Sulfonamide compound and use thereof

Abstract

Provided in the present application is a compound represented by formula (I), or an enantiomer, a diastereoisomer, a racemate, a tautomer, a stereoisomer, a geometric isomer, a nitrogen oxide, a metabolite or a pharmaceutically acceptable salt, an ester, a solvate, a hydrate, an isotope-labeled compound or a prodrug thereof. The compound represented by formula (I) of the present application has a relatively ideal inhibitory activity with regard to KAT6A and / or KAT6B.

Description

Sulfonamide compounds and their applications

[0001] This application claims priority to PCT application No. PCT / CN2023 / 130539 filed on November 8, 2023 and PCT application No. PCT / CN2024 / 096711 filed on May 31, 2024, and incorporates their entire contents into this application by reference. Technical Field

[0002] The present application relates to the field of medicine, and in particular to sulfonamide compounds and their applications in medicine. Background Art

[0003] 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.

[0004] 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.

[0005] Summary of the Invention

[0006] The present application provides a novel sulfonamide compound, which has ideal inhibitory activity against KAT6A and / or KAT6B and has good drug development prospects.

[0007] The first aspect of the present application provides a compound 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,

[0008] m is 0, 1, 2, 3 or 4;

[0009] n is 0, 1, 2, 3 or 4;

[0010] p is 0, 1, 2, or 3;

[0011] q is 0, 1, 2, 3, or 4;

[0012] x is 0 or 1;

[0013] L 1 Selected from single bond, NR 1-1 , O, S, C 2-4 Alkenylene, C 2-5 Alkynylidene, C 1-3 Alkylene, where C 2-4 Alkenylene, C 2-5 Alkynylidene, C 1-3 The alkylene group is optionally substituted with a substituent selected from deuterium, halogen, CN, OH, ═O;

[0014] R 1 Selected from deuterium, hydroxyl, -WR 1-3 ,=O,HC(=O)-,C 1-3 Alkyl-C(=O)-, CN, halogen, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 aromatic ring, 5-12 membered heteroaromatic ring or 4-12 membered heterocyclic ring; or, when n is 2, 3 or 4, two adjacent R 1 Together they form a ring to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; wherein, C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aromatic ring, 5-12 membered heteroaromatic ring, 4-12 membered heterocyclic group, 3-6 membered heterocyclic group are optionally replaced by R 1-2 Replacement; R 1-2 Independently selected from deuterium, hydroxyl, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkylene-OH, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl;

[0015] A is C 6-10 Aromatic ring, 5-12 membered heteroaromatic ring, C4-10 Cycloalkyl or 4-12 membered heterocyclic group;

[0016] R 2 Selected from deuterium, hydroxyl, halogen, -WR 1-3 、HC(=O)-、C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; or, when m is 2, 3 or 4, two adjacent R 2 Together they form a ring to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, benzene ring or 5-6 membered heteroaromatic ring; wherein, C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, benzene ring or 5-6 membered heteroaromatic ring is optionally replaced by R 1-2 Replacement; R 1-2 Independently selected from deuterium, hydroxyl, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkylene-OH, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl;

[0017] R 3 Selected from deuterium, hydroxyl, halogen, -WR 1-3 、HC(=O)-、C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl; or, when p is 2 or 3, two adjacent R 3 Together they form a ring to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, benzene ring or 5-6 membered heteroaromatic ring; wherein, C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, benzene ring or 5-6 membered heteroaromatic ring is optionally replaced by R 1-3replace;

[0018] R 1-3 Independently selected from deuterium, hydroxyl, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkylene-OH, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl;

[0019] L 2 Selected from single bond, NR 1-1 , O, S, C 2-4 Alkenylene, C 2-5 Alkynylidene, C 1-3 Alkylene, where C 2-4 Alkenylene, C 2-5 Alkynylidene, C 1-3 The alkylene group is optionally substituted with a substituent selected from deuterium, halogen, CN, OH, ═O;

[0020] B is a 5-6 membered heteroaromatic ring;

[0021] R 4 Selected from deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl; wherein C 1-6 Alkyl, C 1-6 Alkylene-OH, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl is optionally substituted with a substituent selected from deuterium, halogen, CN, OH;

[0022] W is O, S or NR 1-1 ;

[0023] R 1-1 Selected from hydrogen, deuterium, hydroxyl, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkylene-OH, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl.

[0024] The second aspect of the present application provides a pharmaceutical composition comprising the compound described in the first aspect 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.

[0025] The third aspect of the present application provides the compound of the first aspect 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 pharmaceutical composition of the second aspect for use in treating diseases or conditions mediated by KAT6A and / or KAT6B.

[0026] The fourth aspect of the present application provides use of the compound of the first aspect 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 pharmaceutical composition of the second aspect in the preparation of a medicament for treating a disease or condition mediated by KAT6A and / or KAT6B.

[0027] The fifth aspect of the present application provides 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 the compound of the first aspect 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 pharmaceutical composition of the second aspect.

[0028] BRIEF DESCRIPTION OF THE DRAWINGS

[0029] 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.

[0030] FIG2 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] FIG3 is a curve showing the weight change 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] FIG4 is a tumor growth curve of the test animals in the anti-tumor efficacy study of the test substance in Test Example 12 in a human breast cancer PDX animal model.

[0033] FIG5 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 in a human breast cancer PDX animal model.

[0034] FIG6 is a tumor growth curve of the test animals in the anti-tumor efficacy study of the test substance in Test Example 13 in the human lung cancer PDX animal model.

[0035] FIG7 is a curve showing the weight change of the test animals in the anti-tumor efficacy study of the test substance in Test Example 13 in the human lung cancer PDX animal model. DETAILED DESCRIPTION

[0036] To make the purpose, technical solutions, and advantages of the present application more clearly understood, the present application is further described in detail below in conjunction with the embodiments. The specific embodiments described herein are intended only to explain the present application and are not intended to constitute any limitation thereto. 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.

[0037] definition

[0038] Some embodiments of the present application are now described in detail, and its example is illustrated by the accompanying structural formula and chemical formula. The application is intended to cover all substitutions, modifications and equivalent technical solutions, which are all included within the scope of the application. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to put the application into practice. The application is in no way limited to the methods and materials included herein. In the case where one or more of the combined documents, patents and similar materials are different from or contradictory to the application (including but not limited to defined terms, term applications, described technology, etc.), the application shall prevail.

[0039] It should be further appreciated that certain features of the present application, which for clarity are described in the context of multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present application, which for brevity are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0040] Unless otherwise specified, all technical terms used in this application have the same meaning as commonly understood by those skilled in the art to which this application belongs. All patents and publications involved in this application are incorporated herein by reference in their entirety.

[0041] Unless otherwise indicated, the following definitions used herein shall apply. For the purposes of this application, 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.

[0042] 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.

[0043] 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. In this application, "non-human animals" 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.).

[0044] 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.

[0045] The term "patient" refers to a human (including adults and children) or other animals. In some embodiments, a "patient" refers to a human.

[0046] The term "comprising" is an open expression, that is, including the contents specified in the application, but not excluding other contents.

[0047] 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-.

[0048] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0049] 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.

[0050] The terms "racemate," "racemate," or "racemic mixture" refer to an equimolar mixture of two enantiomers devoid of optical activity.

[0051] 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 present application are within the scope of the present application.

[0052] 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.

[0053] 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.

[0054] 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 its chiral center(s). 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. A compound prefixed with (+) or d is 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.

[0055] 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.

[0056] Depending on the choice of starting materials and process, the compounds of the present invention may exist as one of the possible isomers or a mixture thereof, such as a racemate or a mixture of diastereomers (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.

[0057] 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.

[0058] 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).

[0059] 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.

[0060] 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 administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, this application encompasses metabolites of a compound, including metabolites produced by contacting a compound of this application with a mammal for a period of time.

[0061] 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, "pharmaceutically acceptable" as used 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.

[0062] The term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present application. 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 books and 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 application also contemplates quaternary ammonium salts formed by compounds of any group containing N. 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 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.

[0063] Pharmaceutically acceptable acid addition salts can be formed by the action of the present invention compounds with inorganic acids or organic acids, and pharmaceutically acceptable base addition salts can be formed by the action of the present invention compounds with inorganic bases or organic bases. Pharmaceutically acceptable salts of the present application 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 forms 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 forms 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).

[0064] The term "solvate" refers to an association complex formed by one or more solvent molecules and the compound of the present application. The solvent can be water, acetic acid, ethyl 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.

[0065] The term "hydrate" refers to an association formed by one or more water molecules and a compound of the present application.

[0066] 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 application is intended to include both solvated and unsolvated forms.

[0067] 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.

[0068] The term "isotopically labeled compound" refers to 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.

[0069] The compounds of the present invention containing the aforementioned isotope labels and / or other isotope labels of other atoms and pharmaceutically acceptable salts of the compounds are all included in 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.

[0070] In addition, the substitution of heavier isotopes, particularly deuterium (i.e., 2H or D) can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, an increase in half-life in vivo or a reduction in dosage requirements or an improvement in therapeutic index are brought about. It should be understood that deuterium in the present application is considered a substituent of a compound 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" used in the present application refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. Where a substituent of a compound of the present application 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 herein include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, acetone-d6, DMSO-d6.

[0071] The term "prodrug" as used in this application 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 this application 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 this application 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 phosphorylation of 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.

[0072] Unless otherwise expressly stated, the descriptions used in this application of "each...independently is" and "...each independently is" and "...independently is" are interchangeable 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.

[0073] 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.

[0074] 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.

[0075] The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0076] 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).

[0077] In various parts of this specification, the substituents of the compounds disclosed in this application are disclosed according to group types or ranges. It is specifically pointed out that this application 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.

[0078] In various parts of this application, 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 the alkylene group or arylene group, respectively, of the linking.

[0079] 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 the hydrogen on the nitrogen atom in the 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, RT is a substituent on N). Among the compounds involved in this application, when containing multiple heteroatoms, the compounds composed thereof comply with the covalent rules and composition rules of organic compounds, that is, the compounds containing multiple heteroatoms should exclude compounds that do not comply with the covalent rules and composition rules of organic compounds.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] The term "alkoxy" refers to an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described 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.

[0085] 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 described 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.

[0086] 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,

[0087] 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, S, where S or P is optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, 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, S, where S or P is optionally substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, 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,

[0088] The monocycle described in the present application 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.

[0089] The "bridged ring" described herein refers to a polycyclic group in which any two rings in the system share two atoms that are not directly connected, and may contain one or more double bonds. Optionally, it contains one or more heteroatoms. The heteroatoms have the meanings as described in the present application. 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 such as bicyclic, tricyclic, and tetracyclic rings can be classified according to the number of constituent rings, preferably bicyclic, tricyclic, and tetracyclic, and more preferably bicyclic and tricyclic.

[0090] The "fused ring" described herein 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 herein. 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 member, 3 / 5 member, 3 / 6 member, 4 / 4 member, 4 / 5 member, 4 / 6 member, 5 / 4 member, 5 / 5 member, 5 / 6 member, 6 / 3 member, 6 / 4 member, 6 / 5 member, and 6 / 6 member bicyclic fused rings.

[0091] " spiro ring " described in the present application refers to the polycyclic group that shares an atom (called spiro atom) between the monocycle in the system, and it can contain one or more double bonds. Optionally, it contains more than one heteroatom. The heteroatom has the meaning as described in the present application. In certain embodiments, the spiro ring is a 6-10 membered spiro ring. In other embodiments, the spiro ring is a 6-8 membered spiro ring. According to the number of spiro atoms shared 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.

[0092] 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 meanings described in this application. In some embodiments, the heteroaryl group is a 5-10-atom heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-10 membered heteroaryl group; the heteroaryl group is a 5-10 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 to 8 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-8 membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 to 7 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-7 membered heteroaryl group; in some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 to 6 atoms containing 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 heteroaryl group consisting of 5 atoms containing 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 heteroaryl group consisting of 6 atoms containing 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.

[0093] The term "aryl" or "aromatic ring" refers to a monocyclic, bicyclic, or tricyclic aromatic carbon ring system. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring." A 6-10 membered aryl group refers to an aromatic group containing 6-10 ring atoms. Examples include, but are not limited to, phenyl and naphthyl.

[0094] The term "hydrogen" means 1 H; "deuterium" refers to 2 H.

[0095] The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0096] 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.

[0097] The term "hydroxyl" refers to -OH;

[0098] The term "cyano" refers to -CN;

[0099] The term "nitro" refers to -NO2;

[0100] The term "carboxyl" refers to HO(C=O)-;

[0101] The term "O=" refers to oxo, that is, when the substituent is O=", O is connected to the substituted group through a double bond.

[0102] 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-.

[0103] 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.

[0104] As used herein, the terms "cancer" and "cancerous" refer to or describe a physiological condition in a subject that is typically characterized by unregulated cell growth and / or proliferation. Some cancers consist of cells that divide rapidly, while other cancers consist of cells that divide more slowly than normal cells. Examples of cancer types can include gliomas, glioblastomas, astrocytomas, multiforme tumors, bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, colon cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, bone 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 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.

[0105] 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:

[0106] 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.

[0107] 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 site of the group, and the substituent may be the same or different at each position, i.e., each substitution is independent of each other. It will be understood by those skilled in the art that the combinations of substituents contemplated herein are those that are stable or chemically feasible.

[0108] Description of the compounds of the present application

[0109] The present application provides a sulfonamide compound or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs, which plays a positive role in treating diseases or conditions mediated by KAT6A and / or KAT6B.

[0110] Specifically, the present application provides a compound of 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,

[0111] m is 0, 1, 2, 3 or 4;

[0112] n is 0, 1, 2, 3 or 4;

[0113] p is 0, 1, 2, or 3;

[0114] q is 0, 1, 2, 3, or 4;

[0115] x is 0 or 1;

[0116] L 1 Selected from single bond, NR 1-1 , O, S, C 2-4 Alkenylene, C 2-5 Alkynylidene, C 1-3 Alkylene, where C 2-4 Alkenylene, C 2-5 Alkynylidene, C 1-3 The alkylene group is optionally substituted with a substituent selected from deuterium, halogen, CN, OH, ═O;

[0117] R 1 Selected from deuterium, hydroxyl, -WR 1-3 ,=O,HC(=O)-,C 1-3Alkyl-C(=O)-, CN, halogen, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 aromatic ring, 5-12 membered heteroaromatic ring or 4-12 membered heterocyclic ring; or, when n is 2, 3 or 4, two adjacent R 1 Together they form a ring to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; wherein, C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aromatic ring, 5-12 membered heteroaromatic ring, 4-12 membered heterocyclic group, 3-6 membered heterocyclic group are optionally replaced by R 1-2 Replacement; R 1-2 Independently selected from deuterium, hydroxyl, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkylene-OH, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl;

[0118] A is C 6-10 Aromatic ring, 5-12 membered heteroaromatic ring, C 4-10 Cycloalkyl or 4-12 membered heterocyclic group;

[0119] R 2 Selected from deuterium, hydroxyl, halogen, -WR 1-3 、HC(=O)-、C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; or, when m is 2, 3 or 4, two adjacent R 2 Together they form a ring to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, benzene ring or 5-6 membered heteroaromatic ring; wherein, C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, benzene ring or 5-6 membered heteroaromatic ring is optionally replaced by R 1-2 Replacement; R 1-2 Independently selected from deuterium, hydroxyl, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkylene-OH, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl;

[0120] R 3 Selected from deuterium, hydroxyl, halogen, -WR 1-3 、HC(=O)-、C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl; or, when p is 2 or 3, two adjacent R 3 Together they form a ring to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, benzene ring or 5-6 membered heteroaromatic ring; wherein, C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, benzene ring or 5-6 membered heteroaromatic ring is optionally replaced by R 1-3 replace;

[0121] R 1-3 Independently selected from deuterium, hydroxyl, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkylene-OH, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl;

[0122] L 2 Selected from single bond, NR 1-1 , O, S, C 2-4 Alkenylene, C 2-5 Alkynylidene, C 1-3 Alkylene, where C 2-4 Alkenylene, C 2-5 Alkynylidene, C 1-3The alkylene group is optionally substituted with a substituent selected from deuterium, halogen, CN, OH, ═O;

[0123] B is a 5-6 membered heteroaromatic ring;

[0124] R 4 Selected from deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl; wherein C 1-6 Alkyl, C 1-6 Alkylene-OH, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl is optionally substituted with a substituent selected from deuterium, halogen, CN, OH;

[0125] W is O, S or NR 1-1 ;

[0126] R 1-1 Selected from hydrogen, deuterium, hydroxyl, halogen, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkylene-OH, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl.

[0127] In some embodiments, the compound of Formula I has a structure shown in Formula I-1 or Formula I-2:

[0128] Among them, R 1 、R 2 、R 3 、R 4 , A, B, L 1 , L 2 , m, n, p, q have the same definitions as those defined in formula I above.

[0129] In some embodiments, the compound of Formula I has a structure shown in Formula I-3 or Formula I-4:

[0130] Among them, R 1 、R 2 、R 3 、R 4 , A, L 1 , L 2, m, n, p, q have the same definitions as those defined in formula I above.

[0131] In some embodiments, the compound of Formula I has a structure shown in Formula I-5 or Formula I-6:

[0132] Among them, R 1 、R 2 、R 3 、R 4 , A, B, L 1 , L 2 , n, p, q have the definitions as defined in the above formula I; r is 0, 1, 2 or 3; R 5 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl.

[0133] In some embodiments, in Formula I-5 to Formula I-6, R 5 Selected from C 1-3 Alkyl groups such as methyl, C 1-3 Haloalkyl such as trifluoromethyl or difluoromethyl, C 3-6 Cycloalkyl groups include, for example, cyclopropyl.

[0134] In some embodiments, the compound of Formula I has a structure as shown in any one of Formula I-7 or Formula I-8:

[0135] Among them, R 1 、R 2 、R 3 、R 4 , A, B, L 1 , L 2 , m, n, q have the definitions as defined in the above formula I; s is 0, 1 or 2; R 6 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl.

[0136] In some embodiments, in Formula I-7 to Formula I-8, R 6 Selected from C 1-3 Alkyl groups such as methyl, C 1-3 Haloalkyl such as trifluoromethyl or difluoromethyl, C 3-6Cycloalkyl groups include, for example, cyclopropyl.

[0137] In some embodiments, the compound of Formula I has a structure as shown in any one of Formula I-9 or Formula I-10:

[0138] Among them, R 1 、R 2 、R 3 、R 4 , A, B, L 1 , L 2 , n, q have the definitions as defined in the above formula I; s is 0, 1 or 2; r is 0, 1, 2 or 3; R 5 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl

[0139] R 6 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl.

[0140] In some embodiments, in Formula I-9 to Formula I-10, R 5 Selected from C 1-3 Alkyl groups such as methyl, C 1-3 Haloalkyl such as trifluoromethyl or difluoromethyl, C 3-6 Cycloalkyl groups include, for example, cyclopropyl.

[0141] In some embodiments, in Formula I-9 to Formula I-10, R 6 Selected from C 1-3 Alkyl groups such as methyl, C 1-3 Haloalkyl such as trifluoromethyl or difluoromethyl, C 3-6 Cycloalkyl groups include, for example, cyclopropyl.

[0142] In some embodiments, the compound of Formula I has a structure as shown in any one of Formula I-11 or Formula I-12:

[0143] Among them, R 1 、R 2 、R 3 、R 4 , A, B, L 1 , L 2, n, q have the definitions as defined in the above formula I; r is 0, 1, 2 or 3; t is 0, 1, 2 or 3; R 5 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl; R 7 Selected from deuterium, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkyl, C 1-3 Alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl.

[0144] In some embodiments, in Formula I-11 to Formula I-12, R 5 Selected from C 1-3 Alkyl groups such as methyl, C 1-3 Haloalkyl such as trifluoromethyl or difluoromethyl, C 3-6 Cycloalkyl groups include, for example, cyclopropyl.

[0145] In some embodiments, A involves C 6-10 The aromatic ring and the 5-12 membered heteroaromatic ring are selected from the following structures:

[0146] Among them, Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 、Y 8 、Y 10 、Y 11 Each independently selected from: CH, N; Y 9 Selected from: CH2, NH, O, S.

[0147] In some embodiments, A involves C 4-10 The rings in the cycloalkyl and 4-12 membered heterocyclic groups are selected from the following structures:

[0148] wherein each of t1, t2, and t3 is independently 0, 1, 2, or 3.

[0149] In some embodiments, A is selected from the group consisting of:

[0150] In some embodiments, A is selected from the group consisting of:

[0151] In some embodiments, A is selected from the group consisting of:

[0152] Indicates A and L 1 connection point.

[0153] In some embodiments, in Formula I to Formula I-12, L 1 Selected from single bond, C 2-4 Alkynylidene, C 1-3 Alkylene, where C 2-4 Alkynylidene, C 1-3 The alkylene group is optionally substituted with a substituent selected from deuterium, fluorine, chlorine, CN, OH, =0.

[0154] In some preferred embodiments, in Formula I to Formula I-12, L 1 Selected from a single bond, -CH2-, -CH(CH3)-, -CH(OH)-, -C=O-, -CH(Cl)-, -C≡C-, -C≡C-CH2-.

[0155] In some embodiments, L 2 Selected from C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with a substituent selected from deuterium, fluorine, chlorine, CN, OH, ═O. In some preferred embodiments, L 2 Selected from -CH2-, -CH(CH3)-, -CH(OH)-, -C=O-, -CH(Cl)-.

[0156] In some embodiments, B is selected from:

[0157] or

[0158] Among them, X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、X 9 、X 10 Each independently selected from: CH, N; E 1 Selected from: CH2, NH, O, S.

[0159] In some embodiments, B is selected from the group consisting of:

[0160] In some preferred embodiments, B is selected from: or

[0161] In some embodiments, Ring B is or

[0162] In some preferred embodiments, Ring B is Where S# represents B and L 2 connection point.

[0163] In some embodiments, in Formula I, n is 2, 3 or 4, and two adjacent R 1 Formation C 5-6 Cycloalkyl, 5-6 membered heterocyclic group.

[0164] In some embodiments, in Formula I, m is 2, 3 or 4, and two adjacent R 2 Formation C 5-6 cycloalkyl, 5-6 membered heterocyclic group, benzene ring or 5-6 membered heteroaryl ring.

[0165] In some embodiments, in Formula I, p is 2 or 3, and two adjacent R 3 To form a 5-6 membered heteroaromatic ring, the 5-6 membered heteroaromatic ring is optionally substituted with deuterium, hydroxyl, fluorine, chlorine, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl substitution.

[0166] In some embodiments, R 1 Selected from deuterium, hydroxyl, -NH-R 1-3 、-OR 1-3 , =O, C 1-3 Alkyl-C(=O)-, CN, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkylene-OH, C 1-3 Alkoxy, C 2-6 Alkenyl, C 3-6 Cycloalkyl or 4-8 membered heterocyclic group; wherein, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl, C 1-3 Alkylene-OH, C 1-3 Alkoxy, C 2-6 Alkenyl, C 3-6 Cycloalkyl or 4-8 membered heterocyclic group is optionally replaced by R 1-2 replace.

[0167] In some preferred embodiments, R 1 Selected from deuterium, hydroxyl, CN, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, -CH2OH-, methoxy, vinyl, propenyl, cyclopropyl, -CH3C(=O)-.

[0168] In some embodiments, R 2 Selected from deuterium, hydroxyl, fluorine, chlorine, -OR 1-3 、-NH-R 1-3 、C 1-3 Alkyl, C 1-3 Alkylene-OH, C 2-4 Alkenyl or C 3-6 Cycloalkyl.

[0169] In some preferred embodiments, R 2 Selected from deuterium, hydroxyl, fluorine, chlorine, methoxy, methyl, ethyl, propyl, isopropyl, -O(CHF2)-, vinyl, and propenyl.

[0170] In some embodiments, R 3 Selected from deuterium, hydroxyl, fluorine, chlorine, -OR 1-3 、-NH-R 1-3 、C 1-3 Alkyl, C 1-3 Alkylene -OH or C 2-4 Alkenyl.

[0171] In some preferred embodiments, R 3 Selected from deuterium, hydroxyl, fluorine, chlorine, methoxy, -O(CHF2)-, -O(CH2F)-, -OCF3-,

[0172] In some embodiments, R 4 Selected from deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkylene -OH, preferably hydroxy, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkylene-OH.

[0173] In some preferred embodiments, R 4 Selected from deuterium, hydroxyl, fluorine, methyl, ethyl, isopropyl, -CH(OH)-.

[0174] In some embodiments, Selected from the following groups:

[0175] Specifically, Can be selected from the following groups:

[0176] In some embodiments, R 1 -L 1 yes

[0177] In some embodiments, the compound of Formula I is selected from the group consisting of the following compounds:

[0178] Pharmaceutical compositions and methods of administration

[0179] The present application relates to a pharmaceutical composition comprising the compound described herein 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.

[0180] 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.

[0181] 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).

[0182] The present application also relates to pharmaceutical compositions comprising as active ingredients a compound of formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs thereof and a pharmaceutically acceptable carrier, which can be used, in particular, for the treatment of neoplastic diseases, in particular cancer, as described herein. The composition 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 can comprise the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.

[0183] The compounds of formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12 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 can be processed with pharmaceutically inert inorganic or organic excipients to produce 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, flow agents such as fumed silicon dioxide can be used as such excipients for the preparation 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, etc.

[0184] 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.

[0185] Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants and the like.

[0186] 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.

[0187] 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.

[0188] The compounds of formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12 or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs can also be used in combination with one or more other pharmacologically active compounds, which are also effective. Combating the same disease, preferably using different modes of action, or reducing or preventing possible undesirable side effects of a compound of formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs. 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 than one combination partner).

[0189] The term "therapeutically effective amount" of a compound of the present application refers to an amount of the compound of the present application 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 example, the term "therapeutically effective amount" refers to an amount of a compound of the present application 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.

[0190] 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.

[0191] In some embodiments, the present application provides I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12 compounds or their 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, which are used as drugs.

[0192] In some embodiments, the present application provides compounds I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, or their 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, for use in treating diseases or conditions mediated by KAT6A and / or KAT6B.

[0193] In some embodiments, the present application provides the use of compounds I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12 or their 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.

[0194] In some embodiments, the present application provides 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 compound I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, 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.

[0195] In some embodiments, the disease or condition is cancer.

[0196] In some embodiments, the cancer is selected from the group consisting of: glioma, glioblastoma, astrocytoma, multiforme cell tumor, bannayan-Zonana syndrome, multiple hamartoma 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 lymphoblastic 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.

[0197] Synthesis method

[0198] Compounds of formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12 can be synthesized by the methods given below, by the methods given in the experimental section below, or by analogous methods. The schemes described herein are not intended to present an exhaustive list of methods for preparing compounds of formula I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12; rather, other techniques known to skilled chemists can also be used for compound synthesis.

[0199] The structures of the compounds were determined by nuclear magnetic resonance ( 1 H-NMR, 13 C-NMR or / and 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).

[0200] 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).

[0201] Qingdao GF254 silica gel plates were used for thin-layer chromatography (TLC) and preparative thin-layer chromatography (TLC) using 0.15-0.20 mm silica gel plates, respectively. Silica gel column chromatography typically uses Qingdao 200-300 mesh silica gel as a support. The eluent is calculated by volume. For example, during the preparation of intermediate 1-2, purification was performed using a volume ratio of petroleum ether to ethyl acetate ranging from 100:1 to 1:5.

[0202] The starting materials in the examples of this application are all known and commercially available, or can be synthesized using or according to literature data reported in the art.

[0203] Unless otherwise specified, all reactions in this application were carried out under the protection of dry inert gas (such as nitrogen or argon) with continuous magnetic stirring, and the reaction temperature was ℃.

[0204] 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 group present in each position of the molecule must be compatible with the proposed reagent and reaction. This limitation of the substituent compatible with the reaction conditions is apparent to those skilled in the art, and then an alternative method 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 (about explanation, referring to 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.

[0205] The following examples are provided to help understand the present application. However, it should be understood that these examples are only used to illustrate the present application and do not constitute any limitation. It should be understood that any modifications and changes can be made without departing from the spirit of the present application.

[0206] Example 1. Synthesis of Compound 1

[0207] Synthesis route

[0208] Experimental procedures

[0209] 1) Preparation of intermediate 6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-amine 1-2

[0210] At room temperature, the raw material 4-((1H-pyrazol-1-yl)methyl)-2-fluoro-6-methoxybenzonitrile 1-1 (1.1 g, 4.76 mmol), potassium carbonate (3.3 g, 23.79 mmol), N,N-dimethylformamide (10.0 mL) and water (2.0 mL) were added to a single-necked flask. Acetylhydroxamic acid (1.1 g, 14.27 mmol) was added under stirring and reacted at 80°C for 3 hours. After cooling, the reaction solution was poured into 100 mL of water and extracted three times with 50 mL of ethyl acetate each time. The combined organic phases were washed with 30 mL of saturated brine, 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 1:5) to obtain intermediate 1-2 (700 mg). LC-MS: m / z: 245.2 (M+H) + .

[0211] 2) Preparation of Intermediate N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-bromo-2-methoxybenzenesulfonamide 1-3

[0212] At room temperature, intermediate 1-2 (300 mg, 1.23 mmol), 4-bromo-2-methoxybenzene-1-sulfonyl chloride (876.8 mg, 3.07 mmol), and pyridine (2.0 mL) were added to a single-necked flask and 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 1:1) to obtain intermediate 1-3 (380 mg). LC-MS: m / z: 493.0 (M+H) + .

[0213] 3) Preparation of Intermediate N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-4-(hydroxymethyl)-2-methoxybenzenesulfonamide 1-4

[0214] At room temperature, intermediate 1-3 (100 mg, 0.20 mmol), tetrakistriphenylphosphine palladium (23.4 mg, 0.02 mmol), and anhydrous dioxane (3.0 mL) were added to a single-necked flask. (Tributyltin)methanol (130.2 mL, 0.41 mmol) was added with stirring, and the mixture was reacted at 80°C for 8 hours. The reaction solution was concentrated 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 1-4 (60 mg). LC-MS: m / z: 445.2 (M+H) + 5) Preparation of Compound 4-((1H-pyrazol-1-yl)methyl)-N-(6-((1H-pyrazol-1-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide 1

[0215] To a single-necked flask were added intermediate 1-4 (100 mg, 0.13 mmol), compound 1-(methylsulfonyl)-1H-pyrazole A (29.6 mg, 0.20 mmol), cesium carbonate (88.0 mg, 0.27 mmol), and acetonitrile (3.0 mL) at room temperature. The mixture was allowed to react at 80°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water) to afford compound 1 (22 mg). 1 H NMR (400MHz, DMSO-d6) δ10.23(s,1H),7.87(d,J=2.4Hz,2H),7.73(d,J=8.0Hz,1H),7.53–7.46(m,2H),7.03(s,1H),6. 84–6.73(m,2H),6.70(s,1H),6.34–6.26(m,2H),5.43(s,2H),5.39(s,2H),3.77(s,3H),3.72(s,3H), LC-MS:m / z:495.0 (M+H) + .

[0216] Example 2. Synthesis of Compound 2

[0217] Synthesis route

[0218] Experimental procedures

[0219] 1) Preparation of intermediate 2-2

[0220] At room temperature, raw material 2-1 (3 g, 10.99 mmol), tetrakis(triphenylphosphine)palladium (1.27 g, 1.10 mmol) and anhydrous dioxane (30.0 mL) were added to a single-necked flask, and (tributyltin)methanol (7.06 g, 0.26 mmol) was added with stirring. The mixture was reacted at 100 ° C for 18 hours. 20 mL of saturated potassium fluoride aqueous solution was added to the reaction solution and stirred for 1 hour. 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 1: 5) to obtain intermediate 2-2 (1.5 g). LC-MS: m / z: 225.0 (M + H) + .

[0221] 2) Preparation of intermediate 2-3

[0222] At room temperature, intermediate 2-2 (1.5 g, 6.69 mmol), compound A (1.96 g, 13.38 mmol), and anhydrous acetonitrile (30.0 mL) were added to a single-necked flask. Cesium carbonate (6.54 g, 20.07 mmol) was added with stirring, and the mixture was allowed to react at 70°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 1:1) to obtain intermediate 2-3 (1.7 g). LC-MS: m / z: 275.0 (M+H) + .

[0223] 3) Preparation of Intermediate 2-4

[0224] At room temperature, intermediate 2-3 (1.7 g, 6.20 mmol), tetrahydrofuran (20.0 mL), and water (20.0 mL) were added to a single-necked flask. Lithium hydroxide (520 mg, 12.40 mmol) was added with stirring, and the mixture was allowed to react at 60°C for 3 hours. The reaction solution was adjusted to pH 3 with 1N aqueous hydrochloric acid, filtered, and the filter cake was washed with water and dried to obtain intermediate 2-4 (1.1 g). LC-MS: m / z: 261.0 (M+H) + .

[0225] 4) Preparation of Intermediate 2-5

[0226] Under ice bath, intermediate 2-4 (1.1 g, 4.23 mmol), ammonium chloride (450 mg, 8.45 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.93 g, 5.07 mmol) and N,N-dimethylformamide (20.0 mL) were added to a single-necked flask. N,N-diisopropylethylamine (3.5 mL, 21.14 mmol) was added under stirring and reacted at 25°C for 2 hours. The reaction solution was poured into 100 mL of water and extracted three times with 30 mL of ethyl acetate each time. The combined organic phase was washed with 30 mL of saturated brine, 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 intermediate 2-5 (1 g). LC-MS: m / z: 260.0 (M+H) + .

[0227] 5) Preparation of Intermediate 2-6

[0228] Under ice bath, intermediate 2-5 (900 mg, 3.47 mmol), triethylamine (0.72 mL, 5.21 mmol) and anhydrous dichloromethane (30.0 mL) were added to a single-necked flask, and trifluoroacetic anhydride (0.72 mL, 5.21 mmol) was added under stirring, and the mixture was reacted for 3 hours under ice bath. The reaction solution was poured into 100 mL of water and extracted three times with 30 mL of dichloromethane each time. The combined organic phase was washed with 30 mL of saturated brine, 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 intermediate 2-6 (700 mg). LC-MS: m / z: 242.0 (M+H) + .

[0229] 6) Preparation of Intermediate 2-7

[0230] At room temperature, intermediate 2-6 (650 mg, 2.69 mmol), potassium carbonate (1.86 g, 13.47 mmol), water (5.0 mL) and N, N-dimethylformamide (30.0 mL) were added to a single-necked bottle, and acetohydroxamic acid (607 mg, 8.08 mmol) was added under stirring. The reaction was allowed to react at 70 ° C for 18 hours. The reaction solution was poured into 200 mL of water and extracted three times with 50 mL of ethyl acetate each time. The combined organic phase was washed with 50 mL of saturated brine, 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 1:3) to obtain intermediate 2-7 (300 mg). LC-MS: m / z: 255.0 (M+H) + .

[0231] 7) Preparation of Intermediate 2-8

[0232] At room temperature, intermediate 2-7 (220 mg, 0.87 mmol), compound B (494.2 mg, 1.73 mmol) and anhydrous acetonitrile (20.0 mL) were added to a single-necked flask. The reaction solution was stirred for 30 minutes, followed by the addition of dimethyl sulfoxide (6.8 mg, 0.09 mmol) and 3,5-lutidine (278.2 mg, 2.60 mmol). The mixture was reacted at 25°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 2-8 (220 mg). LC-MS: m / z: 502.8 (M+H) + .

[0233] 8) Preparation of Intermediate 2-9

[0234] At room temperature, intermediate 2-8 (100 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium (18.4 mg, 0.02 mmol), and anhydrous dioxane (5.0 mL) were added to a single-necked flask. (Tributyltin)methanol (102.1 mg, 0.32 mmol) was added with stirring, and 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, which was then purified by silica gel column chromatography (dichloromethane:methanol = 100:1 to 10:1) to obtain intermediate 2-9 (80 mg). LC-MS: m / z: 455.0 (M+H) + .

[0235] 9) Preparation of Compound 2

[0236] To a single-necked flask at room temperature, intermediate 2-9 (30 mg, 0.07 mmol), compound A (19.3 mg, 0.13 mmol), and anhydrous acetonitrile (3.0 mL) were added. Cesium carbonate (68.4 mg, 0.21 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. The crude product was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water) to obtain compound 2 (5.7 mg). 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),8.06(s,1H),7.90(d,J=2.0Hz,1H),7.86(d,J=2.4Hz,1H),7.69(d,J=8.0Hz,1H),7. 49(d,J=2.0Hz,2H),7.25(s,1H),7.05(s,2H),6.73(d,J=8.0Hz,1H),6.34–6.24(m,2H),5.71(s,2H),5.39(s,2H),3.70(s, 3H),LC-MS:m / z:505.0(M+H) + .

[0237] Example 3. Synthesis of Compound 3

[0238] Synthesis route

[0239] Experimental procedures

[0240] 1) Preparation of intermediate 3-2

[0241] At room temperature, bromoacetaldehyde diethyl acetal (3.79 g, 19.21 mmol), sodium hydride (0.65 g, 16.25 mmol), and N,N-dimethylformamide (30.0 mL) were added to a single-necked flask. After stirring for half an hour, raw material 3-1 (3.0 g, 14.78) was added to the reaction solution, and the temperature was raised to 110°C for 18 hours. The reaction solution was poured into 300 mL of ice water to quench, extracted once with 300 mL of ethyl acetate, and the organic phase was washed with 300 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 8:1) to obtain intermediate 3-2 (4.0 g). 1 H NMR (400MHz, DMSO-d6) δ7.21(d,J=2.9Hz,1H),7.03(d,J=9.0Hz,1H),6.96(dd,J=9.0,2.9Hz,1H),4.75(t,J=5.2Hz ,1H),3.92(d,J=5.2Hz,2H),3.78(s,3H),3.66(m,2H),3.55(m,2H),1.14(t,J=7.1Hz,6H), LC-MS:m / z:341.0(M+Na) + .

[0242] 2) Preparation of intermediate 3-3

[0243] To a single-necked flask at room temperature, 3-2 (4.7 g, 14.72 mmol) and toluene (50.0 mL) were added, followed by polyphosphoric acid (4.70 g, 57.28 mmol) with stirring. The mixture was allowed to react at 110°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 5:1) to afford intermediate 3 (2.5 g). 1 H NMR (400MHz, DMSO-d6) δ7.99 (d, J = 2.2 Hz, 1H), 7.92 (d, J = 0.7 Hz, 1H), 7.35 (s, 1H), 6.93 (dd, J = 2.1, 0.9 Hz, 1H), 3.87 (s, 3H).

[0244] 3) Preparation of intermediate 3-4

[0245] To a single-necked flask at room temperature, intermediate 3-3 (1.5 g, 11.01 mmol), benzyl mercaptan (1.94 mL, 16.52), N,N-diisopropylethylamine (5.47 mL, 33.03 mmol), and N,N-dimethylformamide (15.0 mL) were added. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (1.27 g, 2.2 mmol) and tris(dibenzylideneacetone)dipalladium (1.01 g, 1.10 mmol) were added under stirring. The atmosphere was purged with nitrogen three times and the reaction was continued at 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 5:1) to obtain intermediate 3-4 (500 mg). 1 H NMR (400MHz, DMSO-d6) δ7.87(d,J=2.1Hz,1H),7.47(s,1H),7.38(d,J=7.3Hz,2H),7.30(t,J=7 .4Hz,2H),7.23(d,J=7.3Hz,1H),7.19(s,1H),6.86(d,J=1.5Hz,1H),4.21(s,2H),3.84(s,3H).

[0246] 4) Preparation of Intermediate 3-5

[0247] To a single-necked flask at room temperature, 3-4 (510.0 mg, 1.89 mmol) and acetonitrile (20.0 mL) were added. Acetic acid (0.2 mL, 3.77 mmol) and water (0.2 mL, 11.32 mmol) were added with stirring. The atmosphere was replaced with nitrogen three times, then the temperature was lowered to 0°C. 1,3-Dichloro-5,5-dimethylhydantoin (557.47 mg, 2.83 mmol) was added at 0°C, and the mixture was allowed to react at 0°C for 1.5 hours. The reaction mixture was poured into 30 mL of ice water and extracted once with 30 mL of dichloromethane. 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 the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 3:1) to obtain intermediate 3-5 (300.0 mg). 1 H NMR (400MHz, DMSO-d6) δ7.96 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 0.8 Hz, 1H), 7.16 (s, 1H), 6.88 (dd, J = 2.1, 1.0 Hz, 1H), 3.77 (d, J = 5.9 Hz, 3H).

[0248] 5) Preparation of Compound 3

[0249] At room temperature, intermediate 3-5 (50.0 mg, 0.20 mmol), compound A (97.01 mg, 0.39 mmol), and pyridine (2 mL) were added to a single-necked flask and reacted at 120°C under microwave conditions for 2 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 3 (2.9 mg). 1 H NMR (400MHz, DMSO-d6) δ11.27(s,1H),8.13(s,1H),8.08(s,1H),7.97(s,1H),7.90(d,J=1.7Hz,1H),7.48(d,J=1.3Hz,1H),7 .36(s,1H),7.22(s,1H),7.05(s,1H),6.98(s,1H),6.29(t,J=2.0Hz,1H),5.70(s,2H),3.76(s,3H), LC-MS:m / z:465.0(M+H) + .

[0250] Example 4. Synthesis of Compound 4

[0251] Synthesis route

[0252] Experimental procedures

[0253] 1) Preparation of Compound 4

[0254] At room temperature, raw material 4-1 (60 mg, 0.12 mmol), cesium carbonate (38.84 mg, 0.12 mmol), bistriphenylphosphine palladium dichloride (8.37 mg, 0.01 mmol), and N,N-dimethylformamide (2.0 mL) were added to a microwave tube. Compound A (41.52 mg, 0.36 mmol) was added under stirring, and the mixture was reacted at 100°C 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 system) to obtain compound 4 (15 mg). 1 H NMR (400MHz, DMSO-d6) δ11.36(s,1H),8.13(s,1H),7.90(s,1H),7.73(d,J=8.4Hz,1H) ,7.48(d,J=2.0Hz,1H),7.04(m,5H),6.29(t,J=2.0Hz,1H),5.69(s,2H),3.74(s,3H), 3.06-3.01(m,2H),2.77-2.72(m,2H), LC-MS:m / z:539.2(M+H) +

[0255] Example 5. Synthesis of Compound 5

[0256] Synthesis route

[0257] Experimental procedures

[0258] 1) Preparation of intermediate 5-2

[0259] At room temperature, sodium hydroxide (11.01 g, 275.23 mmol) and water (100.0 mL) were added to a 500 mL single-necked flask. Once completely dissolved and cooled to room temperature, starting material 5-1 (10.0 g, 45.87 mmol) and 1,4-dioxane (100.0 mL) were added. The reaction was allowed to react at 60°C for 6 hours. The reaction solution was adjusted to pH 5-6 with hydrochloric acid (1N). The reaction solution was extracted with dichloromethane (200 mL x 3). The organic phase was washed with saturated sodium chloride solution (150 mL), dried over 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 = 100:1 to 20:1) to obtain intermediate 5-2 (7.0 g). 1 H NMR (400MHz, DMSO-d6) δ12.17 (s, 1H), 7.24 (d, 1.6Hz, 1H), 7.02 (t, J = 1.6Hz, 1H).

[0260] 2) Preparation of intermediate 5-3

[0261] At room temperature, sodium hydroxide (14.81 g, 370.35 mmol) and water (20.0 mL) were added to a 250 mL single-necked flask. After complete dissolution and cooling to 0°C, intermediate 5-2 (2.0 g, 9.26 mmol) and acetonitrile (20.0 mL) were added. Stirring was continued for 0.5 hours, followed by the addition of compound A (4.49 g, 18.52 mmol). The reaction was allowed to proceed at 0°C for 4 hours. The reaction solution was extracted with dichloromethane (50 mL * 3), and the organic phase was washed with saturated sodium chloride solution (50 mL), dried over 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 = 100:1 to 20:1) to obtain intermediate 5-3 (1.5 g). 1 H NMR (400MHz, Chloroform-d) δ7.33 (t, J = 1.6Hz, 1H), 7.30 (d, 1.6Hz, 1H), 6.67 (m, 1H).

[0262] 3) Preparation of Intermediate 5-4

[0263] To a 250 mL single-necked flask at room temperature were added intermediate 5-3 (5.0 g, 20.16 mmol), tetrakistriphenylphosphine palladium (2.33 g, 2.02 mmol), compound B (6.54 g, 20.36 mmol), and 1,4-dioxane (100.0 mL). The mixture was reacted at 100°C for 18 hours. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to obtain intermediate 5-4 (2.5 g). 1 H NMR (400MHz, Chloroform-d) δ7.16–7.09(m,2H),6.67(m,1H),4.79(s,2H).

[0264] 4) Preparation of Intermediate 5-5

[0265] At room temperature, intermediate 5-4 (2.5 g, 11.51 mmol), compound C (1.68 g, 11.51 mmol), cesium carbonate (7.50 g, 23.03 mmol), and acetonitrile (100.0 mL) were added to a 100 mL single-necked flask. The mixture was reacted at 70°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 5:1) to obtain intermediate 5-5 (1.9 g). LC-MS: m / z: 268.0 (M+H) + .

[0266] 5) Preparation of Intermediate 5-6

[0267] At room temperature, intermediate 5-5 (1.9 g, 1.85 mmol), compound D (0.42 g, 5.55 mmol), tetramethylguanidine (1.28 g, 11.09 mmol), and acetonitrile (40.0 mL) were added to a 100 mL single-necked flask. The reaction was allowed to proceed at 60°C for 3 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 5-6 (350.0 mg). LC-MS: m / z: 281.0 (M+H) + .

[0268] 6) Preparation of Intermediate 5-7

[0269] At room temperature, intermediate 5-6 (300.0 mg, 1.25 mmol), potassium tert-butoxide (240.25 mg, 2.14 mmol), and tetrahydrofuran (20.0 mL) were added to a 100 mL single-necked flask. After reacting at 0°C for 0.5 hours, compound E (611.37 mg, 2.14 mmol) was added and 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 5:1) to obtain intermediate 5-7 (120.0 mg). LC-MS: m / z: 529.2 (M+H) + .

[0270] 7) Preparation of Intermediate 5-8

[0271] At room temperature, intermediate 5-7 (120.0 mg, 0.23 mmol), tetrakistriphenylphosphine palladium (26.20 mg, 0.02 mmol), compound B (72.79 mg, 0.23 mmol), and 1,4-dioxane (10.0 mL) were added to a 100 mL single-necked flask. The mixture was reacted at 100°C for 6 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 5-8 (90.0 mg). LC-MS: m / z: 481.2 (M+H) + .

[0272] 8) Preparation of Compound 5

[0273] At room temperature, intermediate 5-8 (90.0 mg, 0.19 mmol), compound C (54.76 mg, 0.37 mmol), cesium carbonate (183.11 mg, 0.56 mmol), and acetonitrile (10.0 mL) were added to a 100 mL single-necked flask. The mixture was reacted at 70°C for 2 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 5 (15.0 mg). LC-MS: m / z: 531.2 (M+H)+ . 1 H NMR (400MHz, DMSO-d6) δ10.73(s,1H),7.87(dd,J=6.8,2.4Hz,2H),7.72(d,J=8.0Hz,1H),7.50(dd ,J=6.2,1.6Hz,2H),7.22–6.74(m,5H),6.31-6.30(m,2H),5.49(s,2H),5.40(s,2H),3.72(s,3H).

[0274] Example 6. Synthesis of Compound 6

[0275] Synthesis route

[0276] Experimental procedures

[0277] 1) Preparation of Compound 6

[0278] At room temperature, intermediate 6-1 (50 mg, 0.08 mmol), cesium carbonate (77.7 mg, 0.24 mmol), bistriphenylphosphine palladium dichloride (5.6 mg, 0.01 mmol) and N,N-dimethylformamide (2.0 mL) were added to a microwave tube. 3-Ethynylpyridine (49.2 mg, 0.48 mmol) was added under stirring. After nitrogen substitution three times, the mixture was reacted at 100°C under microwave for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by high performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 6 (26 mg). 1 H NMR (400MHz, DMSO-d6) δ11.43 (s, 1H), 8.78 (t, J = 2.0, 0.8Hz, 1H), 8.61 (dd, J=4.8,2.0Hz,1H),8.07(s,1H),8.04–7.98(m,1H),7.89(d,J=2.4Hz,1H),7 .82(d,J=8.0Hz,1H),7.52–7.46(m,2H),7.36–7.19(m,2H),7.08–6.92(m,2 H), 6.29 (t, J = 2.0Hz, 1H), 5.69 (s, 2H), 3.79 (s, 3H), LC-MS: m / z: 526.0 (M+H) +

[0279] Example 7. Synthesis of Compound 7

[0280] Synthesis route

[0281] Experimental procedures

[0282] 1) Preparation of Intermediate 7-2

[0283] In an ice bath, raw material 7-1 (700 mg, 0.79 mmol) and anhydrous dichloromethane (5.0 mL) were added to a single-necked flask. Phosphorus tribromide (0.22 mL, 2.36 mmol) was slowly added dropwise with stirring. After the addition was complete, the reaction was allowed to react at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure to obtain the crude intermediate 7-2 (500 mg), which was used directly in the next step without purification. LC-MS: m / z: 507.0 (M+H) + .

[0284] 2) Preparation of Compound 7

[0285] Under ice-cooling, pyrrole (47.6 mg, 0.71 mmol) and tetrahydrofuran (5.0 mL) were added to a single-necked flask, and sodium hydride (28.4 mg, 0.71 mmol) was added with stirring. After reacting for 0.5 h, intermediate 7-2 (200 mg, 0.24 mmol) was added to the reaction solution, and the reaction was continued at 60°C for 2 h. 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 7 (22 mg). 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),7.85(d,J=2.0Hz,1H),7.71(d,J=8.0Hz,1H),7.48(d,J=2.0Hz,1H),6.91(s,1H),6.82(t,J=2.0Hz ,2H),6.76–6.54(m,3H),6.29(m,1H),6.02(t,J=2.0Hz,2H),5.40(s,2H),5.11(s,2H),3.79(s,3H),3.69(s,3H), LC-MS:m / z:494.0(M+H) + .

[0286] Example 8. Synthesis of Compound 8

[0287] Synthesis route

[0288] Experimental procedures

[0289] At room temperature, imidazole (50.0 mg, 0.73 mmol) and tetrahydrofuran (5.0 mL) were added to a single-necked flask, and NaH (35.25 mg, 0.88 mmol) was added under stirring. After half an hour of reaction at room temperature, intermediate 8-1 (372.62 mg, 0.73 mmol) was dissolved in tetrahydrofuran and added dropwise to the reaction solution. The temperature was raised to 60 degrees and the reaction was continued for 2 hours. The reaction solution was poured into 20 ml of ice water and extracted three times with 20 ml of ethyl acetate each time. The combined organic phase was washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (formic acid acetonitrile / water system) to obtain compound 8 (5.8 mg). 1 H NMR(400MHz,DMSO-d6)δ7.85(d,J=2.2Hz,1H),7.79(s,1H),7.74(d,J=8.0Hz,1 H),7.49(d,J=1.5Hz,1H),7.22(s,1H),7.06(s,1H),7.03(s,1H),6.92(s,1H), 6.81(d,J=7.7Hz,1H),6.72(s,1H),6.64(s,1H),6.29(t,J=2.0Hz,1H),5.41(s ,2H),5.23(d,J=10.1Hz,2H),3.78(s,3H),3.72(s,3H), LC-MS:m / z:495.2(M+H) + .

[0290] Example 9. Synthesis of Compound 9

[0291] Synthesis route

[0292] Experimental procedures

[0293] Under ice bath, 1,2,3-triazole (49.7 mg, 0.72 mmol) was added to a single-necked flask, followed by sodium hydride (28.4 mg, 0.71 mmol) with stirring. After maintaining the temperature for 0.5 hour, intermediate 9-1 (200 mg, 0.24 mmol) was added and the mixture was allowed to react at 60°C for 2 hours. The reaction solution was quenched with 1 mL of water and concentrated under reduced pressure to obtain a crude product, which was then purified by HPLC (ammonium bicarbonate / acetonitrile / water system) to obtain compound 9 (13 mg). 1H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.23(s,1H),7.86(d,J=2.4Hz,1H),7.80–7.71(m,2H),7.49(d,J=2.0Hz,1H),7.11(s,1H),6.84(d, J=8.0Hz,1H),6.76(s,1H),6.66(s,1H),6.29(t,J=2.0Hz,1H),5.66(s,2H),5.41(s,2H),3.75(d,J=14.4Hz,6H), LC-MS:m / z:496.0(M+H) + .

[0294] Example 10. Synthesis of Compound 10

[0295] Synthesis route

[0296] Experimental procedures

[0297] 1) Preparation of Intermediate 10-2

[0298] Under ice, to a 100 mL three-necked flask, intermediate 10-1 (2 g, 8.73 mmol) and anhydrous dichloromethane (50.0 mL) were added. Triethylsilane (4.23 mL, 26.19 mmol) and a solution of boron trifluoride in ether (8.53 mL, 17.46 mmol) were slowly added with stirring. The mixture was heated to 25°C and reacted for 18 hours. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine (100 mL), 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 = 100:1 to 10:1) to obtain intermediate 10-2 (1.7 g). 1 H NMR (400MHz, DMSO-d6) δ7.24(d,J=8.4Hz,1H),7.13(d,J=2.8Hz,1H),6.90(dd,J=8.4,2.8Hz,1H),3.74(s,3H),2.62(m,2H),1.12(t,J=7.6Hz,3H).

[0299] 2) Preparation of Intermediate 10-3

[0300] Under ice-cooling, intermediate 10-2 (1.7 g, 7.90 mmol) and dichloromethane (20.0 mL) were added to a 100 mL single-necked flask. Chlorosulfonic acid (1.58 mL, 23.71 mmol) was added with stirring and the mixture was allowed to react under ice-cooling for 3 hours. The reaction solution was poured into 100 mL of water and extracted with dichloromethane (30 mL x 3). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over 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 = 100:1 to 3:1) to obtain intermediate 10-3 (1.9 g). 1 H NMR (400MHz, DMSO-d6) δ7.63(s,1H),7.18(s,1H),3.78(s,3H),2.63(m,2H),1.13(t,J=7.6Hz,3H).

[0301] 3) Preparation of Intermediate 10-4

[0302] At room temperature, intermediate 10-3 (385.2 mg, 1.23 mmol), A (200 mg, 0.82 mmol), and anhydrous acetonitrile (5.0 mL) were added to a 10 mL single-necked flask. The reaction solution was stirred for 30 minutes, followed by the addition of dimethyl sulfoxide (6.4 mg, 0.08 mmol) and 3,5-lutidine (263.2 mg, 2.46 mmol). The reaction mixture was allowed to react at room temperature for 18 hours. The solvent was removed by distillation 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 10-4 (340 mg). LC-MS: m / z: 521.0 (M+H) + .

[0303] 4) Preparation of Intermediate 10-5

[0304] At room temperature, intermediate 10-4 (170 mg, 0.33 mmol), tetrakis(triphenylphosphine)palladium (37.7 mg, 0.03 mmol), and anhydrous dioxane (5.0 mL) were added to a 10 mL single-necked flask. (Tributyltin)methanol (209.4 mg, 0.65 mmol) was added with stirring. The atmosphere was purged with nitrogen three times and the reaction was incubated at 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 0:1) to obtain intermediate 10-5 (190 mg). LC-MS: m / z: 473.0 (M+H). + .

[0305] 5) Preparation of Compound 10

[0306] At room temperature, intermediate 10-5 (100 mg, 0.08 mmol), compound B (24.8 mg, 0.17 mmol), and anhydrous acetonitrile (3.0 mL) were added to a 10 mL single-necked flask. Cesium carbonate (78.2 mg, 0.24 mmol) was added with stirring, and the mixture was allowed to react at 80°C 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 system) to obtain compound 10 (4.6 mg). LC-MS: m / z: 523.1 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ11.79(s,1H),7.85(d,J=2.4Hz,1H),7.77(d,J=2.4Hz,1H),7.62(s,1H),7.47(dd,J=6.4,2.0Hz,2H),6.66(s,1H) ,6.61(s,1H),6.58(s,1H),6.31–6.23(m,2H),5.37(d,J=12.0Hz,4H),3.78(s,3H),3.58(s,3H),2.66–2.54(m,2H),1.01(t,J=7.6Hz,3H).

[0307] Example 11. Synthesis of Compound 11

[0308] Synthesis route

[0309] Experimental procedures

[0310] 1) Preparation of Intermediate 11-2

[0311] To a 250 mL single-necked flask were added Intermediate 11-1 (5.0 g, 23.15 mmol), cesium carbonate (11.31 g, 34.72 mmol), fluoroiodomethane (5.55 g, 34.72 mmol), and acetonitrile (50.0 mL) at room temperature for 4 hours. The solvent was removed by distillation under reduced pressure to afford a crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to afford Intermediate 11-2 (5.0 g). 1 H NMR (400MHz, DMSO-d6) δ7.69 (dd, J=8.8, 1.4Hz, 1H), 7.58 (q, J=1.4Hz, 1H), 6.08 (d, J=52.0Hz, 2H).

[0312] 2) Preparation of Intermediate 11-3

[0313] At room temperature, intermediate 11-2 (5.0 g, 20.16 mmol), tetrakistriphenylphosphine palladium (2.33 g, 2.02 mmol), A (6.54 g, 20.36 mmol), and 1,4-dioxane (100.0 mL) were added to a 250 mL single-necked flask. The atmosphere was purged with nitrogen three times and the reaction was carried out at 100°C for 18 hours. The solvent was removed by distillation 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 11-3 (2.5 g). LC-MS: m / z: 199.8 (M+H) + .

[0314] 3) Preparation of Intermediate 11-4

[0315] To a 100 mL single-necked flask were added intermediate 11-3 (2.5 g, 12.55 mmol), B (2.75 g, 18.83 mmol), cesium carbonate (8.18 g, 25.11 mmol), and acetonitrile (100.0 mL) at room temperature and allowed to react at 70°C for 2 hours. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 2:1) to obtain intermediate 11-4 (2.0 g). LC-MS: m / z: 250.0 (M+H). + .

[0316] 4) Preparation of Intermediate 11-5

[0317] To a 100 mL single-necked flask, intermediate 11-4 (2.0 g, 8.03 mmol), acetohydroxamic acid (1.81 g, 24.08 mmol), tetramethylguanidine (2.77 g, 24.08 mmol), and acetonitrile (40.0 mL) were added at room temperature and reacted at 60°C for 3 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 1:5) to obtain intermediate 11-5 (0.9 g). LC-MS: m / z: 263.0 (M+H) + .

[0318] 5) Preparation of Intermediate 11-6

[0319] Under ice bath, intermediate 11-5 (900.0 mg, 3.43 mmol), potassium bis(trimethylsilyl)amide (6.86 mL, 6.86 mmol) and tetrahydrofuran (20.0 mL) were added to a 100 mL single-necked flask. After half an hour of ice bath reaction, 4-bromo-2-methoxybenzene-1-sulfonyl chloride (1.96 g, 6.86 mmol) was added and ice bath reaction was continued for 2 hours. The reaction solution was quenched with saturated ammonium chloride solution (50.0 mL) and extracted with dichloromethane (50.0 mL*3). The organic phases were combined and the solvent was removed by distillation 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 (985.0 mg). LC-MS: m / z: 511.0 (M+H) + .

[0320] 6) Preparation of Intermediate 11-7

[0321] At room temperature, intermediate 11-6 (300.0 mg, 0.59 mmol), tetrakistriphenylphosphine palladium (68 mg, 0.06 mmol), A (283 mg, 0.88 mmol), and 1,4-dioxane (10.0 mL) were added to a 50 mL single-necked flask. After nitrogen substitution three times, the reaction was incubated at 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 1:5) to obtain intermediate 11-7 (81.0 mg). LC-MS: m / z: 463.0 (M+H) + .

[0322] 7) Preparation of Compound 11

[0323] At room temperature, 11-7 (40.0 mg, 0.09 mmol), B (25 mg, 0.17 mmol), cesium carbonate (141 mg, 0.43 mmol), and acetonitrile (2.0 mL) were added to a 50 mL single-necked flask and reacted at 70°C for 2 hours. The solvent was removed by distillation under reduced pressure to obtain a crude product, which was purified by high-performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 11 (4.0 mg). LC-MS: m / z: 513.2 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ7.84(dd,J=7.7,2.1Hz,2H),7.71(d,J=8.0Hz,1H),7.47(dd,J=8.1,1.5Hz,2H),6.85(d,J =11.2Hz,2H),6.69(d,J=7.4Hz,2H),6.30-6.25(m,2H),6.10-5.88(m,2H),5.39(s,2H),5.32(s,2H),3.66(s,3H).

[0324] Example 12. Synthesis of Compound 12

[0325] Synthesis route

[0326] Experimental procedures

[0327] 1) Preparation of Intermediate 12-2

[0328] At room temperature, compound 12-1 (5.0 g, 22.71 mmol) and dimethyl sulfoxide (50.0 mL) were added to a 250 mL single-necked flask. Triethylamine (12.59 mL, 90.85 mmol) and benzylamine (2.98 mL, 27.25 mmol) were slowly added dropwise at room temperature. The mixture was reacted at 100°C for 18 hours. The reaction solution was poured into 200 mL of water and extracted with ethyl acetate (200 mL*2), 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 5:1) to obtain intermediate 12-2 (4.8 g). LC-MS: m / z: 308.0 (M+H) + .

[0329] 2) Preparation of Intermediate 12-3

[0330] At room temperature, intermediate 12-2 (4.8 g, 15.62 mmol), methanol (50.0 mL), and 10% palladium on carbon (0.17 g, 1.56 mmol) were added to a 250 mL single-necked flask. After hydrogen replacement three times, the mixture was reacted at 50°C under a hydrogen balloon atmosphere for 18 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 12-3 (3.30 g), which was used directly in the next step without purification. LC-MS: m / z: 218.0 (M+H) + .

[0331] 3) Preparation of Intermediate 12-4

[0332] At room temperature, intermediate 12-3 (2 g, 9.21 mmol) was dissolved in acetonitrile (60.0 mL). Cuprous cyanide (2.47 g, 27.63 mmol) was added with stirring. The temperature was raised to 65°C, and isoamyl nitrite (0.99 mL, 0.99 mmol) was slowly added dropwise. The mixture was reacted at 65°C for 18 hours. The reaction solution was diluted with 100 mL of ethyl acetate, 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 7:1) to obtain intermediate 12-4 (1.1 g). 1 H NMR (400MHz, CDCl3) δ7.39-7.34 (m, 1H), 4.20 (d, J = 3.2Hz, 3H), 3.97 (s, 3H).

[0333] 4) Preparation of Intermediate 12-5

[0334] At room temperature, intermediate 12-4 (1.0 g, 4.40 mmol) and tetrahydrofuran (20.0 mL) were added to a 50 mL single-necked flask. Lithium borohydride (3.30 mL, 6.60 mmol) was added dropwise in an ice bath and allowed to react at 50°C for 2 hours. The reaction solution was poured into 50 mL of ice water and extracted with ethyl acetate (100 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 12-5 (750 mg). LC-MS: m / z: 199.9 (M+H) +

[0335] 5) Preparation of Intermediate 12-6

[0336] At room temperature, intermediate 12-5 (750 mg, 3.77 mmol) and acetonitrile (20.0 mL) were added to a 100 mL single-necked flask. Cesium carbonate (3685 mg, 11.31 mmol) and A (826 mg, 5.65 mmol) were added with stirring, and the mixture was allowed to react at 70°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 3:1) to obtain intermediate 12-6 (520.0 mg). LC-MS: m / z: 250.0 (M+H) + .

[0337] 6) Preparation of Intermediate 12-7

[0338] At room temperature, intermediate 12-6 (520 mg, 2.09 mmol), acetonitrile (25.0 mL) and water (5.0 mL) were added to a 100 mL single-necked flask. Acetylhydroxamic acid (470 mg, 6.26 mmol) and tetramethylguanidine (1442 mg, 12.52 mmol) were added under stirring and reacted at 60°C for 18 hours. The reaction solution was concentrated, the crude product was diluted with 30 mL of water, the suspension was filtered, and the filter cake was washed with 10 mL of water and 2 mL of petroleum ether:ethyl acetate (10:1) in sequence, and finally dried to obtain intermediate 12-7 (350.0 mg). LC-MS: m / z: 263.0 (M+H) + .

[0339] 7) Preparation of Intermediate 12-8

[0340] Intermediate 12-7 (320 mg, 1.22 mmol) was dissolved in tetrahydrofuran (10.0 mL). Potassium tert-butoxide (411 mg, 3.66 mmol) was added at 0°C and stirred for 30 minutes. 4-Bromo-2-methoxybenzene-1-sulfonyl chloride (697 mg, 2.44 mmol) was added to the reaction solution and reacted at 0°C for 1.5 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 2:1) to obtain Intermediate 12-8 (280.0 mg). LC-MS: m / z: 511.2 / 513.2 (M+H) + .

[0341] 8) Preparation of Intermediate 12-9

[0342] At room temperature, intermediate 12-8 (180 mg, 0.35 mmol) and dioxane (4.0 mL) were added to a 50 mL single-necked flask. B (170 mg, 0.53 mmol) and tetrakis(triphenylphosphine)palladium (61 mg, 0.05 mmol) were added sequentially under stirring. After nitrogen substitution three times, the reaction was carried out at 100°C for 6 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 1:2) to obtain intermediate 12-9 (40.0 mg). LC-MS: m / z: 463.2 (M+H) + .

[0343] 9) Preparation of Compound 12

[0344] At room temperature, intermediate 12-9 (40 mg, 0.09 mmol) and acetonitrile (2.0 mL) were added to a 50 mL single-necked flask. A (40 mg, 0.27 mmol) and cesium carbonate (147 mg, 0.45 mmol) were added under stirring, and the mixture was reacted at 70°C for 2 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 12 (3.0 mg). LC-MS: m / z: 513.2 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),7.85(d,J=6.0Hz,2H),7.72(d,J=8.0Hz,1H),7.50-7.45(m,2H),7.2 1-6.91(m,2H),6.79-6.71(m,1H),6.32-6.27(m,2H),5.47(s,2H),5.38(s,2H),4.03(s,3H),3.72(s,3H).

[0345] Example 13. Synthesis of Compound 13 and Compound 14

[0346] Synthesis route

[0347] Experimental procedures

[0348] At room temperature, 1,2,4-triazole (100.0 mg, 1.45 mmol) and tetrahydrofuran (5.0 mL) were added to a 25 mL single-necked bottle. Sodium hydride (9.46 mg, 0.24 mmol) was added under stirring and reacted at room temperature for half an hour. Intermediate 13-1 (100.0 mg, 0.20 mmol) was added to the reaction solution and reacted at 60°C for 18 hours. The reaction solution was poured into 15 mL of ice water and extracted with ethyl acetate (10.0 mL*3). The combined organic phases were washed with 15 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 high-performance liquid chromatography (formic acid / acetonitrile / water system) to obtain compound 13 (5.0 mg) and compound 14 (2.0 mg). Compound 13: LC-MS: m / z: 496.2 (M+H) + , 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.67 (s, 1H), 7.98 (s, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 1.4 Hz, 1H), 7.01 (s, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.67 (s, 1H), 6.59 (s, 1H), 6.29 (t, J = 2.0 Hz, 1H), 5.43 (s, 2H), 5.39 (s, 2H), 3.79 (s, 3H), 3.71 (s, 3H). Compound 14: LC-MS: m / z: 496.2 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),8.63(s,2H),7.86(d,J=2.4Hz,1H),7.77(d,J=8.0Hz,1H),7.49(d,J=2.0Hz,1H),7.12(s ,1H),6.87(d,J=8.0Hz,1H),6.76(s,1H),6.67(s,1H),6.29(t,J=2.4Hz,1H),5.41(s,2H),5.31(s,2H),3.76(d,J=10.0Hz,6H).

[0349] Example 14. Synthesis of Compound 15

[0350] Synthesis route

[0351] Experimental procedures

[0352] Under ice bath, A (25.5 mg, 0.20 mmol) and tetrahydrofuran (5.0 mL) were added to a 50 mL single-necked flask. Sodium hydride (15.8 mg, 0.39 mmol) was added with stirring and the mixture was allowed to react for 0.5 h under ice bath. Intermediate 15-1 (50 mg, 0.10 mmol) was added and the mixture was allowed to react at 60°C for 2 h. The reaction solution was poured into 15 mL of ice water and extracted with ethyl acetate (10.0 mL*3). The combined organic phases were washed with 15 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 high performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain compound 15 (18.0 mg). LC-MS: m / z: 520.2 (M+H) + , 1H NMR (400MHz, DMSO-d6) δ7.85(d,J=2.4Hz,1H),7.72(d,J=8.0Hz,1H),7.48(d,J=2.0Hz,1H),7.00(s,1H),6.92(d,J=8 .0Hz,1H),6.71(s,1H),6.64(s,1H),6.29(t,J=2.0Hz,1H),5.40(s,2H),3.82(s,3H),3.78–3.69(m,5H),3.62(m,4H).

[0353] Example 15. Synthesis of Compound 16

[0354] Synthesis route

[0355] Experimental procedures

[0356] Under ice bath, 2-pyrrolidone (16.8 mg, 0.20 mmol) and tetrahydrofuran (5.0 mL) were added to a 50 mL single-necked flask, and sodium hydride (7.9 mg, 0.20 mmol) was added with stirring. The temperature was maintained and stirring was continued for 0.5 hours. Intermediate 16-1 (50 mg, 0.10 mmol) was added and reacted at 60°C for 2 hours. The reaction solution was poured into 15 mL of ice water and extracted with ethyl acetate (10.0 mL*3). The combined organic phases were washed with 15 mL of saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate 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 16 (5.0 mg). LC-MS: m / z: 512.2 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),7.87(d,J=2.4Hz,1H),7.76(d,J=8.0Hz ,1H),7.49(d,J=1.6Hz,1H),7.02(d,J=1.6Hz,1H),6.91(dd,J=8.4,1.6Hz,1H) ,6.84(s,1H),6.74(s,1H),6.30(m,1H),5.44(s,2H),4.41(s,2H),3.82(s,3H) ,3.77(s,3H),3.25(t,J=7.2Hz,2H),2.29(t,J=8.0Hz,2H),2.00–1.89(m,2H).

[0357] Example 16. Synthesis of Compound 17

[0358] Synthesis route

[0359] Experimental procedures

[0360] 1) Preparation of Intermediate 17-2

[0361] Under ice, 1,2,3-triazole (1 g, 14.48 mmol), triethylamine (4.01 mL, 28.96 mmol), and dichloromethane (20 mL) were added to a 100 mL single-necked flask. Methanesulfonyl chloride (1.34 mL, 17.37 mmol) was added with stirring and the mixture was allowed to react in an ice bath for 3 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 10:1) to obtain intermediate 17-2 (1 g, 1.36 mmol). LC-MS: m / z: 148.0 (M+H) + .

[0362] 2) Preparation of Compound 17

[0363] In an ice bath, compound A (80 mg, 0.18 mmol), intermediate 17-2 (77.8 mg, 0.53 mmol), and acetonitrile (5 mL) were added to a 10 mL single-necked flask. Cesium carbonate (172.1 mg, 0.53 mmol) was added with stirring, and the mixture was allowed to react at 80°C 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 system) to obtain compound 17 (12 mg). 1 H NMR (400MHz, DMSO-d6) δ7.92–7.79(m,3H),7.74(d,J=8.0Hz,1H),7.48(d,J=2.0Hz,1H),7.00(s,1H),6.76(d,J=8.0Hz,1H), 6.69(s,1H),6.61(s,1H),6.29(t,J=2.4Hz,1H),5.68(s,2H),5.40(s,2H),3.78(s,3H),3.70(s,3H), LC-MS:m / z:496.0(M+H) + .

[0364] Example 17. Synthesis of Compound 18

[0365] Synthesis route

[0366] Experimental procedures

[0367] 1) Preparation of Intermediate 18-2

[0368] At room temperature, compound 18-1 (1 g, 5.16 mmol), cuprous iodide (100 mg, 0.52 mmol), triethylamine (2.14 mL, 15.47 mmol), bistriphenylphosphine palladium dichloride (360 mg, 0.52 mmol), and N,N-dimethylformamide (10.0 mL) were added to a 15 mL single-necked flask. Trimethylacetylsilane (2.20 mL, 15.47 mmol) was added under stirring. After nitrogen substitution three times, the mixture was reacted at 80°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 3:1) to obtain intermediate 18-2 (550.0 mg). LC-MS: m / z: 165.0 (M+H) + .

[0369] 2) Preparation of Intermediate 18-3

[0370] Under ice bath, 18-2 (550 mg, 3.35 mmol), triethylamine (0.93 mL, 6.70 mmol), and anhydrous dichloromethane (10.0 mL) were added to a 100 mL single-necked flask. Methanesulfonyl chloride (0.31 mL, 4.02 mmol) was added under stirring and 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 10:1) to obtain intermediate 18-3 (500 mg). LC-MS: m / z: 243.0 (M+H) + .

[0371] 3) Preparation of Intermediate 18-5

[0372] At room temperature, 18-4 (2.0 g, 8.69 mmol), triethylamine (3.62 mL, 26.08 mmol), dimethyl sulfoxide (30.0 mL), and anhydrous methanol (30.0 mL) were added to a 100 mL single-necked flask. 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) chloride (320 mg, 0.43 mmol) was added with stirring at room temperature. The mixture was replaced with a CO balloon three times and reacted at 80°C under a CO balloon atmosphere for 18 hours. The reaction solution was cooled and poured into water (150 mL). Extraction was performed with ethyl acetate (500 mL*3). The combined organic phases were washed with saturated brine (500 mL), 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 = 100:1 to 5:1) to obtain intermediate 18-5 (1.6 g). LC-MS: m / z: 210.0 (M+H). + .

[0373] 4) Preparation of Intermediate 18-6

[0374] At room temperature, 18-5 (1 g, 4.78 mmol), potassium carbonate (3.30 g, 23.90 mmol), and N,N-dimethylformamide (50.0 mL) were added to a 100 mL single-necked flask. Acetylhydroxamic acid (1.08 g, 14.34 mmol) was added under stirring, and the mixture was reacted at 60°C for 18 hours. After cooling, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phases were washed with saturated brine (30 mL), 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 = 100:1 to 1:1) to obtain intermediate 18-6 (320 mg). LC-MS: m / z: 223.0 (M+H). + .

[0375] 5) Preparation of Intermediate 18-7

[0376] At room temperature, intermediate 18-6 (320 mg, 1.44 mmol), 4-bromo-2-methoxybenzene-1-sulfonyl chloride (822.5 mg, 2.88 mmol), and anhydrous acetonitrile (5.0 mL) were added to a 50 mL single-necked flask. After stirring for 30 minutes, dimethyl sulfoxide (11.3 mg, 0.14 mmol) and 3,5-lutidine (463.0 mg, 4.32 mmol) were added sequentially. 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 silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 2:1) to obtain intermediate 18-7 (570.0 mg). LC-MS: m / z: 471.0 / 473.0 (M+H) + .

[0377] 6) Preparation of Intermediate 18-8

[0378] At room temperature, intermediate 18-7 (500 mg, 1.06 mmol), tetrakis(triphenylphosphine)palladium (122.6 mg, 0.11 mmol), and anhydrous dioxane (20.0 mL) were added to a 100 mL single-necked flask. (Tributyltin)methanol (681.3 mg, 2.12 mmol) was added with stirring, and the mixture was reacted at 80°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 1:5) to obtain 18-8 (450 mg). LC-MS: m / z: 423.0 (M+H) + .

[0379] 7) Preparation of Intermediate 18-9

[0380] At room temperature, 18-8 (450 mg, 0.85 mmol), A (446.4 mg, 3.05 mmol), and anhydrous acetonitrile (3.0 mL) were added to a 50 mL single-necked flask. Cesium carbonate (995.0 mg, 3.05 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 18-9 (150.0 mg). LC-MS: m / z: 473.2 (M+H) + .

[0381] 8) Preparation of Intermediate 18-10

[0382] Under ice bath, 18-9 (150 mg, 0.32 mmol) and anhydrous tetrahydrofuran (5.0 mL) were added to a 50 mL three-necked flask. Diisobutylaluminum hydride (0.95 mL, 0.95 mmol, 1 mol / L) was slowly added under stirring, and the temperature was raised to room temperature for 1 hour. After quenching, sodium sulfate decahydrate was added to the reaction solution in batches, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to obtain intermediate 18-10 (60 mg). The crude product was used directly in the next step without purification. LC-MS: m / z: 445.2 (M+H) + .

[0383] 9) Preparation of Compound 18

[0384] At room temperature, intermediate 18-10 (20 mg, 0.04 mmol), intermediate 18-3 (21.8 mg, 0.09 mmol), and anhydrous acetonitrile (3.0 mL) were added to a 50 mL single-necked flask. Cesium carbonate (29.3 mg, 0.09 mmol) was added under stirring, and the mixture was reacted at 80°C 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 18 (2.0 mg). LC-MS: m / z: 519.1 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ10.26(s,1H),7.93(d,J=2.4Hz,1H),7.86(d,J=2.4Hz,1H),7.73(d,J=8.0Hz,1H),7.48(d,J=2.0Hz,1H),7.00(s,1H),6.85(s ,1H),6.75(d,J=8.0Hz,1H),6.71(s,1H),6.50(d,J=2.4Hz,1H),6.29(t,J= 2.0Hz, 1H), 5.39 (d, J = 10.0Hz, 4H), 4.14 (s, 1H), 3.79 (s, 3H), 3.71 (s, 3H).

[0385] Example 18. Synthesis of Compound 19, Compound 20, and Compound 21

[0386] Synthesis route

[0387] Experimental procedures

[0388] 1) Preparation of Intermediate 19-2

[0389] At room temperature, A (1.91 g, 11.63 mmol) and tetrahydrofuran (15.0 mL) were added to a 100 mL three-necked flask. The temperature was cooled to -60°C, and n-butyllithium (5.58 mL, 2.5 M) was added dropwise. The mixture was stirred at this temperature for 1 hour. 19-1 (2.50 g, 11.63 mmol) was dissolved in tetrahydrofuran (15.0 mL) and added dropwise to the reaction mixture. The mixture was reacted at -60°C for 1 hour. The reaction mixture was poured into 80 mL of ice water and extracted with ethyl acetate (50 x 3). The combined organic phases were dried over anhydrous 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 3:1) to obtain intermediate 19-2 (2.0 g). LC-MS: m / z: 299.9 / 301.9 (M+H). + .

[0390] 2) Preparation of Intermediate 19-3

[0391] Under ice bath, intermediate 19-2 (2.0 g, 6.66 mmol) and dichloromethane (20.0 mL) were added to a 100 mL single-necked flask. Dess-Martin reagent (4.24 g, 9.99 mmol) was added under ice bath and reacted at room temperature for 3 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 5:1) to obtain intermediate 19-3 (1.5 g). LC-MS: m / z: 297.8 / 299.8 (M+H) + .

[0392] 3) Preparation of Intermediate 19-4

[0393] At room temperature, intermediate 19-3 (900 mg, 3.32 mmol) and dioxane (10.0 mL) were added to a 100 mL single-necked flask. N,N-diisopropylethylamine (1.50 mL, 9.06 mmol), benzyl mercaptan (1.06 mL, 9.06 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (349 mg, 0.60 mmol), and tris(dibenzylideneacetone)dipalladium (276 mg, 0.30 mmol) were added sequentially under stirring. The atmosphere was purged with nitrogen three times and the reaction was carried out at 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 5:1) to obtain intermediate 19-4 (1.0 g). LC-MS: m / z: 342.0 (M+H). + .

[0394] 4) Preparation of Intermediate 19-5

[0395] Under ice bath, intermediate 19-4 (500 mg, 1.46 mmol), acetonitrile (10.0 mL), water (158 mg, 8.79 mmol), and acetic acid (86 mg, 1.46 mmol) were added to a 50 mL single-necked flask. 1,3-dichloro-5,5-dimethylhydantoin (433 mg, 2.20 mmol) was added under stirring and the mixture was allowed to react on ice 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 2:1) to obtain intermediate 19-5 (420 mg). LC-MS: m / z: 318.0 (M+H) + .

[0396] 5) Preparation of Compound 19

[0397] At room temperature, B (231 mg, 0.94 mmol) and tetrahydrofuran (3.0 mL) were added to a 50 mL three-necked flask, and potassium tert-butoxide (318 mg, 2.83 mmol) was added under ice bath. The reaction was continued in an ice bath for 30 minutes. 19-5 (300 mg, 0.94 mmol) was dissolved in tetrahydrofuran (2.0 mL) and added dropwise to the reaction solution. The reaction was continued under ice bath for 1.5 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 19 (140 mg). LC-MS: m / z: 526.2 (M+H) + , 1H NMR(400MHz, DMSO-d6)δ10.70(s,1H),8.35(d,J=3.0Hz,1H),8.27(d,J=3.0Hz,1H),8.06(dd,J=8.2,1.3Hz,1H),8.01-7.98(m,2H),7 .87(d,J=2.2Hz,1H),7.49(d,J=1.3Hz,1H),6.85(s,1H),6.74(s,1H),6.30(t,J=2.0Hz,1H),5.44(s,2H),3.86(s,3H),3.79(s,3H).

[0398] 6) Preparation of Compound 20

[0399] At room temperature, compound 19 (80 mg, 0.15 mmol) and methanol (2.0 mL) were added to a 50 mL single-necked flask. Sodium borohydride (17 mg, 0.45 mmol) was added under ice-bath conditions and allowed to react at room temperature for 18 hours. The reaction solution was poured into 30 mL of water and extracted with ethyl acetate (30 mL*3). The combined organic phases were 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 preparative HPLC (formic acid / acetonitrile / water system) to obtain compound 20 (45 mg). LC-MS: m / z: 527.9 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),7.87(d,J=1.9Hz,1H),7.77(d,J=8.1Hz,1H),7.71(d,J=3.2Hz,1H),7.65(d,J=3.2 Hz,1H),7.50(d,J=1.3Hz,1H),7.28(s,1H),7.19-7.14(m,1H),7.00(d,J=4.5Hz,1H),6.83(s,1H) ,6.71(s,1H),6.30(t,J=2.1Hz,1H),6.01(d,J=4.5Hz,1H),5.43(s,2H),3.76(s,3H),3.75(s,3H).

[0400] 7) Preparation of Compound 21

[0401] At room temperature, compound 20 (20 mg, 0.04 mmol) and tetrahydrofuran (2.0 mL) were added to a 25 mL single-necked flask. Imidazole (8 mg, 0.11 mmol), triphenylphosphine (15 mg, 0.06 mmol), and iodine (14 mg, 0.06 mmol) were added sequentially under stirring, and the mixture was reacted at 65°C 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 21 (2.0 mg). LC-MS: m / z: 512.2 (M+H) + , 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),7.87(d,J=2.2Hz,1H),7.74(t,J=5.9Hz,2H),7.61(d,J=3.3Hz,1H),7.49(d,J=1.8Hz,1H),7.2 0(s,1H),7.02(d,J=7.4Hz,1H),6.83(s,1H),6.72(s,1H),6.30(t,J=2.1Hz,1H),5.44(s,2H),4.41(s,2H),3.78(s,3H),3.75(s,3H).

[0402] Example 19. Synthesis of Compound 23

[0403] Synthesis route

[0404] Experimental procedures

[0405] 1) Preparation of Intermediate 23-2

[0406] Under ice-cooling, 23-1 (10.7 g, 43.66 mmol) and anhydrous dichloromethane (20.0 mL) were added to a three-necked flask. Chlorosulfonic acid (8.72 mL, 130.1 mmol) was slowly added with stirring. After the addition was complete, the temperature was raised to 60°C and stirred for 18 hours until the reaction was complete. The reaction solution was poured into water (200 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column (dichloromethane:methanol = 20:1 to 10:1) to obtain compound 23-2 (3.5 g) as a yellow solid. 1 H NMR (400MHz, Chloroform-d) δ8.19(s,1H),7.45(s,1H),4.08(s,3H),3.99(s,3H).

[0407] 2) Preparation of Intermediate 23-3

[0408] Under ice bath, compound 23-2 (1g, 4.09mmol) and anhydrous tetrahydrofuran (50.0mL) were added to a three-necked flask, and potassium bis(trimethylsilyl)amide (8.19mL, 8.19mmol, 1M / L THF) was slowly added dropwise with stirring. The reaction solution was stirred for 30 minutes and then A (2.81g, 8.19mmol) was added. The reaction was completed after 4 hours of reaction at 0°C. The reaction solution was poured into water (200mL), extracted with ethyl acetate (50mL*3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (dichloromethane: methanol = 50:1 to 20:1) to obtain yellow oily compound 23-3 (1.3g). LC-MS: m / z: 551.2 / 553.2[M+1] + .

[0409] 3) Preparation of Intermediate 23-4

[0410] Compound 23-3 (1 g, 0.73 mmol) and anhydrous tetrahydrofuran (20.0 mL) were added to a single-necked flask. Diisobutylaluminum hydride (14.51 mL, 14.51 mmol, 1 M / L hexane) was slowly added dropwise with stirring in an ice bath. The reaction was complete after 4 hours at 0°C. The reaction solution was quenched with solid sodium sulfate decahydrate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified on a silica gel column (dichloromethane:methanol = 50:1 to 20:1) to obtain compound 23-4 (100 mg, crude) as a yellow oil. LC-MS: m / z: 523.2 / 525.2 [M+1] + ,.

[0411] 4) Preparation of Intermediate 23-5

[0412] At room temperature, compound 23-4 (130 mg, 0.25 mmol), cyclopropylboronic acid (64.0 mg, 0.75 mmol), potassium carbonate (103.0 mg, 0.75 mmol), water (1.0 mL) and dioxane (10.0 mL) were added to a 50 mL single-necked flask, and DPPF palladium dichloride (18.43 mg, 0.02 mmol) was added with stirring. The reaction was completed after 3 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 (dichloromethane:methanol = 50:1 to 20:1) to obtain compound 23-5 (80 mg) as a yellow oil. LC-MS: m / z: 484.9 [M+1] +

[0413] 5) Preparation of Compound 23

[0414] At room temperature, 23-5 (80 mg, 0.13 mmol), C (57.0 mg, 0.39 mmol), and anhydrous acetonitrile (3.0 mL) were added to a 10 mL single-necked flask. Cesium carbonate (127 mg, 0.39 mmol) was added under stirring. The reaction was complete after 4 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 a white solid compound (6 mg). LC-MS: m / z: 534.9 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),7.86(dd,J=7.2,2.4Hz,2H),7.50(t,J=2.4Hz,2H),7.42(s,1H),6.82(s,1H),6.70(s,1H),6.59( s,1H),6.34–6.26(m,2H),5.55(s,2H),5.43(s,2H),3.76(s,3H),3.58(s,3H),2.04–1.89(m,1H),0.98–0.81(m,2H),0.59–0.45(m,2H).

[0415] Example 20. Synthesis of Compound 56, Compound 56-1, Compound 56-2, and Compound 87

[0416] Synthesis route

[0417] Experimental procedures

[0418] 1) Preparation of Intermediate 56-2

[0419] At room temperature, compound 56-1 (1.0 g, 4.09 mmol), A (1.75 g, 6.14 mmol) and anhydrous acetonitrile (20.0 mL) were added to a 100 mL single-necked flask. The reaction solution was stirred for 30 minutes, and then dimethyl sulfoxide (0.03 g, 0.41 mmol) and 3,5-lutidine (1.32 g, 12.28 mmol) were added in sequence. The reaction was completed after 18 hours at 20°C. The reaction solution was concentrated under reduced pressure, the crude product was slurried with methanol, the suspension was filtered, and the solid was dried to obtain compound 56-2 (1.7 g) as a white solid. LC-MS: m / z: 493.2 / 495.2 [M+1] +

[0420] 2) Preparation of Intermediate 56-3

[0421] At room temperature, compound 56-2 (800 mg, 1.62 mmol), tetrakis(triphenylphosphine)palladium (187 mg, 0.16 mmol) and anhydrous dioxane (15.0 mL) were added to a 100 mL single-necked flask, and (tributyltin)methanol (781 mg, 2.43 mmol) was added with stirring. The reaction was completed after 4 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 (dichloromethane:methanol = 100:0 to 92:8) to obtain compound 56-3 (360 mg) as a yellow solid. LC-MS: m / z: 445.2 [M+1] +

[0422] 3) Preparation of Intermediate 56-4

[0423] At room temperature, 56-3 (360 mg, 0.81 mmol) and anhydrous dichloromethane (10.0 mL) were added to a 100 mL single-necked flask. Phosphorus tribromide (241 mg, 0.89 mmol) was slowly added dropwise with stirring. After the addition was complete, the reaction was allowed to proceed at 20°C for 2 hours. The reaction solution was poured into water (60 mL), extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 56-4 (350 mg), which was used directly in the next step. LC-MS: m / z: 507.0 / 509.2 [M+1] + .

[0424] 4) Preparation of Compound 87

[0425] At room temperature, 56-4 (320 mg, 0.63 mmol), dioxane (10.0 mL) and water (2.0 mL) were added to a 100 mL single-necked bottle. B (185 mg, 0.95 mmol), potassium carbonate (261 mg, 1.89 mmol) and 1,1-bis(diphenylphosphine)dichloropalladium iron (47 mg, 0.06 mmol) were added sequentially under stirring. The reaction was completed at 80°C for 1 hour. After cooling, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol = 100:0 to 92:8) to obtain a yellow solid compound 87 (180 mg). LC-MS: m / z: 497.2 [M+1] + .

[0426] 5) Preparation of Compound 56

[0427] At room temperature, 87 (160 mg, 0.32 mmol), tetrahydrofuran (10.0 mL) and methanol (10.0 mL) were added to a 50 mL single-necked bottle, and palladium carbon (7 mg, 0.06 mmol) was added under stirring. The reaction was completed after 6 hours of reaction at room temperature. The reaction solution was filtered and the filtrate 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 compound 56 (70 mg). LC-MS: m / z: 499.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),7.88(d,J=2.2Hz,1H),7.70(d,J=8.0Hz,1H),7.5 0(d,J=1.6Hz,1H),7.05(s,1H),6.94(d,J=8.0Hz,1H),6.83(s,1H),6.74(s,1H),6.30(t ,J=2.0Hz,1H),5.44(s,2H),3.83(s,3H),3.79-3.73(m,4H),3.72-3.59(m,2H),3.33-3 .28(m,1H),2.75-2.62(m,2H),2.49-2.43(m,1H),1.93-1.82(m,1H),1.58-1.46(m,1H).

[0428] 6) Preparation of Compounds 56-P1 and 56-P2

[0429] Compound 56 (60 mg, 0.12 mmol) was separated by chiral column (Instrument: Waters UPC2 analytical SFC (SFC-H), Column: ChiralPak IG, 100×4.6 mm ID, 3 μm, Mobile phase: A for CO2 and B for Methanol (0.1% DEA), Gradient: B 45%, Flow rate: 3.0 mL / min, Back pressure: 2000 psi, Column temperature: 40°C, Wavelength: 214 nm) to give compound 56-P1 (22 mg, 0.04 mmol) and compound 56-P2 (24 mg, 0.05 mmol).

[0430] 56-P1: 1H NMR (400MHz, DMSO-d6) δ10.03 (s, 1H), 7.87 (d, J = 2.2Hz, 1H), 7.70 (d, J = 8.0 Hz,1H),7.49(d,J=1.6Hz,1H),7.05(s,1H),6.94(d,J=8.0Hz,1H),6.83(s,1H),6.74(s,1H),6.30(t,J=2.0Hz,1H),5.44(s,2H),3.83(s, 3H),3.79-3.72(m,4H),3.72-3.59(m,2H),3.32-3.29(m,1H),2.74-2 .62(m,2H),2.49-2.43(m,1H),1.93-1.82(m,1H),1.58-1.46(m,1H).

[0431] 56-P2: 1 H NMR (400MHz, DMSO-d6) δ10.04(s,1H),7.87(d,J=2.2Hz,1H),7.70(d,J=8.0Hz,1H),7.4 9(d,J=1.4Hz,1H),7.05(s,1H),6.94(d,J=8.0Hz,1H),6.83(s,1H),6.74(s,1H),6.30(t ,J=2.0Hz,1H),5.44(s,2H),3.83(s,3H),3.79-3.72(m,4H),3.72-3.58(m,2H),3.32-3 .29(m,1H),2.76-2.63(m,2H),2.49-2.43(m,1H),1.94-1.83(m,1H),1.58-1.46(m,1H).

[0432] Example 21. Synthesis of Compound 86

[0433] Synthesis route

[0434] Experimental procedures

[0435] 1) Preparation of Intermediate 86-2

[0436] At room temperature, 3-iodopyrazole (1 g, 5.16 mmol), trimethylethynylsilane (1.52 g, 15.47 mmol), cuprous iodide (100 mg, 0.52 mmol), triethylamine (2.14 mL, 15.47 mmol), and N,N-dimethylformamide (10.0 mL) were added to a 100 mL single-necked flask. Bistriphenylphosphine palladium dichloride (360 mg, 0.52 mmol) was added with stirring. The reaction was complete after 18 hours at 80°C. The reaction solution was poured into water, extracted with ethyl acetate (50 mL x 3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain compound 86-2 (550 mg) as a yellow solid. LC-MS: m / z: 165.0 [M+1] + .

[0437] 2) Preparation of Intermediate 86-3

[0438] Under ice bath, 86-2 (550 mg, 3.35 mmol), triethylamine (0.93 mL, 6.70 mmol) and anhydrous dichloromethane (10.0 mL) were added to a 100 mL three-necked flask, and methylsulfonyl chloride (0.31 mL, 4.02 mmol) was slowly added under stirring. The temperature was raised to room temperature and stirring was continued for 2 hours until the reaction was complete. The reaction solution was poured into water (100 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain white solid compound 86-3 (500 mg, 2.06 mmol) with a yield of 61.62%. LC-MS: m / z: 243.0 [M+1] + .

[0439] 3) Preparation of Intermediate 86-5

[0440] At room temperature, 86-4 (10.0 g, 45.87 mmol) and tetrahydrofuran (50.0 mL) were added to a 100 mL single-necked flask. A solution of sodium methoxide in methanol (8.5 mL, 45.87 mmol, 5.4 mol / L) was slowly added dropwise with stirring. The reaction was complete after 18 hours at 25°C. 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 = 10:1 to 1:1) to obtain intermediate 86-5 (10.55 g, 45.64 mmol) as a white solid in a 99.53% yield. LC-MS: m / z: 230.1 / 232.1 [M+1]. + .

[0441] 4) Preparation of Intermediate 86-6

[0442] At room temperature, 86-5 (5.2 g, 22.60 mmol), triethylamine (9.4 mL, 67.81 mmol), dimethyl sulfoxide (50.0 mL) and anhydrous methanol (50.0 mL) were added to a 250 mL single-necked flask. DPPF palladium dichloride (830 mg, 1.13 mmol) was added under stirring at room temperature. The reaction was completed after 18 hours at 80°C under a carbon monoxide environment. After cooling, the reaction solution was poured into water (300 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1) to obtain compound 86-6 (3.5 g) as a white solid. LC-MS: m / z: 210.0 [M+1] +

[0443] 5) Preparation of Intermediate 86-7

[0444] At room temperature, compound 86-6 (7 g, 33.46 mmol), potassium carbonate (23.12 g, 167.32 mmol), and N,N-dimethylformamide (50.0 mL) were added to a 100 mL single-necked flask. Acetylhydroxamic acid (7.54 g, 100.39 mmol) was added under stirring. The reaction was completed after 18 hours at 60°C. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was washed with water, filtered, and dried to obtain compound 86-7 (2 g) as a green solid. LC-MS: m / z: 223.0 [M+1] + .

[0445] 6) Preparation of Intermediate 86-8

[0446] At room temperature, compound 86-7 (1 g, 4.50 mmol), A (3.21 g, 11.25 mmol) and anhydrous acetonitrile (20.0 mL) were added to a 100 mL single-necked flask. The reaction solution was stirred for 30 minutes, followed by the addition of dimethyl sulfoxide (40 mg, 0.45 mmol) and 3,5-lutidine (1.45 g, 13.50 mmol). 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 (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain compound 86-8 (1.5 g, 3.18 mmol) as a white solid with a yield of 70.72%. LC-MS: m / z: 471.0 [M+1] +

[0447] 7) Preparation of Intermediate 86-9

[0448] At room temperature, compound 86-8 (2 g, 4.24 mmol), tetrakis(triphenylphosphine)palladium (490 mg, 0.42 mmol) and anhydrous dioxane (30.0 mL) were added to a 100 mL single-necked flask, and (tributyltin)methanol (1.50 g, 4.67 mmol) was added with stirring. The reaction was completed after 18 hours at 80°C. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (dichloromethane:methanol = 50:1 to 10:1) to obtain compound 86-9 (1.6 g) as a yellow solid. LC-MS: m / z: 423.2 / 425.2 [M+1] + .

[0449] 8) Preparation of Intermediate 86-10

[0450] To a 10 mL single-necked flask at room temperature were added 86-9 (1.6 g, 3.03 mmol), B (1.33 g, 9.09 mmol), and anhydrous acetonitrile (30.0 mL). Cesium carbonate (2.96 g, 9.09 mmol) was added with stirring. After 3 hours at 70°C, the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified on a silica gel column (dichloromethane:methanol = 100:0 to 10:1) to afford compound 86-10 (750 mg) as a yellow solid in a 52.39% yield. LC-MS: m / z: 473.2 [M+1]. + .

[0451] 9) Preparation of Intermediate 86-11

[0452] Under ice bath, 86-10 (700 mg, 1.48 mmol) and anhydrous tetrahydrofuran (20.0 mL) were added to a 100 mL three-necked flask, and lithium aluminum hydride (2.96 mL, 2.96 mmol, 1 mol / L) was slowly added under stirring. The reaction was completed after warming to room temperature for 2 hours. After quenching, sodium sulfate decahydrate was added to the reaction solution in batches, and the mixture was filtered through celite and concentrated under reduced pressure to give compound 86-11 (600 mg) as a white solid with a yield of 91.12%. LC-MS: m / z: 444.9 [M+1] + .

[0453] 10) Preparation of Compound 86

[0454] At room temperature, 86-11 (300 mg, 0.67 mmol), 86-3 (327.19 mg, 1.35 mmol), and anhydrous acetonitrile (5.0 mL) were added to a 10 mL single-necked flask. Cesium carbonate (659.76 mg, 2.02 mmol) was added under stirring. The reaction was complete after 3 hours at 70°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 a white solid compound (6 mg). LC-MS: m / z: 519.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.85(d,J=2.4Hz,1H),7.72(d,J=8.0Hz,1H),7.59(d,J=2.0Hz,1H),7.48(d,J=2.0Hz,1H),6.97(s,1H),6 .74(d,J=8.0Hz,1H),6.70–6.51(m,3H),6.28(t,J=2.0Hz,1H),5.49(s,2H),5.36(s,2H),4.85(s,1H),3.77(s,3H),3.69(s,3H).

[0455] Example 22. Synthesis of Compound 88

[0456] Synthesis route

[0457] Experimental procedures

[0458] 1) Preparation of Intermediate 88-2

[0459] At room temperature, 88-1 (5.0 g, 20.40 mmol), dichloromethane (40.0 mL), and acetonitrile (40.0 mL) were added to a 250 mL three-necked flask. Sodium iodide (6.12 g, 40.80 mmol) was added with stirring. Aluminum chloride (5.44 g, 40.80 mmol) was slowly added portionwise at 0°C. The reaction was allowed to react at room temperature for 5 hours until complete. The reaction solution was poured into 200 mL of saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 3:1) to obtain 88-2 (4.5 g, 19.48 mmol) as a yellow solid in a 95.54% yield. LC-MS: 231.0 / 233.0 [M+1]. + .

[0460] 2) Preparation of Intermediate 88-3

[0461] At room temperature, 88-2 (4.5 g, 19.48 mmol) and N,N-dimethylformamide (50.0 mL) were added to a 250 mL single-necked flask. Potassium carbonate (8.08 g, 58.43 mmol) and methyl bromoacetate (4.47 g, 29.22 mmol) were added under stirring. After reacting at room temperature for 1 hour, the temperature was raised to 80°C and the reaction was completed after 17 hours. The reaction solution was poured into 200 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 3:1) to obtain 88-3 (3.80 g) as a yellow solid. LC-MS: 285.0 / 287.0 [M+1] + .

[0462] 3) Preparation of Intermediate 88-4

[0463] At room temperature, 88-3 (3.60 g, 12.63 mmol) and dichloromethane (80.0 mL) were added to a 250 mL single-necked flask. Boron tribromide (2.43 mL, 25.26 mmol) was added dropwise at -60°C. The reaction was allowed to complete after 18 hours at room temperature. The reaction solution was poured into 200 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 88-4 (3.25 g) as a yellow solid. LC-MS: m / z: 254.8 / 256.8 [M-1] - .

[0464] 4) Preparation of Intermediate 88-5

[0465] At room temperature, 88-4 (2 g, 9.21 mmol) was dissolved in methanol (40.0 mL). Concentrated sulfuric acid (3 mL, 55.98 mmol) was added under ice-cooling conditions, and the mixture was heated to 60°C and stirred for 3 hours to produce the product. The reaction mixture was poured into 200 mL of ice water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 2:1) to afford 88-5 (3.30 g, 12.17 mmol) as a yellow solid in a 96.28% yield. LC-MS: 271.0 / 273.0 [M+1]. + .

[0466] 5) Preparation of Intermediate 88-6

[0467] At room temperature, 88-5 (1.0 g, 3.69 mmol) and N,N-dimethylformamide (10.0 mL) were added to a 50 mL single-necked flask. Potassium carbonate (1.53 g, 11.07 mmol), potassium iodide (0.12 g, 0.74 mmol), and bromoacetaldehyde diethyl acetal (0.87 g, 4.43 mmol) were added under stirring. The reaction was allowed to proceed at 100°C for 18 hours until complete. 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. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0 to 4:1) to obtain 88-6 (900 mg) as a yellow solid. LC-MS: 409.0 / 411.0 [M+Na] + .

[0468] 6) Preparation of Intermediate 88-7

[0469] At room temperature, 88-6 (870 mg, 2.25 mmol) and toluene (15.0 mL) were added to a 100 mL single-necked flask. Polyphosphoric acid (553 mg, 6.74 mmol) was then added with stirring. The reaction was complete at 100°C for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether:ethyl acetate = 100:0 to 4:1) to afford 88-7 (550 mg, 1.86 mmol) as a white solid in an 82.96% yield. LC-MS: m / z: 295.0 / 297.0 [M+1]. + .

[0470] 7) Preparation of Intermediate 88-8

[0471] At room temperature, 88-7 (200 mg, 0.68 mmol) and dioxane (4.0 mL) were added to a 50 mL single-necked flask. (Tributyltin)methanol (326 mg, 1.02 mmol) and tetrakis(triphenylphosphine)palladium (78 mg, 0.07 mmol) were added sequentially under stirring. The reaction was allowed to proceed at 100°C for 18 hours to completion. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 3:1) to obtain the yellow solid intermediate 88-8 (70 mg, 0.28 mmol) in a yield of 41.95%. LC-MS: m / z: 247.0 [M+1] + .

[0472] 8) Preparation of Intermediate 88-9

[0473] At room temperature, 88-8 (60 mg, 0.24 mmol) and acetonitrile (2.0 mL) were added to a 50 mL single-necked flask. Cesium carbonate (238 mg, 0.73 mmol) and 8a (71 mg, 0.49 mmol) were added with stirring. The reaction was complete after 2 hours at 75°C. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 3:1) to obtain intermediate 88-9 (50 mg) as a yellow solid in a yield of 69.25%. LC-MS: m / z: 297.0 [M+1]. + .

[0474] 9) Preparation of Intermediate 88-10

[0475] At room temperature, 88-9 (50 mg, 0.17 mmol), tetrahydrofuran (2.0 mL), and methanol (1.0 mL) were added to a 50 mL single-necked flask. A solution of lithium hydroxide (21 mg, 0.51 mmol) in water (1.0 mL) was added under stirring. The reaction was complete after 3 hours at 20°C. The reaction solution was poured into water, adjusted to pH 3, extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford intermediate 88-10 (45 mg) as a yellow solid in a 94.47% yield. LC-MS: m / z: 283.0 [M+1] + .

[0476] 10) Preparation of Compound 88

[0477] At room temperature, 88-10 (25 mg, 0.09 mmol) and dichloromethane (2.0 mL) were added to a 25 mL single-necked flask. 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (25 mg, 0.13 mmol), 4-dimethylaminopyridine (22 mg, 0.18 mmol), and 10a (24 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 (14 mg) with a yield of 31.14%. LC-MS: m / z: 508.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.82(s,1H),8.27(s,1H),8.11(d,J=2.1Hz,1H),7.90(d,J=2.0Hz,1H),7.89(d,J=2.5Hz,1H),7.71(d,J=8.6Hz,1H), 7.48(d,J=1.2Hz,1H),7.36(s,1H),7.16(d,J=8.8Hz,1H),7.09(d,J=2. 1Hz, 1H), 6.29 (t, J = 1.9Hz, 1H), 5.71 (s, 2H), 3.83 (s, 3H), 1.31 (s, 9H).

[0478] Example 23. Synthesis of Compound 89

[0479] Synthesis route

[0480] Experimental procedures

[0481] 1) Preparation of Intermediate 89-2

[0482] Under ice bath, 3-bromo-4-methylanisole (2 g, 9.95 mmol) and dichloromethane (20.0 mL) were added to a 100 mL single-necked bottle, and chlorosulfonic acid (3.31 mL, 49.74 mmol) was added under stirring. After 2 hours of reaction at room temperature, the reaction was completed. The reaction solution was poured into water (100.0 mL), extracted with dichloromethane (50 mL x 3), and the combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 89-2 (1.8 g).

[0483] 2) Preparation of Intermediate 89-3

[0484] At room temperature, compound 89-2 (921.15 mg, 3.08 mmol), A (300 mg, 1.23 mmol) and anhydrous acetonitrile (5.0 mL) were added to a 100 mL single-necked bottle. The reaction solution was stirred for 30 minutes, and then dimethyl sulfoxide (9.60 mg, 0.12 mmol) and 3,5-lutidine (394.86 mg, 3.68 mmol) were added in sequence. 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 (dichloromethane: methanol = 50:1 to 10:1) to obtain compound 89-3 (400 mg). LC-MS: m / z: 507.0 [M+1] + .

[0485] 3) Preparation of Intermediate 89-4

[0486] At room temperature, compound 89-3 (200 mg, 0.39 mmol), tetrakis(triphenylphosphine)palladium (45.55 mg, 0.04 mmol), and anhydrous dioxane (5.0 mL) were added to a 10 mL single-necked flask. (tributyltin)methanol (253.15 mg, 0.79 mmol) was added with stirring. The reaction was completed 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 to obtain compound 89-4 (100 mg). LC-MS: m / z: 459.2 [M+1] + .

[0487] 4) Preparation of Compound 89

[0488] At room temperature, 89-4 (100 mg, 0.22 mmol), B (63.76 mg, 0.44 mmol), and anhydrous acetonitrile (3.0 mL) were added to a 10 mL single-necked flask. Cesium carbonate (213.19 mg, 0.65 mmol) was added under stirring. The reaction was completed 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 compound 89 (8 mg) with a yield of 7.21%. LC-MS: m / z: 509.2 [M+1]. + . 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),7.87(d,J=2.4Hz,1H),7.81(d,J=2.4Hz,1H),7.59(s,1H),7.49(d,J=2.0Hz,2H),6.7 9(s,1H),6.69(s,1H),6.63(s,1H),6.29(q,J=2.0Hz,2H),5.42(s,2H),5.37(s,2H),3.78(s,3H),3.60(s,3H),2.24(s,3H).

[0489] Example 24. Synthesis of Compound 90

[0490] Synthesis route

[0491] Experimental procedures

[0492] 1) Preparation of Compound 90

[0493] Under ice bath, (2R)-3,3-difluoro-2-methylazetidine hydrochloride (43.07 mg, 0.30 mmol) was added to a 50 mL single-necked flask. Sodium hydride (20.00 mg, 0.50 mmol) was added with stirring and the temperature was maintained and stirring was continued for 0.5 hours. Compound 56-4 (50 mg, 0.10 mmol) was added. After 18 hours of reaction at 60°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 (6.24 mg) with a yield of 11.87%. LC-MS: m / z: 534.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.09(s,1H),7.86(d,J=2.4Hz,1H),7.74(d,J=8.0Hz,1H),7.49(d,J=2.0Hz,1H),7. 08(s,1H),7.01(d,J=8.0Hz,1H),6.80(s,1H),6.72(s,1H),6.29(t,J=2.0Hz,1H),5.43(s,2H),3.83(s,4H), 3.78(s,3H),3.74–3.60(m,3H),3.31–3.24(m,1H),0.99(d,J=6.4Hz,3H).

[0494] Example 25. Synthesis of Compound 91

[0495] Synthesis route

[0496] Experimental procedures

[0497] 1) Preparation of Compound 91

[0498] Under ice bath, 4,4-difluoropiperidine (36.34 mg, 0.30 mmol) was added to a 50 mL single-necked flask. Sodium hydride (20 mg, 0.50 mmol) was added while stirring, and stirring was continued for 0.5 hours while maintaining the temperature. Compound 56-4 (50 mg, 0.10 mmol) was added. After reacting at 60°C for 2 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 high performance liquid chromatography (ammonium bicarbonate / acetonitrile / water system) to obtain a white solid compound (25 mg). LC-MS: m / z: 548.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ7.85(d,J=2.4Hz,1H),7.73(d,J=8.0Hz,1H),7.48(d,J=2.0Hz,1H),7.28(s,1H),7.00(s,1H),6.93(d,J=8.0Hz,1H) ,6.68(s,1H),6.62(s,1H),6.28(t,J=2.0Hz,1H),5.39(s,2H),3.82(s ,3H),3.74(s,3H),3.55(s,2H),2.49–2.43(m,4H),2.06–1.84(m,4H).

[0499] Biological test methods

[0500] Test 1. KATs acetyltransferase activity assay

[0501] The inhibitory effect of the compounds of the present application on the acetyltransferase activity of KATs was evaluated by the TR-FRTE method.

[0502] The assay reactions were performed in 384-well plates (Greiner, 784075) with a total reaction volume of 10 μl. All reactions were performed in assay buffer (50 mM Tris-HCl, pH 7.5, 0.1 mM EDTA, 1 mM DTT, 330 nM TSA, 0.01% BSA, 0.01% Tween 20).

[0503] 1) Dilute the compound in DMSO, transfer 50 nanoliters of the compound to a 384-well plate using an Echo. Add 2.5 microliters of enzyme solution (KAT6: active motif, 81223; KAT6B: active motif, 81224; KAT5: SignalChem, K314-380G; KAT7: ICE, S2210F-H21HF; KAT8: active motif, 81225) and incubate at room temperature for 15 minutes.

[0504] 2) Subsequently, add 2.5 μL of the mixture of KAT6A / KAT6B: Biotin-H3(1-21) (Genscript, C6829GL060) or KAT5 / 7 / 8: Bio-H4(1-25) (Genscript, C736BGL100) and AcCOA (Sigma, A2056), and react at room temperature for 90 minutes. The final reaction concentrations of the enzyme and the substrate are: KAT6A: 2 nM; KAT6B: 2 nM; KAT5: 1.5 nM; KAT7: 0.5 nM; KAT8: 2 nM; Biotin-H3(1-21): 200 nM; KAT7 / 8: Bio-H4(1-25): 300 nM; KAT5: Bio-H4(1-25): 200 nM; AcCOA: 2 μM.

[0505] 3) After the reaction, add 5 μL of the detection reagent mixture of europium anti-acetyl histone H4 lysine (H4Kac-pan) antibody (Europium-anti-acetyl-Histone H4 Lysine(H4Kac pan)Antibody) (Perkin Elmer, TRF0412) and LANCE Ultra ULight TM -Streptavidin (Perkin Elmer, TRF0102). The detection reagent buffer solution is LANCETM Detection buffer (10x) (Perkin Elmer, CR97-100). React at room temperature for 60 minutes, and read the HTRF signal value (Ratio: 665 / 620 nm) using BMG PHERAstar FSX.

[0506] Perform IC50 fitting using the non-linear fitting - four-parameter formula in GraphPad Prism 8 software. The results of some representative compounds are shown in Table 1.

[0507] Table 1 Activity data

[0508] A indicates IC50 ≤ 10 nM, B indicates 10 nM < IC50 ≤ 50 nM, and C indicates IC50 > 50 nM

[0509] Table 2

[0510] A indicates IC50 ≤ 100 nM, B indicates 100 nM < IC50 ≤ 500 nM, and C indicates IC50 > 500 nM

[0511] As described above, the compounds of the present application have good inhibitory activity against lysine acetyltransferase, better inhibitory activity against KAT6A and good selectivity for KAT6B. At the same time, they have good selectivity for KAT5, KAT7, and KAT8.

[0512] Test 2. ZR-75-1 cell proliferation experiment

[0513] The inhibitory effect of the compounds of the present application on tumor cell proliferation was evaluated by the CTG detection method.

[0514] ZR-75-1 cells (1000 cells / well / 100 μL) were seeded in a 96-well plate (Corning, 3603) and incubated overnight in a 37 °C & 5% CO2 incubator. The compounds were diluted with the medium and added to the 96-well plate, and then continued to be cultured in the incubator. The medium containing the same concentration of the compound was replaced every 5 days for a total of 10 days. After the culture was completed, 60 μL of CellTiter-Glo reagent (CTG, Promega, G7573) was added to each well, and the cells were lysed by shaking in the dark for 2 minutes and then incubated at room temperature in the dark for another 30 minutes. The light signal value was read using a BMG PHERAstar FSX.

[0515] Nonlinear fitting - four-parameter formula in GraphPad Prism 8 software was used for IC 50 fitting. The results of some representative compounds are shown in Table 3.

[0516] Table 3 Activity data

[0517] A indicates IC50 ≤ 50 nM, B indicates 50 nM < IC50 ≤ 100 nM, and C indicates IC50 > 100 nM

[0518] As described above, the compounds of the present invention have good inhibitory activity against the proliferation of ZR-75-1 tumor cells.

[0519] Test 3. Histone H3 acetylation experiment

[0520] The inhibitory effect of the compounds of the present application on histone H3 acetylation in tumor cells was evaluated.

[0521] ZR-75-1 cells (500 cells / well) were seeded in 384-well plates and cultured overnight in a 37°C & 5% CO2 incubator. 50 nanoliters of diluted compounds were added to the 384-well plates using an Echo and incubated for a further 72 hours. The supernatant was discarded, and 8% paraformaldehyde was added and fixed at room temperature for 20 minutes. After washing twice with PBS, the cells were permeabilized by adding methanol and incubating for 10 minutes. After washing twice with PBS, the cells were blocked by adding Li-Cor blocking buffer (Licor, 927-70001) and incubating at room temperature for 1 hour. The blocking buffer was discarded, and primary antibodies (recombinant Anti-Histone H3 (acetyl K23) antibody, abcam, ab177275; Anti-Histone H4 antibody, abcam, ab31830) diluted in the blocking buffer were added and incubated at 4°C overnight. After washing three times with PBST (0.05% Tween-20 in PBS), fluorescent secondary antibodies (IRDye 680RD Goat anti-mouse, Licor, 926-68070; IRDye 800CW Goat anti-rabbit, Licor, 926-32211) diluted in blocking buffer were added and incubated at room temperature in the dark for 1 hour. After washing three times with PBST, the fluorescence signal of each well was scanned and quantified using the Odyssey CLx.

[0522] IC was calculated using the nonlinear fitting-four-parameter formula in GraphPad Prism 8 software. 50 Fitting.

[0523] The compound of the present application has good inhibitory activity on histone H3 acetylation.

[0524] Test 4. Kinetic Solubility Experiment

[0525] Evaluate the kinetic solubility of the compound. Add 30 μL of 10 mM test compound to the bottom of a 1.5 mL glass tube. Add 970 μL of buffer solution according to test requirements. Add a stirring bar, cover the lid, place in a mixer, and shake at 25°C and 1100 rpm for 2 hours. After 2 hours, observe whether there is a solid compound in the glass tube and take a photo to record. Remove the stirring bar, transfer 200 μL of sample to the filter plate, filter, and collect the filtrate. Preparation of filtrate sample: Take 10 μL of filtrate and add 10 μL of DMSO equilibration matrix, then add 980 μL of internal standard stop solution, dilute 10 times with 50% methanol water or acetonitrile water, vortex mix, and analyze by LCMS / MS. The dilution factor can be adjusted according to the compound response signal. Dilute the 10 mM stock solution to 300 μM with DMSO. Standard sample preparation: 10 μL of 300 μM stock solution was added to 10 μL of assay buffer to equilibrate the matrix. Then, 980 μL of internal standard stop solution was added. Dilute 10-fold with 50% methanol or acetonitrile, vortex mix, and analyze by LC-MS / MS. Using the internal standard method, the ratio of the sample peak area to the internal standard peak area was used for calculation. Dilution factor.

[0526] Table 4 Note: FaSSIF (Fasting State Simulated Intestinal Fluid), FeSSIF (Fed State Simulated Intestinal Fluid)

[0527] The compound of the present application has good kinetic solubility.

[0528] Test 5. Liver microsome metabolic stability experiment

[0529] The metabolic stability of the compounds was assessed in an in vitro liver microsome incubation system. To a 96-well plate, 358 μL of a 0.5587 mg / mL microsomal solution and 40 μL of NADPH solution were added. For negative samples, 40 μL of phosphate buffer solution was added. The mixture was vortexed at 800 rpm for 10 seconds and preincubated in a 37°C water bath for 10 minutes. After preincubation, 2 μL of compound working solution was added to each well to initiate the reaction. After mixing, 50 μL of the reaction mixture was removed from each well at 0.5, 15, 30, 45, and 60 minutes and added to 200 μL of internal standard stop solution to terminate the reaction. The reaction was performed in a 37°C water bath at 60 rpm. After vortexing at 800 rpm for 3-5 minutes, the mixture was centrifuged at 3220 g for 30 minutes at 4°C. Take 100 μL of supernatant and mix it with 100 μL of ultrapure water (the ratio of supernatant to ultrapure water can be adjusted according to the sample chromatographic peak shape and signal response) for liquid chromatography-mass spectrometry analysis. Using the internal standard method, the ratio of the sample peak area to the internal standard peak area is used to calculate the residual percentage (the ratio of the sample to the internal standard peak area at 0.5 minutes is 100%). The natural logarithm of the residual percentage is plotted against the incubation time. The slope of the straight line is the elimination rate constant k, and the half-life is calculated. and clearance

[0530] Table 5

[0531] The compound of the present application has good metabolic stability in an in vitro liver microsome incubation system.

[0532] Test 6. Cytochrome P450 enzyme inhibition assay in human liver microsomes

[0533] Evaluate compound inhibition of cytochrome P450 enzymes in human liver microsomes. Prepare substrate working solution at the optimized substrate concentration. Dilute the test compound with DMSO as needed. Prepare the assay system at a ratio of 176 μL phosphate buffer solution: 2 μL human liver microsomes: 1 μL substrate. Add 1 μL of the test compound working solution to the bottom of a 96-well plate. Add 179 μL of the assay system to the plate and pre-incubate in a 37°C water bath for 5 minutes. Initiate the reaction by adding 20 μL of 10 mM NADPH to the plate, mix at 800 rpm for 10 seconds, and then incubate at 37°C in a water bath at 60 rpm. Incubate for different CYP enzymes for varying reaction times. Terminate the reaction by adding 300 μL of internal standard stop solution to the plate. Mix the terminated sample and centrifuge at 3220 g for 30 minutes at 4°C. Mix 100 μL of supernatant with 100 μL of ultrapure water (the ratio of supernatant to ultrapure water can be adjusted based on sample chromatographic peak shape and signal response) for LC / MS analysis. To detect metabolites of specific substrates, use the internal standard method to calculate the peak area ratio of the sample and internal standard. Use this ratio to calculate the percentage inhibition or use the XLfit4 parameter formula to fit the half-maximal inhibitory concentration (IC50).

[0534] Table 6

[0535] The compound of the present application has weak inhibitory activity on cytochrome P450 enzymes in human liver microsomes.

[0536] Test 7. Evaluation of compound permeability in Caco2 cells

[0537] 50 μL and 25 mL of cell culture medium were added to the upper and lower chambers of each well of the 3391 Transwell plate, respectively. The Transwell plate was pre-incubated at 37°C, 5% CO2 for 1 hour before seeding the cells. 550 μL of a cell suspension at 10 cells / mL was seeded into the upper chamber and cultured in a cell culture incubator at 37°C, 5% CO2, and 95% relative humidity for 14-30 days, with medium replacement every two days. The electrical resistance (TEER) of the monolayer was measured using an EVOM3. The transwell plate was washed twice with prewarmed HBSS (10 mM HEPES, pH 7.4) and then incubated at 37°C for 30 minutes. A 1 mM DMSO stock solution of the test compound was prepared and diluted to a 5 μM working solution in buffer (pH 7.2-7.4). The working solution was added to the upper chamber, and HBSS (10 mM HEPES, pH 7.4) was added to the lower chamber. 50 μL of the working solution was transferred to a sample plate containing 200 μL of pre-chilled methanol as the internal standard, as the zero point. The plate was incubated at 37°C, 5% CO2, and 95% relative humidity for 2 hours. At the end of the incubation period, 50 μL of the solution was transferred from each well to a sample plate containing 200 μL of the methanol internal standard and centrifuged at 4000 rpm for 30 minutes. Transfer 100 μL of supernatant to an assay plate containing 100 μL of water and centrifuge for 10 minutes before LCMS / MS analysis. Discard all liquid from the transwell plate, add 100 μL of 100 μM Lucifer Yellow solution to the upper chamber, and 300 μL of HBSS (10 mM HEPES, pH 7.4) to the lower chamber. After a half-hour incubation, transfer 80 μL from each chamber to the plate and read fluorescence at 427 nM excitation and 536 nM emission.

[0538] Table 7

[0539] The compound of the present application has good permeability in Caco2 cells.

[0540] Test 8. Plasma protein binding rate measurement by equilibrium dialysis

[0541] The binding rate of the compound to plasma protein was detected by equilibrium dialysis. Take 2 μL of 200uM compound working solution, add it to 398 μL of plasma, and vortex to mix. Take 50 μL of the sample after drug addition, add 50 μL of PBS, then add 300 μL of internal standard stop solution and vortex to mix, and record it as T0. After the equilibrium dialysis device (HTD) is installed, add 120 μL of the sample after drug addition and 120 μL of PBS to both sides of the HTD dialysis device, seal the HTD device with a gas permeable membrane, and incubate the dialysis device and the remaining sample at 37°C, 100 rpm, and 5% CO2 for 6 hours. Take 50 μL of the sample on the plasma side of the HTD dialysis device after incubation, add 50 μL of PBS, then add 300 μL of internal standard stop solution, vortex to mix, and record it as P. Take 50 μL of the sample from the PBS side of the HTD dialysis device after incubation, add 50 μL of plasma, then add 300 μL of internal standard stop solution, vortex mix, and record it as B. Take 50 μL of the remaining sample after incubation, add 50 μL of PBS, then add 300 μL of internal standard stop solution, vortex mix, and record it as T6. Centrifuge all samples at 3220g and 4°C for 30 minutes, take 100 μL of supernatant and mix it with 100 μL of ultrapure water (the ratio of supernatant to ultrapure water can be adjusted according to the sample chromatographic peak shape and signal response) for liquid chromatography-mass spectrometry analysis. Using the internal standard method, the ratio of the sample peak area to the internal standard peak area Ratio is used for calculation. Fu% = Ratio B / Ratio P ×100%, Bond%=100%-Fu.

[0542] Table 8

[0543] The compound of the present application has a relatively reasonable binding rate with plasma proteins.

[0544] Test 9. Pharmacokinetic Experiment

[0545] Animal Dosing: Add the solvents sequentially to a clear glass vial containing a specific mass of compound according to the order of the solvent formulation. Vortex and sonicate immediately after each addition to achieve the desired concentration for animal dosing. Administer the drug intravenously or orally according to the prescribed dosing volume and route, based on animal weight.

[0546] Sample collection: According to the prescribed blood collection method (rats: jugular vein blood collection; mice: orbital venous plexus blood collection), a certain volume of blood sample (rats: 0.2 mL; mice: 0.03 mL) was collected, and then transferred to a microcentrifuge tube containing EDTA-K2 anticoagulant. After centrifugation at 4°C and 4000g for 5 min, the supernatant was collected and stored in a refrigerator at -75°C ± 15°C.

[0547] Sample Preparation: Preparation of Standard Samples: Dilute two 1 mg / mL stock solutions with an appropriate diluent (acetonitrile:water = 1:1, v / v) to prepare working solutions for the standard curve and quality control samples, respectively. Testing: Perform spot checks at intervals, and estimate the sample concentration range based on the test data. Plasma Sample Dilution: Dilute plasma samples that may exceed the upper limit of quantitation with blank plasma. Plasma Sample Preparation: Add 200 μL or 300 μL of internal standard precipitant (acetonitrile:methanol = 1:1, v / v) to plasma samples, standard curve samples, and quality control samples. For double blank samples, add an equal volume of organic solvent (acetonitrile:methanol = 1:1, v / v). Vortex for 1-2 minutes, freeze at -20°C for approximately 20 minutes, centrifuge at 4000 g for 40 minutes at 4°C, dilute proportionally with diluent (methanol:water = 1:1, v / v), vortex for 1-2 minutes, and centrifuge at 4000 g for 5 minutes at 4°C. The samples were detected using LC-MS / MS method.

[0548] Table 9. Pharmacokinetic parameters of the proposed compounds in mice Note: Yangshen compound refers to Example 45 in WO2020 / 254946A1, namely 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide

[0549] The compounds of the present application have high blood concentrations, large exposure amounts, and long half-lives in mice, and have pharmacokinetic advantages; in particular, the half-life of compound 1 is much longer than that of other compounds and Yangshen compounds.

[0550] Table 10. Pharmacokinetic parameters of the proposed compounds in rats

[0551] The compound of the present application has high blood concentration, large exposure, and long half-life in rats, and has pharmacokinetic advantages.

[0552] Test Example 10: Study on antitumor efficacy in a human breast cancer ZR-75-1 cell xenograft model

[0553] This study evaluated the anti-tumor effect of the test substance in a human breast cancer ZR-75-1 cell xenograft model.

[0554] Approximately 1×10 7 ZR-75-1 cells were injected subcutaneously into Mice (Biocytogen Pharmaceuticals (Beijing) Co., Ltd., Cat#: B-CM-002). When the tumor volume of the mice reached approximately 200±50mm 3 At 4 hr, mice were randomly divided into groups (6 mice per group) based on tumor volume. The test substance was then administered orally. The specific dosing schedule is shown in the table below.

[0555] Table 11. Group dosing regimen Note: Yangshen compound refers to Example 45 in WO2020 / 254946A1, namely 2-methoxy-N-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-sulfonamide.

[0556] The tumor volume was measured twice a week and the weight of the mice was recorded. 3 When , it was euthanized.

[0557] The lengths of the major and minor axes of the tumor were measured, and the tumor volume was calculated as 0.5×(major axis)×(minor axis)2. The tumor growth inhibition rate (TGI) was calculated using the following formula: TGI (%) = [1-(Ti-T0) / (Vi-V0)]×100%. Wherein, Ti is the average tumor volume of the treatment group on day i. T0 is the average tumor volume of the treatment group on day zero. Vi is the average tumor volume of the control group on day i. V0 is the average tumor volume of the control group on day zero. Statistical analysis was performed using a t-test. P < 0.05 was considered a significant difference.

[0558] Results: No significant abnormalities were observed in the mice during the experiment, indicating that the compound was safe. On day 28, the TGIs in the G2-G5 groups were 90.7%, 105.3%, 93.5%, and 105.5%, respectively, demonstrating that compound 1 exhibited a significant tumor-suppressing effect (see Figure 1).

[0559] Test Example 11: Study on anti-tumor efficacy in human pancreatic cancer PDX animal model

[0560] The purpose of this experiment is to evaluate the anti-tumor effect of the test substance in a human pancreatic cancer PDX animal model.

[0561] Patient-derived pancreatic tumor fragments (2 mm × 2 mm × 2 mm) were inoculated into Right side of the mouse. When the tumor volume in the mouse reaches about 250-300mm 3At 4 hr, mice were randomly divided into different groups based on tumor volume. Compound 1 was then administered orally to the mice at a dose of 3 mg / kg once daily for 21 days. The negative control group (NC) was administered 5% DMSO + 40% PEG400 + 55% PBS.

[0562] The results showed that compound 1 exhibited a good tumor-suppressing effect, with a TGI of 54.4% on day 21 of administration (see Figure 2). Furthermore, the mice showed no obvious abnormalities during the experiment, indicating that the compound had good safety (see Figure 3).

[0563] Test Example 12: Anti-tumor efficacy study in human breast cancer PDX animal model

[0564] The purpose of this experiment is to evaluate the anti-tumor effect of the test substance in a human breast cancer PDX animal model.

[0565] Patient-derived breast cancer tumor fragments (2 mm × 2 mm × 2 mm) were inoculated into Right side of the mouse. When the tumor volume in the mouse reaches about 150-200mm 3 At 4 hr, mice were randomly divided into different groups based on tumor volume. Compound 1 was then administered orally to the mice at a dose of 3 mg / kg once daily for 22 days. The negative control group (NC) received 5% DMSO + 40% PEG400 + 55% PBS.

[0566] The results showed that compound 1 exhibited tumor inhibition effects, with a TGI of 48.3% on day 22 of administration (see Figure 4 ). Furthermore, there were no obvious abnormalities in the mice during the experiment, indicating that the compound had good safety (see Figure 5 ).

[0567] Test Example 13: Anti-tumor efficacy study in human lung cancer PDX animal model

[0568] The purpose of this experiment is to evaluate the anti-tumor effect of the test substance in a human lung cancer PDX animal model.

[0569] Patient-derived lung cancer tumor fragments (2 mm × 2 mm × 2 mm) were inoculated into Right side of the mouse. When the tumor volume in the mouse reaches about 150-200mm 3 At 4 hr, mice were randomly divided into different groups based on tumor volume. Compound 1 was then orally administered to mice at a dose of 3 mg / kg once daily for 32 days. The negative control group (NC) was administered 5% DMSO + 40% PEG400 + 55% PBS.

[0570] The results showed that compound 1 exhibited tumor inhibition effects, with a TGI of 51.2% on day 22 of administration (see Figure 6 ). Furthermore, the mice showed no obvious abnormalities during the experiment, indicating that the compound had good safety (see Figure 7 ).

[0571] The technical solution of the present application is not limited to the above-mentioned specific embodiments. Any technical variations made according to the technical solution of the present application fall within the protection scope of the present application.

Claims

1. A compound of formula I, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug thereof, m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; p is 0, 1, 2 or 3; q is 0, 1, 2, 3, or 4; x is 0 or 1; L 1 Selected from single bond, NR 1-1 , O, S, C 2-4 Alkenylene, C 2-5 Alkynylidene, C 1-3 Alkylene, where C 2-4 Alkenylene, C 2-5 Alkynylidene, C 1-3 The alkylene group is optionally substituted with a substituent selected from deuterium, halogen, CN, OH, =O; R 1 Selected from deuterium, hydroxyl, -WR 1-3 ,=O,HC(=O)-,C 1-3 Alkyl-C(=O)-, CN, halogen, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 aromatic ring, 5-12 membered heteroaromatic ring or 4-12 membered heterocyclic ring; or, when n is 2, 3 or 4, two adjacent R 1 Together they form a ring to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group; wherein, C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aromatic ring, 5-12 membered heteroaromatic ring, 4-12 membered heterocyclic group, 3-6 membered heterocyclic group are optionally replaced by R 1-2 Replacement; R 1-2 independently selected from deuterium, hydroxyl, halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkylene-OH, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl; A is C 6-10 Aromatic ring, 5-12 membered heteroaromatic ring, C 4-10 Cycloalkyl or 4-12 membered heterocyclic group; R 2 Selected from deuterium, hydroxyl, halogen, -WR 1-3 , HC(=O)-, C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl; or, when m is 2, 3 or 4, two adjacent R 2 Together they form a ring to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, benzene ring or 5-6 membered heteroaromatic ring; wherein, C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 A cycloalkyl group, a 3-6 membered heterocyclic group, a benzene ring or a 5-6 membered heteroaromatic ring is optionally replaced by R 1-2 Replacement; R 1-2 independently selected from deuterium, hydroxyl, halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkylene-OH, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl; R 3 Selected from deuterium, hydroxyl, halogen, -WR 1-3 , HC(=O)-, C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl; or, when p is 2 or 3, two adjacent R 3 Together they form a ring to form C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, benzene ring or 5-6 membered heteroaromatic ring; wherein, C 1-3 Alkyl-C(=O)-, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 A cycloalkyl group, a 3-6 membered heterocyclic group, a benzene ring or a 5-6 membered heteroaromatic ring is optionally replaced by R 1-3 replace; R 1-3 independently selected from deuterium, hydroxyl, halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkylene-OH, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl; L 2 Selected from single bond, NR 1-1 , O, S, C 2-4 Alkenylene, C 2-5 Alkynylidene, C 1-3 Alkylene, where C 2-4 Alkenylene, C 2-5 Alkynylidene, C 1-3 The alkylene group is optionally substituted with a substituent selected from deuterium, halogen, CN, OH, =O; B is a 5-6 membered heteroaromatic ring; R 4 Selected from deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkylene-OH, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl; wherein C 1-6 Alkyl, C 1-6 Alkylene-OH, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The cycloalkyl group is optionally substituted with a substituent selected from deuterium, halogen, CN, OH; W is O, S or NR 1-1 ; R 1-1 Selected from hydrogen, deuterium, hydroxyl, halogen, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkylene-OH, C 1-6 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl.

2. The compound according to claim 1, wherein The compound shown in Formula I has the structure shown in Formula I-1 or Formula I-2: Among them, R 1 , R 2 , R 3 , R 4 , A, B, L 1 , L 2 , m, n, p, q have the definitions as defined in formula I in claim 1.

3. The compound according to claim 1, wherein The compound shown in Formula I has the structure shown in Formula I-3 or Formula I-4: Among them, R 1 , R 2 , R 3 , R 4 , A, L 1 , L 2 , m, n, p, q have the definitions as defined in formula I in claim 1.

4. The compound according to claim 1, wherein The compound shown in Formula I has a structure shown in any one of Formula I-5 to Formula I-6: Among them, R 1 , R 2 , R 3 , R 4 , A, B, L 1 , L 2 , n, p, q have the definitions as defined in formula I in claim 1; r is 0, 1, 2 or 3; R 5 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl; preferably, R 5 Selected from C 1-3 Alkyl groups such as methyl, C 1-3 Haloalkyl such as trifluoromethyl or difluoromethyl, C 3-6 Cycloalkyl is, for example, cyclopropyl.

5. The compound according to claim 1, wherein The compound shown in Formula I has a structure shown in any one of Formula I-7 to Formula I-8: Among them, R 1 , R 2 , R 3 , R 4 , A, B, L 1 , L 2 , m, n, q have the definitions as defined in formula I in claim 1; s is 0, 1 or 2; R 6 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl; preferably, R 6 Selected from C 1-3 Alkyl groups such as methyl, C 1-3 Haloalkyl such as trifluoromethyl or difluoromethyl, C 3-6 Cycloalkyl is, for example, cyclopropyl.

6. The compound according to claim 1, wherein The compound shown in Formula I has a structure shown in any one of Formula I-9 to Formula I-10: Among them, R 1 , R 2 , R 3 , R 4 , A, B, L 1 , L 2 , n, q have the definitions as defined in formula I in claim 1; s is 0, 1 or 2; r is 0, 1, 2 or 3; R 5 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl; preferably, R 5 Selected from C 1-3 Alkyl groups such as methyl, C 1-3 Haloalkyl such as trifluoromethyl or difluoromethyl, C 3-6 Cycloalkyl groups such as cyclopropyl; R 6 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl; preferably, R 6 Selected from C 1-3 Alkyl groups such as methyl, C 1-3 Haloalkyl such as trifluoromethyl or difluoromethyl, C 3-6 Cycloalkyl is, for example, cyclopropyl.

7. The compound according to claim 1, wherein The compound represented by Formula I has a structure represented by any one of Formula I-11 to Formula I-12: Among them, R 1 , R 2 , R 3 , R 4 , A, B, L 1 , L 2 , n, q have the definitions as defined in formula I in claim 1; r is 0, 1, 2 or 3; t is 0, 1, 2 or 3; R 5 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl; preferably, R 5 Selected from C 1-3 Alkyl groups such as methyl, C 1-3 Haloalkyl such as trifluoromethyl or difluoromethyl, C 3-6 Cycloalkyl groups such as cyclopropyl; R 7 Selected from deuterium, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Alkylene-OH, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl.

8. The compound according to any one of claims 1 to 7, wherein A involves C 6-10 The aromatic ring and the 5-12 membered heteroaromatic ring are selected from the following structures: Among them, Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 10 , Y 11 Each independently selected from: CH, N; Y 9 Selected from: CH2, NH, O, S; A involves C 4-10 The rings in the cycloalkyl and 4-12 membered heterocyclic groups are selected from the following structures: wherein each t1, t2, and t3 are independently 0, 1, 2, or 3; Preferably, A is selected from the group consisting of the following structures: More preferably, A is More preferably, A is Indicates A and L 1 connection point.

9. The compound according to any one of claims 1 to 8, wherein L 1 Selected from single bond, C 2-4 Alkynylidene, C 1-3 Alkylene, where C 2-4 Alkynylidene, C 1-3 The alkylene group is optionally substituted with a substituent selected from deuterium, fluorine, chlorine, CN, OH, =O; Preferably, L 1 Selected from a single bond, -CH2-, -CH(CH3)-, -CH(OH)-, -C=O-, -CH(Cl)-, -C≡C-, -C≡C-CH2-.

10. The compound according to any one of claims 1 to 9, wherein L 2 Selected from C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with a substituent selected from deuterium, fluorine, chlorine, CN, OH, =O; Preferably, L 2 Selected from -CH2-, -CH(CH3)-, -CH(OH)-, -C=O-, -CH(Cl)-.

11. The compound according to any one of claims 1 to 10, wherein B is selected from: or Among them, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 Each independently selected from: CH, N; E 1 Selected from: CH2, NH, O, S; Preferably, B is selected from the group consisting of the following structures: Preferably, B is More preferably, B is Where S# represents B and L 2 connection point.

12. The compound according to any one of claims 1 to 11, wherein n is 2, 3 or 4, two adjacent R 1 Formation C 5-6 Cycloalkyl, 5-6 membered heterocyclic group; m is 2, 3 or 4, two adjacent R 2 Formation C 5-6 Cycloalkyl, 5-6 membered heterocyclic group, benzene ring or 5-6 membered heteroaromatic ring; and / or p is 2 or 3, two adjacent R 3 To form a 5-6 membered heteroaromatic ring, the 5-6 membered heteroaromatic ring is optionally substituted with deuterium, hydroxyl, fluorine, chlorine, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl substitution.

13. A compound according to any one of claims 1 to 12, wherein R 1 Selected from deuterium, hydroxyl, -NH-R 1-3 、-OR 1-3 , =O, C 1-3 Alkyl-C(=O)-, CN, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkylene-OH, C 2-6 Alkenyl, C 3-6 Cycloalkyl or 4-8 membered heterocyclic group; Among them, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl, C 1-3 Alkylene-OH, C 2-6 Alkenyl, C 3-6 The cycloalkyl or 4-8 membered heterocyclic group is optionally substituted by R 1-2 replace; R 2 Selected from deuterium, hydroxyl, fluorine, chlorine, -OR 1-3 、-NH-R 1-3 , C 1-3 Alkyl, C 1-3 Alkylene-OH, C 2-4 Alkenyl or C 3-6 Cycloalkyl; and / or R 3 Selected from deuterium, hydroxyl, fluorine, chlorine, -OR 1-3 、-NH-R 1-3 , C 1-3 Alkyl, C 1-3 Alkylene -OH or C 2-4 alkenyl; and / or R 4 Selected from deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkylene -OH, preferably hydroxy, fluorine, chlorine, C 1-3 Alkyl, C 1-3 Alkylene-OH.

14. The compound according to claim 1, wherein The compound is selected from the group consisting of the following compounds:

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 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.

16. A compound according to any one of claims 1 to 15 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 or the pharmaceutical composition according to claim 15 for use as a drug.

17. A compound according to any one of claims 1 to 15 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 pharmaceutical composition according to claim 15 for use in treating a disease or condition mediated by KAT6A and / or KAT6B.

18. Use of a compound according to any one of claims 1 to 15 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 pharmaceutical composition according to claim 15 in the preparation of a medicament for treating a disease or condition mediated by KAT6A and / or KAT6B.

19. 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 14 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 pharmaceutical composition according to claim 15.

20. A compound according to any one of claims 1 to 14 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 pharmaceutical composition according to claim 15 or the use according to claim 16 or 17 or the method according to claim 18, wherein, The disease or condition 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, 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 disease, 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.

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