 mg, 0.83 mmol), diisopropylethylamine (214.59 mg, 1.66 mmol), and 1,4-dioxane (10 mL). The reaction was allowed to proceed at 60°C for 18 hours. The reaction solution was then concentrated under reduced pressure to yield a crude product. The crude product was purified by HPLC (ammonium bicarbonate / acetonitrile / water) to afford compound 004 (10.0 mg). 1 H NMR(400MHz, DMSO-d6)δ8.07(d,J=2.0Hz,1H),7.85(dd,J=7.6,2.0Hz,1H),7.70(d,J=7.6Hz,1H),7.46–7.39(m,1H),7.28–7.22(m,2H),7 .04(d,J=8.4Hz,1H),6.98(d,J=7.6Hz,1H),4.50–4.38(m,2H),3.86(d,J=12.4Hz,4H),3.74(s,3H),2.25(m,2H); LC-MS:m / z:401.2(M+H) + .

[0255] Example 4. Synthesis of Compound 005

[0256] Synthesis route

[0257] Experimental procedures

[0258] 1) Preparation of intermediate 5-2

[0259] At room temperature, 5-1 (50 mg, 0.2 mmol) and 1,4-dioxane (5.0 mL) were added to a single-necked flask. Compound M6 (22.39 g, 0.39 mmol), cesium carbonate (195.49 mg, 0.60 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13.61 mg, 0.02 mmol), and palladium acetate (5.28 mg, 0.02 mmol) were then added sequentially under a nitrogen atmosphere. The mixture was allowed to react at 80°C for 18 hours. 50 mL of water was added to the reaction solution, which was then extracted once with 50 mL of ethyl acetate. The organic phase was washed with 100 mL of saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) to yield intermediate 5-2 (50 mg). 1HNMR(400MHz,DMSO-d6)δ7.93(d,J =2.2Hz,1H),7.70(d,J=8.6Hz,1H),7.01(d,J=2.4Hz,1H),6.13(d,J=8.6Hz,1H) ,4.21(t,J=7.4Hz,4H),3.81(s,3H),2.45-2.36(m,2H); LC-MS:m / z:232.0(M+H) + .

[0260] 2) Preparation of intermediate 5-3

[0261] At room temperature, 5-2 (50 mg, 0.22 mmol), tetrahydrofuran (0.3 mL), methanol (0.1 mL), and water (0.1 mL) were added to a single-necked flask. Lithium hydroxide (15.54 mg, 0.65 mmol) was added under stirring. The reaction was allowed to react at 60 degrees Celsius for 18 hours. 2N aqueous hydrochloric acid was added to the reaction solution to adjust the pH to approximately 3. The solution was extracted with 10 mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 5-3 (30 mg). 1 HNMR(400MHz,DMSO-d6)δ12.12(s,1H),7.89(d,J=2.0Hz,1H),7.67(d,J=8.4Hz,1H),6 .98(d,J=2.2Hz,1H), 6.11(d,J=8.4Hz,1H), 4.19(t,J=7.4Hz,4H), 2.44–2.35(m,2H).

[0262] 3) Preparation of Compound 005

[0263] At room temperature, intermediate 5-3 (20 mg, 0.09 mmol) and dichloromethane (1.0 mL) were added to a single-necked flask. M4 (26.48 mg, 0.14 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (123 mg, 0.95 mmol), and 4-dimethylaminopyridine (22.5 mg, 0.18 mmol) were added sequentially under stirring. The reaction was allowed to react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then separated and purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 005 (3 mg). 1H NMR (400MHz, DMSO-d6) δ11.14(s,1H),7.97(s,1H),7.90(d,J=7.8Hz,1H),7.63(d,J=8.4Hz,2H),7.20(d,J=8.2Hz,1H),7.14(t, J=7.2Hz,1H),7.02(s,1H),6.11(d,J=8.4Hz,1H),4.21(t,J=7.0Hz,4H),3.81(s,3H),2.45–2.36(m,2H); LC-MS:m / z:387.0(M+H) + .

[0264] Example 5. Synthesis of Compound 008

[0265] Synthesis route

[0266] Experimental procedures

[0267] 1) Preparation of intermediate 8-2

[0268] At room temperature, 8-1 (2.0 g, 12.18 mmol) and dichloromethane (20.0 mL) were added to a single-necked flask, and chlorosulfonic acid (2.68 mL, 40.18 mmol) was added under stirring. The reaction was allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate 8-2 (3 g). 1 H NMR (400MHz, DMSO-d6) δ7.72 (d, J = 2.6 Hz, 1H), 7.4-7.35 (m, 1H), 6.94 (d, J = 8.6 Hz, 1H), 3.75 (s, 3H), 1.25 (s, 9H).

[0269] 2) Preparation of Intermediate 8-3

[0270] At room temperature, 8-2 (2 g, 8.19 mmol) and thionyl chloride (10.0 mL) were added to a single-necked flask. N,N-dimethylformamide (0.64 mL, 8.19 mmol) was added under stirring. The mixture was allowed to react at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate 8-3 (2.1 g). This was used directly in the next step without further purification.

[0271] 3) Preparation of Intermediate 8-4

[0272] At room temperature, 8-3 (900 mg, 3.43 mmol) and tetrahydrofuran (5.0 mL) were added to a single-necked flask, and aqueous ammonia (2.64 mL, 68.51 mmol) was added under stirring. The reaction was allowed to react at room temperature for 2 hours. 10 mL of water was added to the reaction solution, and the mixture was extracted with 10 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 1:1) to obtain intermediate 8-4 (30 mg). 1 H NMR(400MHz, DMSO-d6)δ7.72(d,J=2.5Hz,1H),7.62-7.55(m,1H),7.13(d,J=8.7Hz,1H),7.04(s,2H),3.87(s,3H),1.27(s,9H); LC-MS:m / z:244.0(M+H) + .

[0273] 4) Preparation of Compound 008

[0274] At room temperature, 8-4 (10.04 mg, 0.04 mmol) and 1-6 (10.0 mg, 0.04 mmol) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.87 mg, 0.06 mmol) and 4-dimethylaminopyridine (10.09 mg, 0.08 mg) were added sequentially under stirring. The reaction was allowed to react at room temperature for 3 hours. The reaction solution was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 008 (5 mg). 1 H NMR (400MHz, DMSO-d6) δ7.97(s,1H),7.88(s,1H),7.84(s,1H),7.65(d,J=7.8Hz,1H),7.46(s,1H),7.41(s,1H),7.11 (s,1H),7.02-6.92(m,2H),6.89(s,1H),6.27(s,1H),5.58(s,2H),3.71(s,3H),1.28(s,9H); LC-MS:m / z:468.0(M+H) + .

[0275] Example 6. Synthesis of Compound 009

[0276] Synthesis route

[0277] Experimental procedures

[0278] 1) Preparation of Intermediate 9-2

[0279] At 0°C, 9-1 (500 mg, 2.11 mmol) and tetrahydrofuran (10.0 mL) were added to a single-necked flask, and ammonia methanol (7N) (10 mL) was added under stirring. The reaction was allowed to proceed at 0°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate 9-2 (50 mg), which was used directly in the next step without purification. LC-MS: m / z: 218.0 (M+H) + .

[0280] 2) Preparation of Compound 009

[0281] At room temperature, 9-2 (26.91 mg, 0.12 mmol), dichloromethane (2.0 mL), and 1-6 (20.0 mg, 0.08 mmol) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.74 mg, 0.12 mmol) and 4-dimethylaminopyridine (30.26 mg, 0.25 mg) were added sequentially under stirring. The reaction was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 009 (5 mg). 1 H NMR (400MHz, DMSO-d6) δ12.01(s,1H),8.15(d,J=2.0Hz,1H),7.92(d,J=2.4Hz,1H),7.63(d,J=8.0Hz,1H),7.56-7.43(m,2H),7.06(d ,J=8.0Hz,1H),7.01(d,J=2.4Hz,1H),6.79(d,J=8.4Hz,2H),6.30(t,J=2.0Hz,1H),5.66(s,2H),3.77(s,6H).LC-MS:m / z:442.0(M+H) + .

[0282] Example 7. Synthesis of Compounds 010 and 012

[0283] Synthesis route

[0284] Experimental procedures

[0285] 1) Preparation of Intermediate 12-2

[0286] To a single-necked flask at 0°C, 12-1 (1.0 g, 4.61 mmol) and dichloromethane (20.0 mL) were added, followed by the addition of chlorosulfonic acid (0.92 mL, 13.82 mmol) with stirring. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to afford crude product 12-2 (1.46 g), which was used directly in the next step without further purification.

[0287] 2) Preparation of Intermediate 12-3

[0288] To a single-necked flask, 12-2 (1.46 g, 4.61 mmol) and ammonia methanol (7N) (50 mL) were added at 0°C. The mixture was allowed to react at 0°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 12-3 (200 mg). 1 H NMR (400MHz, DMSO-d6) δ7.08 (s, 2H), 6.99 (s, 2H), 3.84 (s, 6H).

[0289] 3) Preparation of Compound 012

[0290] At room temperature, 12-3 (75.51 mg, 0.26 mmol), 1-6 (40.0 mg, 0.17 mmol), and dichloromethane (10.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (47.48 mg, 0.25 mmol) and 4-dimethylaminopyridine (60.52 mg, 0.50 mg) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 012 (70 mg). 1 H NMR (400MHz, DMSO-d6) δ12.17(s,1H),8.15(d,J=2.4Hz,1H),7.92(d,J=2.4Hz,1H),7.62(d,J=8.0Hz,1H),7.4 9(d,J=2.0Hz,1H),7.07-6.97(m,4H),6.30(t,J=2.0Hz,1H),5.66(s,2H),3.81(s,6H); LC-MS:m / z:520.1(M+H) + .

[0291] 4) Preparation of Intermediate 10-1

[0292] Compound 012 (70.00 mg, 0.13 mmol), trimethylethynylsilane (39.64 mg, 0.40 mmol), triethylamine (68.06 mg, 0.67 mmol), dimethyl sulfoxide (4.0 mL) and ditriphenylphosphine palladium dichloride (9.44 mg, 0.01 mmol) were added to a microwave tube. The mixture was microwaved at 100 degrees Celsius for 2 hours. 20 mL of water was added to the reaction solution, which was then extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over Na2SO4, and concentrated under reduced pressure to give a crude product 10-1 (72.33 mg). The crude product was used directly in the next step without purification. LC-MS: m / z: 538.2 (M+H) + .

[0293] 5) Preparation of Compound 010

[0294] To a single-necked flask at room temperature were added 10-1 (72.33 mg, 0.13 mmol), potassium carbonate (92.96 mg, 0.67 mmol), and methanol (10.0 mL). The reaction was allowed to proceed for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water) to obtain compound 010 (2.10 mg). 1 H NMR (400MHz, CD3CN) δ7.95(d,J=2.4Hz,1H),7.80(d,J=8.0Hz,1H),7.64(d,J=2.4Hz,2H),7.48(d,J=2.0Hz,1H),7.13(d,J=8.0H z,1H),6.89(d,J=2.4Hz,1H),6.85(s,2H),6.30(t,J=2.0Hz,1H),5.62(s,2H),3.81(s,6H),3.60(s,1H); LC-MS:m / z:466.2(M+H) + .

[0295] Example 8. Synthesis of Compound 011

[0296] Synthesis route

[0297] Experimental procedures

[0298] 1) Preparation of Intermediate 11-2

[0299] At 0 degrees Celsius, 11-1 (5.0 g, 33.74 mmol), diisopropylamine (340.0 mg, 3.37 mmol) and dichloromethane (300.0 mL) were added to a three-necked flask, and N-bromosuccinimide (6.6 g, 37.11 mmol) was added under stirring. The reaction was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 7:1) to obtain intermediate 11-2 (5.7 g). 1 H NMR (400MHz, DMSO-d6) δ8.79 (s, 1H), 7.19 (d, J = 8.0Hz, 1H), 6.52 (d, J = 8.0Hz, 1H), 2.64-2.55 (m, 4H), 1.74-1.64 (m, 4H).

[0300] 2) Preparation of Intermediate 11-3

[0301] At room temperature, 11-2 (5.7 g, 25.10 mmol), iodomethane (10.69 g, 75.30 mmol), and potassium carbonate (10.41 g, 75.30 mmol) were added to a single-necked flask. The reaction was allowed to proceed at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 11-3 (3.0 g). 1 H NMR (400MHz, DMSO-d6) δ7.29 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 3.69 (s, 3H), 2.71-2.64 (m, 4H), 1.72-1.65 (m, 4H).

[0302] 3) Preparation of Intermediate 11-4

[0303] To a single-necked flask at room temperature were added 11-3 (3.0 g, 12.44 mmol), benzyl mercaptan (2.4 g, 19.28 mmol), tris(dibenzylideneacetone)dipalladium (1.18 g, 1.29 mmol), diisopropylethylamine (8.31 g, 64.28 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (1.49 g, 2.57 mmol), and 1,4-dioxane (130 mL). The mixture was allowed to react at 100°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain crude compound 11-4 (2.0 g). The crude product was used directly in the next step without further purification.

[0304] 4) Preparation of Intermediate 11-5

[0305] At 0°C, 11-4 (2.0 g, 7.03 mmol), water (2.0 mL), acetic acid (2.0 mL), and acetonitrile (50 mL) were added to a single-necked flask. N-chlorosuccinimide (1.13 g, 8.44 mmol) was added under stirring. The mixture was allowed to react at 0°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 11-5 (2.0 g). The crude product was used directly in the next step without purification.

[0306] 5) Preparation of Intermediate 11-6

[0307] At room temperature, a methanol solution of ammonia (30 mL) was added to a single-necked flask, and 11-5 (550.0 mg, 2.11 mmol) was added under stirring. The reaction was allowed to react at 25 degrees Celsius for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 1:1) to obtain intermediate 11-6 (300.0 mg). 1 H NMR (400MHz, DMSO-d6) δ7.49 (d, J = 8.0 Hz, 1H), 7.05 (s, 2H), 6.98 (d, J = 8.0 Hz, 1H), 3.81 (s, 3H), 2.80-2.70 (m, 4H), 1.74-1.71 (m, 4H).

[0308] 6) Preparation of Compound 011

[0309] At room temperature, 11-6 (43.44 mg, 0.18 mmol), dichloromethane (2.0 mL), and 1-6 (30.0 mg, 0.12 mmol) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.61 mg, 0.19 mmol) and 4-dimethylaminopyridine (45.39 mg, 0.37 mmol) were added sequentially under stirring. The reaction was allowed to react at room temperature for 18 hours, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain compound 011 (17.12 mg). 1H NMR (400MHz, DMSO-d6) δ12.33(s,1H),8.11(d,J=2.4Hz,1H),7.89(d,J=2.4Hz,1H), 7.68(d,J=8.0Hz,1H),7.63(d,J=8.0Hz,1H),7.47(d,J=2.0Hz,1H),7.08(d,J=8.0Hz ,2H),6.99(d,J=2.0Hz,1H),6.29(t,J=2.0Hz,1H),5.65(s,2H),3.79(s,3H),2.81(t ,J=5.6Hz,2H),2.69(t,J=5.6Hz,2H),1.72(p,J=4.8Hz,4H); LC-MS:m / z:466.2(M+H) + .

[0310] Example 9. Synthesis of Compound 013

[0311] Synthesis route

[0312] Experimental procedures

[0313] 1) Preparation of Intermediate 13-2

[0314] Under ice bath, 13-1 (1.0 g, 5.20 mmol) and dichloromethane (10.0 mL) were added to a single-necked flask, and chlorosulfonic acid (1.04 mL, 15.61 mmol) was added under stirring. The reaction was completed after 2 hours under ice bath. The reaction solution was concentrated under pressure to obtain crude product 13-2 (1.51 g), which was used directly in the next step without purification.

[0315] 2) Preparation of Intermediate 13-3

[0316] Under ice-cooling, crude product 13-2 (1.51 g, 5.20 mmol) was added to a single-necked flask, and ammonia methanol solution (40.0 mL, 7 mol / L) was added under stirring. The mixture was allowed to react under ice-cooling for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain compound 13-3 (350 mg). 1 H NMR (400MHz, CDCl3) δ7.76 (d, J=2.8Hz, 1H), 7.40 (dd, J=9.2, 2.8Hz, 1H), 7.06 (d, J=9.2Hz, 1H), 5.22 (s, 2H), 4.03 (s, 3H); LC-MS: m / z: 272.0 (M+H) + .

[0317] 3) Preparation of Compound 013

[0318] At room temperature, 13-3 (33.59 mg, 0.12 mmol), 1-6 (20.0 mg, 0.08 mmol), and dichloromethane (5.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.74 mg, 0.12 mmol) and 4-dimethylaminopyridine (30.26 mg, 0.25 mg) were added sequentially under stirring. The reaction was allowed to react at room temperature for 18 hours. The reaction solution was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (ammonium bicarbonate / acetonitrile / water) to obtain compound 013 (33 mg). 1 H NMR(400MHz, DMSO-d6)δ8.00(s,1H),7.85(d,J=2.4Hz,1H),7.78(d,J=3.2Hz,1H),7.66(d,J=8.0Hz,1H),7.59–7.42(m,2H),7 .23–7.08(m,2H),7.01(d,J=8.0Hz,1H),6.92(s,1H),6.27(t,J=2.0Hz,1H),5.60(s,2H),3.79(s,3H), LC-MS:m / z:496.0(M+H) + .

[0319] Example 10. Synthesis of Compound 014

[0320] Synthesis route

[0321] Experimental procedures

[0322] 1) Preparation of Intermediate 14-2

[0323] Under ice-cooling, 14-1 (1.0 g, 5.68 mmol) and dichloromethane (10.0 mL) were added to a single-necked flask, and chlorosulfonic acid (1.13 mL, 17.03 mmol) was added under stirring. The reaction was allowed to proceed under ice-cooling for 2 hours. The reaction solution was concentrated under pressure to obtain the crude product 14-2 (1.55 g), which was used directly in the next step without purification.

[0324] 2) Preparation of Intermediate 14-3

[0325] Under ice-cooling, crude product 14-2 (1.55 g, 5.68 mmol) was added to a single-necked flask, followed by stirring with ammonia methanol solution (40.0 mL, 7 mol / L). The mixture was allowed to react under ice-cooling for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 14-3 (500 mg). 1H NMR (400MHz, DMSO-d6) δ7.98-7.96 (m, 2H), 7.42 (d, J = 9.2Hz, 1H), 7.35 (s, 2H), 4.00 (s, 3H).

[0326] 3) Preparation of Compound 014

[0327] At room temperature, 14-3 (47.41 mg, 0.19 mmol), 1-6 (30.0 mg, 0.12 mmol), and dichloromethane (5.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.61 mg, 0.19 mmol) and 4-dimethylaminopyridine (45.39 mg, 0.37 mg) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain compound 014 (30 mg). 1 H NMR (400MHz, DMSO-d6) δ12.67(s,1H),8.14(dd,J=9.2,2.4Hz,2H),8.08(dd,J=8.8,2.4Hz,1H),7.90(d,J=2.4Hz,1H),7.62(d,J=8.0Hz,1H ),7.52-7.43(m,2H),7.07(d,J=8.0Hz,1H),7.00(d,J=2.4Hz,1H),6.29(t,J=2.0Hz,1H),5.65(s,2H),3.97(s,3H); LC-MS:m / z:480.2(M+H) + .

[0328] Example 11. Synthesis of Compound 015

[0329] Synthesis route

[0330] Experimental procedures

[0331] 1) Preparation of Intermediate 15-2

[0332] Under ice bath, 15-1 (900 mg, 3.59 mmol) and thionyl chloride (5.0 mL) were added to a single-necked flask and reacted at room temperature for 18 hours. The reaction solution was then cooled to 0 degrees Celsius, and anhydrous methanol (20.0 mL) was slowly added under stirring and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude product 15-2 (900 mg), which was used directly in the next step without purification. LC-MS: m / z: 265.0 (M+H) + .

[0333] 2) Preparation of Intermediate 15-3

[0334] Under ice-cooling, ammonia methanol solution (40.0 mL, 7 mol / L) was added to a single-necked flask, followed by compound 15-2 (900 mg, 3.40 mmol) under stirring. The mixture was allowed to react at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 15-3 (700 mg). LC-MS: m / z: 246.0 (M+H). + .

[0335] 3) Preparation of Intermediate 15-4

[0336] Under ice bath, 15-3 (300 mg, 1.22 mmol) and anhydrous tetrahydrofuran (10.0 mL) were added to a three-necked flask, and diisobutylaluminum hydride (7.5 mL, 7.50 mmol, 1 mol / L) was slowly added under stirring, and the reaction was carried out in an ice bath for 1 hour. After quenching, sodium sulfate decahydrate was added to the reaction solution in batches, and the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1 to 10: 1) to obtain 15-4 (200 mg). LC-MS: m / z: 218.0 (M+H) + .

[0337] 4) Preparation of Intermediate 15-5

[0338] Under ice bath, 15-4 (80 mg, 0.37 mmol) and anhydrous dichloromethane (2.0 mL) were added to a single-necked flask, and phosphorus tribromide (109.5 mg, 0.41 mmol) was added under stirring. The mixture was reacted at 25 degrees Celsius for 1 hour. After cooling, the reaction solution was poured into water (50 mL) and extracted three times with 30 mL of dichloromethane each time. The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product 15-5 (220 mg). The crude product was used directly in the next step without purification. LC-MS: m / z: 280.0 (M+H) + .

[0339] 5) Preparation of Intermediate 15-6

[0340] At room temperature, 15-5 (220 mg, 0.31 mmol) and anhydrous acetonitrile (10.0 mL) were added to a single-necked flask. Pyrazole (107 mg, 1.57 mmol) was added with stirring, and the mixture was allowed to react at 70°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 15-6 (80 mg). LC-MS: m / z: 268.0 (M+H) + .

[0341] 6) Preparation of Compound 15

[0342] At room temperature, 15-6 (33.10 mg, 0.12 mmol), 1-6 (20.0 mg, 0.08 mmol), and dichloromethane (2 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.74 mg, 0.12 mmol) and 4-dimethylaminopyridine (30.26 mg, 0.25 mg) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 015 (14 mg). 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),8.12(s,1H),7.93–7.80(m,3H),7.60(d,J=8.0Hz,1H),7.56–7.42(m,3H),7.20(d,J=8.4Hz,1 H),7.06(d,J=8.0Hz,1H),6.99(d,J=2.4Hz,1H),6.34–6.19(m,2H),5.64(s,2H),5.38(s,2H),3.82(s,3H); LC-MS:m / z:492.0(M+H) + .

[0343] Example 12. Synthesis of Compound 016

[0344] Synthesis route

[0345] Experimental procedures

[0346] 1) Preparation of Intermediate 16-2

[0347] Under ice bath, phenylethanol (1.26 g, 10.35 mmol) and anhydrous tetrahydrofuran (50.0 mL) were added to a three-necked flask, and sodium hydride (620 mg, 15.53 mmol) was added under stirring. After reacting at 0 degrees Celsius for 0.5 hours, a solution of compound 16-1 (2 g, 10.35 mmol) in anhydrous tetrahydrofuran (50.0 mL) was slowly added dropwise to the reaction solution and reacted at room temperature for 18 hours. The reaction solution was quenched with 10 mL of saturated ammonium chloride and then concentrated under reduced pressure to obtain a crude product, which was purified by high performance liquid chromatography (trifluoroacetic acid / acetonitrile / water system) to obtain intermediate 16-2 (300 mg). LC-MS: m / z: 318.0 (M+23) + .

[0348] 2) Preparation of Intermediate 16-3

[0349] Compound 16-2 (150 mg, 0.51 mmol) and methanol (5.0 mL) were added to a microwave tube at room temperature. A methanol solution of sodium methoxide (2.5 mL, 13.50 mmol) was added under stirring and the mixture was reacted at 90°C for 24 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 16-3 (80 mg). LC-MS: m / z: 330.0 (M+23) + .

[0350] 3) Preparation of Compound 016

[0351] At room temperature, 16-3 (20 mg, 0.08 mmol), 1-6 (38.07 mg, 0.12 mmol), and dichloromethane (5 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.74 mg, 0.12 mmol) and 4-dimethylaminopyridine (30.26 mg, 0.25 mmol) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 016 (6 mg). 1 H NMR (400MHz, DMSO-d6) δ11.89(s,1H),8.18–8.12(m,1H),7.91(d,J=2.4Hz,1H),7.68(d,J=8.0Hz,1H),7.49(d,J=2.0Hz,2H),7.27–7. 21(m,4H),7.22–7.14(m,1H),7.08(d,J=8.0Hz,1H),7.02(s,1H),6.85–6.75(m,2H),6.30(t,J=2.0Hz,1H),5.67(s,2H),4.20(s,2H), 3.76(s,3H),2.92(m,2H); LC-MS:m / z:532.2(M+H) + .

[0352] Example 13. Synthesis of Compound 017

[0353] Synthesis route

[0354] Experimental procedures

[0355] 1) Preparation of Intermediate 17-2

[0356] At room temperature, M7 (0.64 g, 5.71 mmol) and N,N-dimethylformamide (20.0 mL) were added to a single-necked flask, replaced with nitrogen three times, cooled to 0 degrees Celsius, and sodium hydroxide (0.46 g, 11.42 mmol) was added in batches. The reaction was maintained at 0 degrees Celsius for 1 hour. Compound 17-1 (1 g, 5.71 mmol) was added, the temperature was raised to 90 degrees Celsius, and the reaction was continued for 19 hours. 100 mL of water was added to the reaction solution, and the mixture was extracted once with 50 mL of ethyl acetate. The organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 1:1) to obtain intermediate 17-2 (170 mg). LC-MS: m / z: 268.0 (M+H) + .

[0357] 2) Preparation of Compound 017

[0358] At room temperature, 17-2 (40.0 mg, 0.15 mmol), 1-6 (27.0 mg, 0.11 mmol), and dichloromethane (2.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (32.05 mg, 0.17 mmol) and 4-dimethylaminopyridine (27.24 mg, 0.22 mmol) were added sequentially under stirring. The reaction was allowed to react at room temperature for 3 hours. The reaction solution was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (formic acid / acetonitrile / water system) to obtain compound 017 (9.5 mg). 1 HNMR (400MHz, DMSO-d6) δ12.05(s,1H),8.02(s,1H),7.91(d,J=10.2Hz,2H),7.60(s,2H),7.47(d,J=10.0Hz,2H),7.40-7.25(m,2 H),7.11(s,1H),7.06(d,J=7.8Hz,1H),6.99(s,1H),6.29(s,1H),5.65(s,2H),5.13(s,2H),3.59(s,3H); LC-MS:m / z:492.2(M+H) + .

[0359] Example 14. Synthesis of Compound 018

[0360] Synthesis route

[0361] Experimental procedures

[0362] 1) Preparation of Intermediate 18-2

[0363] At room temperature, 18-1 (2.0 g, 9.01 mmol) and tetrahydrofuran (20.0 mL) were added to a three-necked flask, and sodium hydroxide (10.81 mL, 27.02 mmol, 2.5 M) and hydrogen peroxide (2.71 mL, 27.02 mmol) were added dropwise under ice bath, and the mixture was reacted under ice bath for 2 hours. 50 mL of water was added to the reaction solution, the pH was adjusted to 2 with 1N hydrochloric acid, and 50 mL of ethyl acetate was extracted three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 5:1) to obtain intermediate 12-2 (250 mg). LC-MS: m / z: 113.0 (M+H) + .

[0364] 2) Preparation of Intermediate 18-3

[0365] At room temperature, M8 (70 mg, 0.40 mmol), toluene (1.0 mL) and N-methylpyrrolidone (1.0 mL) were added to a single-necked flask, and potassium carbonate (166 mg, 1.20 mmol) and 18-2 (45 mg, 0.40 mmol) were added under stirring. The reaction was carried out at 140 degrees Celsius for 18 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 1:1) to obtain intermediate 18-3 (60 mg). LC-MS: m / z: 268.0 (M+H) + .

[0366] 3) Preparation of Compound 018

[0367] At room temperature, 18-3 (20 mg, 0.08 mmol) and dichloromethane (2.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (24 mg, 0.12 mmol), 4-dimethylaminopyridine (20 mg, 0.16 mg), and 1-6 (22 mg, 0.08 mmol) were added sequentially under stirring. The reaction was allowed to react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (formic acid / acetonitrile / water system) to obtain compound 018 (14 mg). 1H NMR (400MHz, DMSO-d6) δ12.57 (s, 1H), 8.09-8.02 (m, 1H), 7.99 (d, J = 7.6Hz, 1H),7.91-7.84(m,1H),7.73-7.53(m,3H),7.47(d,J=1.2Hz,1H),7.32-7.22 (m,1H),7.21(s,1H),7.03(d,J=7.6Hz,2H),6.96(s,1H),6.28(t,J=1.9Hz,1 H),5.63(s,2H),3.98(m,2H),1.25(t,J=7.2Hz,3H); LC-MS:m / z:492.2(M+H) + .

[0368] Example 15. Synthesis of Compound 020

[0369] Synthesis route

[0370] Experimental procedures

[0371] 1) Preparation of Intermediate 20-2

[0372] To a single-necked flask at room temperature were added 20-1 (5.0 g, 33.74 mmol), iodomethane (9.58 g, 67.47 mmol), potassium carbonate (9.32 g, 67.47 mmol), and acetone (100.0 mL). The mixture was allowed to react at 60°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 20-2 (3 g). 1 H NMR (400MHz, CDCl3) δ7.07(t,J=8.0Hz,1H),6.70(d,J=7.6Hz,1H),6.66(d,J=8.0Hz ,1H),3.82(s,3H),2.76(t,J=6.0Hz,2H),2.65(t,J=6.0Hz,2H),1.82-1.73(m,4H).

[0373] 2) Preparation of Intermediate 20-3

[0374] Under ice bath, 20-2 (1.0 g, 6.16 mmol) and dichloromethane (10.0 mL) were added to a single-necked flask, and chlorosulfonic acid (1.23 mL, 18.49 mmol) was added under stirring. The reaction was allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 20-3 (1.6 g), which was used directly in the next step without purification.

[0375] 3) Preparation of Intermediate 20-4

[0376] Under ice-cooling, crude product 20-3 (1.6 g, 6.16 mmol) was added to a single-necked flask, followed by stirring with ammonia methanol solution (50.0 mL, 7 mol / L). The mixture was allowed to react under ice-cooling for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain compound 20-4 (1 g). 1 H NMR (400MHz, DMSO-d6) δ7.72(d,J=8.8Hz,1H),7.16(s,2H),6.88(d,J=8.8Hz,1H ), 3.82 (s, 3H), 3.06 (t, J = 4.8Hz, 2H), 2.60 (t, J = 4.8Hz, 2H), 1.72-1.68 (m, 4H).

[0377] 4) Preparation of Compound 020

[0378] At room temperature, 20-4 (29.89 mg, 0.12 mmol), 1-6 (30.0 mg, 0.12 mmol), and dichloromethane (4.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.61 mg, 0.19 mmol) and 4-dimethylaminopyridine (45.39 mg, 0.37 mg) were added sequentially under stirring. The reaction was allowed to react at room temperature for 18 hours. The reaction solution was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain compound 020 (30.00 mg). 1 H NMR (400MHz, DMSO-d6) δ12.32(s,1H),8.11(d,J=2.4Hz,1H),7.96(d,J=8.8Hz ,1H),7.88(d,J=2.4Hz,1H),7.55(d,J=8.0Hz,1H),7.47(d,J=2.0Hz,1H),7.0 7(d,J=8.0Hz,1H),7.04-6.97(m,2H),6.28(t,J=2.0Hz,1H),5.64(s,2H),3.8 7(s,3H),3.11(s,2H),2.59(s,2H),1.70-1.67(m,4H); LC-MS:m / z:466.2(M+H) + .

[0379] Example 16. Synthesis of Compound 021

[0380] Synthesis route

[0381] Experimental procedures

[0382] 1) Preparation of Intermediate 21-2

[0383] At room temperature, 21-1 (3.0 g, 10.51 mmol) and acetonitrile (30.0 mL) were added to a single-necked bottle, cooled to 0 degrees Celsius, and ammonia (8.09 mL) was slowly added to react for two hours. The reaction solution was concentrated to obtain the crude intermediate 21-2 (2.6 g). 1 HNMR (400MHz, DMSO-d6) δ7.79 (d, J=2.5Hz, 1H), 7.75 (dd, J=8.8, 2.6Hz, 1H), 7.34 (s, 2H), 7.20 (d, J=8.8Hz, 1H), 3.90 (s, 3H); LC-MS: m / z: 265.8 (M+H) + .

[0384] 2) Preparation of Intermediate 21-3

[0385] To a single-necked flask at room temperature were added 21-2 (200 mg, 0.75 mmol), M9 (184.04 mg, 0.83 mmol), 1,4-dioxane (2.0 mL), and water (0.4 mL). Potassium carbonate (311.60 mg, 2.25 mmol) and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (27.50 mg, 0.04 mmol) were added with stirring. The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 100°C for 18 hours. The reaction mixture was then added with 10 mL of water and extracted once with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to yield intermediate 21-3 (70 mg). 1 H NMR (400MHz, DMSO-d6) δ7.65(d,J=2.2Hz,1H),7.59(dd,J=8.5,2.2Hz,1H),7.31(d,J=8.6Hz,1H),7.17(s, 2H),3.95(s,3H),2.38(s,3H),2.20(s,3H); LC-MS:m / z:283.0(M+H) + .

[0386] 3) Preparation of Compound 021

[0387] At room temperature, 21-3 (30.0 mg, 0.11 mmol), 1-6 (25.74 mg, 0.11 mmol), and dichloromethane (0.5 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (30.56 mg, 0.16 mmol) and 4-dimethylaminopyridine (29.57 mg, 0.21 mg) were added sequentially under stirring. The reaction was allowed to react at room temperature for 3 hours. The reaction solution was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain compound 021 (22.8 mg). 1 H NMR(400MHz, DMSO-d6)12.43(s,1H),8.14(d,J=1.9Hz,1H),7.90(d,J=2.0Hz,1H),7.85 (d,J=2.3Hz,1H),7.71(d,J=7.4Hz,1H),7.62(d,J=7.8Hz,1H),7.48(d,J=1.3Hz,1H),7 .35(d,J=8.6Hz,1H),7.07(d,J=7.8Hz,1H),7.00(d,J=2.2Hz,1H),6.29(t,J=2.0Hz,1H ),5.66(d,J=9.1Hz,2H),3.92(s,3H),2.43(s,3H),2.24(s,3H); LC-MS:m / z:507.0(M+H) + .

[0388] Example 17. Synthesis of Compound 022

[0389] Synthesis route

[0390] Experimental procedures

[0391] 1) Preparation of Intermediate 22-2

[0392] To a single-necked flask at room temperature were added 22-1 (500 mg, 1.88 mmol), M10 (807.0 mg, 9.39 mmol), 1,4-dioxane (5 mL), and water (1 mL). Potassium carbonate (779.0 mg, 5.64 mmol) and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (68.74 mg, 0.09 mmol) were added with stirring. After nitrogen substitution three times, the mixture was allowed to react at 100°C for 18 hours. The reaction mixture was added with 10 mL of water and extracted once with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to afford intermediate 22-2 (370 mg). 1HNMR(400MHz,DMSO-d6)δ7.43(d,J=2.3Hz,1H),7.27(dd,J=8.6,2.4Hz,1H),7.08(d,J=8.5Hz,1H),6.99(s,2H),3.85(s,3H), 1.97-1.90(m,1H),0.97-0.89(m,2H),0.64-0.54(m,2H); LC-MS:m / z:228.0(M+H) + .

[0393] 2) Preparation of Compound 022

[0394] At room temperature, 22-2 (50.0 mg, 0.22 mmol), 1-6 (53.29 mg, 0.22 mmol), and dichloromethane (0.5 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (63.26 mg, 0.33 mmol) and 4-dimethylaminopyridine (53.75 mg, 0.44 mmol) were added sequentially under stirring. The reaction was allowed to react at room temperature for 18 hours. The reaction solution was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (formic acid / acetonitrile / water system) to obtain compound 022 (40.0 mg). 1 H NMR (400MHz, DMSO-d6) δ12.32(s,1H),8.14(d,J=2.1Hz,1H),7.91(d,J=2.1Hz,1H),7.64(d,J= 2.3Hz,1H),7.60(d,J=7.8Hz,1H),7.48(d,J=1.4Hz,1H),7.34(dd,J=8.6,2.0Hz,1H),7.12(d, J=8.6Hz,1H),7.06(d,J=7.8Hz,1H),7.00(d,J=2.2Hz,1H),6.29(t,J=2.0Hz,1H),5.65(s,2H) ,3.81(s,3H),2.06–1.97(m,1H),1.01–0.93(m,2H),0.68–0.61(m,2H); LC-MS:m / z:452.2(M+H) + .

[0395] Example 18. Synthesis of Compound 023

[0396] Synthesis route

[0397] Experimental procedures

[0398] 1) Preparation of Intermediate 23-2

[0399] At -30 ° C, 23-1 (5.0 g, 24.49 mmol) and anhydrous tetrahydrofuran (100.0 mL) were added to a three-necked flask, and methylmagnesium chloride (16.3 mL, 48.98 mmol) was slowly added dropwise under stirring. After the addition was completed, the temperature was raised to room temperature and the reaction was carried out for 18 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution (100.0 mL) and extracted three times with 30 mL of ethyl acetate each time. The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product 23-2 (6 g), which was directly used in the next reaction. LC-MS: m / z: 203.0 (M+H-18) + .

[0400] 2) Preparation of Intermediate 23-3

[0401] Under ice bath, 23-2 (3.0 g, 13.62 mmol) and anhydrous dichloromethane (40.0 mL) were added to a single-necked flask, and titanium tetrachloride (2.58 g, 13.62 mmol) was added under stirring. The reaction was allowed to react at room temperature for 2 hours. The reaction solution was poured into water (150.0 mL) and extracted three times with 50 mL of dichloromethane each time. The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 8:1) to obtain intermediate 23-3 (2.6 g). 1 H NMR (400MHz, CDCl3) δ7.64–7.54(m,2H), 6.96–6.88(m,2H), 3.83(s,3H), 2.17–2.09(m,3H).

[0402] 3) Preparation of Intermediate 23-4

[0403] Under ice bath, 23-3 (2.6 g, 10.90 mmol) and anhydrous n-hexane (50.0 mL) were added to a single-necked flask, and trimethylaluminum solution (21.8 mL, 43.58 mmol) was added under stirring. The mixture was reacted at 70 degrees Celsius for 2 hours. The reaction solution was slowly poured into ice water (150.0 mL) and extracted three times with 50 mL of dichloromethane each time. The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain crude product 23-4 (1.8 g), which was used directly in the next step without purification. 1 H NMR (400MHz, CDCl3) δ7.46–7.37(m,2H),6.93–6.85(m,2H),3.82(s,3H),1.57(s,6H).

[0404] 4) Preparation of Intermediate 23-5

[0405] In a 100 mL single-necked flask under ice-cooling, 23-4 (800 mg, 3.67 mmol) and dichloromethane (30.0 mL) were added, followed by chlorosulfonic acid (0.73 mL, 11.00 mmol) under stirring, and the mixture was allowed to react at room temperature for 18 hours. The reaction mixture was carried on to the following step without further treatment.

[0406] 5) Preparation of Intermediate 23-6

[0407] Under ice-cooling, ammonia methanol solution (40.0 mL, 7 mol / L) was added to a single-necked flask, followed by the reaction mixture from the previous step under stirring. The mixture was allowed to react under ice-cooling for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 23-6 (300 mg). 1 H NMR (400MHz, DMSO-d6) δ7.84 (d, J=2.8Hz, 1H), 7.73 (dd, J=8.8, 2.8Hz, 1H),7.23(d,J=8.8Hz,1H),7.16(s,2H),3.91(s,3H),1.55(s,6H); LC-MS:m / z:298.0(M+H) + .

[0408] 6) Preparation of Compound 023

[0409] To a single-necked flask at room temperature were added 23-6 (36.82 mg, 0.12 mmol), 1-6 (30.0 mg, 0.12 mmol), and dichloromethane (5 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.61 mg, 0.19 mmol) and 4-dimethylaminopyridine (45.39 mg, 0.37 mg) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water) to afford compound 023 (30 mg). 1H NMR (400MHz, DMSO-d6) δ12.44(s,1H),8.14(d,J=2.4Hz,1H),8.00(d,J=2.8Hz,1H ),7.91(d,J=2.4Hz,1H),7.88–7.80(m,1H),7.61(d,J=8.0Hz,1H),7.48(d,J=2.0 Hz,1H),7.27(d,J=9.2Hz,1H),7.06(d,J=8.0Hz,1H),7.00(d,J=2.4Hz,1H),6.30 (t,J=2.0Hz,1H),5.65(s,2H),3.89(s,3H),1.58(s,6H),LC-MS:m / z:522.0(M+H) + .

[0410] Example 19. Synthesis of Compound 024

[0411] Synthesis route

[0412] Experimental procedures

[0413] 1) Preparation of Intermediate 24-2

[0414] Under ice bath, 24-1 (250.0 mg, 1.21 mmol), phosphorus tribromide (361.01 mg, 1.33 mmol) and dichloromethane (50.0 mL) were added to a single-necked flask. The reaction was allowed to react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 10:1) to obtain intermediate 24-2 (100.0 mg). 1 H NMR (400MHz, DMSO-d6) δ8.22(d,J=2.4Hz,1H),7.86(d,J=8.0Hz,1H),7.47(d,J=8.0Hz,1H),7.28(d,J=2.4Hz,1H),5.02(s,2H),3.92(s,3H).

[0415] 2) Preparation of Intermediates 24-3 and 24-3a

[0416] At room temperature, 24-2 (70.0 mg, 0.26 mmol), M11 (26.95 mg, 0.39 mmol), potassium carbonate (53.93 mg, 0.39 mmol), potassium iodide (1.32 mg, 0.03 mmol) and acetone (10 mL) were added to a single-necked flask. The mixture was reacted at 60 degrees Celsius for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 7:1) to obtain intermediate 24-3 (20.0 mg).1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.68–7.59 (m, 2H), 7.25–7.17 (m, 1H), 6.81 (dd, J = 2.4, 0.8 Hz, 1H), 5.86 (s, 2H), 3.99 (d, J = 0.8 Hz, 3H) and intermediate 24-3a (40.0 mg), 1 H NMR (400MHz, CDCl3) δ7.91(d,J=8.0Hz,1H),7.71(d,J=2.4Hz,1H),7.67(d,J=1.2Hz,1H),7. 47(d,J=1.2Hz,1H),7.15(d,J=8.0Hz,1H),6.68(d,J=2.4Hz,1H),5.81(s,2H),3.96(s,3H).

[0417] 3) Preparation of Intermediate 24-4

[0418] At room temperature, 24-3 (20.0 mg, 0.08 mmol), sodium hydroxide (9.33 mg, 0.23 mmol), water (1 mL), and methanol (3 mL) were added to a single-necked flask. The reaction was allowed to react at 50°C for 2 hours. The reaction solution was adjusted to pH = 2 with hydrochloric acid (4N), filtered, and the filter cake was dried under reduced pressure to obtain intermediate 24-4 (12.0 mg). LC-MS: m / z: 244.0 (M+H) + .

[0419] 4) Preparation of Compound 024

[0420] At room temperature, 24-4 (12.00 mg, 0.05 mmol), dichloromethane (2.0 mL), and M12 (12.00 mg, 0.05 mmol) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.38 mg, 0.08 mmol) and 4-dimethylaminopyridine (18.33 mg, 0.15 mmol) were added sequentially under stirring. The reaction was allowed to react at room temperature for 18 hours, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 024 (7.73 mg). 1H NMR (400MHz, DMSO-d6) δ12.29(s,1H),8.14(d,J=2.4Hz,1H),7.87(d,J=2.4Hz,1H),7.83(s,2H),7.70(d,J=8.4Hz,1H),7.62(d, J=8.0Hz,1H),7.16(dd,J=8.4,5.1Hz,2H),6.96(d,J=2.4Hz,1H),5.98(s,2H),3.84(s,3H),1.30(s,9H); LC-MS:m / z:469.2(M+H) + .

[0421] Example 20. Synthesis of Compound 026

[0422] Synthesis route

[0423] Experimental procedures

[0424] 1) Preparation of Intermediate 26-2

[0425] Under ice-cooling, 26-1 (2.0 g, 9.21 mmol) and anhydrous acetonitrile (20.0 mL) were added to a three-necked flask. N-bromosuccinimide (1.8 g, 10.13 mmol) was added under stirring, and the mixture was reacted at 0°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 8:1) to obtain intermediate 26-2 (2.5 g). LC-MS: m / z: 295.9 (M+H) + .

[0426] 2) Preparation of Intermediate 26-3

[0427] At room temperature, 26-2 (1.0 g, 3.38 mmol), isopropenylboronic acid pinacol ester (850 mg, 5.07 mmol), sodium carbonate (720 mg, 6.75 mmol), tetrakistriphenylphosphine palladium (390 mg, 0.34 mmol), dioxane (5.0 mL) and water (1.0 mL) were added to a single-necked flask. After nitrogen substitution three times, the reaction was continued at 100 degrees Celsius for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 26-3 (700 mg). LC-MS: m / z: 258.0 (M+H) + .

[0428] 3) Preparation of Intermediate 26-4

[0429] At room temperature, 26-3 (100 mg, 0.39 mmol) and anhydrous methanol (10.0 mL) were added to a single-necked flask. Palladium carbon (41.4 mg, 0.39 mmol) was added under stirring. The atmosphere was replaced with hydrogen three times and the reaction was carried out at room temperature under a hydrogen balloon atmosphere for 18 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain crude product 26-4 (100 mg), which was used directly in the next step without purification. LC-MS: m / z: 260.0 (M+H) + .

[0430] 4) Preparation of Compound 026

[0431] At room temperature, 26-4 (48.17 mg, 0.19 mmol), 1-6 (30.0 mg, 0.12 mmol), and dichloromethane (5 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.61 mg, 0.19 mmol) and 4-dimethylaminopyridine (45.39 mg, 0.37 mg) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain compound 026 (27 mg). 1 H NMR (400MHz, DMSO-d6) δ12.10(s,1H),8.16(d,J=2.4Hz,1H),7.92(d,J=2.4Hz,1H),7. 66(d,J=8.0Hz,1H),7.56(d,J=8.8Hz,1H),7.49(d,J=2.0Hz,1H),7.06(d,J=8.0Hz,1H) ,7.02(d,J=2.4Hz,1H),6.98(d,J=8.8Hz,1H),6.30(t,J=2.0Hz,1H),5.66(s,2H),3.86 (s,3H),3.74(s,3H),3.29–3.17(m,1H),1.18(d,J=7.2Hz,6H); LC-MS:m / z:484.0(M+H) + .

[0432] Example 21. Synthesis of Compound 027

[0433] Synthesis route

[0434] Experimental procedures

[0435] 1) Preparation of Intermediate 27-2

[0436] Under ice, methyltriphenylphosphonium bromide (2.2 g, 6.12 mmol) and anhydrous tetrahydrofuran (50.0 mL) were added to a three-necked flask. n-Butyllithium solution (3.7 mL, 5.88 mmol) was slowly added dropwise with stirring. After completion of the addition, the mixture was stirred at 0°C for 10 minutes. The reaction solution was cooled to -78°C, and 27-1 (0.8 mL, 4.90 mmol) was slowly added dropwise with stirring. After completion of the addition, the mixture was warmed to room temperature and reacted for 1 hour. The reaction solution was quenched with saturated aqueous ammonium chloride (100.0 mL) and extracted three times with 30 mL of ethyl acetate each time. The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 27-2 (760 mg). 1 H NMR (400MHz, CDCl3) δ7.44–7.36(m,2H),6.97–6.81(m,2H),5.91–5.83(m,1H),5.74–5.68(m,1H),3.83(s,3H).

[0437] 2) Preparation of Intermediate 27-3

[0438] Under ice-cooling, 27-2 (200 mg, 0.99 mmol), methyl biphenylthiotetrafluoroborate (1.5 mL, 1.29 mmol), and anhydrous tetrahydrofuran (2.0 mL) were added to a single-necked flask. Sodium bis(trimethylsilyl)amide (1.58 mL, 1.58 mmol) was added with stirring, and the mixture was allowed to react in an ice-cooling bath for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 27-3 (130 mg). 1 H NMR (400MHz, CDCl3) δ7.42–7.36(m,2H),6.91–6.83(m,2H),3.81(s,3H),1.34–1.29(m,2H),1.02–0.93(m,2H).

[0439] 3) Preparation of Intermediate 27-4

[0440] Under ice bath, 27-3 (130 mg, 0.60 mmol) and dichloromethane (10.0 mL) were added to a single-necked flask, and chlorosulfonic acid (0.12 mL, 1.80 mmol) was added under stirring. The reaction was allowed to react at room temperature for 18 hours. The reaction solution was used directly in the next step without further treatment.

[0441] 4) Preparation of Intermediate 27-5

[0442] Under ice bath, ammonia methanol solution (20.0 mL, 7 mol / L) was added to a single-necked flask and the reaction solution from the previous step was added under stirring. The reaction was allowed to react at 0°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 27-5 (110 mg). LC-MS: m / z: 296.0 (M+H) + .

[0443] 5) Preparation of Compound 027

[0444] At room temperature, 27-5 (54.86 mg, 0.19 mmol), 1-6 (30.0 mg, 0.12 mmol), and dichloromethane (5 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.61 mg, 0.19 mmol) and 4-dimethylaminopyridine (45.39 mg, 0.37 mg) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain 027 (31 mg). 1 H NMR (400MHz, DMSO-d6) δ12.46(s,1H),8.11(s,1H),7.95(d,J=2.4Hz,1H),7.90(d,J=2.4Hz,1H),7.71(s,1H),7.61(d,J =8.0Hz,1H),7.47(d,J=2.0Hz,1H),7.23(s,1H),7.04(d,J=8.0Hz,1H),6.98(s,1H),6.29(t,J =2.0Hz,1H),5.64(s,2H),3.85(s,3H),1.43–1.32(m,2H),1.13(s,2H); LC-MS:m / z:520.0(M+H) + .

[0445] Example 22. Synthesis of Compound 028

[0446] Synthesis route

[0447] Experimental procedures

[0448] 1) Preparation of Intermediate 28-2

[0449] At room temperature, 28-1 (700.0 mg, 2.36 mmol), M10 (406.11 mg, 4.73 mmol), bistriphenylphosphine palladium dichloride (172.96 mg, 0.24 mmol), potassium carbonate (980.04 mg, 7.09 mmol), 1,4-dioxane (20.0 mL) and water (4.0 mL) were added to a single-necked bottle and reacted at 100 degrees Celsius for 18 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted three times with 50 mL of ethyl acetate each time. The organic phases were combined, dried over sodium sulfate, filtered, and distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100:1 to 10:1) to obtain intermediate 28-2 (400.0 mg), LC-MS: m / z: 258.2 (M+H) + .

[0450] 2) Preparation of Compound 028

[0451] At room temperature, 28-2 (31.87 mg, 0.12 mmol), 1-6 (30.0 mg, 0.12 mmol), and dichloromethane (4.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.61 mg, 0.19 mmol) and 4-dimethylaminopyridine (45.39 mg, 0.37 mg) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC (formic acid / acetonitrile / water system) to obtain compound 028 (12.02 mg). 1 H NMR (400MHz, DMSO-d6) δ12.10(s,1H),8.14(s,1H),7.92(d,J=2.4Hz,1H),7.66(d,J=7.8Hz,1H),7.48(d,J=2.0Hz,1H),7.18-6.98(m,3H) ,6.87(d,J=8.8Hz,1H),6.30(t,J=2.0Hz,1H),5.66(s,2H),3.92(s,3H),3.71(s,3H),2.11-2.04(m,1H),0.98-0.93(m,2H),0.68-0.64(m, 2H); LC-MS:m / z:482.2(M+H) + .

[0452] Example 23. Synthesis of Compound 030

[0453] Synthesis route

[0454] Experimental procedures

[0455] 1) Preparation of Intermediate 30-1

[0456] At room temperature, 24-3a (40.0 mg, 0.16 mmol), sodium hydroxide (18.66 mg, 0.47 mmol), water (2 mL), and methanol (6 mL) were added to a single-necked flask. The reaction was allowed to proceed at 50°C for 2 hours. The reaction solution was adjusted to pH 2 with hydrochloric acid (4N), filtered, and the filter cake was dried under reduced pressure to obtain intermediate 30-1 (22.0 mg, 0.09 mmol). LC-MS: m / z: 244.0 (M+H) + .

[0457] 2) Preparation of Compound 030

[0458] At room temperature, 30-1 (22.00 mg, 0.09 mmol), dichloromethane (2.0 mL), and M12 (22.01 mg, 0.08 mmol) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (26.01 mg, 0.14 mmol) and 4-dimethylaminopyridine (33.15 mg, 0.27 mmol) were added sequentially under stirring. The reaction was allowed to proceed at room temperature for 18 hours, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 030 (18.25 mg, 0.04 mmol). 1 H NMR (400MHz, DMSO-d6) δ12.30(s,1H),8.24(d,J=1.2Hz,1H),8.17(d,J=2.4Hz,1H),7.87(d,J=2.4Hz,1H),7.76(d,J=1.2Hz,1H),7.74–7. 67(m,1H),7.63(d,J=8.0Hz,1H),7.20–7.13(m,2H),7.09(d,J=2.4Hz,1H),5.95(s,2H),3.84(s,3H),1.30(s,9H); LC-MS:m / z:469.2(M+H) + .

[0459] Example 24. Synthesis of Compound 031

[0460] Synthesis route

[0461] Experimental procedures

[0462] 1) Preparation of Compound 031

[0463] At room temperature, 26-3 (47.80 mg, 0.19 mmol), 1-6 (30.0 mg, 0.12 mmol), and dichloromethane (4.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.61 mg, 0.19 mmol) and 4-dimethylaminopyridine (45.39 mg, 0.37 mg) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 031 (32 mg). 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),8.14(d,J=2.4Hz,1H),7.92(d,J=2.4Hz,1H),7 .65(d,J=8.0Hz,1H),7.49(d,J=2.0Hz,1H),7.42(d,J=8.8Hz,1H),7.06(d,J=8.0Hz,1 H),7.01(d,J=2.4Hz,1H),6.95(d,J=8.8Hz,1H),6.30(t,J=2.0Hz,1H),5.66(s,2H), 5.21(s,1H),5.10(s,1H),3.75(d,J=2.8Hz,6H),2.07(s,3H); LC-MS:m / z:482.2(M+H) + .

[0464] Example 25. Synthesis of Compound 032

[0465] Synthesis route

[0466] Experimental procedures

[0467] 1) Preparation of Intermediate 32-2

[0468] At room temperature, 32-1 (900.0 mg, 6.07 mmol) and ethanol (9.0 mL) were added to a single-necked flask. 10% palladium on carbon (64.6 mg, 0.61 mmol) was added under stirring. After H2 substitution three times, the reaction was allowed to proceed under a hydrogen balloon atmosphere for 18 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 7:1) to obtain intermediate 32-2 (720 mg). LC-MS: m / z: 151.0 (M+H). + , 1HNMR (400MHz, DMSO-d6) δ7.12–7.04(m,1H),6.42–6.25(m,2H),4.51(t,J=8.6Hz,2H),3.68(s,3H),3.07(t,J=8.6Hz,2H).

[0469] 2) Preparation of Intermediate 32-3

[0470] At room temperature, 32-2 (720.0 mg, 4.79 mmol) and acetonitrile (10.0 mL) were added to a single-necked flask. N-bromosuccinimide (853.33 mg, 4.79 mmol) was added under stirring and the mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 32-3 (500.0 mg). 1 H NMR (400MHz, DMSO-d6) δ7.36 (s, 1H), 6.63 (s, 1H), 4.55 (t, J = 8.7Hz, 2H), 3.77 (s, 3H), 3.11 (t, J = 8.7Hz, 2H).

[0471] 3) Preparation of Intermediate 32-4

[0472] To a single-necked flask at room temperature, 32-4 (400.0 mg, 1.75 mmol) and dichloromethane (6.0 mL) were added. The temperature was cooled to 0°C, and chlorosulfonic acid (0.35 mL, 5.24 mmol) was added with stirring. The mixture was reacted in an ice bath for 1 hour, then warmed to room temperature for 2 hours. The reaction solution was used in the next step without purification.

[0473] 4) Preparation of Intermediate 32-5

[0474] At room temperature, ammonia (5.0 mL) and acetonitrile (5.0 mL) were added to a single-necked flask. The temperature was lowered to 0°C, and the reaction mixture of Intermediate 32-4 was added dropwise with stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain Intermediate 32-5 (50.0 mg). 1 H NMR (400MHz, DMSO-d6) δ7.59 (s, 1H), 7.18 (s, 2H), 4.73 (t, J = 8.8Hz, 2H), 3.89 (s, 3H), 3.31 (t, J = 8.7Hz, 2H); LC-MS: m / z: 330.0 (M + Na) + .

[0475] 5) Preparation of Intermediate 32-6

[0476] At room temperature, 32-5 (50.0 mg, 0.16 mmol) and methanol (5.0 mL) were added to a single-necked flask. 10% palladium on carbon (17.27 mg, 0.16 mmol) was added under stirring. After H2 replacement three times, the reaction was continued under a hydrogen balloon atmosphere for 16 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain intermediate 32-5 (30.0 mg). LC-MS: m / z: 252.0 (M+Na) + .

[0477] 6) Preparation of Compound 032

[0478] To a single-necked flask at room temperature were added 32-6 (30.0 mg, 0.13 mmol), 1-6 (31.7 mg, 0.13 mmol), and dichloromethane (2 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.63 mg, 0.2 mmol) and 4-dimethylaminopyridine (31.97 mg, 0.26 mg) were added sequentially with stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by HPLC (formic acid / acetonitrile / water) to afford compound 032 (1.1 mg). 1 H NMR (400MHz, DMSO-d6) δ12.10(s,1H),8.05(s,1H),7.86(d,J=7.2Hz,1H),7.70(s,1H),7.62(d,J=7.6Hz,1H),7.46(s,1H),7.01(d,J=7.0Hz,1H), 6.94(s,1H),6.59(d,J=42.8Hz,1H),6.28(s,1H),5.61(s,2H),4.62(s,2 H), 3.70 (d, J=18.7Hz, 3H), 3.16 (t, J=8.2Hz, 2H); LC-MS: m / z: 454.2 (M+H) + .

[0479] Example 26. Synthesis of Compound 034

[0480] Synthesis route

[0481] Experimental procedures

[0482] 1) Preparation of Intermediate 34-2

[0483] At room temperature, 34-1 (2.0 g, 12.04 mmol) and tetrahydrofuran (30.0 mL) were added to a single-necked flask, and N,N-diisopropylethylamine (7.98 mL, 48.14 mmol), dimethylamine hydrochloride (0.65 g, 14.44 mmol) and (7-azabenzotriazole-1-oxy)tripyrrophosphonium hexafluorophosphate (5.49 g, 14.44 mmol) were added under stirring. The reaction was allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 10:1) to obtain intermediate 34-2 (2.0 g). LC-MS: m / z: 194.0 (M+H) + .

[0484] 2) Preparation of Intermediate 34-3

[0485] Under ice bath, 34-2 (500 mg, 2.59 mmol) and dichloromethane (10.0 mL) were added to a single-necked flask, and chlorosulfonic acid (0.86 mL, 12.94 mmol) was added under stirring. The reaction was allowed to react at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 34-3 (753 mg), which was used directly in the next step without purification.

[0486] 3) Preparation of Intermediate 34-4

[0487] Under ice, crude product 34-3 (753 mg, 2.59 mmol) and acetonitrile (10.0 mL) were added to a single-necked flask. Ammonia (7.11 mL, 51.69 mmol) was added with stirring. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain compound 34-4 (330 mg). 1 H NMR (400MHz, DMSO-d6) δ7.59(d,J=2.2Hz,1H),7.39(dd,J=8.5,2.2Hz,1H),7.13(d,J=8.5Hz, 1H),7.04(s,2H),3.88(s,3H),3.69(s,2H),3.01(s,3H),2.82(s,3H); LC-MS:m / z:273.0(M+H) + .

[0488] 4) Preparation of Compound 034

[0489] At room temperature, 34-4 (50 mg, 0.18 mmol) and dichloromethane (2.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol), 4-dimethylaminopyridine (44 mg, 0.37 mg), and 1-6 (44 mg, 0.18 mmol) were added sequentially under stirring. The reaction was allowed to react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (formic acid / acetonitrile / water system) to obtain compound 034 (42 mg). 1 H NMR (400MHz, DMSO-d6) δ12.31(s,1H),8.14(s,1H),7.91(d,J=2.1Hz,1H),7.78 (d,J=2.1Hz,1H),7.61(d,J=7.8Hz,1H),7.54-7.44(m,2H),7.17(d,J=8.4Hz,1H ),7.06(d,J=7.8Hz,1H),7.00(d,J=2.0Hz,1H),6.30(t,J=2.0Hz,1H),5.65(s,2 H),3.83(s,3H),3.76(s,2H),3.03(s,3H),2.84(s,3H); LC-MS:m / z:497.2(M+H) + .

[0490] Example 27. Synthesis of Compounds 035 and 078

[0491] Synthesis route

[0492] Experimental procedures

[0493] 1) Preparation of Intermediate 35-2

[0494] At room temperature, 35-1 (230 mg, 0.41 mmol) and trifluoroacetic acid (2.0 mL) were added to a single-necked bottle and reacted at room temperature for 3 hours. The reaction solution was adjusted to pH 8 with aqueous sodium bicarbonate solution (100.0 mL), extracted three times with 30 mL of dichloromethane each time, and the combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1 to 1: 1) to obtain compound 35-2 (100 mg). LC-MS: m / z: 315.0 (M + H) + .

[0495] 2) Preparation of Compound 078

[0496] At room temperature, 35-2 (97.33 mg, 0.31 mmol), 1-6 (50.0 mg, 0.21 mmol), and dichloromethane (4 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (59.35 mg, 0.31 mmol) and 4-dimethylaminopyridine (50.44 mg, 0.41 mg) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 078 (100 mg). 1 H NMR (400MHz, DMSO-d6) δ12.24(s,1H),8.18–8.08(m,1H),7.91(d,J=2.4Hz,1H),7.62(d,J=8 .0Hz,1H),7.48(d,J=2.0Hz,1H),7.10(d,J=9.2Hz,1H),7.08–6.97(m,3H),6.75(d,J=9.2Hz, 1H),6.29(t,J=2.0Hz,1H),5.65(s,2H),4.35–4.24(m,1H),3.73(s,3H),3.64(s,3H),3.49–3 .40(m,1H),3.33–3.25(m,1H),2.36–2.23(m,1H),2.14–1.94(m,3H); LC-MS:m / z:539.0(M+H) + .

[0497] 3) Preparation of Compound 035

[0498] At room temperature, 078 (75 mg, 0.14 mmol) and aqueous ammonia (20.0 mL) were added to a microwave tube and reacted at 100°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain compound 035 (4 mg). 1H NMR (400MHz, DMSO-d6) δ12.25(s,1H),8.08(s,1H),7.89(d,J=2.4Hz,1H),7.63(d,J=8 .0Hz,1H),7.56–7.36(m,2H),7.15–6.99(m,4H),6.99–6.90(m,1H),6.71–6.50(m,1H), 6.28(t,J=2.0Hz,1H),5.62(s,2H),3.87–3.79(m,1H),3.73–3.65(m,3H),3.61–3.52(m ,1H),3.23–3.10(m,1H),2.29–2.15(m,1H),2.03–1.91(m,3H); LC-MS:m / z:524.0(M+H) + .

[0499] Example 28. Synthesis of Compound 036

[0500] Synthesis route

[0501] Experimental procedures

[0502] 1) Preparation of Intermediate 36-2

[0503] To a single-necked flask, 36-1 (5.0 g, 17.51 ​​mmol), M13 (4.51 g, 17.51 ​​mmol), N,N-diisopropylethylamine (3.39 g, 26.27 mmol), and dichloromethane (150.0 mL) were added and allowed to react at room temperature for 18 hours. The reaction solution was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) to obtain intermediate 36-2 (8.5 g). 1 H NMR (400MHz, DMSO-d6) δ7.77(dd,J=8.8,2.4Hz,1H),7.74(d,J=2.4Hz,1H),7.16(d,J=8 .8Hz,1H),6.99–6.95(m,4H),6.82–6.78(m,4H),4.26(s,4H),3.81(s,3H),3.71(s,6H).

[0504] 2) Preparation of Intermediate 35-1

[0505] At room temperature, 36-2 (5.0 g, 9.87 mmol), M14 (2.55 g, 19.75 mmol), and toluene (100.0 mL) were added to a single-necked flask. Tris(dibenzylideneacetone)dipalladium (0.90 g, 0.99 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.94 g, 1.97 mmol), and cesium carbonate (9.65 g, 29.62 mmol) were added sequentially under stirring. The mixture was reacted at 120 degrees Celsius for 18 hours. The reaction solution was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain intermediate 35-1 (1.2 g). LC-MS: m / z: 555.4 (M+H) + .

[0506] 3) Preparation of Intermediate 36-3

[0507] At room temperature, 35-1 (200.0 mg, 0.36 mmol) and a 33 wt.% ethanol solution of methylamine (4.0 mL) were added to a microwave tube and reacted at 80°C for 18 hours. The reaction solution was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain intermediate 36-3 (190.0 mg). LC-MS: m / z: 554.4 (M+H) + .

[0508] 4) Preparation of Intermediate 36-4

[0509] At room temperature, 36-3 (100.0 mg, 0.18 mmol) and trifluoroacetic acid (10.0 mL) were added to a single-necked flask and reacted at room temperature for 2 hours. The reaction solution was distilled under reduced pressure to obtain a crude intermediate 36-4 (64 mg). The crude product was used directly in the next step without purification. LC-MS: m / z: 314.0 (M+H) + .

[0510] 5) Preparation of Compound 036

[0511] At room temperature, 36-4 (64 mg, 0.20 mmol), 1-6 (40.0 mg, 0.17 mmol), and dichloromethane (4.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (47.48 mg, 0.25 mmol) and 4-dimethylaminopyridine (60.52 mg, 0.50 mg) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC (formic acid / acetonitrile / water system) to obtain 036 (18.29 mg). 1H NMR (400MHz, DMSO-d6) δ13.12(s,1H),12.21(s,1H),8.12(dd,J=6.8,2.4Hz,1H),7.90(d,J=2.0Hz, 1H),7.62(d,J=7.6Hz,1H),7.48(dd,J=3.6,2.0Hz,1H),7.13-6.96(m,4H),6.72-6.57(m,1H),6.30 (q,J=2.0Hz,1H),5.66(d,J=7.6Hz,2H),3.94-3.86(m,1H),3.79-3.72(m,3H),3.58-3.57(m,1H),3 .19-3.10(m,1H),2.58-2.49(m,3H),2.23-2.16(m,1H),1.97-1.92(m,3H); LC-MS:m / z:537.9(M+H) + .

[0512] Example 29. Synthesis of Compound 037

[0513] Synthesis route

[0514] Experimental procedures

[0515] 1) Preparation of Intermediate 37-2

[0516] At room temperature, 37-1 (2.0 g, 8.02 mmol), dimethylamine (0.72 g, 8.82 mmol), and dichloromethane (50.0 mL) were added to a single-necked flask. Triethylamine (2.44 g, 24.07 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.84 g, 9.62 mmol), and 1-hydroxybenzotriazole (1.30 g, 9.62 mmol) were added sequentially under stirring. The reaction was allowed to react at room temperature for 18 hours. The reaction solution was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 37-2 (1.5 g). LC-MS: m / z: 277.0 (M+H) + .

[0517] 2) Preparation of Intermediate 37-3

[0518] At room temperature, 37-2 (1.5 g, 5.43 mmol), 10% palladium on carbon (150.0 mg), and methanol (50.0 mL) were added to a single-necked flask. After replacement with H2 three times, the reaction was allowed to proceed under a hydrogen balloon atmosphere at room temperature for 18 hours. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to obtain crude product 3 (1.0 g), which was used directly in the next step without purification.

[0519] 3) Preparation of Intermediate 37-4

[0520] At room temperature, 36-2 (1.0 g, 1.97 mmol), 37-3 (0.56 g, 3.95 mmol) and toluene (100.0 mL) were added to a single-necked flask. Tris(dibenzylideneacetone)dipalladium (0.36 g, 0.39 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (0.38 g, 0.79 mmol) and cesium carbonate (1.93 g, 5.92 mmol) were added in one portion under stirring. After N2 replacement three times, the reaction was carried out at 120°C for 18 hours. The reaction solution was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) to obtain intermediate 37-4 (300 mg). LC-MS: m / z: 568.2 (M+H) + .

[0521] 4) Preparation of Intermediate 37-5

[0522] At room temperature, 37-4 (150.0 mg, 0.26 mmol) and trifluoroacetic acid (10.0 mL) were added to a single-necked flask and reacted at room temperature for 2 hours. The reaction solution was distilled under reduced pressure to obtain crude product 37-5 (100 mg), which was used directly in the next step without purification. LC-MS: m / z: 328.0 (M+H) + .

[0523] 5) Preparation of Compound 037

[0524] At room temperature, 37-5 (111.32 mg, 0.34 mmol), 1-6 (40.0 mg, 0.17 mmol), and dichloromethane (4.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (47.48 mg, 0.25 mmol) and 4-dimethylaminopyridine (60.52 mg, 0.50 mg) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (formic acid / acetonitrile / water system) to obtain compound 037 (6.57 mg). 1H NMR (400MHz, DMSO-d6) δ8.07(d,J=2.0Hz,1H),7.88(d,J=2.4Hz,1H),7.64(d,J=7.6 Hz,1H),7.47(d,J=2.0Hz,1H),7.05–6.93(m,4H),6.51(d,J=8.8Hz,1H),6.28(t,J= 2.0Hz,1H),5.62(s,2H),4.63(d,J=8.4Hz,1H),3.67(s,3H),3.44-3.39(m,2H),3.0 9(s,3H),2.80(s,3H),2.34–2.25(m,1H),2.04–1.85(m,3H); LC-MS:m / z:552.2(M+H) + .

[0525] Example 30. Synthesis of Compound 038

[0526] Synthesis route

[0527] Experimental procedures

[0528] 1) Preparation of Intermediate 38-1

[0529] At room temperature, 36-2 (1 g, 1.79 mmol), 2-phenylpyrrolidine (580 mg, 3.95 mmol), cesium carbonate (1.29 g, 3.95 mmol), tris(dibenzylideneacetone)dipalladium (180 mg, 0.20 mmol), cesium carbonate (1.29 g, 3.95 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (190 mg, 0.39 mmol) and toluene (15.0 mL) were added to a microwave tube. After N2 substitution three times, the reaction was continued at 10 degrees Celsius for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) to obtain intermediate 38-1 (1 g). LC-MS: m / z: 573.4 (M+H) + .

[0530] 2) Preparation of Intermediate 38-2

[0531] At room temperature, 38-1 (1 g, 0.70 mmol) and trifluoroacetic acid (10.0 mL) were added to a single-necked bottle and reacted at room temperature for 2 hours. The reaction solution was adjusted to pH 8 with aqueous sodium bicarbonate solution (100.0 mL), extracted three times with 30 mL of dichloromethane each time, and the combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1 to 10: 1) to obtain intermediate 38-2 (200 mg). LC-MS: m / z: 333.0 (M+H) + .

[0532] 3) Preparation of Compound 038

[0533] At room temperature, 38-2 (82.34 mg, 0.25 mmol), 1-6 (30.0 mg, 0.12 mmol), and dichloromethane (4 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.61 mg, 0.19 mmol) and 4-dimethylaminopyridine (45.39 mg, 0.37 mg) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 038 (8 mg). 1 H NMR (400MHz, DMSO-d6) δ12.16(s,1H),8.19–8.05(m,1H),7.90(d,J=2.4Hz,1H),7.60(d,J=8.0Hz,1H),7.47(d,J=2.0Hz,1H),7.33–7.2 6(m,2H),7.25–7.18(m,3H),7.07–6.94(m,4H),6.59(s,1H),6.29(t,J=2.0Hz,1H),5.64(s,2H),4.78–4.65(m,1H),3.75–3.69(m,1H), 3.66(s,3H),3.40–3.35(m,1H),2.47–2.37(m,1H),2.05–1.91(m,2H),1.85–1.75(m,1H); LC-MS:m / z:557.0(M+H) + .

[0534] Example 31. Synthesis of Compound 039

[0535] Synthesis route

[0536] Experimental procedures

[0537] 1) Preparation of Intermediate 39-2

[0538] To a single-necked flask at room temperature, 39-1 (4.2 g, 30.4 mmol) and dichloromethane (16.0 mL) were added. Hydrobromic acid (0.37 g, 4.56 mmol), ferric bromide (2.7 g, 9.12 mmol), and tert-butyl alcohol (2.25 g, 30.4 mmol) were added under stirring. The mixture was allowed to react at 50°C for 24 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 39-2 (3.5 g). 1 H NMR (400MHz, DMSO-d6) δ7.08 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 6.42 (dd, J = 8.6, 2.6 Hz, 1H), 3.78 (s, 3H), 3.73 (d, J = 2.4 Hz, 3H), 1.29 (s, 9H).

[0539] 2) Preparation of Intermediate 39-3

[0540] To a single-necked flask, add 39-2 (80.0 mg, 0.41 mmol) and dichloromethane (2.0 mL) under ice. Add chlorosulfonic acid (83 μL, 1.24 mmol) with stirring. Allow to react under ice for 1 hour, then warm to room temperature and stir for 2 hours. The reaction mixture was used directly in the next step without post-treatment.

[0541] 3) Preparation of Intermediate 39-4

[0542] At room temperature, ammonia (5.0 mL) and acetonitrile (5.0 mL) were added to a single-necked flask, cooled to 0°C, and the reaction solution from the previous step was added with stirring. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 39-4 (60 mg). 1 H NMR (400MHz, DMSO-d6) δ7.57(s,1H),6.88(s,2H),6.75(s,1H),3.92(s,6H),1.30(s,9H).

[0543] 3) Preparation of Compound 039

[0544] To a 25 mL single-necked flask at room temperature were added 39-4 (50 mg, 0.18 mmol), 1-6 (44.31 mg, 0.18 mmol), and dichloromethane (5 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (52.6 mg, 0.27 mmol) and 4-dimethylaminopyridine (44.69 mg, 0.37 mg) were added sequentially under stirring. The mixture was allowed to react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by HPLC (formic acid / acetonitrile / water system) to afford compound 039 (1.1 mg). 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),7.90(d,J=1.7Hz,1H),7.72(s,1H),7.61(d,J=7.8Hz,1H),7.48(d,J=1.4Hz,1H),7.04(d,J=7.8Hz,1 H),6.98(s,1H),6.71(s,1H),6.29(t,J=2.0Hz,1H),5.64(s,2H),3.92(s,3H),3.85(d,J=8.4Hz,3H),1.33(s,9H); LC-MS:m / z:498.2(M+H) + .

[0545] Example 32. Synthesis of Compound 040

[0546] Synthesis route

[0547] Experimental procedures

[0548] 1) Preparation of Intermediate 40-2

[0549] At room temperature, M15 (4.75 mL, 31.87 mmol) and tetrahydrofuran (100.0 mL) were added to a three-necked flask. The atmosphere was replaced with nitrogen three times, and the temperature was cooled to 0°C in an ice bath. Sodium hydroxide (1.27 g, 31.87 mmol) was added portionwise, and the reaction was maintained in the ice bath for 1 hour. 40-1 (8.0 mg, 31.87 mmol) was added with stirring, and the reaction was continued at room temperature for 18 hours. The reaction solution was poured into 100 mL of ice water and extracted once with 100 mL of ethyl acetate. The organic phase was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 40-2 (7 g). 1H NMR (400MHz, DMSO-d6) δ7.29(m,2H),4.73(t,J=5.3Hz,1H),4.07(d,J=5.3Hz,2H),3.82 (d,J=4.7Hz,3H),3.66(m,2H),3.53(m,2H),1.13–1.06(m,6H); LC-MS:m / z:387.0(M+Na) + .

[0550] 2) Preparation of Intermediate 40-3

[0551] To a single-necked flask at room temperature, 40-2 (6.68 g, 18.29 mmol) and toluene (80.0 mL) were added. Polyphosphoric acid (4.50 g, 54.87 mmol) was added with stirring, and the mixture was allowed to react at 60°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 40-3 (2.3 g). 1 H NMR (400MHz, DMSO-d6) δ8.28 (d, J=2.3Hz, 1H), 7.72 (d, J=10.8Hz, 1H), 7.05 (d, J=2.3Hz, 1H), 3.93 (s, 3H); LC-MS: m / z: 273.0 / 275.0 (M+H) + .

[0552] 3) Preparation of Intermediate 40-4

[0553] At room temperature, 40-3 (2.3 g, 8.42 mmol) and 1,4-dioxane (30.0 mL) were added to a single-necked flask. M2 (4.06 g, 12.63 mmol) and tetrakis(triphenylphosphine)palladium (0.97 g, 0.84 mmol) were added under stirring. The atmosphere was purged with nitrogen three times and the temperature was raised to 100°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 40-4 (1.3 g). LC-MS: m / z: 225.0 (M+H). + .

[0554] 4) Preparation of Intermediate 40-5

[0555] At room temperature, 40-4 (600.0 mg, 2.67 mmol) and acetonitrile (10.0 mL) were added to a single-necked flask. Intermediate M3 (450 mg, 3.07 mmol) and potassium carbonate (502 mg, 3.62 mmol) were added under stirring and allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) to obtain intermediate 40-5 (600.0 mg). LC-MS: m / z: 275.0 (M+H) + .

[0556] 5) Preparation of Intermediate 40-6

[0557] At room temperature, 40-5 (50.0 mg, 0.18 mmol), tetrahydrofuran (0.3 mL), methanol (0.1 mL) and water (0.1 mL) were added to a single-necked flask. Lithium hydroxide (13.1 mg, 0.55 mmol) was added under stirring and the mixture was allowed to react at room temperature for 3 hours. The reaction solution was poured into ice water, the pH was adjusted to 3 with 1N hydrochloric acid, and the mixture was extracted once with 15 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 40-6 (40.0 mg). LC-MS: m / z: 261.0 (M+H) + .

[0558] 6) Preparation of Compound 040

[0559] At room temperature, 40-6 (20.0 mg, 0.08 mmol) and M16 (25.04 mg, 0.12 mmol) and dichloromethane (2 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (22.1 mg, 0.12 mmol) and 4-dimethylaminopyridine (18.78 mg, 0.15 mg) were added sequentially under stirring. The mixture was reacted at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high performance liquid chromatography (formic acid acetonitrile / water system) to obtain compound 040 (5 mg). 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),8.10(s,1H),7.93(s,1H),7.56(s,1H),7.50(d,J=1.4Hz,1H) ,6.95(s,2H),6.81(d,J=7.6Hz,2H),6.31(s,1H),5.63(s,2H),3.78(s,6H); LC-MS:m / z:460.2(M+H) + .

[0560] Example 33. Synthesis of Compound 041

[0561] Synthesis route

[0562] Experimental procedures

[0563] 1) Preparation of Intermediate 41-1

[0564] At room temperature, 40-5 (500.0 mg, 1.82 mmol) and methanol (10.0 mL) were added to a single-necked flask, and sodium methoxide (147.73 mg, 2.73 mmol) was added under stirring. The reaction was carried out at 70 degrees Celsius for 18 hours. The reaction solution was poured into ice water, and the pH was adjusted to 4 with 1N hydrochloric acid. The mixture was extracted once with 50 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 3:1) to obtain intermediate 41-1 (50.0 mg). LC-MS: m / z: 287.0 (M+H) + .

[0565] 2) Preparation of Intermediate 41-2

[0566] At room temperature, 41-1 (40.0 mg, 0.14 mmol), tetrahydrofuran (0.3 mL), methanol (0.1 mL) and water (0.1 mL) were added to a single-necked flask. Lithium hydroxide (10.04 mg, 0.42 mmol) was added under stirring and the mixture was allowed to react at room temperature for 3 hours. The reaction solution was poured into ice water, the pH was adjusted to 4 with 1N hydrochloric acid, and the mixture was extracted once with 20 mL of ethyl acetate. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 41-2 (35.0 mg, 0.13 mmol). LC-MS: m / z: 273.0 (M+H) + .

[0567] 3) Preparation of Compound 041

[0568] At room temperature, 41-2 (30.0 mg, 0.11 mmol), M16 (23.94 mg, 0.11 mmol), and dichloromethane (1.5 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.68 mg, 0.17 mmol) and 4-dimethylaminopyridine (26.92 mg, 0.22 mmol) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain compound 041 (3.4 mg). 1H NMR (400MHz, DMSO-d6) δ7.90–7.84(m,2H),7.47(d,J=1.5Hz,2H),6.91(s,1H),6.75(dd,J=5.3,3 .1Hz,3H),6.28(t,J=2.0Hz,1H),5.56(s,2H),3.76(s,6H),3.76(s,3H); LC-MS:m / z:472.2(M+H) + .

[0569] Example 34. Synthesis of Compound 077

[0570] Synthesis route

[0571] Experimental procedures

[0572] 1) Preparation of Intermediate 77-1

[0573] At room temperature, 28-1 (200.0 mg, 0.68 mmol), cuprous iodide (514.50 mg, 2.70 mmol) and a methanol solution of sodium methoxide (5.4 N) (3.0 mL) were added to a microwave tube and reacted at 80 degrees Celsius for 18 hours. The reaction solution was adjusted to pH 5 using dilute hydrochloric acid (2 N), extracted once with 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude intermediate 77-1 (145 mg). The crude product was used directly in the next step without purification. LC-MS: m / z: 248.0 (M+H) + .

[0574] 2) Preparation of Compound 077

[0575] To a single-necked flask at room temperature were added 77-1 (49.0 mg, 0.20 mmol), 1-6 (40.0 mg, 0.17 mmol), and dichloromethane (4.0 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (47.48 mg, 0.25 mmol) and 4-dimethylaminopyridine (60.52 mg, 0.50 mg) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC (formic acid / acetonitrile / water system) to obtain compound 077 (18.14 mg). 1H NMR (400MHz, DMSO-d6) δ8.13(d,J=2.4Hz,1H),7.91(d,J=2.4Hz,1H),7.66( d,J=8.0Hz,1H),7.48(d,J=2.0Hz,1H),7.27(d,J=9.2Hz,1H),7.05(d,J=8.0 Hz,1H),6.99(d,J=2.0Hz,1H),6.88(d,J=9.2Hz,1H),6.30(t,J=2.0Hz,1H), 5.65(s,2H),3.81(s,3H),3.80(s,3H),3.69(s,3H); LC-MS:m / z:472.0(M+H) + .

[0576] Example 35. Synthesis of Compound 093

[0577] Synthesis route

[0578] Experimental procedures

[0579] 1) Preparation of Intermediate 93-2

[0580] Under ice bath, 93-1 (1 g, 5.18 mmol) and methanol (10.0 mL) were added to a microwave tube, and a methanol solution of sodium methoxide (4.8 mL, 25.90 mmol) was added under stirring. The reaction was allowed to proceed at 85°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 0:1) to obtain intermediate 93-2 (400 mg). LC-MS: m / z: 206.0 (M+H) + .

[0581] 2) Preparation of Intermediate 93-3

[0582] Compound 93-2 (200 mg, 0.97 mmol) and ethanol (10.0 mL) were added to a microwave tube at room temperature. Sodium ethoxide (664 mg, 9.75 mmol) was added with stirring, and the mixture was reacted at 100°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 0:1) to obtain intermediate 93-3 (50 mg). LC-MS: m / z: 232.0 (M+H) + .

[0583] 3) Preparation of Compound 093

[0584] To a single-necked flask at room temperature were added 93-3 (19.10 mg, 0.08 mmol), 1-6 (20.00 mg, 0.08 mmol), and dichloromethane (3 mL). 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.74 mg, 0.12 mmol) and 4-dimethylaminopyridine (20.17 mg, 0.17 mmol) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by HPLC (ammonium bicarbonate / acetonitrile / water) to afford compound 093 (10 mg). 1 H NMR (400MHz, DMSO-d6) δ11.94(s,1H),8.12(d,J=2.4Hz,1H),7.90(d,J=2.4H z,1H),7.67(d,J=8.0Hz,1H),7.53–7.41(m,2H),7.05(d,J=8.0Hz,1H),6.99( d,J=2.4Hz,1H),6.76(d,J=8.4Hz,2H),6.30(t,J=2.0Hz,1H),5.65(s,2H),4 .12–4.01(m,2H),3.75(s,3H),1.17(t,J=7.2Hz,3H); LC-MS:m / z:456.0(M+H) + .

[0585] Example 36. Synthesis of Compound 095

[0586] Synthesis route

[0587] Experimental procedures

[0588] 1) Preparation of Intermediate 95-2

[0589] At room temperature, 95-1 (1.0 g, 7.45 mmol) and N,N-dimethylformamide (10.0 mL) were added to a single-necked flask. Potassium carbonate (2.06 g, 14.90 mmol) and iodomethane (1.59 g, 11.18 mmol) were added with stirring, and the mixture was reacted at 55°C for 4 hours. The reaction solution was poured into 100 mL of water and extracted once with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 8:1) to obtain intermediate 95-2 (0.75 g). 1H NMR (400MHz, DMSO-d6) δ7.10(d,J=8.2Hz,1H),6.80(d,J=1.9Hz,1H),6.67(dd,J=8.2,2 .4Hz,1H),3.70(s,3H),2.81(t,J=7.4Hz,2H),2.76(t,J=7.4Hz,2H),2.03-1.92(m,2H).

[0590] 2) Preparation of Intermediate 95-3

[0591] At room temperature, 95-2 (300 mg, 2.02 mmol) and dichloromethane (5.0 mL) were added to a three-necked flask. Chlorosulfonic acid (706 mg, 6.06 mmol) was added dropwise in an ice bath. The mixture was reacted at 0°C for 1 hour and then at room temperature for 3 hours. The reaction solution was directly used in the next step without post-treatment.

[0592] 3) Preparation of Intermediate 95-4

[0593] Under ice, ammonia (6.23 mL, 40.45 mmol) and acetonitrile (6.0 mL) were added to a three-necked flask. The reaction mixture from the previous step was then added dropwise to the flask under ice. The mixture was heated to 20°C and allowed to react for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to afford Intermediate 95-4 (330 mg). 1 H NMR(400MHz,DMSO-d6)δ7.55(s,1H),7.09(s,1H),6.92(s,2H),3.86(s,3H),2.90( t,J=7.4Hz,2H),2.82(t,J=7.4Hz,2H),2.09-1.98(m,2H); LC-MS:m / z:228.0(M+H) + .

[0594] 4) Preparation of Compound 095

[0595] At room temperature, 95-4 (40 mg, 0.18 mmol) and dichloromethane (2.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (51 mg, 0.26 mmol), 4-dimethylaminopyridine (43 mg, 0.35 mmol), and 1-6 (43 mg, 0.18 mmol) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by HPLC (formic acid / acetonitrile / water system) to obtain compound 095 (7 mg). 1H NMR (400MHz, DMSO-d6) δ12.19(s,1H),8.14(d,J=1.8Hz,1H),7.91(d,J=1.9Hz ,1H),7.73(s,1H),7.60(d,J=7.8Hz,1H),7.48(d,J=1.2Hz,1H),7.12(s,1H), 7.06(d,J=7.8Hz,1H),7.00(d,J=2.1Hz,1H),6.30(t,J=2.0Hz,1H),5.65(s,2 H),3.81(s,3H),2.95-2.85(m,4H),2.10-2.02(m,2H); LC-MS:m / z:452.2(M+H) + .

[0596] Example 37. Synthesis of Compound 096

[0597] Synthesis route

[0598] Experimental procedures

[0599] 1) Preparation of Intermediate 96-2

[0600] At room temperature, 96-1 (1.5 g, 9.13 mmol) and N,N-dimethylformamide (20.0 mL) were added to a single-necked flask. Potassium carbonate (2.52 g, 18.26 mmol) and iodomethane (1.94 g, 13.70 mmol) were added with stirring. The mixture was reacted at 50°C for 3 hours. TLC showed the formation of a major spot with decreasing polarity. The reaction solution was poured into 200 mL of water and extracted with 200 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 96-2 (1.40 g).

[0601] 2) Preparation of Intermediate 96-3

[0602] In an ice bath, 96-2 (400 mg, 2.24 mmol) and dichloromethane (5 mL) were added to a single-necked flask, followed by chlorosulfonic acid (0.43 mL, 6.47 mmol) under stirring. The mixture was reacted at room temperature for 4 hours. The reaction solution was used directly in the next step without post-treatment.

[0603] 3) Preparation of Intermediate 96-4

[0604] Under ice bath, ammonia (6.91 mL, 44.87 mmol) and acetonitrile (10.0 mL) were added to a single-necked flask, and the reaction solution from the previous step was added under stirring. The reaction was allowed to react at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 96-4 (150 mg). LC-MS: m / z: 258.0 (M+H) + .

[0605] 4) Preparation of Compound 096

[0606] At room temperature, 96-4 (30 mg, 0.12 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (34 mg, 0.17 mmol), 4-dimethylaminopyridine (28 mg, 0.23 mmol), and 1-6 (31 mg, 0.12 mmol) were added sequentially under stirring. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by HPLC (formic acid / acetonitrile / water system) to obtain compound 096 (21 mg). 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),8.14(s,1H),7.91(d,J=2.1Hz,1H),7.81(d ,J=2.4Hz,1H),7.67-7.57(m,2H),7.48(d,J=1.6Hz,1H),7.17(d,J=8.6Hz,1H),7. 06(d,J=7.8Hz,1H),7.00(d,J=2.1Hz,1H),6.29(t,J=2.0Hz,1H),5.65(s,2H),3.8 5(s,3H),1.62(m,2H),1.26(s,6H),0.65(t,J=7.4Hz,3H); LC-MS:m / z:482.2(M+H) + .

[0607] Example 38. Synthesis of Compound 047 and Compound 100

[0608] Synthesis route

[0609] Experimental procedures

[0610] 1) Preparation of Intermediate 47-2

[0611] Under ice bath, lithium diisopropylamide (60.2mL, 2M / THF) and anhydrous tetrahydrofuran (120.0mL) were added to a three-necked flask, and n-butyl lithium (48.2mL, 2.5M / THF) was slowly added dropwise under ice bath conditions. After the addition was complete, the ice bath was stirred for 10 minutes. Under ice bath conditions, a solution of 47-1 (5g, 30.09mmol) in anhydrous tetrahydrofuran (30.0mL) was slowly added dropwise. After the addition was complete, the ice bath was continued to stir for 1 hour. Methyl iodide (11.3mL, 180.5mmol) was slowly added dropwise under ice bath conditions. After the addition was complete, the reaction was completed by stirring at room temperature for 18 hours. The reaction solution was poured into 1N aqueous hydrochloric acid solution (300.0mL) and extracted with ethyl acetate (50mLx3). The combined organic phases were washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 47-2 (5.5g). LC-MS: m / z: 195.0 [M+H] + .

[0612] 2) Preparation of Intermediate 47-3

[0613] At room temperature, 47-2 (3 g, 15.45 mmol) and anhydrous methanol (30.0 mL) were added to a single-necked flask, and thionyl chloride (2.24 mL, 30.89 mmol) was added under ice bath conditions. The reaction was completed after 18 hours of reaction at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 5:1) to obtain a white solid compound 47-3 (2.2 g). LC-MS: m / z: 209.0 [M+H] + .

[0614] 3) Preparation of Intermediate 4

[0615] At room temperature, 47-3 (2.2 g, 10.56 mmol) and dichloromethane (20.0 mL) were added to a single-necked flask. Chlorosulfonic acid (2.11 mL, 31.69 mmol) was then added under ice-cooling. The reaction was complete after 18 hours at room temperature. The reaction solution was used directly in the next step without further treatment.

[0616] 4) Preparation of Intermediate 47-5

[0617] At room temperature, ammonia methanol solution (40.0 mL, 7 mol / L) was added to a single-necked flask, and the reaction solution from the previous step was added under ice bath conditions. The reaction was completed after 2 hours at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain compound 47-5 (540 mg) as a white solid. LC-MS: m / z: 288.0 [M+H] + .

[0618] 5) Preparation of Compound 100

[0619] At room temperature, 47-5 (170.8 mg, 0.59 mmol), 1-6 (120.0 mg, 0.50 mmol) and dichloromethane (5.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (142.5 mg, 0.74 mmol) and 4-dimethylaminopyridine (121.1 mg, 0.99 mg) were added sequentially under stirring. The reaction was completed after 18 hours at room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain a white solid compound (200 mg). LC-MS: m / z: 512.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.35(s,1H),8.13(s,1H),7.90(d,J=2.4Hz,1H),7.83(d,J=2.4Hz,1H),7.65–7.53(m,2H),7.48(d,J=2.0Hz,1H),7. 19(d,J=8.8Hz,1H),7.06(d,J=8.0Hz,1H),6.99(d,J=2.4Hz,1H),6.29(t,J=2.0Hz,1H),5.64(s,2H),3.84(s,3H),3.61(s,3H),1.53(s,6H).

[0620] 6) Preparation of Compound 047

[0621] At room temperature, 100 (100.0 mg, 0.20 mmol) and anhydrous tetrahydrofuran (3.0 mL) were added to a single-necked flask. Diisobutylaluminum hydride (0.98 mL, 1 M / THF) was slowly added dropwise under ice-cooling. The reaction was complete after 1 hour at room temperature. The reaction solution was quenched with solid sodium sulfate decahydrate under ice-cooling, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified on a preparative silica gel plate (dichloromethane:methanol 10:1) to obtain compound 047 (40 mg) as a white solid. LC-MS: m / z: 484.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.23(s,1H),8.14(d,J=2.4Hz,1H),7.94–7.89(m,1H),7.87(d ,J=2.4Hz,1H),7.67(dd,J=8.8,2.4Hz,1H),7.61(d,J=8.0Hz,1H),7.48(dd,J=2.0,0.8 Hz,1H),7.16(d,J=8.8Hz,1H),7.06(d,J=8.0Hz,1H),7.00(d,J=2.4Hz,1H),6.30(t,J= 2.0Hz,1H),5.65(s,2H),4.78(s,1H),3.83(s,3H),3.41(d,J=3.2Hz,2H),1.24(s,6H).

[0622] Example 39. Synthesis of Compound 052

[0623] Synthesis route

[0624] Experimental procedures

[0625] 1) Preparation of Intermediate 52-2

[0626] To a 100 mL three-necked flask at room temperature, 52-1 (1.0 g, 6.66 mmol) and tetrahydrofuran (10.0 mL) were added dropwise, followed by the addition of methylmagnesium bromide (2.89 mL, 8.66 mmol) in an ice bath. The reaction mixture was allowed to react at 65°C for 3 hours to produce the product. The reaction mixture was poured into 50 mL of saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0 to 1:1) to afford intermediate 52-2 (1.0 g) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ7.41-7.32(m,2H),6.90-6.79(m,2H),4.90(s,1H),3.73(s,3H),1.40(s,6H).

[0627] 2) Preparation of Intermediate 52-3

[0628] To a 50 mL single-necked flask, 52-2 (650 mg, 3.91 mmol) and N,N-dimethylformamide (10.0 mL) were added. N-bromosuccinimide (766 mg, 4.30 mmol) was added under stirring. The reaction was complete after 4 hours at room temperature. The reaction solution was poured into 50 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0 to 1:1) to obtain intermediate 52-3 (350 mg) as a yellow oil. LC-MS: m / z: 227.0 / 229.0 [M-18+H] + .

[0629] 3) Preparation of Intermediate 52-4

[0630] To a 100 mL single-necked flask at room temperature, 52-3 (320 mg, 1.31 mmol) and dioxane (6.0 mL) were added. N,N-diisopropylethylamine (506 mg, 3.92 mmol), benzyl mercaptan (0.46 mL, 3.92 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (151 mg, 0.26 mmol), and tris(dibenzylideneacetone)dipalladium (120 mg, 0.13 mmol) were added sequentially under stirring. The reaction was allowed to proceed at 100°C for 18 hours until complete. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0 to 1:1) to afford intermediate 52-4 (300 mg) as a yellow oil. LC-MS: m / z: 271.2 [M-18+H]. + .

[0631] 4) Preparation of Intermediate 52-5

[0632] Under ice bath, 52-4 (100 mg, 0.35 mmol), acetonitrile (2.0 mL), water (37 μL, 2.08 mmol), and acetic acid (20 μL, 0.35 mmol) were added to a 50 mL single-necked flask. 1,3-Dichloro-5,5-dimethylhydantoin (102 mg, 0.52 mmol) was added under ice bath conditions. The reaction was completed after 2 hours of ice bath. The reaction solution was used directly in the next step without any treatment. LC-MS: m / z: 247.0 / 249.0 [M-18+H] + .

[0633] 5) Preparation of Intermediate 52-6

[0634] Ammonia (1.06 mL, 6.88 mmol) and acetonitrile (2.0 mL) were mixed and cooled to 0°C. The reaction mixture from the previous step was added dropwise to the mixture. The reaction was allowed to react at 20°C for 1 hour, and the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain intermediate 52-6 (50 mg) as a white solid. LC-MS: m / z: 228.0 [M-18+H] + .

[0635] 6) Preparation of Compound 052

[0636] At room temperature, 6 (30 mg, 0.12 mmol) and dichloromethane (3.0 mL) were added to a 25 mL single-necked bottle, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35 mg, 0.18 mmol), 4-dimethylaminopyridine (30 mg, 0.24 mmol) and 1-6 (30 mg, 0.12 mmol) were added sequentially under stirring. The reaction was completed after 18 hours at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain a white solid compound (6 mg). LC-MS: m / z: 452.2 [M-18+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.23(s,1H),8.14(d,J=2.0Hz,1H),8.04(d,J= 2.4Hz,1H),7.91(d,J=2.0Hz,1H),7.71(d,J=8.8Hz,1H),7.61(d,J=7.8Hz,1H),7.48(d,J=1.2Hz,1H),7.16(d,J=8.8Hz,1H ),7.07(d,J=7.8Hz,1H),7.00(d,J=2.0Hz,1H),6.30(t,J=2.2Hz,1H),5.65(s,2H),5.23(s,1H),3.83(s,3H),1.44(s,6H).

[0637] Example 40. Synthesis of Compound 097

[0638] Synthesis route

[0639] Experimental procedures

[0640] 1) Preparation of Intermediate 97-2

[0641] At room temperature, 97-1 (2.0 g, 13.97 mmol) and chlorosulfonic acid (10.0 mL) were added to a single-necked flask. The temperature was raised to 110°C and the reaction was complete after 20 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product (3.0 g). LC-MS: m / z: 241.9 [M+H] + .

[0642] 2) Preparation of Intermediate 97-3

[0643] At room temperature, ammonia (20.0 mL) and acetonitrile (20.0 mL) were added to a single-necked flask, cooled to 0°C, and intermediate 97-2 (3.0 g, 12.41 mmol) was added under stirring. The reaction was completed after 2 hours of reaction at room temperature. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 0:1) to obtain white solid intermediate 97-3 (1.8 g). LC-MS: m / z: 223.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.43(d,J=8.6Hz,1H),8.26(d,J=7.4Hz,1H),8.22(d,J=8 .0Hz,1H),7.68(t,J=7.8Hz,1H),7.61(d,J=8.6Hz,1H),7.20(s,2H),2.78(s,3H).

[0644] 3) Preparation of Compound 097

[0645] At room temperature, 97-3 (30.0 mg, 0.13 mmol), 1-6 (32.70 mg, 0.13 mmol) and dichloromethane (3 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (38.81 mg, 0.20 mmol) and 4-dimethylaminopyridine (32.98 mg, 0.27 mmol) were added sequentially under stirring. The reaction was completed after 18 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain a white solid compound (6.0 mg). LC-MS: m / z: 447.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.44(d,J=7.0Hz,1H),8.34(d,J=7.8Hz,1H),8.25–8.04(m,2H),7.86(d,J=1.8Hz,1H),7.72(d ,J=7.8Hz,2H),7.52-7.41(m,2H),7.03(d,J=7.8Hz,1H),6.95(s,1H),6.28(t,J=1.8Hz,1H),5.62(s,2H),2.59(s,3H).

[0646] Example 41. Synthesis of Compound 098

[0647] Synthesis route

[0648] Experimental procedures

[0649] 1) Preparation of Intermediate 98-2

[0650] To a 25 mL single-necked flask at room temperature, add 98-1 (100.0 mg, 0.57 mmol) and dichloromethane (2.0 mL). Chlorosulfonic acid (199 mg, 1.71 mmol) was added under stirring. The mixture was allowed to react at 0°C for 1 hour. After stirring at room temperature for 2 hours, the reaction was complete. The reaction solution was used directly in the next step without purification.

[0651] 2) Preparation of Intermediate 98-3

[0652] At room temperature, ammonia (5.0 mL) and acetonitrile (5.0 mL) were added to a single-necked flask, and the reaction solution from the previous step was added under ice bath conditions. The reaction was complete after 2 hours at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain intermediate 98-3 (80 mg) as a white solid. LC-MS: m / z: 255.0 [M+H] + .

[0653] 3) Preparation of Compound 098

[0654] At room temperature, 98-3 (50 mg, 0.20 mmol), 1-6 (47.63 mg, 0.20 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (56.54 mg, 0.29 mmol) and 4-dimethylaminopyridine (48.04 mg, 0.39 mg) were added sequentially under stirring. After 2 hours of reaction at room temperature, the reaction was complete and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain a white solid compound (45 mg). LC-MS: m / z: 479.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.47(s,1H),8.12(s,1H),8.00(d,J=2.6Hz,1H),7.90(d,J=1.8Hz,1H),7.82(s,1H),7.62(d,J=7.8Hz,1H),7.48(d,J=1.6Hz, 1H),7.29(s,1H),7.05(d,J=7.8Hz,1H),6.99(s,1H),6.29(t,J=2.0Hz,1H),5.64(s,2H),3.86(s,3H),1.71(s,6H).

[0655] Example 42. Synthesis of Compound 099

[0656] Synthesis route

[0657] Experimental procedures

[0658] 1) Preparation of Intermediate 99-2

[0659] At room temperature, 99-1 (500.0 mg, 3.67 mmol) and dichloromethane (5.0 mL) were added to a single-necked flask. Chlorosulfonic acid (0.73 mL, 11.01 mmol) was then added under ice-cooling. The reaction was complete after 2 hours at room temperature. The reaction solution was used directly in the next step without purification.

[0660] 2) Preparation of Intermediate 99-3

[0661] At room temperature, ammonia methanol (50 mL, 7 N) was added to a 100 mL single-necked flask, and the reaction mixture from the previous step was added under ice. After 2 hours of ice bath reaction, the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain intermediate 99-3 (600 mg) as a white solid. LC-MS: m / z: 216.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ7.56(d,J=2.4Hz,1H),7.40(dd,J=8.4,2.4Hz,1H),7.11(d,J =8.4Hz,1H),7.00(s,2H),3.86(s,3H),2.59(q,J=7.6Hz,2H),1.15(t,J=7.6Hz,3H).

[0662] 3) Preparation of Compound 099

[0663] At room temperature, 99-3 (36.60 mg, 0.17 mmol), 1-6 (40.0 mg, 0.17 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (47.48 mg, 0.25 mmol) and 4-dimethylaminopyridine (60.52 mg, 0.50 mg) were added sequentially under stirring. The reaction was completed after 18 hours at room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain a white solid compound (26.62 mg). LC-MS: m / z: 440.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),8.12(s,1H),7.90(d,J=2.4Hz,1H),7.73(d,J=2.4Hz,1H),7.61(d, J=7.6Hz,1H),7.47(d,J=2.0Hz,2H),7.14(d,J=8.4Hz,1H),7.05(d,J=7.6Hz,1H),6.99(d,J=2.4Hz,1H), 6.29(t,J=2.0Hz,1H),5.64(s,2H),3.81(s,3H),2.65(q,J=7.6Hz,2H),1.19(t,J=7.6Hz,3H).

[0664] Example 43. Synthesis of Compound 101

[0665] Synthesis route

[0666] Experimental procedures

[0667] 1) Preparation of Intermediate 101-2

[0668] At room temperature, 101-1 (300.0 mg, 1.18 mmol), water (0.5 mL) and N,N-dimethylformamide (5 mL) were added to a single-necked flask, and cesium carbonate (1.15 g, 3.53 mmol) and methanesulfonic acid-2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl(2-amino-1,1'-biphenyl-2-yl)palladium(II) (100.61 mg, 0.12 mmol) were added under stirring. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 100 ° C. for 3 hours to complete the reaction. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 2:1) to obtain a yellow solid intermediate 101-2 (200 mg). LC-MS: m / z: 191.0 [MH] - . 1 HNMR (400MHz, DMSO-d6) δ10.95(s,1H),7.97(d,J=2.2Hz,1H),7.76(d,J=8.4Hz,1H),7.04(d,J=2.2Hz,1H),6.72(d,J=8.4Hz,1H),3.85(s,3H).

[0669] 2) Preparation of Intermediate 101-3

[0670] At room temperature, 101-2 (200.0 mg, 1.04 mmol), M17 (187.7 mg, 1.14 mmol) and N,N-dimethylformamide (5 mL) were added to a single-necked flask. Cesium carbonate (1.01 g, 3.12 mmol) was added under stirring and the reaction was completed at 100°C for 48 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 2:1) to obtain a transparent oily intermediate 101-3 (30.0 mg). LC-MS: m / z: 276.2 [M+H] + .

[0671] 3) Preparation of Intermediate 101-4

[0672] At room temperature, 101-3 (30.0 mg, 0.11 mmol), tetrahydrofuran (0.6 mL), methanol (0.2 mL), and water (0.2 mL) were added to a single-necked flask. Lithium hydroxide (7.83 mg, 0.33 mmol) was added with stirring and allowed to react at room temperature for 2 hours until the reaction was complete. The reaction solution was poured into ice water, adjusted to pH 3 with 1N hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 101-4 (20.0 mg). LC-MS: m / z: 262.0 [M+H] + .

[0673] 4) Preparation of Compound 101

[0674] At room temperature, 101-4 (20.0 mg, 0.08 mmol), M12 (18.63 mg, 0.08 mmol) and dichloromethane (1 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (22.01 mg, 0.11 mmol) and 4-dimethylaminopyridine (18.71 mg, 0.15 mmol) were added sequentially under stirring. After 18 hours of reaction at room temperature, the reaction was completed, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (formic acid acetonitrile / water system) to obtain a white solid compound (6.2 mg). LC-MS: m / z: 487.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.01(s,1H),7.89(d,J=2.6Hz,1H),7.78(d,J=8.2Hz,1H),7.38(s,1H),7. 32(d,J=3.8Hz,1H),7.27(s,1H),7.18(s,1H),6.94(s,1H),6.79(s,1H),3.71(s,3H),1.28(s,9H).

[0675] Example 44. Synthesis of Compound 102

[0676] Synthesis route

[0677] Experimental procedures

[0678] 1) Preparation of Intermediate 102-2

[0679] At room temperature, 102-1 (1.0 g, 6.66 mmol) and dichloromethane (10.0 mL) were added to a single-necked flask. Chlorosulfonic acid (1.33 mL, 20.0 mmol) was then added under ice-cooling. The reaction was complete after 18 hours at room temperature. The reaction solution was used directly in the next step without purification.

[0680] 2) Preparation of Intermediate 102-3

[0681] Under ice bath, ammonia methanol solution (40.0 mL, 7 mol / L) was added to the single-necked flask and the reaction solution from the previous step was added under stirring. The reaction was completed after 3 hours at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 1:1) to obtain compound 102-3 (800 mg) as a white solid. LC-MS: m / z: 230.0 [M+H] + .

[0682] 3) Preparation of Compound 102

[0683] At room temperature, 102-3 (42.60 mg, 0.19 mmol), 1-6 (30.0 mg, 0.12 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.61 mg, 0.19 mmol) and 4-dimethylaminopyridine (30.26 mg, 0.25 mg) were added sequentially under stirring. After 3 hours of reaction at room temperature, the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain a white solid compound (20 mg). LC-MS: m / z: 454.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),8.08(s,1H),7.88(d,J=2.4Hz,1H),7.74(d,J=2.4Hz,1H),7.62(d,J=8.0Hz,1H),7.53–7.35(m,2H),7.1 8–7.06(m,1H),7.04(d,J=8.0Hz,1H),6.96(s,1H),6.28(t,J=2.0Hz,1 H),5.63(s,2H),3.78(s,3H),3.01–2.86(m,1H),1.21(d,J=6.8Hz,6H).

[0684] Example 45. Synthesis of Compound 103

[0685] Synthesis route

[0686] Experimental procedures

[0687] 1) Preparation of Intermediate 103-2

[0688] At room temperature, 103-2 (3.0 g, 16.84 mmol) and pyridine (30.0 mL) were added to a single-necked flask, followed by the addition of hydroxylamine hydrochloride (1.29 g, 18.52 mmol) under stirring. The reaction was allowed to proceed at 90°C for 18 hours to produce the product. The reaction solution was poured into 200 mL of ice water and the pH was adjusted to 2 with 2N hydrochloric acid. A solid precipitated and was filtered. The filter cake was washed with 50 mL of ice water and dried to afford the intermediate 103-2 (2.6 g) as a white solid. LC-MS: m / z: 194.0 [M+H]+.

[0689] 2) Preparation of Intermediate 103-3

[0690] At room temperature, 103-2 (1.6 g, 8.28 mmol) and dichloromethane (20.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.91 g, 9.94 mmol), 4-dimethylaminopyridine (0.10 g, 0.83 mmol), and M18 (0.93 g, 8.28 mmol) were added sequentially with stirring. The reaction was complete after 18 hours at room temperature. The reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain intermediate 103-3 (2.3 g) as a yellow solid. LC-MS: m / z: 310.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ7.91(d,J=8.4Hz,1H),7.51(d,J=2.4Hz,1H),7.41(dd,J=8.4,2.4Hz,1H),3.96(s,3H),2.58(s,1H),2.28(s,6H).

[0691] 3) Preparation of Intermediate 103-4

[0692] At room temperature, 103-3 (1.0 g, 3.48 mmol) and N,N-dimethylacetamide (10.0 mL) were added to a single-necked flask. 4-iodoanisole (0.81 g, 3.48 mmol), sodium iodide (0.26 g, 1.74 mmol), zinc powder (0.91 g, 13.92 mmol), nickel iodide (0.22 g, 0.70 mmol), and pyridine-2,6-bis(carboxamidine) dihydrochloride (0.14 g, 0.70 mmol) were added with stirring. The reaction was allowed to proceed at 100°C for 18 hours to yield the product. The reaction mixture was poured into 50 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to yield the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to afford intermediate 103-4 (160 mg) as a colorless oil. 1H NMR (400MHz, DMSO-d6) δ7.11(d,J=8.8Hz,2H),6.85(d,J=8.8Hz,2H),3.72(s,3H),2.52(s,1H),2.01(s,6H).

[0693] 4) Preparation of Intermediate 103-5

[0694] At room temperature, 103-4 (60 mg, 0.34 mmol) and dichloromethane (2.0 mL) were added to a three-necked flask, and chlorosulfonic acid (120 mg, 1.03 mmol) was added dropwise under ice bath. The mixture was reacted at 0°C for 1 hour, then heated to room temperature for 3 hours until the reaction was complete. The reaction solution was used directly in the next step.

[0695] 5) Preparation of Intermediate 103-6

[0696] Ammonia (1.05 mL, 6.82 mmol) and acetonitrile (5.0 mL) were mixed and cooled to 0°C. The reaction mixture from the previous step was added and heated to 20°C for 1 hour to complete the reaction. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 103-6 (10 mg) as a white solid. LC-MS: m / z: 254.0 [M+H] + .

[0697] 6) Preparation of Compound 103

[0698] At room temperature, 103-6 (10 mg, 0.04 mmol) and dichloromethane (2.0 mL) were added to a single-necked flask, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (11 mg, 0.06 mmol), 4-dimethylaminopyridine (10 mg, 0.08 mmol) and 1-6 (10 mg, 0.04 mmol) were added sequentially under stirring. The reaction was completed after 18 hours at room temperature. The reaction solution was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain a white solid compound (5 mg). LC-MS: m / z: 477.9 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.33(s,1H),8.12–7.98(m,1H),7.88(d,J=1.2Hz,1H),7.67(d,J=2.2Hz,1H),7.62(d,J=7.8Hz,1H),7.53–7.28( m,2H),7.23–7.06(m,1H),7.04(d,J=7.6Hz,1H),6.96(s,1H),6.28(t,J=2.0Hz,1H),5.63(s,2H),3.78(s,3H),2.56(s,1H),2.07(s,6H).

[0699] Example 46. Synthesis of Compound 104

[0700] Synthesis route

[0701] Experimental procedures

[0702] 1) Preparation of Intermediate 104-2

[0703] To a 250 mL three-necked flask at -78°C, 104-1 (2.0 g, 10.69 mmol) and tetrahydrofuran (40.0 mL) were added dropwise with stirring. n-Butyl lithium (2.5N / hexane) (5.13 mL, 12.83 mmol) was added dropwise. After stirring at -78°C for 2 hours, cyclobutanone (0.90 g, 12.83 mmol) was added dropwise. The reaction was allowed to react at room temperature for 18 hours, resulting in completion. The reaction mixture was quenched with saturated ammonium chloride solution (30.0 mL) and extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (150 mL), dried over sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to afford the crude product. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 100:0 to 10:1) to afford intermediate 104-2 (1.7 g) as a white solid.

[0704] 1 H NMR(400MHz,Chloroform-d)δ7.44–7.36(m,2H),6.93–6.83(m,2H),3.78(s,3H) ),2.56–2.46(m,2H),2.39–2.26(m,2H),2.02–1.87(m,2H),1.69–1.59(m,1H).

[0705] 2) Preparation of Intermediate 104-3

[0706] To a 100 mL three-necked flask at -78°C, 104-2 (1.0 g, 5.61 mmol) and dichloromethane (20.0 mL) were added dropwise with stirring. Titanium tetrachloride (1.23 mL, 11.22 mmol) was added dropwise. After stirring at -78°C for 1 hour, dimethylzinc (1N / hexane) (22.44 mL, 22.44 mmol) was added dropwise. The reaction was allowed to react at room temperature for 18 hours until completion. The reaction mixture was quenched with saturated ammonium chloride solution (50.0 mL) and extracted with dichloromethane (150 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (150 mL), dried over sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 100:0 to 10:1) to afford the intermediate 104-3 (60.0 mg) as a white solid. 1 H NMR (400MHz, Chloroform-d) δ7.14–7.07(m,2H),6.90–6.82(m,2H),3.80(s,3H),2.39–2.31(m,2H),2.12–1.97(m,3H),1.86–1.78(m,1H),1.44(s,3H).

[0707] 3) Preparation of Intermediate 104-4

[0708] To a 100 mL single-necked flask at 0°C was added 104-3 (200.0 mg, 1.13 mmol) and dichloromethane (10.0 mL). Chlorosulfonic acid (0.23 mL, 3.40 mmol) was then added under stirring. The reaction was complete after 2 hours at room temperature. The reaction solution was used directly in the next step without further purification.

[0709] 4) Preparation of Intermediate 104-5

[0710] To a 100 mL single-necked flask at room temperature, 7N ammonia methanol (50 mL) was added, and Intermediate 4 was added dropwise at 0°C. The reaction was complete after 2 hours at 0°C. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified on a silica gel column (petroleum ether:ethyl acetate = 100:0 to 1:1) to afford Intermediate 104-5 (40.0 mg) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ7.50(d,J=2.4Hz,1H),7.36(dd,J=8.4,2.4Hz,1H),7.14(d,J=8.4Hz,1H) ,7.02(s,2H),3.87(s,3H),2.27–2.22(m,2H),2.09–2.01(m,3H),1.78–1.75(m,1H),1.39(s,3H).

[0711] 5) Preparation of Compound 104

[0712] At room temperature, 104-5 (40.00 mg, 0.16 mmol), 1-6 (40.0 mg, 0.17 mmol) and dichloromethane (4.0 mL) were added to a 25 mL single-necked bottle. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (47.48 mg, 0.25 mmol) and 4-dimethylaminopyridine (60.52 mg, 0.50 mg) were added sequentially under stirring. The reaction was completed after 18 hours at room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain a white solid compound (4.45 mg). LC-MS: m / z: 480.0 (M+H) + 1H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.13 (s, 1H), 7.89 (s, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 2.0 Hz, 2H), 7.16 (s, 1H), 7.04–7.98 (m, 2H), 6.29 (t, J = 2.0 Hz, 1H), 5.64 (s, 2H), 3.81 (s, 3H), 2.31–2.26 (m, 2H), 2.12–2.05 (m, 3H), 1.84–1.79 (m, 1H), 1.43 (s, 3H). Example 47. Synthesis of Compound 105

[0713] Synthesis route

[0714] Experimental procedures

[0715] 1) Preparation of Intermediate 105-2

[0716] Under ice bath, ammonia methanol solution (20.0 mL, 7 mol / L) was added to a single-necked flask, and 105-1 (500 mg, 1.75 mmol) was added under stirring. The reaction was completed after 18 hours at 25°C. The reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain compound 105-2 (450 mg) as a white solid. LC-MS: m / z: 265.8 / 267.8 [M+H] + .

[0717] 2) Preparation of Compound 105

[0718] At room temperature, 105-2 (164.8 mg, 0.62 mmol), 1-6 (100.0 mg, 0.41 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (118.7 mg, 0.62 mmol) and 4-dimethylaminopyridine (100.9 mg, 0.83 mmol) were added sequentially under stirring. The reaction was completed after 18 hours at room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain a white solid compound (180 mg). LC-MS: m / z: 490.0 / 492.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.61(s,1H),8.11(d,J=2.4Hz,1H),7.96(d,J=2.8Hz,1H),7.90(d,J=2.4Hz,1H),7.88–7.77(m,1H),7.62(d,J=8.0Hz, 1H),7.47(d,J=2.0Hz,1H),7.21(d,J=8.8Hz,1H),7.05(d,J=8.0Hz,1H) ,6.98(d,J=2.4Hz,1H),6.29(t,J=2.0Hz,1H),5.64(s,2H),3.84(s,3H).

[0719] Example 48. Synthesis of Compound 106

[0720] Synthesis route

[0721] Experimental procedures

[0722] 1) Preparation of Intermediate 106-2

[0723] At room temperature, titanium tetrachloride (2.73 mL, 24.66 mmol) and dichloromethane (20.0 mL) were added to a three-necked flask. The temperature was lowered to -45°C, and dimethylzinc (24.66 mL, 1M / hexane) was slowly added dropwise with stirring. The reaction was maintained at -45°C for 0.5 hours. Compound 106-1 (2 g, 12.33 mmol) was dissolved in dichloromethane (10.0 mL) and slowly added to the reaction mixture. The temperature was raised to room temperature and stirred for 18 hours until the reaction was complete. The reaction mixture was quenched with ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1) to obtain intermediate 106-2 (1 g) as a colorless oil. 1H NMR (400MHz, DMSO-d6) δ7.07(d,J=8.2Hz,1H),6.79(s,1H),6.74(dd,J=8.2,2.4 Hz,1H),3.74(s,3H),2.84(t,J=7.2Hz,2H),1.89(t,J=7.2Hz,2H),1.22(s,6H).

[0724] 2) Preparation of Intermediate 106-3

[0725] At room temperature, 106-2 (200.0 mg, 1.13 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask. Chlorosulfonic acid (0.22 mL, 3.4 mmol) was then added under ice-cooling. The mixture was reacted at 0°C for 1 hour. After stirring at room temperature for 2 hours, the reaction was complete. The reaction solution was used directly in the next step without purification.

[0726] 3) Preparation of Intermediate 106-4

[0727] At room temperature, ammonia (3.0 mL) and acetonitrile (3.0 mL) were added to a single-necked flask, cooled to 0°C, and the reaction solution from the previous step was added. The reaction was complete after 2 hours at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain a white solid intermediate 106-4 (100 mg). LC-MS: m / z: 256.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.47(s,1H),7.05(s,1H),6.91(s,2H),3.86(s,3H),2.89(t,J=7.2Hz,2H),1.90(t,J=7.2Hz,2H),1.21(s,6H).

[0728] 4) Preparation of Compound 106

[0729] At room temperature, 106-4 (20 mg, 0.08 mmol), 1-6 (18.97 mg, 0.08 mmol) and dichloromethane (2 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (225.52 mg, 0.12 mmol) and 4-dimethylaminopyridine (19.14 mg, 0.16 mmol) were added sequentially under stirring. After 18 hours of reaction at room temperature, the reaction was complete and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain a white solid compound (15.5 mg). LC-MS: m / z: 480.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ12.15(s,1H),8.13(d,J=3.8Hz,1H),7.89(s,1H),7.63(s,1H),7.61(d,J=7.8Hz,1H),7.48(d,J=1.4Hz,1H),7.05 (d,J=7.8Hz,2H),6.99(s,1H),6.29(t,J=2.0Hz,1H),5.64(s,2H),3.80(s,3H),2.91(t,J=7.2Hz,2H),1.92(t,J=7.2Hz,2H),1.25(s,6H).

[0730] Example 49. Synthesis of Compound 107

[0731] Synthesis route

[0732] Experimental procedures

[0733] 1) Preparation of Intermediate 107-2

[0734] At room temperature, 107-1 (5.75 mL, 77.98 mmol) and diethyl ether (50.0 mL) were added to a three-necked flask. Methylmagnesium bromide (28.59 mL, 3M / Et2O) was added dropwise under ice-cooling. Stirring was continued on ice for 10 minutes, and the reaction was continued at 38°C for 3 hours. The reaction solution was poured into 100 mL of saturated ammonium chloride solution, extracted with diethyl ether, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 107-2 (2.60 g) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ4.17 (s, 1H), 1.09 (s, 3H).

[0735] 2) Preparation of Intermediate 107-3

[0736] At room temperature, 107-2 (0.5 g, 6.24 mmol) and 1,2-dichloroethane (10.0 mL) were added to a single-necked flask. Anisole (2.0 mL, 18.31 mmol), ferric bromide (553 mg, 1.87 mmol), and hydrobromic acid (0.11 mL, 0.94 mmol) were added under stirring. The reaction was allowed to proceed at 55°C for 18 hours until complete. The reaction mixture was filtered, and the filtrate was poured into 50 mL of water, extracted with dichloromethane, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1) to obtain intermediate 107-3 (350 mg) as a colorless oil. 1H NMR (400MHz, DMSO-d6) δ7.28 (d,J=8.8Hz,2H),6.84(d,J=8.8Hz,2H),3.72(s,3H),1.24(s,3H).

[0737] 3) Preparation of Intermediate 107-4

[0738] At room temperature, 3 (200 mg, 1.17 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask, and chlorosulfonic acid (411 mg, 3.52 mmol) was added dropwise under ice bath. The reaction was carried out at 0°C for 1 hour, then heated to room temperature for 3 hours until the reaction was complete. The reaction solution was used directly in the next step.

[0739] 4) Preparation of Intermediate 107-5

[0740] Ammonia / methanol solution (2.34 mL, 16.41 mmol) and acetonitrile (3.0 mL) were mixed and cooled to 0°C. The reaction mixture from the previous step was added and heated to 20°C for 1 hour. The reaction was complete after 1 hour. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 107-5 (90 mg) as a white solid. LC-MS: m / z: 250.0 [M+H] + .

[0741] 5) Preparation of Compound 107

[0742] At room temperature, 107-5 (30 mg, 0.12 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35 mg, 0.18 mmol), 4-dimethylaminopyridine (29 mg, 0.24 mmol) and 1-6 (29 mg, 0.12 mmol) were added sequentially under stirring. The reaction was completed after 18 hours at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain a white solid compound (20 mg). LC-MS: m / z: 474.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.29(s,1H),8.08(s,1H),7.92–7.84(m,2H),7.63(d,J=7.8Hz,2H),7.47(d,J=1 .6Hz,1H),7.18–7.00(m,2H),6.96(s,1H),6.29(t,J=2.0Hz,1H),5.63(s,2H),3.79(s,3H),1.28(s,3H).

[0743] Example 50. Synthesis of Compound 108

[0744] Synthesis route

[0745] Experimental procedures

[0746] 1) Preparation of Intermediate 108-2

[0747] At room temperature, 108-1 (7 g, 46.6 mmol) and N,N-dimethylacetamide (70.0 mL) were added to a single-necked flask, and M5 (8.6 mL, 55.92 mmol) and potassium hydroxide (7.84 g, 139.79 mmol) were added under stirring. The reaction was completed at 150°C for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed with 100 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 5:1) to obtain a colorless oily intermediate 108-2 (11.0 g). 1 H NMR (400MHz, DMSO-d6) δ7.31–7.26(m,2H),6.90–6.84(m,2H),4.79(t,J=5.2Hz,1H),3.91(d,J=5.2H z,2H),3.67(dd,J=9.6,7.0Hz,2H),3.56(dd,J=9.6,7.0Hz,2H),1.25(s,9H),1.14(t,J=7.0Hz,6H).

[0748] 2) Preparation of Intermediate 108-3

[0749] At room temperature, 108-2 (7.0 g, 26.28 mmol) and toluene (70.0 mL) were added to a single-necked flask, and polyphosphoric acid (5.39 g, 65.70 mmol) was added under stirring. The reaction was completed at 110°C for 18 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 5:1) to obtain a colorless oily intermediate 108-3 (4 g).

[0750] 1 H NMR (400MHz, DMSO-d6) δ7.94(d,J=2.2Hz,1H),7.63(d,J=2.0Hz,1H),7.49(d,J=8 .8Hz,1H),7.37(dd,J=8.8,2.0Hz,1H),6.91(dd,J=2.2,0.8Hz,1H),1.34(s,9H).

[0751] 3) Preparation of Intermediate 108-4

[0752] At room temperature, 108-3 (2.0 g, 11.48 mmol) and methanol (20.0 mL) were added to a single-necked flask. Palladium on carbon (200 mg, 1.88 mmol) was added with stirring. The reaction was allowed to proceed at room temperature for 48 hours until completion. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford intermediate 108-4 (1.1 g) as a clear oil.

[0753] 4) Preparation of Intermediate 108-5

[0754] At room temperature, 108-4 (788.0 mg, 4.47 mmol) and N,N-dimethylformamide (10.0 mL) were added to a single-necked flask, and N-bromosuccinimide (875.31 mg, 4.92 mmol) was added under stirring. The temperature was raised to 50°C and the reaction was completed for 18 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic phase was washed with 30 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain a transparent oily intermediate 108-5 (1.0 g). 1 H NMR (400MHz, DMSO-d6) δ7.96(s,1H),7.26(s,1H),4.57(t,J=8.8Hz,2H),3.27(t,J=8.8Hz,2H),1.24(s,9H).

[0755] 5) Preparation of Intermediate 108-6

[0756] To a single-necked flask at room temperature, 108-5 (400.0 mg, 1.57 mmol) and 1,4-dioxane (5.0 mL) were added. The intermediate benzyl mercaptan (292.05 mg, 2.35 mmol) and N,N-diisopropylethylamine (0.78 mL, 4.7 mmol) were then added under stirring. Tris(dibenzylideneacetone)dipalladium (143.55 mg, 0.16 mmol) and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (181.42 mg, 0.31 mmol) were then added. The reaction was allowed to proceed at 100°C for 18 hours until completion. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to afford intermediate 108-6 (300.0 mg) as a colorless oil.

[0757] 1H NMR(400MHz,DMSO-d6)δ7.28(dd,J=7.0,4.6Hz,4H),7.23–7.19(m,1H),7.11(s,1H),6.90 (d,J=1.8Hz,1H),4.54(t,J=8.8Hz,2H),4.13(s,2H),3.17(t,J=8.8Hz,2H),1.17(s,9H).

[0758] 6) Preparation of Intermediate 108-7

[0759] At room temperature, 108-6 (200.0 mg, 0.67 mmol), acetonitrile (3.0 mL), acetic acid (80.49 mg, 1.34 mmol), and water (144.9 mg, 8.04 mmol) were added to a single-necked flask. The temperature was lowered to 0°C, and 1,3-dichloro-5,5-dimethylhydantoin (264.05 mg, 1.34 mmol) was added. The reaction was allowed to proceed in an ice bath for 4 hours until complete. The reaction mixture was used directly in the next step without purification.

[0760] 7) Preparation of Intermediate 108-8

[0761] At room temperature, ammonia (3.0 mL) and acetonitrile (3.0 mL) were added to a single-necked flask. The reaction mixture from the previous step was added under an ice bath and allowed to react for 1 hour at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified on a preparative silica gel plate (petroleum ether:ethyl acetate 1:1) to obtain intermediate 108-8 (20.0 mg) as a transparent oil. LC-MS: m / z: 278.0 [M+Na] + .

[0762] 8) Preparation of Compound 108

[0763] At room temperature, 108-8 (10.0 mg, 0.04 mmol), 1-6 (9.49 mg, 0.04 mmol) and dichloromethane (2 mL) were added to a single-necked flask, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.26 mg, 0.06 mmol) and 4-dimethylaminopyridine (9.57 mg, 0.08 mmol) were added sequentially under stirring. The reaction was completed after 18 hours of reaction at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance liquid chromatography (formic acid acetonitrile / water system) to obtain a white solid compound (1.1 mg). LC-MS: m / z: 480.2 [M+H] + . 1H NMR (400MHz, MeOD) δ8.46(s,1H),7.85(d,J=7.8Hz,1H),7.82(d,J=2.2Hz,1H),7.72(s,1H),7.69(d,J=2.2Hz,1H),7.53(d,J=1.6Hz,1H),7.49(s ,1H),7.02(d,J=7.8Hz,1H),6.78(d,J=2.2Hz,1H),6.34(t,J=2.0Hz,1H) ,5.63(s,2H),4.59(t,J=8.8Hz,2H),3.21(t,J=8.8Hz,2H),1.30(s,9H).

[0764] Example 51. Synthesis of Compound 109

[0765] Synthesis route

[0766] Experimental procedures

[0767] 1) Preparation of Intermediate 109-2

[0768] At room temperature, 109-1 (5.0 g, 40.28 mmol), potassium carbonate (11.14 g, 80.56 mmol), and N,N-dimethylformamide (100.0 mL) were added to a single-necked flask, followed by the addition of methyl chloroacetate (3.55 mL, 40.28 mmol) under stirring. The reaction was complete after 18 hours at 50°C. The reaction solution was diluted with water (500 mL) and extracted three times with 80 mL of ethyl acetate each time. The organic phases were combined, washed with saturated sodium chloride solution (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to afford intermediate 109-2 (7.0 g) as a colorless oil. LC-MS: m / z: 197.0 [M+H] + .

[0769] 2) Preparation of Intermediate 109-3

[0770] Under ice, 109-2 (3.5 g, 17.84 mmol) and diethyl ether (35.0 mL) were added to a three-necked flask, and methylmagnesium bromide (13.08 mL, 3 M / hexane) was added dropwise with stirring. The reaction was complete after 3 hours at room temperature. The reaction solution was quenched with saturated ammonium chloride solution (20.0 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 2:1) to afford intermediate 109-3 (1.5 g) as a colorless oil. 1H NMR (400MHz, CDCl3) δ7.18 (t, J = 8.0Hz, 1H), 6.57–6.47 (m, 3H), 3.80 (s, 3H), 3.78 (s, 2H), 1.34 (s, 6H).

[0771] 3) Preparation of Intermediate 109-4

[0772] At room temperature, 109-3 (1.5 g, 7.64 mmol) and Eaton's reagent (20.0 mL) were added to a single-necked flask. The reaction was complete after 2 hours at room temperature. The reaction solution was poured into ice water (300 mL) and extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 109-4 (1.0 g) as a colorless oil.

[0773] 1 H NMR (400MHz, CDCl3) δ7.00(d,J=8.0Hz,1H),6.38(dd,J=8.0,2.4Hz,1H),6.34(d,J=2.4Hz,1H),3.76(s,3H),2.94(s,2H),1.47(s,6H).

[0774] 4) Preparation of Intermediate 109-5

[0775] At room temperature, 109-4 (500.0 mg, 2.81 mmol), N-bromosuccinimide (499.33 mg, 2.81 mmol), and acetonitrile (10.0 mL) were added to a single-necked flask. The reaction was complete after 4 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 109-5 (700.0 mg) as a colorless oil.

[0776] 1 H NMR (400MHz, CDCl3) δ7.24(s,1H),6.38(s,1H),3.83(s,3H),2.94(s,2H),1.46(s,6H).

[0777] 5) Preparation of Intermediate 109-6

[0778] To a single-necked flask at room temperature were added 109-5 (660.0 mg, 2.57 mmol), tris(dibenzylideneacetone)dipalladium (235.05 mg, 0.26 mmol), N,N-diisopropylethylamine (2.12 mL, 12.83 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (297.04 mg, 0.51 mmol), benzyl mercaptan (478.19 mg, 3.85 mmol), and 1,4-dioxane (10.0 mL). The reaction was complete after 18 hours at 100°C. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to afford the green solid intermediate 109-6 (350.0 mg).

[0779] 1 H NMR (400MHz, CDCl3) δ7.25–7.16(m,5H),7.00(d,J=1.2Hz,1H),6.34(s,1H),3.94(s,2H),3.81(s,3H),2.86(d,J=1.2Hz,2H),1.45(s,6H).

[0780] 6) Preparation of Intermediate 109-7

[0781] At room temperature, 109-6 (310.0 mg, 1.03 mmol), acetonitrile (5.0 mL), acetic acid (0.5 mL), and water (0.5 mL) were added to a single-necked flask. N-chlorosuccinimide (551.15 mg, 4.13 mmol) was added under ice. The reaction was complete after 2 hours at 0°C. The reaction mixture was used directly in the next step.

[0782] 7) Preparation of Intermediate 109-8

[0783] At room temperature, ammonia methanol (10 mL, 7 M) was added to a single-necked flask, and the first-stage reaction solution was added dropwise under ice bath. The reaction was complete after 2 hours at 0°C. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 109-8 (30.0 mg) as a white solid. LC-MS: m / z: 258.0 [M+H] + .

[0784] 8) Preparation of Compound 109

[0785] At room temperature, 109-8 (28.24 mg, 0.12 mmol), 1-6 (30.0 mg, 0.12 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (33.53 mg, 0.27 mmol) and 4-dimethylaminopyridine (42.73 mg, 0.35 mg) were added sequentially under stirring. The reaction was completed after 18 hours at room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain a white solid compound (3.21 mg). LC-MS: m / z: 482.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.02(s,1H),7.85(d,J=2.0Hz,1H),7.68–7.61(m,2H),7.46(d,J=2.0Hz,1H),7.01(d,J= 7.6Hz,1H),6.92(s,1H),6.47(s,1H),6.27(t,J=2.0Hz,1H),5.60(s,2H),3.70(s,3H),2.98(s,2H),1.43(s,6H).

[0786] Example 52. Synthesis of Compound 110

[0787] Synthesis route

[0788] Experimental procedures

[0789] 1) Preparation of Intermediate 110-2

[0790] At -78 ° C, 2-bromothiazole (1.0 mL, 11.16 mmol) was added to a three-necked flask, and n-butyl lithium (5.6 mL, 2.5 M / THF) was slowly added dropwise with stirring. After the addition was completed, stirring was continued for 0.5 hours, 110-1 (2 g, 9.30 mmol) was added to the reaction solution, and stirring was continued at -78 ° C for 1.5 hours to complete the reaction. The reaction solution was poured into a saturated aqueous ammonium chloride solution (100 mL), extracted with ethyl acetate (30 mL x 3), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 2:1) to obtain a yellow oily compound 110-2 (2.7 g). LC-MS: m / z: 299.8 / 301.8 [M+H] + .

[0791] 2) Preparation of Intermediate 110-3

[0792] At room temperature, compound 110-2 (2.7 g, 8.99 mmol), trifluoroacetic acid (30.0 mL), and 1,2-dichloroethane (30.0 mL) were added to a single-necked flask, followed by the addition of triethylsilane (7.3 mL, 44.97 mmol) under stirring. The reaction was complete after 18 hours at 80°C. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain compound 110-3 (2.2 g) as a yellow oil. LC-MS: m / z: 283.9 / 285.9 [M+H] + .

[0793] 3) Preparation of Intermediate 110-4

[0794] At room temperature, 110-3 (2.2 g, 4.65 mmol), benzyl mercaptan (0.8 mL, 6.97 mmol), tris(dibenzylideneacetone)dipalladium (430 mg, 0.46 mmol), N,N-diisopropylethylamine (4.1 mL, 23.23 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (540 mg, 0.93 mmol), and anhydrous dioxane (22.0 mL) were added to a single-necked flask. The reaction was allowed to proceed at 100°C for 18 hours, and the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 5:1) to obtain compound 110-4 (940 mg) as a yellow oil. LC-MS: m / z: 328.0 [M+H] + .

[0795] 4) Preparation of Intermediate 110-5

[0796] At room temperature, 110-4 (940 mg, 2.44 mmol), acetic acid (0.14 mL, 2.44 mmol), water (0.26 mL, 14.64 mmol) and acetonitrile (10.0 mL) were added to a single-necked flask, and N-chlorosuccinimide (980 mg, 7.32 mmol) was added under ice bath conditions. The reaction was completed after 2 hours at 0°C. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 2:1) to obtain a yellow oily compound 110-5 (600 mg). LC-MS: m / z: 303.9 [M+H] + .

[0797] 5) Preparation of Intermediate 110-6

[0798] At room temperature, ammonia methanol solution (20.0 mL) was added to a single-necked flask, followed by compound 110-5 (250 mg, 0.82 mmol) under ice-bath conditions. The reaction was allowed to proceed for 2 hours at 25°C until complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain compound 110-6 (160 mg) as a white solid. LC-MS: m / z: 285.0 [M+H] + .

[0799] 6) Preparation of Compound 110

[0800] At room temperature, 110-6 (34.1 mg, 0.12 mmol), 1-6 (30 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35.6 mg, 0.19 mmol), 4-dimethylaminopyridine (30.3 mg, 0.25 mmol) and dichloromethane (3.0 mL) were added to a single-necked bottle. The reaction was completed after 18 hours at 25°C. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain a white solid compound (16 mg). LC-MS: m / z: 509.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.41(s,1H),8.05(s,1H),7.87(d,J=2.4Hz,1H),7.83(d,J=8.0Hz,1H),7.73(d,J=3.2Hz,1H),7.66–7.57(m, 2H),7.47(d,J=2.0Hz,1H),7.14(s,1H),7.07–6.96(m,2H),6.94(s,1H),6.28(t,J=2.0Hz,1H),5.61(s,2H),4.40(s,2H),3.78(s,3H).

[0801] Example 53. Synthesis of Compound 111 and Compound 122

[0802] Synthesis route

[0803] Experimental procedures

[0804] 1) Preparation of Intermediate 111-2

[0805] To a three-necked flask at room temperature were added 111-1 (1.0 g, 5.32 mmol), M19 (1.06 g, 6.38 mmol), potassium carbonate (2.21 g, 15.96 mmol), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (0.39 g, 0.53 mmol), 1,4-dioxane (20.0 mL), and water (4.0 mL). The reaction was allowed to proceed at 100°C for 18 hours until completion. The reaction mixture was added with water (50.0 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1) to afford the intermediate 111-2 (1.0 g) as a red solid. LC-MS: m / z: 230.0 [M+H] + .

[0806] 2) Preparation of Intermediates 111-3 and 122-1

[0807] At room temperature, 111-2 (400.0 mg, 1.74 mmol) and dichloromethane (5.0 mL) were added to a single-necked flask. Chlorosulfonic acid (1.16 mL, 17.45 mmol) was then added under ice-cooling conditions. The reaction was allowed to proceed at room temperature for 24 hours until completion. The reaction solution was used directly in the next step without purification.

[0808] 3) Preparation of Intermediates 111-4 and 122-2

[0809] Ammonia methanol (50 mL, 7 M) was added to a single-necked flask at room temperature, and the first-stage reaction solution was added dropwise at 0°C. The reaction was complete after 2 hours at 0°C. The reaction solution was concentrated under reduced pressure, and the crude product was purified by HPLC (ammonium bicarbonate / acetonitrile / water) to afford intermediates 111-4 (50.0 mg) and 122-2 (30.0 mg) as white solids.

[0810] 111-4: 1 H NMR(400MHz,DMSO-d6)δ7.73(dd,J=6.8,2.0Hz,1H),7.48(s,1H),7.44–7.36(m, 3H),7.21(s,1H),6.27(t,J=6.8Hz,1H),3.73(s,3H),3.47(s,3H),2.50(s,3H).

[0811] 122-2: 1H NMR (400MHz, DMSO-d6) δ7.80 (dd, J=6.8, 2.0Hz, 1H), 7.54 (d, J= 2.4Hz,1H),7.48(dd,J=6.8,2.0Hz,1H),7.33(d,J=2.4Hz,1H),7.16(s,2H),6.33(t,J=6.8Hz,1H),3.51(s,3H),3.45(s,3H),2.31(s,3H).

[0812] 4) Preparation of Compound 111

[0813] At room temperature, 111-4 (30.00 mg, 0.12 mmol), 1-6 (38.19 mg, 0.12 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.61 mg, 0.19 mmol) and 4-dimethylaminopyridine (45.39 mg, 0.37 mg) were added sequentially under stirring. The reaction was completed after 18 hours of reaction at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain a white solid compound (42.13 mg). LC-MS: m / z: 533.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.62 (s, 1H), 8.08 (s, 1H), 7.87 (d, J = 2.4Hz, 1H), 7. 72(dd,J=6.8,2.0Hz,1H),7.65(d,J=7.6Hz,1H),7.62(s,1H),7.47(d,J=2.0 Hz,1H),7.45–7.41(m,1H),7.18(s,1H),7.04(d,J=7.6Hz,1H),6.98–6.93(m ,1H),6.31–6.24(m,2H),5.62(s,2H),3.75(s,3H),3.47(s,3H),2.52(s,3H).

[0814] 5) Preparation of Compound 122

[0815] At room temperature, 122-2 (25.00 mg, 0.10 mmol), 1-6 (30.0 mg, 0.10 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (29.68 mg, 0.15 mmol) and 4-dimethylaminopyridine (37.83 mg, 0.31 mg) were added sequentially under stirring. The reaction was completed after 18 hours of reaction at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain a white solid compound (27.41 mg). LC-MS: m / z: 533.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.48(s,1H),8.08(s,1H),7.89(d,J=2.4Hz,1H),7.76(d,J=6.8Hz,1H),7.71(d,J=2.4Hz,1H),7.65(d,J=7.6 Hz,1H),7.50–7.31(m,3H),7.05(d,J=8.0Hz,1H),6.97(s,1H),6.33–6.24(m,2H),5.63(s,2H),3.49(s,3H),3.37(s,3H),2.35(s,3H).

[0816] Example 54. Synthesis of Compound 112

[0817] Synthesis route

[0818] Experimental procedures

[0819] 1) Preparation of Intermediate 112-2

[0820] At room temperature, 112-1 (0.80 g, 3.59 mmol) and acetonitrile (10.0 mL) were added to a single-necked flask. Potassium hydroxide (604 mg, 10.76 mmol) and iodomethane (1018 mg, 7.17 mmol) were added sequentially under stirring. The reaction was completed at 55°C for 3 hours. The reaction solution was poured into 50 mL of water and extracted three times with 40 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to obtain the intermediate 112-2 (0.80 g) as a white solid. 1H NMR (400MHz, DMSO-d6) δ8.24(s,1H),7.84(t,J=8.4Hz,2H),7.54-7.49(m,1H),7.48(s,1H),7.42-7.37(m,1H),3.96(s,3H).

[0821] 2) Preparation of Intermediate 112-3

[0822] At room temperature, 112-2 (350 mg, 1.48 mmol) and dioxane (10.0 mL) were added to a single-necked flask. N,N-diisopropylethylamine (572 mg, 4.43 mmol), benzyl mercaptan (550 mg, 4.43 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (170 mg, 0.30 mmol), and tris(dibenzylideneacetone)dipalladium (135 mg, 0.15 mmol) were added sequentially under stirring. The reaction was allowed to proceed at 100°C for 18 hours until completion. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 20:1) to afford the intermediate 112-3 (400 mg) as a white solid.

[0823] 3) Preparation of Intermediate 112-4

[0824] To a single-necked flask, 112-4 (400 mg, 1.43 mmol), acetonitrile (10.0 mL), water (154 mg, 8.56 mmol), and acetic acid (86 mg, 1.43 mmol) were added under ice. 1,3-Dichloro-5,5-dimethylhydantoin (422 mg, 2.14 mmol) was then added under ice. The reaction was complete after 2 hours of ice cooling. The reaction solution was used directly in the next step without further treatment.

[0825] 4) Preparation of Intermediate 112-5

[0826] Ammonia (2.20 mL, 14.26 mmol) and acetonitrile (10.0 mL) were mixed and cooled to 0°C. The reaction mixture from the previous step was added dropwise to the mixture. The reaction was allowed to react at 20°C for 1 hour, and the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to afford intermediate 112-5 (150 mg) as a yellow oil. LC-MS: m / z: 238.0 [M+H] + .

[0827] 5) Preparation of Compound 112

[0828] At room temperature, 112-5 (30 mg, 0.13 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (36 mg, 0.19 mmol), 4-dimethylaminopyridine (31 mg, 0.25 mmol), and 1-6 (31 mg, 0.13 mmol) were added sequentially under stirring. The reaction was complete after 18 hours at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain a white solid compound (3 mg). 1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),8.68-8.48(m,1H),8.12-7.96(m,2H),7.92-7.83(m,2H),7.68-7.58(m ,2H),7.54-7.39(m,3H),7.03(d,J=7.2Hz,1H),6.95(s,1H),6.28(t,J=2.0Hz,1H),5.62(s,2H),3.89(s,3H). LC-MS:m / z:462.2[M+H] + .

[0829] Example 55. Synthesis of Compound 113

[0830] Synthesis route

[0831] Experimental procedures

[0832] 1) Preparation of Intermediate 113-2

[0833] At room temperature, 113-1 (10.0 g, 99.88 mmol) and dichloromethane (120.0 mL) were added to a three-necked flask. Anisole (5.40 g, 49.94 mmol) was added under stirring, and then aluminum chloride (26.63 g, 199.76 mmol) was slowly added in batches. The reaction was allowed to proceed at 40°C for 18 hours until complete. The reaction solution was slowly poured into 500 mL of ice water, the pH was adjusted to 3 with 2N hydrochloric acid, and the product was extracted three times with 100 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 113-2 (2.20 g) as a light yellow oil. 1 H NMR (400MHz, DMSO-d6) δ11.80(s,1H),7.32-7.25(m,2H),6.87-6.80(m,2H),3.72(s,3H),2.52(s,2H),1.35(s,6H). LC-MS:m / z:207.0[MH]- .

[0834] 2) Preparation of Intermediate 113-3

[0835] At room temperature, 113-2 (2.2 g, 10.56 mmol) and methanol (30.0 mL) were added to a single-necked flask, and concentrated sulfuric acid (3 mL, 54.00 mmol) was added under stirring. The reaction was completed after 3 hours at 50°C. The reaction solution was slowly poured into 100 mL of ice water and extracted three times with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 113-3 (2.2 g) as a light yellow oil. 1 H NMR (400MHz, DMSO-d6) δ7.30-7.24(m,2H),6.86-6.80(m,2H),3.72(s,3H),3.44(s,3H),2.60(s,2H),1.34(s,6H).

[0836] 3) Preparation of Intermediate 113-4

[0837] At room temperature, 113-3 (200 mg, 0.90 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask, and chlorosulfonic acid (524 mg, 4.50 mmol) was added dropwise in an ice bath. The reaction was carried out at 0°C for 1 hour and then at room temperature for 3 hours. The reaction was complete and the reaction solution was directly used for the next step.

[0838] 4) Preparation of Intermediate 113-5

[0839] Ammonia (2.07 mL, 13.47 mmol) and acetonitrile (10.0 mL) were mixed and cooled to 0°C. The reaction mixture from the previous step was added dropwise to the mixture. The reaction was allowed to react at 20°C for 1 hour, and the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 113-5 (190 mg) as a white oil. LC-MS: m / z: 302.0 [M+H] + .

[0840] 5) Preparation of Intermediate 113-6

[0841] At room temperature, 113-5 (60 mg, 0.20 mmol) and dichloromethane (5.0 mL) were added to a single-necked flask, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (57 mg, 0.30 mmol), 4-dimethylaminopyridine (49 mg, 0.40 mmol) and 1-6 (48 mg, 0.20 mmol) were added sequentially under stirring. The reaction was completed after 18 hours at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 1:2) to obtain a yellow oily intermediate 113-6 (50 mg). LC-MS: m / z: 526.0 [M+]) + .

[0842] 6) Preparation of Compound 113

[0843] At room temperature, 113-6 (50 mg, 0.10 mmol) and tetrahydrofuran (3.0 mL) were added to a three-necked flask. Diisopropylaluminum hydride (tetrahydrofuran solution) (1.00 mL, 1.00 mmol) was added dropwise under ice-cooling. After 1 hour of ice-cooling, the reaction was complete. The reaction solution was quenched with sodium sulfate decahydrate and filtered. The filter cake was washed with dichloromethane:methanol (10:1) (5.0 mL). The filtrates were combined and dried by evaporation. The crude product was purified by HPLC (formic acid / acetonitrile / water system) to obtain the compound as a white solid (10 mg). 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),8.10(s,1H),7.89(s,1H),7.83(d,J= 2.4Hz,1H),7.62(d,J=7.6Hz,2H),7.47(d,J=1.2Hz,1H),7.12(s,1H),7.04( d,J=7.6Hz,1H),6.97(s,1H),6.29(t,J=2.0Hz,1H),5.63(s,2H),4.28(t,J= 4.8Hz,1H),3.81(s,3H),3.27-3.18(m,2H),1.84-1.74(m,2H),1.28(s,6H). LC-MS: m / z: 498.2 [M+H] + .

[0844] Example 56. Synthesis of Compound 114

[0845] Synthesis route

[0846] Experimental procedures

[0847] 1) Preparation of Intermediate 114-2

[0848] At room temperature, 113-3 (700 mg, 3.15 mmol) and tetrahydrofuran (20.0 mL) were added to a three-necked flask, and diisopropylaluminum hydride (tetrahydrofuran solution) (9.45 mL, 9.45 mmol) was added dropwise under ice bath. The reaction was completed after 3 hours of ice bath reaction. The reaction solution was quenched with sodium sulfate decahydrate, filtered, and the filter cake was washed with ethyl acetate (20.0 mL). The filtrates were combined and then dried. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 5:1) to obtain yellow oily intermediate 114-2 (580 mg). LC-MS: 217.0 [M+Na] + .

[0849] 2) Preparation of Intermediate 114-3

[0850] At room temperature, 114-2 (580 mg, 2.99 mmol) and N,N-dimethylformamide (10.0 mL) were added to a three-necked flask. Sodium hydride (239 mg, 5.97 mmol) was added under ice-cooling conditions. After stirring on ice for 1 hour, iodomethane (0.28 mL, 4.48 mmol) was added dropwise. The reaction was allowed to proceed on ice for 2 hours, resulting in a complete reaction. The reaction solution was slowly poured into 50 mL of ice water and extracted three times with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 114-3 (540 mg) as a light yellow oil. 1 H NMR (400MHz, DMSO-d6) δ7.29-7.20(m,2H),6.89-6.78(m,2H),3.72(s,3H),3.10(s,3H),3.09-3.04(m,2H),1.85-1.74(m,2H),1.24(s,6H).

[0851] 3) Preparation of Intermediate 114-4

[0852] At room temperature, 114-3 (180 mg, 0.86 mmol) and dichloromethane (3.0 mL) were added to a three-necked flask, and chlorosulfonic acid (301 mg, 2.58 mmol) was added dropwise under ice bath. The reaction was carried out at 0°C for 1 hour and then at room temperature for 3 hours. The reaction was complete and the reaction solution was directly used for the next step.

[0853] 4) Preparation of Intermediate 114-5

[0854] Ammonia (1.32 mL, 8.57 mmol) and acetonitrile (5.0 mL) were mixed and cooled to 0°C. The reaction mixture from the previous step was added dropwise to the mixture. The reaction was allowed to react at 20°C for 1 hour, and the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 114-5 (90 mg) as a white oil. LC-MS: m / z: 288.2 [M+H] + .

[0855] 5) Preparation of Compound 114

[0856] At room temperature, 114-5 (30 mg, 0.10 mmol) and dichloromethane (3.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (30 mg, 0.16 mmol), 4-dimethylaminopyridine (26 mg, 0.21 mmol), and 1-6 (25 mg, 0.10 mmol) were added sequentially under stirring. The reaction was complete after 18 hours at room temperature. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain a white solid compound (4 mg). 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),8.10-7.95(m,1H),7.89-7.82(m,2H),7.64(d,J=7.6Hz,1H),7.55-7.35(m,2H),7.12-6.98(m,2H),6 .93(s,1H),6.28(t,J=2.0Hz,1H),5.61(s,2H),3.77(s,3H),3.16-3.09(m,5H),1.84(t,J=7.2Hz,2H),1.28(s,6H).LC-MS:m / z:512.2[M+H] + .

[0857] Example 57. Synthesis of Compound 115

[0858] Synthesis route

[0859] Experimental procedures

[0860] 1) Preparation of Intermediate 115-2

[0861] At room temperature, 115-1 (5 g, 21.46 mmol) and N,N-dimethylformamide (50.0 mL) were added to a single-necked flask and reacted at 70°C for 3 hours. The reaction was completed, and the reaction solution was poured into ice water and extracted three times with 100 mL of ethyl acetate. The organic phase was washed with 200 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 10:1) to obtain a colorless oily intermediate 115-2 (1.7 g). 1 H NMR (400MHz, DMSO-d6) δ7.91(d,J=2.0Hz,1H),7.83(d,J=8.4Hz,1H),7.42(dd,J= 8.4,2.0Hz,1H),5.58(s,1H),3.84(d,J=4.0Hz,3H).LC-MS:m / z:244.8 / 246.8[MH] - .

[0862] 2) Preparation of Intermediate 115-3

[0863] At room temperature, 115-2 (1.7 g, 6.88 mmol) and N,N-dimethylformamide (20.0 mL) were added to a single-necked flask, and M5 (1.27 mL, 8.26 mmol) and potassium carbonate (2.85 g, 20.64 mmol) were added under stirring. The reaction was completed at 80°C for 3 hours. The reaction solution was poured into ice water and extracted three times with 50 mL of ethyl acetate. The organic phase was washed with 50 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 10:1) to obtain a colorless oily intermediate 115-3 (2 g). 1 H NMR (400MHz, DMSO-d6) δ7.76(d,J=8.4Hz,1H),7.68(d,J=1.6Hz,1H),7.44(dd,J=8.4,1.6Hz,1H),4.68(t,J=5.2Hz,1H),3.83(s,3H), 3.64(dq,J=9.2,7.2Hz,2H),3.50(dq,J=9.2,7.2Hz,2H),3.20(d,J=5.2Hz,2H),1.11(t,J=7.2Hz,6H).LC-MS:m / z:387.0 / 389.0[M+Na] + .

[0864] 3) Preparation of Intermediate 115-4

[0865] At room temperature, 115-3 (1.5 g, 4.13 mmol) and toluene (20.0 mL) were added to a single-necked flask. Polyphosphoric acid (1.54 g, 18.75 mmol) was added under stirring. The reaction was allowed to proceed at 60°C for 18 hours until complete. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 115-4 (950 mg) as a clear oil. 1 H NMR (400MHz, DMSO-d6) δ8.07(d,J=5.6Hz,1H),7.97(d,J=8.0Hz,1H),7.82(d,J=8.0Hz,1H),7.56(d,J=5.7Hz,1H),3.96(s,3H).

[0866] 4) Preparation of Intermediate 115-5

[0867] At room temperature, 115-4 (200.0 mg, 0.74 mmol) and 1,4-dioxane (5.0 mL) were added to a single-necked flask. (tributyltin)methanol (355.28 mg, 1.11 mmol) and tetrakis(triphenylphosphine)palladium (85.24 mg, 0.07 mmol) were added under stirring. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 100°C for 18 hours. The reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 115-5 (110 mg) as a clear oil. LC-MS: m / z: 223.0 [M+H] + .

[0868] 5) Preparation of Intermediate 115-6

[0869] To a 25 mL single-necked flask at room temperature, 115-5 (110.0 mg, 0.49 mmol) and 1,4-dioxane (2.0 mL) were added. Intermediate M3 (108.51 mg, 0.74 mmol) and cesium carbonate (645.01 mg, 1.98 mmol) were added under stirring. The reaction was allowed to proceed at 70°C for 18 hours until complete. The reaction solution was poured into ice water and extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 115-6 (70 mg) as a colorless oil. 1H NMR (400MHz, DMSO-d6) δ8.04(d,J=7.6Hz,1H),7.96(d,J=5.6Hz,1H),7.90(d,J=2.4Hz,1H),7.74(d,J=5.6Hz,1H),7 .50(d,J=1.2Hz,1H),7.16(d,J=7.6Hz,1H),6.30(t,J=2.0Hz,1H),5.81(s,2H),3.95(s,3H).LC-MS:m / z:273.0[M+H] + .

[0870] 6) Preparation of Intermediate 115-7

[0871] At room temperature, 115-6 (50.0 mg, 0.18 mmol), tetrahydrofuran (3.0 mL), methanol (1.0 mL), and water (1.0 mL) were added to a single-necked flask. Lithium hydroxide (13.19 mg, 0.55 mmol) was added with stirring and allowed to react at room temperature for 3 hours. The reaction mixture was poured into ice water, and the pH was adjusted to 2-3 with sodium hydroxide solution (1N). The mixture was extracted three times with 20 mL of ethyl acetate. The organic phases were combined, washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 115-6 (30.0 mg). 1 H NMR(400MHz,DMSO-d6)δ8.00(d,J=7.6Hz,1H),7.91(dd,J=10.4,3.6Hz,2H),7.71(d,J=5.6H z,1H),7.49(s,1H),7.15(d,J=7.6Hz,1H),6.30(s,1H),5.79(s,2H).LC-MS:m / z:259.0[M+H] + .

[0872] 7) Preparation of Compound 115

[0873] At room temperature, 115-7 (20.0 mg, 0.08 mmol), M4 (14.5 mg, 0.08 mmol), and dichloromethane (2 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (22.26 mg, 0.12 mmol) and 4-dimethylaminopyridine (18.92 mg, 0.15 mmol) were added sequentially under stirring. After 18 hours of reaction at room temperature, the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (acetonitrile / water system) to obtain a white solid compound (16.0 mg). 1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),8.21–8.09(m,1H),7.95–7.84(m,2H),7.80(s,1H),7.61(d,J=5.2Hz,1 H),7.55–7.49(m,2H),7.12(d,J=7.6Hz,3H),6.28(s,1H),5.74(s,2H),3.76(s,3H).LC-MS:m / z:428.0[M+H] + .

[0874] Example 58. Synthesis of Compound 116

[0875] Synthesis route

[0876] Experimental procedures

[0877] 1) Preparation of Intermediate 116-2

[0878] Under an ice-salt bath, chlorosulfonic acid (10.0 mL) was added to a single-necked flask, and 116-1 (10 g, 53.46 mmol) was slowly added dropwise with stirring. After the addition was complete, stirring was continued for 10 minutes until the reaction was complete. The reaction solution was poured into ice water (100 mL) and extracted three times with 30 mL of ethyl acetate. The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 116-2 (180 mg) as a white solid. 1 H NMR (400MHz, Chloroform-d) δ7.81 (dd, J=8.4, 1.6Hz, 1H), 7.28 (d, J=2.0Hz, 1H), 7.26 (dd, J=6.8, 1.2Hz, 1H), 4.07 (s, 3H).

[0879] 2) Preparation of Intermediate 116-3

[0880] At room temperature, ammonia methanol solution (10.0 mL) was added to a single-necked flask, and compound 116-2 (180 mg, 0.63 mmol) was added with stirring. The reaction was completed after 18 hours at 25°C. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 2:1) to obtain compound 116-3 (120 mg) as a white solid. LC-MS: m / z: 288.8 [M+Na] + .

[0881] 3) Preparation of Intermediate 116-4

[0882] At room temperature, 116-3 (98.5 mg, 0.37 mmol), 1-6 (90 mg, 0.37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106.8 mg, 0.56 mmol), 4-dimethylaminopyridine (90.8 mg, 0.74 mmol) and dichloromethane (5.0 mL) were added to a single-necked bottle. The reaction was completed after 3 hours at 25°C. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 1:1) to obtain compound 116-4 (130 mg) as a white solid. LC-MS: m / z: 489.8 [M+H] + .

[0883] Preparation of Intermediate 116-5: 116-4 (80 mg, 0.16 mmol), tetrakistriphenylphosphine palladium (18.9 mg, 0.02 mmol), and anhydrous dioxane (5.0 mL) were added to a single-necked flask at room temperature. (Tributyltin)methanol (104.8 mg, 0.33 mmol) was added under stirring. The reaction was allowed to proceed at 80°C for 18 hours until completion. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain compound 116-5 (50 mg) as a yellow oil. LC-MS: m / z: 442.2 [M+H] + .

[0884] 4) Preparation of Compound 116

[0885] At room temperature, 116-5 (50 mg, 0.11 mmol), M3 (33.1 mg, 0.23 mmol), cesium carbonate (110.7 mg, 0.34 mmol), and acetonitrile (5.0 mL) were added to a single-necked flask. The reaction was complete after 18 hours at 80°C. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain the compound as a white solid (6 mg). 1 H NMR (400MHz, DMSO-d6) δ12.33(s,1H),8.08(s,1H),7.88(d,J=2.4Hz,2H),7.83(d,J=8.4Hz,1H),7.61(d,J=8.0Hz,1H),7.48(dd,J=9.2,2.0Hz,2 H),7.03(d,J=8.0Hz,2H),6.96(s,1H),6.80(d,J=8.0Hz,1H),6.35–6.2 4(m,2H),5.62(s,2H),5.40(s,2H),3.77(s,3H).LC-MS:m / z:492.0[M+H] + .

[0886] Example 59. Synthesis of Compound 117

[0887] Synthesis route

[0888] Experimental procedures

[0889] 1) Preparation of Intermediate 117-2

[0890] At room temperature, 117-1 (500 mg, 1.75 mmol), N,N-diisopropylethylamine (0.43 mL, 2.63 mmol), and dichloromethane (20.0 mL) were added to a single-necked flask. Bis-(4-methoxybenzyl)-amine (450.3 mg, 1.75 mmol) was added with stirring. After 3 hours at 25°C, the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain compound 117-2 (850 mg) as a white solid.

[0891] 2) Preparation of Intermediate 117-3

[0892] At room temperature, 117-2 (500 mg, 0.99 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (295.5 mg, 1.97 mmol), cesium carbonate (1.29 g, 3.95 mmol), palladium acetate (22.2 mg, 0.10 mmol), cesium carbonate (965.1 mg, 2.96 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (114.3 mg, 0.20 mmol), and toluene (10.0 mL) were added to a single-necked flask. The reaction was complete after 18 hours at 100°C. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain compound 117-3 (300 mg) as a colorless oil. LC-MS: m / z: 539.2 [M+H] + .

[0893] 3) Preparation of Intermediate 117-4

[0894] At room temperature, 117-3 (280 mg, 0.52 mmol) and trifluoroacetic acid (10.0 mL) were added to a single-necked bottle. The reaction was completed after 2 hours of reaction at room temperature. The reaction solution was concentrated under reduced pressure and the pH was adjusted to 8 with aqueous sodium bicarbonate solution (100.0 mL). It was extracted three times with 30 mL of dichloromethane. The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain yellow solid compound 117-4 (150 mg). LC-MS: m / z: 299.2 [M+H] + .

[0895] 4) Preparation of Compound 117

[0896] At room temperature, 117-4 (71.6 mg, 0.24 mmol) and 1-6 (30.0 mg, 0.12 mmol) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (35.61 mg, 0.19 mmol), 4-dimethylaminopyridine (45.39 mg, 0.37 mg), and dichloromethane (3.0 mL) were added sequentially under stirring. After 18 hours at room temperature, the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain a white solid compound (4 mg). 1 H NMR (400MHz, DMSO-d6) δ8.20 (s, 1H), 8.02 (d, J = 2.0Hz, 1H), 7.85 (d, J = 2.4Hz, 1H) ,7.66–7.60(m,2H),7.46(d,J=2.0Hz,1H),7.01(d,J=8.0Hz,1H),6.92(d,J=2.4H z,1H),6.42(d,J=8.8Hz,1H),6.38(d,J=2.0Hz,1H),6.27(t,J=2.0Hz,1H),5.60( s,2H),4.27(s,2H),3.73(s,3H),3.68(d,J=10.8Hz,2H),3.45(d,J=10.8Hz,2H), 1.99–1.86(m,4H).LC-MS:m / z:523.0[M+H] + .

[0897] Example 60. Synthesis of Compound 118

[0898] Synthesis route

[0899] Experimental procedures

[0900] 1) Preparation of Intermediate 118-2

[0901] At room temperature, 118-1 (1.0 g, 4.11 mmol) and dichloromethane (10.0 mL) were added to a single flask. Chlorosulfonic acid (1.10 mL, 16.45 mmol) was added dropwise in an ice bath. The mixture was allowed to react for 1 hour in an ice bath and then for 3 hours at room temperature, with the formation of new spots. The reaction solution was slowly poured into 50 mL of ice water and extracted three times with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield an off-white solid intermediate 118-2 (1.10 g).

[0902] 2) Preparation of Intermediate 118-3

[0903] At room temperature, 118-2 (1.10 g, 3.22 mmol) and dichloromethane (20.0 mL) were added to a single-necked flask. N,N-diisopropylamineethylamine (3 mL, 54.00 mmol) and bis-(4-methoxybenzyl)-amine (0.91 g, 3.54 mmol) were then added under ice-cooling conditions. The reaction was complete after 18 hours at 20°C. The reaction solution was poured into 50 mL of water and extracted three times with 50 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 2:1) to obtain the intermediate 118-3 (1.30 g) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.69(s,1H),7.32(s,1H),7.02(d,J=8.6Hz,4H),6.78(d,J=8.6Hz,4H),4.29(s,4H),3.84(s,3H),3.71(s,6H),1.44(s,9H).

[0904] 3) Preparation of Intermediate 118-4

[0905] At room temperature, 118-3 (700 mg, 1.24 mmol) and N,N-dimethylformamide (10.0 mL) were added to a single-necked flask. Zinc cyanide (102 mg, 0.87 mmol) and tetrakis(triphenylphosphine)palladium (215 mg, 0.19 mmol) were added with stirring. The reaction was complete after 18 hours at 110°C. The reaction solution was poured into 50 mL of water and extracted three times with 50 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 2:1) to obtain intermediate 118-4 (520 mg) as a yellow solid.

[0906] 4) Preparation of Intermediate 118-5

[0907] Compound 118-4 (240 mg, 0.47 mmol) was dissolved in trifluoroacetic acid (3.0 mL) and the reaction was completed at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain intermediate 118-5 (126 mg) as a yellow solid. LC-MS: m / z: 269.0 [M+H] + .

[0908] 5) Preparation of Intermediate 118-6

[0909] At room temperature, 5 (126 mg, 0.47 mmol) and dichloromethane (10.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (135 mg, 0.70 mmol), 4-dimethylaminopyridine (115 mg, 0.94 mmol), and 1-6 (114 mg, 0.47 mmol) were added sequentially under stirring. After 18 hours at room temperature, the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain intermediate 118-6 (200 mg) as a yellow solid. LC-MS: m / z: 493.0 [M+H]+.

[0910] 6) Preparation of Compound 118

[0911] At room temperature, 118-6 (160 mg, 0.32 mmol) and toluene (10.0 mL) were added to a single-necked flask. Azidotrimethylsilane (1.00 mL, 1.00 mmol) and dibutyltin diacetate (114 mg, 0.32 mmol) were then added under stirring. The product was obtained after 18 hours of reaction at 130°C. The reaction solution was filtered, and the solid was washed with petroleum ether (10.0 mL). The solid was purified by HPLC (formic acid / acetonitrile / water) to afford the compound as a yellow solid (4 mg). 1 H NMR (400MHz, DMSO-d6) δ8.12-8.05(m,2H),7.89(d,J=2.0Hz,1H),7.65(d,J=7.6Hz,1H),7.47(d,J=1.2Hz,1H),7.10-7. 02(m,2H),6.96(d,J=2.0Hz,1H),6.29(t,J=2.0Hz,1H),5.63(s,2H),3.77(s,3H),1.14(s,9H).LC-MS:m / z:536.3[M+H] + .

[0912] Example 61. Synthesis of Compound 119

[0913] Synthesis route

[0914] Experimental procedures

[0915] 1) Synthesis of Intermediate 119-2

[0916] At room temperature, titanium tetrachloride (1.0 mL, 4.37 mmol) and dichloromethane (20.0 mL) were added to a three-necked flask. The temperature was lowered to -40°C, and dimethylzinc (n-hexane solution) (9.6 mL, 9.6 mmol) was slowly added dropwise. The mixture was stirred for half an hour. 119-1 (1.0 g, 4.37 mmol) was dissolved in dichloromethane (5 mL) and slowly added dropwise to the reaction mixture. The mixture was allowed to return to room temperature naturally and reacted for 18 hours until the reaction was complete. The reaction mixture was poured into ice water and extracted three times with 50 mL of dichloromethane. The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 119-2 (700 mg). 1 H NMR (400MHz, DMSO-d6) δ7.37(d,J=8.8Hz,1H),7.16(d,J=2.8Hz,1H),6.90(dd,J=8.8,2.8Hz,1H),3.74(s,3H),1.44(s,9H).

[0917] 2) Synthesis of Intermediate 119-3

[0918] At room temperature, 119-2 (300.0 mg, 1.23 mmol) and dichloromethane (5.0 mL) were added to a single-necked flask. The temperature was lowered to 0°C, and chlorosulfonic acid (0.25 mL, 3.7 mmol) was slowly added dropwise. The mixture was reacted on ice for 1 hour, then warmed to room temperature for 3 hours. The reaction was complete. The reaction solution was used directly in the next step without purification.

[0919] 3) Preparation of Intermediate 119-4

[0920] At room temperature, ammonia (5.0 mL) and acetonitrile (5.0 mL) were added to a single-necked flask, cooled to 0°C, and the reaction solution intermediate 119-3 (300.0 g, 0.88 mmol) was added in batches under stirring. After 1 hour of reaction at room temperature, the reaction was complete. The reaction solution was poured into ice water and extracted three times with 20 mL of ethyl acetate. The organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1 to 10:1) to obtain a white solid intermediate 119-4 (150.0 mg). 1 H NMR(400MHz,DMSO-d6)δ7.82(s,1H),7.43(s,1H),7.17(s,2H),3.91(s,3H),1.46(s,9H).LC-MS:m / z:322.0 / 324.0[M+H]+ .

[0921] 4) Synthesis of Intermediate 119-5

[0922] At room temperature, 119-4 (80.0 mg, 0.25 mmol), 1-6 (60.14 mg, 0.25 mmol), and dichloromethane (4.0 mL) were added to a single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (71.39 mg, 0.37 mmol) and 4-dimethylaminopyridine (60.66 mg, 0.50 mmol) were added sequentially under stirring. After 18 hours of reaction at room temperature, the reaction was complete. The reaction solution was poured into water and extracted three times with 20 mL of ethyl acetate. The organic phase was washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to obtain the intermediate 119-5 (70.0 mg) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.20(d,J=7.6Hz,1H),8.07(s,1H),7.97(s,1H),7.88(d,J=2.0Hz,1H),7.63(d,J=7.6Hz,1H),7.47(d,J=1.2Hz,1H),7.37(s, 1H),7.03(d,J=7.6Hz,1H),6.95(d,J=2.0Hz,1H),6.29(t,J=2.0Hz,1H),5 .62(s,2H),3.82(s,3H),3.18(s,2H),1.48(s,9H).LC-MS:m / z:546.2[M+H] + .

[0923] 5) Synthesis of Intermediate 119-6

[0924] At room temperature, 119-5 (30.0 mg, 0.13 mmol), triethylamine (16.67 mg, 0.16 mmol) and methanol (3 mL) were added to a single-necked flask. 1,1-bis(diphenylphosphine)dichloroferroni (8.03 mg, 0.01 mmol) was added under stirring. A carbon monoxide balloon was inserted and the gas was replaced three times. After 18 hours at 70°C, the reaction was complete and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain a white solid compound (20.0 mg). LC-MS: m / z: 526.0 [M+H] + .

[0925] 6) Preparation of Compound 119

[0926] At room temperature, 119-6 (10.0 mg, 0.02 mmol), sodium hydroxide (2.4 mg, 0.06 mmol), methanol (1 mL), and water (0.2 mL) were added to a single-necked flask. The temperature was raised to 70°C and the reaction was complete after 72 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (formic acid / acetonitrile / water system) to obtain a white solid compound (0.9 mg). 1 H NMR...

Claims

1. A compound having a structure as shown in Formula I or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; Ring A is a 5-membered or 6-membered heteroaromatic ring; preferably, ring A is a 5-membered heteroaromatic ring, and the heteroatom is selected from O, S or N; preferably, ring A is a 5-membered heteroaromatic ring, and the heteroatom is O; Ring B is phenyl or a 5-6-membered heteroaryl; preferably, ring B is phenyl or a 6-membered heteroaryl; Each R 1 Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, R 1a R 1b N-、C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, R 1a R 1b NC(=O)-、R 1a R 1b NS(=O)2-or R 1c O(C=O)-; each R 1a , R 1b and R 1c Independently selected from: hydrogen, deuterium, C 1-6 Alkyl; wherein R 1 C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, R 1a R 1b NC(=O)-、R 1a R 1b NS(=O)2-or R 1c O(C=O)- is optionally substituted by one or more R 1d Replacement; each R 1d Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, -NH2, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkylamino-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkylamino-C(=O)-, NH2-(C=O)-, C 1-6 Alkylamino-S(=O)2-, NH2-S(=O)2- or C 1-6 Alkyl O(C=O)-; wherein R 1d C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkylamino-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkylamino-C(=O)-, C 1-6 Alkylamino-S(=O)2- or C 1-6 alkylO(C=O)- are each independently optionally substituted with one or more selected from deuterium, halogen, cyano, nitro, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, (C 1-6 Alkyl)2N(C=O)-, C 1-6 Alkyl NH(C=O)-, NH2-(C=O)-, C 1-6 Alkyl (C=O)-, C 3-6 substituted with a cycloalkyl or phenyl substituent; optionally, two R 1 The atoms to which they are connected, together form a 5-8 membered monocyclic ring, a 6-10 membered bridged ring, a 6-10 membered spirocyclic ring or a 6-10 membered condensed ring; wherein the 5-8 membered monocyclic ring, the 6-10 membered bridged ring, the 6-10 membered spirocyclic ring or the 6-10 membered condensed ring are each independently and optionally substituted by one or more R 1e Replacement; each R 1e Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, -NH2, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkylamino-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkylamino-C(=O)-, NH2-(C=O)-, C 1-6 Alkylamino-S(=O)2-, NH2-S(=O)2- or C 1-6 Alkyl O(C=O)-; wherein R 1e C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkenyloxy, C 2-6 Alkynyl, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-6 Alkylamino-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkylamino-C(=O)-, C 1-6 Alkylamino-S(=O)2-, or C 1-6 Alkyl O(C=O)- is each independently optionally substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, hydroxyl, amino; Preferably, each R 1 Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, R 1a R 1b N-、C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, R 1a R 1b NC(=O)-、R 1a R 1b NS(=O)2-or R 1c O(C=O)-; each R 1a , R 1b and R 1c Independently selected from: hydrogen, deuterium, C 1-4 Alkyl; wherein R 1 C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, R 1a R 1b NC(=O)-、R 1a R 1b NS(=O)2-or R 1c O(C=O)- is optionally substituted by one or more R 1d Replacement; each R 1d Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, -NH2, carboxyl, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-4 Alkylamino-, C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, C 1-4 Alkylamino-C(=O)-, NH2-(C=O)-, C 1-4 Alkylamino-S(=O)2-, NH2-S(=O)2- or C 1-4 Alkyl O(C=O)-; wherein R 1d C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-4 Alkylamino-, C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, C 1-4 Alkylamino-C(=O)-, C 1-4 Alkylamino-S(=O)2- or C 1-4 alkylO(C=O)- are each independently optionally substituted with one or more selected from deuterium, halogen, cyano, nitro, hydroxyl, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 substituted with a haloalkoxy, (CH3)2N(C=O)-, CH3NH(C=O)-, NH2-(C=O)-, CH3(C=O)-, cyclopropyl or phenyl substituent; optionally, two R 1 The atoms to which they are connected, together form a 5-7 membered monocyclic ring, a 6-8 membered bridged ring, a 6-8 membered spirocyclic ring or a 6-8 membered condensed ring; wherein the 5-7 membered monocyclic ring, the 6-8 membered bridged ring, the 6-8 membered spirocyclic ring or the 6-8 membered condensed ring are each independently and optionally substituted by one or more R 1e Replacement; each R 1e Independently selected from: deuterium, halogen, cyano, nitro, hydroxyl, -NH2, carboxyl, oxo, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-4 Alkylamino-, C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, C 1-4 Alkylamino-C(=O)-, NH2-(C=O)-, C 1-4 Alkylamino-S(=O)2-, NH2-S(=O)2- or C 1-4 Alkyl O(C=O)-; wherein R 1e C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-4 Alkylamino-, C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, C 1-4 Alkylamino-C(=O)-, C 1-4 Alkylamino-S(=O)2- or C 1-4 Alkyl O(C=O)- is each independently optionally substituted by one or more substituents selected from deuterium, halogen, cyano, nitro, hydroxyl, amino; Preferably, each R 1 are independently selected from: deuterium, fluorine, chlorine, bromine, cyano, nitro, hydroxyl, amino, carboxyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-4 Alkylamino-, C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, C 1-4 Alkylamino-C(=O)-, NH2-(C=O)-, C 1-4 Alkylamino-S(=O)2-, NH2-S(=O)2-, C 1-4 Alkyl O(C=O)-, C 3-6 Cycloalkyl C 1-2 Alkylene, C 3-6 Cycloalkyl C 1-2 Alkyleneoxy, 3-6 membered heterocyclic group C 1-2 Alkylene, 3-6 membered heterocyclic group C 1-2 Alkyleneoxy, C 6-10 Aryl C 1-2 Alkylene, C 6-10 Aryl C 1-2 Alkyleneoxy, 5-10 membered heteroaryl C 1-2 Alkylene or 5-10 membered heteroaryl C 1-2 Alkyleneoxy; wherein R 1 C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkenyloxy, C 2-4 Alkynyl, C 2-4 Alkynyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-10 Aryl, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 1-4 Alkylamino-, C 1-4 Alkyl-C(=O)-, C 1-4 Alkyl-C(=O)NH-, C 1-4 Alkyl-S(=O)2-, C 1-4 Alkylamino-C(=O)-, C 1-4 Alkylamino-S(=O)2-, C 1-4 Alkyl O(C=O)-, C 3-6 Cycloalkyl C 1-2 Alkylene, C 3-6 Cycloalkyl C 1-2 Alkyleneoxy, 3-6 membered heterocyclic group C 1-2 Alkylene, 3-6 membered heterocyclic group C 1-2 Alkyleneoxy, C 6-10 Aryl C 1-2 Alkylene, C 6-10 Aryl C 1-2 Alkyleneoxy, 5-10 membered heteroaryl C 1-2 Alkylene, 5-10 membered heteroaryl C 1-2 The alkyleneoxy radicals are each independently optionally substituted by one or more radicals selected from the group consisting of: deuterium, fluorine, chlorine, bromine, cyano, hydroxy, oxo, methyl, ethyl, isopropyl, tert-butyl, trifluoromethane, substituted with a substituent selected from the group consisting of cyclopropyl, trifluoromethoxy, (CH3)2N(C=O)-, CH3NH(C=O)-, NH2-(C=O)-, CH3(C=O)-, CH3-O(C=O)-, cyclopropyl or phenyl; optionally, two R 1 The atoms to which they are connected, together form a 5-7 membered monocyclic ring, a 6-8 membered bridged ring, a 6-8 membered spirocyclic ring or a 6-8 membered condensed ring; wherein the 5-7 membered monocyclic ring, the 6-8 membered bridged ring, the 6-8 membered spirocyclic ring or the 6-8 membered condensed ring are each independently and optionally substituted by one or more R 1e Replacement; each R 1e substituted with a substituent independently selected from the group consisting of deuterium, fluorine, chlorine, bromine, cyano, nitro, hydroxyl, amino, carboxyl, oxo, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, (CH3)2N(C=O)-, CH3NH(C=O)-, CH3(C=O)-, cyclopropyl or phenyl; Preferably, each R 1 Independently selected from: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, C 6-10 Aryl C 1-2 Alkyleneoxy, 5-10 membered heteroaryl C 1-2 Alkylene; wherein R 1 C 1-4 Alkyl, C 3-6 The cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl or 5-10 membered heteroaryloxy groups are each independently optionally substituted by one or more substituents selected from: methyl, ethyl, cyano, trifluoromethyl, trifluoromethoxy, (CH3)2N(C=O)-, CH3NH(C=O)-, NH2-(C=O)-, CH3-O(C=O)- or phenyl; optionally, the two R 1 The atoms to which they are attached, together form a 5-7 membered monocyclic ring; wherein the 5-7 membered monocyclic ring is optionally substituted by one or more R 1e Replacement; each R 1e Independently selected from: methyl, ethyl; Preferably, each R 1 Independently selected from: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy, C 3-6 Cycloalkyl, 5-10 membered heteroaryl; wherein R 1 C 1-4 Alkyl, C 3-6 Cycloalkyl and 5-10 membered heteroaryl are each independently optionally substituted by one or more methyl, cyano or trifluoromethyl groups; Preferably, each R 1 independently selected from: deuterium, fluorine, chlorine, bromine, cyano, nitro, hydroxyl, amino, carboxyl, ethynyl, methyl, ethyl, -CHF2, -CH2F, trifluoromethyl, 2,2,2-trifluoroethyl, propyl, isopropyl, 2-fluoro-propan-2-yl, 2-hydroxy-propan-2-yl tert-butyl, butan-2-yl, 1-hydroxy-2-methyl-propan-2-yl 2-(1,1,1-Trifluoro-methyl)-propan-2-yl Prop-1-en-2-yl Methoxy, ethoxy, trifluoromethoxy, cyclopropyl, 1-methylcyclopropyl 1-Trifluoromethylcyclopropyl 1-Cyanocyclopropyl 1-Fluorocyclopropyl Cyclobutyloxy, cyclopentyl, oxetanyl, pyrazolylmethylene (preferred ), benzyloxy, phenylethyleneoxy, (CH3)2N(C=O)-CH2-, (1-methyl-1H-pyrazol-4-yl)methyleneoxy 1-Ethyl-1H-pyrazole-4-oxy 3,5-Dimethylisoxazol-4-yl Pyrrolidin-1-yl, 2-(N,N-dimethylaminoacyl)-pyrrolidin-1-yl 2-(N-methylaminoacyl)-pyrrolidin-1-yl 2-Aminoacyl-pyrrolidin-1-yl 2-Phenyl-pyrrolidin-1-yl 2-Acetyl-pyrrolidin-1-yl 2-Cyclopropyl-pyrrolidin-1-yl CH3(C=O)-,5-methyl-pyrazine-2-yl 6-Methyl-pyridin-3-yl Hydroxy(pyridin-3-yl)methyl 2H-1,2,3-Triazol-2-yl 1,3-Dimethyl-1H-pyrazol-4-yl 4-Azaspiro[2.4]heptane-4-yl 1H-pyrazol-1-yl Proline methyl ester-1-yl 1-methoxy-4-(tert-pentyl)phenyl-2-yl 2-Cyano-2-propan-2-yl 2-Methyl-propionic acid methyl ester-2-yl Bicyclo[1,1,1]pentane Optionally, two R 1 The atoms to which they are attached, together with ring B, form the following radical group: Preferably, each R 1 Independently selected from: bromo, ethyl, methoxy, tert-butyl, ethynyl, trifluoromethoxy, trifluoromethyl, Phenylethyleneoxy, Cyclopropyl, Isopropyl, <h2 style=";text-align:left;direction:ltr">(CH3)2N(C=O)-CH2-、<h2 style=";text-align:left;direction:ltr"> Optionally, two R 1 Together with the atoms to which they are attached and ring B, they form the following group: Preferably, each R 1 Independently selected from: bromo, ethyl, methoxy, tert-butyl, trifluoromethoxy, trifluoromethyl, Cyclopropyl, R 2 Selected from: -OR 2a 、-NR 2b R 2c , 5-6 membered heteroaryl, 4-6 membered heterocyclic group; wherein the 5-6 membered heteroaryl, 4-6 membered heterocyclic group are each independently optionally substituted by one or more selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkynyl, C 2-6 Hydroxyalkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, -NH(C 1-6 Alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl) is substituted; preferably, R 2 Selected from: 5-6 membered heteroaryl, 4-6 membered heterocyclic group; the 5-6 membered heteroaryl, 4-6 membered heterocyclic group are each independently optionally substituted by one or more selected from deuterium, halogen, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, -NH(C 1-4 Alkyl) or -N(C 1-4 Alkyl)(C 1-4 alkyl) is substituted; preferably, R 2 is selected from: 5-6 membered heteroaryl, 4-6 membered heterocyclic group; the 5-6 membered heteroaryl, 4-6 membered heterocyclic group are each independently optionally substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, amino or hydroxymethyl; preferably, R 2 Selected from: pyrazolyl, oxazolyl, isoxazolyl, triazole (including 1,2,3-triazole, 1,2,4-triazole, 1,3,4-triazole), pyridinyl, pyrazinyl, pyrimidinyl or azetidinyl; wherein the pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidinyl or azetidinyl are each independently substituted with one or more substituents selected from deuterium, fluorine, chlorine, bromine, hydroxyl or hydroxymethyl; R 2a , R 2b and R 2c Each independently selected from: hydrogen, deuterium, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; wherein the C 1-6 Alkyl, C 3-6 The cycloalkyl and 4-6 membered heterocyclic groups are each independently optionally substituted by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, amino, -NH(C 1-6 Alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl) is substituted; preferably, R 2a , R 2b and R 2c Each independently selected from: hydrogen, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or 4-6 membered heterocyclic group; wherein the C 1-4 Alkyl, C 3-6 The cycloalkyl and 4-6 membered heterocyclic groups are each independently optionally substituted by one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, amino, -NH(C 1-4 Alkyl) or -N(C 1-4 Alkyl)(C 1-4 alkyl) is substituted; preferably, R 2a , R 2b and R 2c Each is independently selected from: hydrogen, deuterium or methyl; R 3 Selected from: deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl); preferably, R 3 Selected from: deuterium, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, -NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)(C 1-4 alkyl); preferably, R 3 Selected from: deuterium, fluorine, chlorine, bromine, methyl, ethyl or trifluoromethyl; R 4a and R 4b Each is independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-6 Preferably, R 4a and R 4b are independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy or C 3-6 Preferably, R 4a and R 4b Each independently selected from: hydrogen or deuterium; X 1 Select from N or CR X1 ;X 2 Select from N or CR X2 ; R X1 and R X2 Each is independently selected from: hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-6 Preferably, X 1 Select from N or CR X1 , X 2 CR X2 or X 1 CR X1 , X 2 Select from N or CR X2 ; R X1 and R X2 are independently selected from: hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, amino, cyano, C 1-4 Alkyl or C 1-4 Alkoxy Preferably, X 1 CR X1 , X 2 CR X2 ; R X1 and R X2 Each is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, methyl, ethyl, methoxy, ethoxy; n is 0, 1, 2, 3, 4 or 5; preferably, n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; preferably, m is 0 or 1; preferably, m is 0; t is 0, 1, 2 or 3; preferably, t is 0 or 1.

2. The compound according to claim 1 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; the compound has the structure shown in formula II-1 or II-2; in, Each X 3 Independently selected from: CH2, O, NH or S; X 4 and X 5 Each is independently selected from: CH or N.

3. The compound according to claim 1 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; the compound has the structure shown in formula III-1 or III-2; in, Each X 3 Independently selected from: CH2, O, NH or S; X 4 , X 5 , X 6 , X 7 and X 8 Each is independently selected from: CH or N; Each R 5 Independently selected from: deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, -NH(C 1-6 Alkyl) or -N(C 1-6 Alkyl)(C 1-6 alkyl); preferably, each R 5 Independently selected from: deuterium, halogen, hydroxyl, cyano, amino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Halogenated cycloalkyl, -NH(C 1-4 Alkyl) or -N(C 1-4 Alkyl)(C 1-4 alkyl); preferably, each R 5 Independently selected from: deuterium, fluorine, chlorine, bromine, hydroxyl, cyano, amino or hydroxymethyl; Each p is independently 0, 1 or 2.

4. The compound according to claim 1 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; the compound has the structure shown in formula IV-1, IV-2, IV-3, IV-4, IV-5 or IV-6; 5. The compound according to claim 1 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; the compound has the structure shown in Formula V; 6. The compound of claim 1 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug; the compound has the structure shown in Formula VI; in, R 1f Selected from: C 1-6 Alkyl, C 6-10 Aryl C 1-2 Alkylene, 5-10 membered heteroaryl C 1-2 Alkylene or C 3-6 Cycloalkyl; preferably, R 1f Selected from: methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, pyrazolyl methylene or pyrazolyl ethylene; n1 is 0, 1, 2, 3 or 4; preferably n1 is 0, 1 or 2.

7. A compound according to any one of claims 1 to 6 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof; the compound has the structure shown below; 8. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 7 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug and at least one pharmaceutically acceptable carrier.

9. A compound according to any one of claims 1 to 7 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or the composition according to claim 8 for use in treating a disease or condition mediated by KAT6A and / or KAT6B.

10. Use of a compound according to any one of claims 1 to 7 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or the composition according to claim 8 in the preparation of a medicament for treating a disease or condition mediated by KAT6A and / or KAT6B.

11. A method for treating a disease or condition mediated by KAT6A and / or KAT6B, comprising administering to an individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 7 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug or the composition according to claim 8.

12. The compound according to claim 9 or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug or the composition, the use according to claim 10 or the method according to claim 11, wherein, The disease or disorder is cancer; preferably, the cancer is selected from the group consisting of: glioma, glioblastoma, astrocytoma, pleomorphic cell tumor, bannayan-Zonana syndrome, Cowden disease, cerebellar dysplastic ganglioneuroma (Lhermitte-Duclos disease), breast cancer, colon cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, bone cancer, colon cancer, germ cell cancer, melanoma, ovarian cancer, pancreatic cancer, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate cancer, sarcoma and thyroid cancer, lymphoblastic T-cell leukemia, chronic myeloid leukemia, long-term lymphocytic leukemia, hairy cell leukemia, Acute lymphocytic leukemia, acute myeloid leukemia, chronic neutrophilic leukemia, acute lymphocytic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin lymphoma, non-Hodgkin malignant lymphoma, lymphoblastic T-cell lymphoma, Burkitt lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulvar cancer, uterine / cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharyngeal cancer, oral cancer, cancer, gastrointestinal stromal tumor (GIST), neuroendocrine cancer, testicular cancer, and virus-related cancers.

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