Bet inhibitor and use thereof

Abstract

Provided in the present application is a compound as shown in formula I, wherein each symbol is as defined in the description. The present application further relates to a pharmaceutical composition containing the compound and the use thereof.

Description

BET inhibitors and their applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese patent application No. 2024104054273 filed on April 3, 2024, the entire contents of which are incorporated by reference into this application. Technical Field

[0003] The present application belongs to the field of biomedicine technology, and specifically relates to a BET inhibitor and its application. Background Art

[0004] Epigenetics refers to changes in the modification of genetic materials such as DNA, RNA, and histones. These modifications do not involve changes in bases, distinguishing them from classical genetics, hence the term epigenetic inheritance. Epigenetic modification and regulation are involved in many cellular processes, including apoptosis, the cell cycle, cell growth, and differentiation, and are closely linked to the development and progression of cancer.

[0005] Histone acetylation is an important epigenetic modification. Histone sites such as H3K4, H3K9, and K3K27 can be modified by acetyl groups. Bromodomains (BRDs) are a type of domain that recognizes and binds to acetylated lysine. They contain approximately 110 amino acid residues and are evolutionarily conserved. Currently, 46 BRD family proteins have been identified in human cells, containing a total of 61 BRD domains (some with two). These 46 BRD family proteins can be divided into seven families based on sequence conservation, with BET family proteins belonging to the second family of BRD proteins.

[0006] BET stands for bromodomain and extraterminal domain. The BET family of proteins consists of four members: BRD2, BRD3, BRD4, and BRDT. They share structural similarities, including two tandem bromodomains (BD1 and BD2) at the N-terminus and an extraterminal domain (ET). In addition, BRD4 and BRDT contain an extended C-terminal domain (CTM). BET proteins are important epigenetic "readers" that specifically bind to N-ε-acetylysine (Kac) residues on histones H3 and H4 or non-histone proteins through BD1 and BD2, participating in transcriptional regulation and chromatin remodeling. BET inhibitors, by blocking the interaction between BDs and acetylated lysine residues on histones, play a crucial role in human cancers and other diseases, such as triple-negative breast cancer, inflammatory diseases, fibrotic disorders, human acute myeloid leukemia (AML), multiple myeloma, and cardiovascular disease.

[0007] BET bromodomains are generally structurally conserved, but the ZA and BC loops of BD1 and BD2 differ slightly in sequence and length, which facilitates specific binding to acetylated lysine residues. The sequence differences between BD1 and BD2 also provide the structural basis for the design of selective inhibitors for BD1 or BD2. Furthermore, BD1 and BD2 differ in function. BD1 primarily functions as a chromatin-binding module, essential for steady-state gene expression, while BD2 is typically used to recruit various factors. Both BD1 and BD2 are essential for acute gene responses induced by inflammatory stimuli.

[0008] BET-BD inhibitors are primarily categorized as pan-BET inhibitors (binding to all eight BDs with similar affinity), selective BRD4 inhibitors, BET-BD1 or BET-BD2 selective inhibitors, BRD4-BD1 specific inhibitors, BET interaction inhibitors, and covalent BET inhibitors. Although no FDA-approved BET inhibitors are currently on the market, several pan-BET inhibitors and BET-BD1 or BET-BD2 selective inhibitors are in various stages of clinical trials, primarily for the treatment of cancer, cardiovascular disease, and other areas. Summary of the Invention

[0009] The purpose of this application is to provide an inhibitor targeting the BD2 domain of the BET family with a novel structure and its application.

[0010] In one aspect, 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:

[0011] Ring C is absent, 3-6 membered cycloalkyl, 6-10 membered aryl, 5-6 membered heterocyclyl containing N, O or S, 5-6 membered heteroaryl containing N, O or S, or 7-10 membered fused bicyclic ring containing N, O or S, and the 3-6 membered cycloalkyl, 6-10 membered aryl, 5-6 membered heterocyclyl containing N, O or S, 5-6 membered heteroaryl containing N, O or S, or 7-10 membered fused bicyclic ring containing N, O or S is optionally substituted with one or more substituents Rs;

[0012] A is selected from the group consisting of: phenyl, 5-10 membered heteroaryl, 3-6 membered cycloalkyl, 4-10 membered heterocyclyl, -NHSO2NH2, -SO2NH2, -NHSO2NH-C1-C6 alkyl, -NHSO2-C1-C6 alkyl, -SO2NH-C1-C6 alkyl, wherein the phenyl, 5-10 membered heteroaryl, 3-6 membered cycloalkyl, 4-10 membered heterocyclyl is optionally substituted with one or more substituents Rs;

[0013] Ring B is selected from: phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl is optionally substituted with one or more substituents Rs;

[0014] X1 and X2 are each independently CR3 or N;

[0015] L1 is -N(R a1 )-、-O-、-OR b1 -、-N(R a1 )-R b1 -、-NHC(O)N(R a1 )-、NHC(O)(R a1 ) or -NHC(O)N(R a1 )-R b1 -;

[0016] L2 is a bond, -N(R a2 )-、-C(R a2 )-、-O-、-OR b2 -、-N(R a2 )-R b2 -、-NHC(O)N(R a2 )-or-NHC(O)N(R a2 )-R b2 -;

[0017] R1 is selected from H, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, nitro, alkyl-NH2 such as C1-C3 alkyl-NH2, 6-10 membered aryl with or without substituent Rs, 5-10 membered heteroaryl with or without substituent Rs, 4-10 membered heterocyclyl with or without substituent Rs;

[0018] R2 is selected from H, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, nitro, phenoxy, alkyl-NH2 such as C1-C3 alkyl-NH2, 6-10 membered aryl with or without substituents Rs, 5-10 membered heteroaryl with or without substituents Rs, 4-10 membered heterocyclyl with or without substituents Rs, the phenoxy is optionally substituted with a substituent selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxy, carboxyl, nitro, halogen, amino, cyano;

[0019] R3 is selected from H and Rs;

[0020] R a1 and R a2Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered oxacycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered oxacycloalkyl are optionally substituted with one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, carboxyl, hydroxy, hydroxy-substituted C1-C6 alkyl, nitro, halogen, amino, and cyano;

[0021] R b1 and R b2 Each is independently selected from C1-C6 alkylene, wherein the C1-C6 alkylene is optionally substituted with one or more substituents selected from C1-C6 alkoxy, hydroxy, halogen, amino, and cyano;

[0022] Rs is selected from deuterium, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxy, nitro, carboxyl, aldehyde such as -C(=O)-(C1-C6 alkyl), ester such as -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-3-6 membered cycloalkyl, -O-5-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), said C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxy, nitro, carboxyl, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-3-6 membered cycloalkyl, -O-4-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl) are optionally substituted with one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxy, nitro, halogen, amino, cyano;

[0023] When ring C is absent, at least one of X1 and X2 is N, and R1 is a 5- to 10-membered heteroaryl group which may contain a substituent Rs, or a 4- to 10-membered heterocycloalkyl group which may contain a substituent Rs.

[0024] On the other hand, the present application provides a pharmaceutical composition comprising a compound as described above 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.

[0025] On the other hand, the present application provides a method for regulating gene transcription in a cell, comprising exposing a protein comprising a bromodomain to a compound as described above 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 a pharmaceutical composition as described above.

[0026] On the other hand, the present application provides a method for inhibiting bromodomain-mediated recognition of the acetyl lysine region of a protein, comprising exposing the bromodomain to a compound as described above 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 a pharmaceutical composition as described above.

[0027] On the other hand, the present application provides a method for treating cancer, comprising administering to a patient a compound as described above 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 a pharmaceutical composition as described above.

[0028] On the other hand, the present application provides the use of the compound as described above 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 as described above in the preparation of a drug for regulating gene transcription in a cell.

[0029] On the other hand, the present application provides the use of a compound as described above 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 a pharmaceutical composition as described above in the preparation of a drug for inhibiting bromodomain-mediated recognition of the acetyl lysine region of a protein.

[0030] On the other hand, the present application provides the use of the compound as described above 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 as described above in the preparation of a medicament for treating cancer.

[0031] The compounds provided herein, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or their pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs, and pharmaceutical compositions comprising the compounds or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or their pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs, have high enzyme inhibitory activity against the BET family and exhibit cell proliferation inhibitory activity in multiple tumor cell lines, thus representing a new generation of BET family BD2 selective inhibitors. DETAILED DESCRIPTION

[0032] 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.

[0033] definition

[0034] Some embodiments of the present application are now described in detail, and examples thereof are illustrated by the accompanying structural formula and chemical formula. The application is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the present application as defined in the claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present application. The application is in no way limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials are different from or contradictory to the present application (including but not limited to defined terms, term applications, described technology, etc.), the present application shall prevail.

[0035] 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.

[0036] 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.

[0037] Unless otherwise indicated, the following definitions used herein shall apply. For the purposes of this application, the chemical elements are referred to in accordance with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0038] 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.

[0039] 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.

[0040] The term "patient" refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

[0041] The term "including" is an open expression, that is, including the contents specified in this application, but not excluding other contents.

[0042] 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-.

[0043] The term "enantiomers" refers to two non-superimposable isomers of a compound that are mirror images of each other.

[0044] 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.

[0045] The terms "racemate," "racemate," or "racemic mixture" refer to an equimolar mixture of two enantiomers devoid of optical activity.

[0046] 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. For example, the hydrogen on the 1-nitrogen atom on the imidazole ring can be transferred to the 3-nitrogen atom, and the two forms of the imidazole ring are tautomers, that is, the group containing the imidazole ring in this article has tautomers, such as and are tautomers; and and Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0047] 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.

[0048] 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.

[0049] The stereochemical definitions and conventions used herein generally follow those of SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about one or more of its chiral centers. The prefixes d and l or (+) and (-) are 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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).

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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 from 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 comprising 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, C1-8 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.

[0058] 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).

[0059] 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.

[0060] The term "hydrate" refers to an association formed by one or more water molecules and a compound of the present application.

[0061] 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.

[0062] 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.

[0063] The term "isotopically labeled compound" means a compound of the present invention that is labeled with an isotope. It is identical to those compounds described herein except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that may also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0064] Compounds of the present invention containing the aforementioned isotopes and / or other isotopes of other atoms and pharmaceutically acceptable salts of the compounds are included within the scope of the present invention. Isotope-labeled compounds of the present invention, such as radioactive isotopes, 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.

[0065] 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 this application is considered a substituent of compounds of formula (I) to (IV). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" used in this 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0070] Throughout this specification, substituents of compounds disclosed herein are disclosed by group class or range. It is specifically noted that this application includes each independent subcombination of the individual members of these group classes and ranges. For example, the term "C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0071] The term "alkyl" as used herein includes 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, saturated linear or branched monovalent hydrocarbon groups, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. In one embodiment, the alkyl group contains 1-6 carbon atoms, i.e., C 1-6 Alkyl; In another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., C 1-4 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.

[0072] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp2 double bond, including "cis" and "tans" positioning, or "E" and "Z" positioning. 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), and the like.

[0073] The term "alkynyl" refers to a monovalent hydrocarbon radical having 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, which is linear or branched and has at least one site of unsaturation, i.e., a carbon-carbon triple bond, sp. 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), and the like.

[0074] 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 3-6 carbon atoms, such as a C3-C6 saturated or partially unsaturated cycloalkyl group. 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 group is selected from the group consisting of a saturated monocyclic cycloalkyl group, a saturated bicyclic cycloalkyl group, a saturated tricyclic cycloalkyl group, a partially unsaturated monocyclic cycloalkyl group, a partially unsaturated bicyclic cycloalkyl group, and a partially unsaturated tricyclic cycloalkyl group. Bicyclic cycloalkyl groups refer to cycloalkyl groups in bicyclic ring systems, such as spirobicyclic cycloalkyl groups, bridged bicyclic cycloalkyl groups, and fused bicyclic cycloalkyl groups. Monocyclic cycloalkyl groups refer to cycloalkyl groups in monocyclic ring systems. The 4- to 7-membered cycloalkyl group refers to a cycloalkyl group having 4 to 7 ring atoms. The 3- to 6-membered cycloalkyl group refers to a cycloalkyl group having 3 to 6 ring atoms.

[0075] 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.

[0076] 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.

[0077] 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 in this application. The bicyclic or tricyclic ring system can be a spirocyclic, bridged or fused ring, for example, a bicyclic system includes a cyclospirobicyclic, a bridged bicyclic, and a fused bicyclic. Saturated or partially unsaturated heterocyclic groups can be fully saturated or contain one or more degrees of unsaturation, but cannot have an aromatic ring. In one embodiment, the heterocyclyl group is a 3-6 membered ring, such as a 3-6 membered saturated or partially unsaturated heterocyclic group (2-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally replaced by 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 refers to a heterocyclyl group in a bicyclic ring system, such as a bicyclic heterocyclyl system including a cyclospiro bicyclic heterocycle, a bridged bicyclic heterocycle, and a fused bicyclic heterocycle. A monocyclic heterocyclyl refers to a heterocyclyl group in a monocyclic ring system. A 5-6 membered heterocyclyl refers to a heterocyclyl group having 5-6 ring atoms. A 4-7 membered heterocyclyl refers to a heterocyclyl group having 4-7 ring atoms. A 3-6 membered heterocyclyl refers to a heterocyclyl group having 3-6 ring atoms.

[0078] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic ring system. The term "aryl" can be used interchangeably with the terms "aromatic ring" or "aromatic ring." A 6- to 10-membered aryl group refers to an aromatic group containing 6-10 ring atoms. Examples include, but are not limited to, phenyl and naphthyl.

[0079] The term "heteroaryl" refers to a monocyclic, bicyclic and tricyclic aromatic system containing 5 to 10 ring atoms. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5 to 10 atoms 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 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 5-6-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-6-membered heteroaryl group; In some embodiments, the heteroaryl group is a 5-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 5-membered heteroaryl group; In some embodiments, the heteroaryl group is a 6-atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, i.e., a 6-membered heteroaryl group.

[0080] The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). The term "amino" refers to -NH2. The term "hydroxy" refers to -OH.

[0081] The term "cyano" refers to -CN. The term "nitro" refers to -NO2. The term "carboxyl" refers to HO(C=O)-. The term "O=" refers to oxo, i.e., when the substituent is O=, the O is connected to the substituted group through a double bond.

[0082] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through 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., C1-C6 alkoxy; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms, i.e., C1-C4 alkoxy; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms, i.e., C1-C3 alkoxy.

[0083] The term "alkylamino" refers to an alkyl group attached to the rest of the molecule through a nitrogen atom, wherein the alkyl group has the meaning as described herein. In one embodiment, the alkylamino group is a monoalkylamino group, represented as "alkyl-NH-". In one embodiment, the alkylamino group is a dialkylamino group, represented as "(alkyl)2N-". In one embodiment, the alkylamino group contains 1-6 carbon atoms, i.e., C1-C6 alkylamino; in another embodiment, the alkylamino group contains 1-4 carbon atoms, i.e., C1-C4 alkylamino; in yet another embodiment, the alkylamino group contains 1-3 carbon atoms, i.e., C1-C3 alkylamino. The term "haloalkyl" refers to an alkyl group in which a hydrogen atom is replaced by one or more halogens (F, Cl, Br); the term "hydroxyalkyl" refers to an alkyl group in which a hydrogen atom is replaced by one or more hydroxyl (OH) groups; and the term "aminoalkyl" refers to an alkyl group in which a hydrogen atom is replaced by one or more amino (NH2) groups.

[0084] One or more halophenyl groups refer to phenyl groups which are substituted with 1, 2, 3, 4 or 5 halogen groups. The halogen groups have the same meaning as described herein. One or more halophenyl groups also refer to phenyl groups which are substituted with one or more halogen groups.

[0085] The term "phenyl substituted with one or more hydroxy groups" means that the phenyl group is substituted with 1, 2, 3, 4 or 5 hydroxy groups. The hydroxy groups have the meanings described herein.

[0086] The terms "fused bicyclic ring," "fused ring," "fused bicyclyl," and "fused cyclyl" refer to saturated or unsaturated fused ring systems, including non-aromatic bicyclic ring systems. Such systems may contain isolated or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatic rings may be substituents thereon). Each ring in a fused bicyclic ring is either carbocyclic or heteroalicyclic. Examples include, but are not limited to, hexahydrofuro[3,2-b]furan, 2,3,3a,4,7,6-hexahydro-1H-indene, 7-azabicyclo[2.3.0]heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, and 1,2,3,4,4a,5,8,8a-octahydronaphthalene. And the fused bicyclic group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, haloalkyl, oxo (=O), hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyalkoxy, etc.

[0087] When two ring system groups are linked by "and", it indicates that the two ring systems are fused together, and the two corresponding rings have their respective definitions as described herein. For example, "phenyl-4-7-membered cycloalkyl" means a phenyl group fused together with a cycloalkyl group having 4-7 ring atoms as described herein; "5-6-membered heteroaryl-4-7-membered cycloalkyl" means a heteroaryl group having 5-6 ring atoms as described herein fused together with a cycloalkyl group having 4-7 ring atoms as described herein.

[0088] 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 1-6 Alkoxy-C 1-6 Alkyl represents C 1-6 Alkoxy through C 1-6 The alkylene group is connected to the rest of the molecule, and the hydroxyl group C 1-6 Alkyl represents a hydroxyl group through C 1-6 The alkylene group is attached to the rest of the molecule.

[0089] As described in this application, the substituent R is connected to the central ring by a bond to form a ring system (as shown below), which means that the substituent R is limited to any substitutable or any reasonable position on the A ring. For example, formula f represents any possible position on the A ring, such as formula f 1 -f 4 As shown:

[0090] As described in this application, the substituent R is formed by a ring system connected by a bond through multiple rings (as shown in the figure below), which means that the substituent R can be substituted at any substitutable or any reasonable position on Ring A and Ring B. For example, Formula e represents any possible substituted position on Ring A, such as Formula e 1 -e 7 As shown:

[0091] As described in this application, the substituents are connected to the 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.

[0092] 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.

[0093] As used herein, the term "bromodomain" refers to an evolutionarily and structurally conserved module (approximately 110 amino acids in length) that binds to acetylated lysine residues, such as those on the N-terminal tails of histones. They are protein domains found as part of much larger bromodomain-containing proteins (BCPs), many of which play a role in regulating gene transcription and / or chromatin remodeling. The human genome encodes at least 57 bromodomains.

[0094] As used herein, the term "BET" refers to bromodomain-containing proteins of the bromodomain and extra-terminal domain family, which includes BRD2, BRD3, BRD4, and BRDT.

[0095] As used herein, the term "BET inhibitor" refers to a compound that is capable of inhibiting the binding of one or more BET family bromodomain-containing proteins (eg, BRD2, BRD3, BRD4, or BRDT) to, for example, acetylated lysine residues.

[0096] Description of the Invention

[0097] The present application provides a compound or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound or prodrug, which has high enzyme inhibitory activity against the BET family and shows cell proliferation inhibitory activity in multiple tumor cell lines. It is a new generation of BET family BD2 selective inhibitors.

[0098] In one aspect, the present application provides a compound having a structure shown in Formula I, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof:

[0099] Ring C is absent, 3-6 membered cycloalkyl, 6-10 membered aryl, 5-6 membered heterocyclyl containing N, O or S, 5-6 membered heteroaryl containing N, O or S, or 7-10 membered fused bicyclic ring containing N, O or S, and the 3-6 membered cycloalkyl, 6-10 membered aryl, 5-6 membered heterocyclyl containing N, O or S, 5-6 membered heteroaryl containing N, O or S, or 7-10 membered fused bicyclic ring containing N, O or S is optionally substituted with one or more substituents Rs;

[0100] A is selected from the group consisting of: phenyl, 5-10 membered heteroaryl, 3-6 membered cycloalkyl, 4-10 membered heterocyclyl, -NHSO2NH2, -SO2NH2, -NHSO2NH-C1-C6 alkyl, -NHSO2-C1-C6 alkyl, -SO2NH-C1-C6 alkyl, wherein the phenyl, 5-10 membered heteroaryl, 3-6 membered cycloalkyl, 4-10 membered heterocyclyl is optionally substituted with one or more substituents Rs;

[0101] Ring B is selected from: phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl is optionally substituted with one or more substituents Rs;

[0102] X1 and X2 are each independently CR3 or N;

[0103] L1 is -N(R a1 )-、-O-、-OR b1 -、-N(R a1 )-R b1 -、-NHC(O)N(R a1 )-、-NHC(O)(R a1 )-or-NHC(O)N(R a1 )-R b1 -;

[0104] L2 is a bond, -N(R a2 )-、-C(R b2 )-、-O-、-OR b2 -、-N(R a2 )-R b2 -、-NHC(O)N(R a2 )-or-NHC(O)N(R a2 )-R b2 -;

[0105] R1 is selected from H, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, nitro, alkyl-NH2-, such as C1-C3 alkyl-NH2, 6-10 membered aryl with or without substituent Rs, 5-10 membered heteroaryl with or without substituent Rs, 5-10 membered heterocyclyl with or without substituent Rs;

[0106] R2 is selected from H, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, hydroxy, nitro, phenoxy, alkyl-NH2 such as C1-C3 alkyl-NH2, 6-10 membered aryl with or without substituents Rs, 5-10 membered heteroaryl with or without substituents Rs, 4-10 membered heterocyclyl with or without substituents Rs, the phenoxy is optionally substituted with a substituent selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxy, carboxyl, nitro, halogen, amino, cyano;

[0107] R3 is selected from H and Rs;

[0108] R a1 and R a2 Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered oxacycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered oxacycloalkyl are optionally substituted with one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, carboxyl, hydroxy, hydroxy-substituted C1-C6 alkyl, nitro, halogen, amino, and cyano;

[0109] R b1 and R b2 Each is independently selected from C1-C6 alkylene, wherein the C1-C6 alkylene is optionally substituted with one or more substituents selected from C1-C6 alkoxy, hydroxy, halogen, amino, and cyano;

[0110] Rs is selected from deuterium, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxy, nitro, carboxyl, aldehyde such as -C(=O)-(C1-C6 alkyl), ester such as -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-3-6 membered cycloalkyl, -O-5-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), said C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxy, nitro, carboxyl, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-3-6 membered cycloalkyl, -O-4-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl) are optionally substituted with one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxy, nitro, halogen, amino, cyano;

[0111] When ring C is absent, at least one of X1 and X2 is N, and R1 is a 5- to 10-membered heteroaryl group which may contain a substituent Rs, or a 4- to 10-membered heterocycloalkyl group which may contain a substituent Rs.

[0112] In some embodiments, the compounds described herein have a structure represented by Formula II, III, IV, or V, 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:

[0113] wherein A, ring B, ring C, R1, R2, R3, L1 and L2 have the definitions described in the present application.

[0114] In some embodiments, the compounds described herein have a structure shown in any one of Formulas I-1 to I-12, 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:

[0115] wherein n1 is 0 or 1; n2 is 0, 1 or 2; n3 is selected from an integer of 0-3; n4 is selected from an integer of 0-4; n5 is 0, 1 or 2; n6 is 0 or 1; n7 is 0, 1 or 2; n8 is selected from an integer of 0-3; n9 is 0 or 1; n10 is selected from an integer of 0-5; n11 is 0, 1 or 2; n12 is 0, 1 or 2;

[0116] A, Ring B, R1, R2, Rs, L1 and L2 have the meanings described in the present invention.

[0117] In some embodiments, the compounds described herein have a structure as shown in any one of the following formulae, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug thereof:

[0118] Optionally, any of the above general formulas may be further substituted by one or more substituents Rs; wherein A, ring B, R2, Rs, L1 and L2 have the definitions described in the present application.

[0119] In some embodiments, A is selected from phenyl, which may be substituted or unsubstituted, pyridyl, which may be substituted or unsubstituted, benzopyrazolyl, which may be substituted or unsubstituted, C3-C6 cycloalkyl, which may be substituted or unsubstituted, pyranyl, which may be substituted or unsubstituted, tetrahydropyranyl, which may be substituted or unsubstituted, tetrahydrofuranyl, which may be substituted or unsubstituted, oxazolyl, which may be substituted or unsubstituted, benzoxazine;

[0120] The substituents are selected from deuterium, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, carboxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl).

[0121] In some embodiments, the substituents in A are selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -C(=O)-(C1-C4 alkyl), -C(=O)O-(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -O-5-6 membered azacycloalkyl, 5-6 membered azacycloalkyl, -O-5-6 membered oxacycloalkyl, 5-6 membered oxacycloalkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl).

[0122] In some embodiments, A is selected from the following groups:

[0123] In some embodiments, ring B is selected from phenyl which may be substituted, pyridyl which may be substituted, imidazolyl which may be substituted, pyrazolyl which may be substituted, triazolyl which may be substituted, indanyl which may be substituted, benzofuranyl which may be substituted, benzothiophenyl which may be substituted, tetrahydroisoquinolinyl which may be substituted, benzopyrrolyl which may be substituted;

[0124] The substituents are selected from deuterium, halogen, hydroxy, oxo, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-4-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl).

[0125] In some embodiments, the substituents in ring B are selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -C(=O)-(C1-C4 alkyl), -C(=O)O-(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -O-5-6 membered azacycloalkyl, -O-5-6 membered oxacycloalkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl).

[0126] In some embodiments, Ring B is selected from the following groups:

[0127] In some embodiments, L1 is -NH-, -O-, -NHR b1 -、-NHC(O)NH-、-NHC(O)(R a1 )-or-NHC(O)NHR b1 -, preferably, R b1 is C1-C6 straight chain alkylene or C2-C6 branched chain alkylene; for example, C1-C3 straight chain alkylene; C3-C4 branched chain alkylene.

[0128] In some embodiments, L2 is a bond, -NH-, -NHRb2, -C(Rb2)-, or -ORb2-. Preferably, R b2 is C1-C6 straight chain alkylene or C2-C6 branched chain alkylene; for example, C1-C3 straight chain alkylene; C3-C4 branched chain alkylene.

[0129] In some embodiments, R1 is selected from H, fluorine, chlorine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, nitro, C1-C3 alkyl-NH2, a 5-6 membered nitrogen-containing heteroaryl group containing or not substituents Rs, a 5-6 membered oxygen-containing heteroaryl group containing or not substituents Rs, and a 5-6 membered oxygen-containing heterocyclic group containing or not substituents Rs.

[0130] In some embodiments, R2 is selected from H, fluorine, chlorine, bromine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, nitro, phenoxy, C1-C3 alkyl-NH2, a 5-6 membered nitrogen-containing heteroaryl group containing or not substituents Rs, a 5-6 membered oxygen-containing heteroaryl group containing or not substituents Rs, a 5-6 membered oxygen-containing heterocyclic group containing or not substituents Rs, and the phenoxy group is optionally substituted with a C1-C4 alkyl group, a C1-C4 alkoxy group, a C3-C6 cycloalkyl group, a hydroxyl group, a carboxyl group, a nitro group, a halogen group, an amino group, or a cyano group.

[0131] In some embodiments, Rs is selected from deuterium, fluorine, chlorine, bromine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, hydroxyl, nitro, -C(=O)-(C1-C4 alkyl), -C(=O)O-(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -O-3-6 membered cycloalkyl, -O-5-7 membered heterocycloalkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl), the C1-C4 alkyl C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, hydroxy, nitro, -C(=O)-(C1-C4 alkyl), -C(=O)O-(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -O-3-6 membered cycloalkyl, -O-5-7 membered heterocycloalkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl) are optionally substituted by one or more substituents selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, nitro, halogen, amino, and cyano.

[0132] According to some embodiments, the compounds described herein are not

[0133] According to some embodiments, the compounds described herein are not

[0134] In some embodiments, the compounds described herein have the structure shown in Formula I-1 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs:

[0135] wherein A, ring B, R1, R2, Rs, L1 and L2 have the definitions of this application, and n1 is 0 or 1.

[0136] In some embodiments, A is selected from phenyl which may be substituted, 5-10 membered heteroaryl which may be substituted, 3-6 membered cycloalkyl which may be substituted, 5-10 membered heterocyclyl which may be substituted, and the substituents are selected from deuterium, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, carboxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-4-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl).

[0137] In some embodiments, the substituents in A are selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, carboxyl, C1-C4 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C4 alkyl), -C(=O)O-(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -O-5-7 membered heterocycloalkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl).

[0138] In some embodiments, A is selected from phenyl which may be substituted, pyridinyl which may be substituted, benzopyrazolyl which may be substituted, cyclopropyl which may be substituted, pyranyl which may be substituted, tetrahydropyranyl which may be substituted, tetrahydrofuranyl which may be substituted, oxazolyl which may be substituted, cyclohexyl which may be substituted, benzoxazinyl which may be substituted, and the substituents are selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -O-5-6 membered azacycloalkyl, 5-6 membered azacycloalkyl, -O-5-6 membered oxacycloalkyl, 5-6 membered oxacycloalkyl.

[0139] In some embodiments, ring B is selected from phenyl with or without substituents, 5-10 membered heterocycloalkyl with or without substituents, and 5-10 membered heteroaryl with or without substituents, wherein the substituents are selected from deuterium, halogen, hydroxy, oxo, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-4-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), and -N(C1-C6 alkyl)(C1-C6 alkyl).

[0140] In some embodiments, the substituents in ring B are selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C4 alkyl), -C(=O)O-(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -O-5-7 membered heterocycloalkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl).

[0141] In some embodiments, ring B is selected from phenyl which may be substituted, pyridinyl which may be substituted, imidazolyl which may be substituted, pyrazolyl which may be substituted, triazolyl which may be substituted, indanyl which may be substituted, benzofuranyl which may be substituted, benzothiophenyl which may be substituted, benzopyrrolyl which may be substituted, tetrahydroisoquinolinyl which may be substituted, and the substituents are selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl).

[0142] In some embodiments, R1 is selected from H, halogen, hydroxy, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, nitro, or C1-C3 alkyl-NH2.

[0143] In some embodiments, R2 is selected from H, halogen, hydroxy, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, nitro, phenoxy, imidazolyl.

[0144] In some embodiments, Rs is selected from deuterium, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy, hydroxy, nitro, halogen, amino, cyano, aldehyde, ester, and carboxyl.

[0145] In some embodiments, Rs is selected from fluorinated C1-C4 alkoxy, such as trifluoromethoxy.

[0146] In some embodiments, L1 is -NH-, -O-, -NHR b1 -, -NHC(O)NH- or -NHC(O)NHR b1 -; preferably, R b1 is C1-C6 straight chain alkylene or C2-C6 branched chain alkylene; for example, C1-C3 straight chain alkylene; C3-C4 branched chain alkylene.

[0147] In some embodiments, L2 is a bond, -NH-, or -NHR b2 -; preferably, R b2 is C1-C6 straight chain alkylene or C2-C6 branched chain alkylene; for example, C1-C3 straight chain alkylene; C3-C4 branched chain alkylene.

[0148] The compounds described herein have the structure shown in Formula I-4 or I-13, or enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs thereof:

[0149] wherein A, Ring B, R1, R2, Rs, L1 and L2 have the definitions of this application, n4 is 0, 1, 2, 3 or 4, and n13 is 0, 1, 2 or 3.

[0150] In some embodiments, A is selected from phenyl which may be substituted, 5-10 membered heteroaryl which may be substituted, 3-6 membered cycloalkyl which may be substituted, 5-10 membered heterocyclyl which may be substituted, and the substituents are selected from deuterium, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, carboxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-4-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl).

[0151] In some embodiments, the substituents in A are selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, carboxyl, C1-C4 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C4 alkyl), -C(=O)O-(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -O-5-7 membered heterocycloalkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl).

[0152] In some embodiments, A is selected from phenyl which may be substituted, pyridinyl which may be substituted, benzopyrazolyl which may be substituted, cyclopropyl which may be substituted, pyranyl which may be substituted, tetrahydropyranyl which may be substituted, tetrahydrofuranyl which may be substituted, oxazolyl which may be substituted, and the substituents are selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -O-5-6 membered azacycloalkyl, 5-6 membered azacycloalkyl, -O-5-6 membered oxacycloalkyl, 5-6 membered oxacycloalkyl.

[0153] In some embodiments, ring B is selected from phenyl with or without substituents, 4-10 membered heterocycloalkyl with or without substituents, and 5-10 membered heteroaryl with or without substituents, wherein the substituents are selected from deuterium, halogen, hydroxy, oxo, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-4-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl).

[0154] In some embodiments, the substituents in ring B are selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, carboxyl, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C4 alkyl), -C(=O)O-(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -O-5-7 membered heterocycloalkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl).

[0155] In some embodiments, ring B is selected from phenyl which may be substituted, pyridinyl which may be substituted, imidazolyl which may be substituted, pyrazolyl which may be substituted, triazolyl which may be substituted, indanyl which may be substituted, benzofuranyl which may be substituted, benzothiophenyl which may be substituted, tetrahydroisoquinolinyl which may be substituted, and the substituents are selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl).

[0156] In some embodiments, R1 is selected from H, halogen, hydroxy, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, nitro, or C1-C3 alkyl-NH2.

[0157] In some embodiments, R2 is selected from H, halogen, hydroxy, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, nitro, phenoxy, imidazolyl.

[0158] In some embodiments, Rs is selected from deuterium, C1-C4 alkyl, C1-C4 alkoxy, halo-C1-C4 alkoxy, hydroxy, nitro, halogen, amino, cyano, aldehyde, ester, and carboxyl.

[0159] In some embodiments, Rs is selected from fluorinated C1-C4 alkoxy, such as trifluoromethoxy.

[0160] In some embodiments, L1 is -NH-, -O-, -NHR b1 -, -NHC(O)NH- or -NHC(O)NHR b1 -; preferably, R b1 is C1-C6 straight chain alkylene or C2-C6 branched chain alkylene; for example, C1-C3 straight chain alkylene; C3-C4 branched chain alkylene.

[0161] In some embodiments, L2 is a bond, -NH-, or -NHR b2 -; preferably, R b2 is C1-C6 straight chain alkylene or C2-C6 branched chain alkylene; for example, C1-C3 straight chain alkylene; C3-C4 branched chain alkylene.

[0162] In some embodiments, the compounds of the present application have the structure shown below or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug thereof;

[0163] Pharmaceutical compositions and methods of administration

[0164] 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, labeled compound or prodrug and a pharmaceutically acceptable excipient.

[0165] 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.

[0166] 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).

[0167] The present invention also relates to pharmaceutical compositions comprising as active ingredients a compound of formula I, II, III, IV, V, I-1 to I-13 and other formulae herein, or a pharmaceutically acceptable salt thereof, which can be used, in particular, for the treatment of neoplastic diseases, in particular cancer, as described herein. The compositions can be formulated for non-parenteral administration, such as nasal, oral, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, or in particular for oral administration, for example in the form of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard and soft capsules or hydroxypropylmethylcellulose (HPMC) capsules (coated where applicable), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration to mammals, in particular humans, for example in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. These compositions may contain the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.

[0168] Compounds of Formula I, II, III, IV, V, I-1 to I-13, and other structural formulae herein, or pharmaceutically acceptable salts 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 or sugar-coated tablets, effervescent tablets, hard capsules, HPMC capsules, or orally disintegrating tablets. Fillers such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch, or its derivatives, binders such as cellulose, starch, polyvinylpyrrolidone, or its derivatives, glidants such as talc, stearic acid, or its salts, and flow agents such as fumed silica can be used as such excipients for the formulation and manufacture of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard capsules, HPMC capsules, or orally disintegrating tablets. Suitable excipients for soft capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, and the like.

[0169] 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.

[0170] Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants and the like.

[0171] 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.

[0172] 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.

[0173] Compounds of Formula I, II, III, IV, V, I-1 to I-13, and other formulae herein may also be used in combination with one or more other pharmacologically active compounds that are also effective against the same disease, preferably using different modes of action, or that reduce or prevent possible undesirable side effects of compounds of Formula I, II, III, IV, V, I-1 to I-13, and other formulae herein. The combination partners can be administered simultaneously in such treatments, for example, by incorporating them into a single pharmaceutical formulation, or sequentially by administering two or more different dosage forms (each containing one or more combination partners).

[0174] Other pharmacologically active compounds may be other anticancer agents, and other anticancer agents are selected from: anastrozole Bicalutamide Bleomycin sulfate Busulfan Busulfan Injection Capecitabine N4-pentyloxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin Carmustine Chlorambucil Cisplatin Cladribine Cyclophosphamide ( or ), cytarabine, cytarabine Cytarabine liposome injection Daqaba Actinomycin (Actinomycin D, Cosmegan), daunomycin hydrochloride Daunocycin Citrate Liposomal Injection Dexamethasone, docetaxel Doxorubicin hydrochloride Etoposide Fludarabine phosphate 5-Fluorouracil Flutamide tezacitibine, gemcitabine (difluorodeoxycytidine), hydroxyurea Idabit Ifosfamide Ephedrine L-asparaginase Calcium methyltetrahydrofolate, mycophenolate mofetil 6-Mercaptopurine Methotrexate Mitoxantrone Gemtuzumab (mylotarg), paclitaxel Phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20, and carmustine implants Tamoxifen citrate Teniposide 6-Thioguanine, thiotepa, tirapazamine Topotecan Hydrochloride for Injection Vinblastine vincristine and vinorelbine

[0175] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will cause 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.).

[0176] 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.

[0177] On the other hand, the present application provides a method for regulating gene transcription in a cell, comprising exposing a protein comprising a bromodomain to a compound represented by Formula I, II, III, IV, V, Formula I-1 to Formula I-13, and other structural formulas herein, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs, or a combination thereof.

[0178] On the other hand, the present application provides a method for inhibiting bromodomain-mediated recognition of the acetyl lysine region of a protein, comprising exposing the bromodomain to a compound represented by Formula I, II, III, IV, V, Formula I-1 to Formula I-13, and other structural formulas herein, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs, or a combination thereof.

[0179] On the other hand, the present application provides a method for treating cancer, comprising administering to a patient a compound represented by Formula I, II, III, IV, V, Formula I-1 to Formula I-13, and other structural formulas herein, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds, or prodrugs, or a combination thereof.

[0180] On the other hand, the present application provides the use of compounds represented by Formula I, II, III, IV, V, Formula I-1 to Formula I-13 and other structural formulas herein, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs, or compositions thereof, in the preparation of drugs for regulating gene transcription in cells.

[0181] On the other hand, the present application provides the use of compounds represented by Formula I, II, III, IV, V, Formula I-1 to Formula I-13 and other structural formulas herein, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or their pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs, or their compositions in the preparation of drugs for inhibiting bromodomain-mediated recognition of the acetyl lysine region of a protein.

[0182] On the other hand, the present application provides the use of compounds represented by Formula I, II, III, IV, V, Formula I-1 to Formula I-13 and other structural formulas herein, or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotope-labeled compounds or prodrugs, or compositions thereof, in the preparation of drugs for treating cancer.

[0183] In some embodiments, the cancer is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplastic changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, tumor), fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphocytic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple Myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (epithelial cancers and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0184] The following examples are provided to assist in understanding the present application. However, it should be understood that these examples are intended to illustrate the present application only and are not intended to limit the present application in any way. The actual scope of protection of the present application is set forth in the claims. It should be understood that any modifications and variations may be made without departing from the spirit of the present application.

[0185] Part I Compound Synthesis

[0186] 1. Synthesis of intermediate INT-A

[0187] Synthesis route of INT-A

[0188] Preparation of INT-1

[0189] PCl5 (22.20 mL, 170.59 mmol) was added to a mixed solution of SM-1 (7 g, 42.65 mmol) and POCl3 (100 mL), and the temperature was gradually raised to 110°C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to give the crude product INT-1 (20 g).

[0190] MS m / z(ESI):402.9[2M+1] + .

[0191] Preparation of INT-A

[0192] To a mixed solution of INT-1 (3 g, 8.95 mmol) and DCM (30 mL) was added DIEA (2.89 g, 22.39 mmol) dropwise at 0°C. After the addition was complete, SM-2 (0.96 g, 8.95 mmol) was added and stirred for 0.5 hours. After the reaction was complete, the mixture was poured into water (80 mL) and extracted with DCM (50 mL × 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to give a crude product. The crude product was separated and purified by column chromatography (eluent: PE:EA = 50:1 to 10:1) to give INT-1 (1.4 g) with a yield of 57.54%. MS m / z (ESI): 272.0 [M+H] + .

[0193] 2. Synthesis of intermediate INT-B

[0194] Synthesis route of INT-B

[0195] Preparation of INT-2

[0196] To a mixed solution of SM-3 (5 g, 30.65 mmol), N-cyclohexyl-N-methylcyclohexylamine (7.18 g, 36.78 mmol) and THF (50 mL) was slowly added SEM-Cl (6.13 g, 36.78 mmol) and stirred at room temperature for 2 hours. After the reaction was completed, 1 M sodium hydroxide solution was slowly added to the mixed solution to quench the reaction, extracted with EtOAc (50 mL × 3), the organic phases were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was separated and purified by column chromatography (eluent: PE: EA = 100: 1 to 8: 1) to give INT-2 (1.6 g, 17.8%). MS m / z (ESI): 294.1 [M+H] + .

[0197] Preparation of INT-B

[0198] To a mixed solution of INT-2 (1.6 g, 5.45 mmol) and MeOH (20 mL) was added 10% Pd / C (1.6 g, 15.03 mmol). The atmosphere was replaced with hydrogen three times and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was filtered and concentrated to afford INT-B (1.35 g) in a yield of 93.98%. MS m / z (ESI): 264.0 [M+H] + .

[0199] 3. Synthesis of intermediate INT-C

[0200] Synthesis route of INT-C

[0201] Preparation of INT-C

[0202] To a solution of INT-1 (57 mg, 0.33 mmol) and DIEA (259 mg, 2.0 mmol) in THF (1.5 mL) was slowly added dropwise at 0°C. After the addition was complete, the mixture was warmed to room temperature and allowed to react for 16 hours. After completion, the reaction was concentrated to afford the crude product. The crude product was purified by column chromatography (eluent: PE:EA = 2:1) to afford INT-C (80 mg, 0.24 mmol) in a 71% yield. MS m / z (ESI): 338.2 [M+H] + .

[0203] 4. Synthesis of intermediate INT-D

[0204] Synthesis route of INT-D

[0205] Preparation of INT-3

[0206] SM-3 (1 g, 6.1 mmol, 1 eq), (Boc)2O (2 g, 9.2 mmol, 1.5 eq), Et3N (0.93 g, 9.2 mmol, 1.5 eq), and DMAP (0.75 g, 6.1 mmol, 1 eq) were added to a round-bottom flask and dissolved in DCM (20 mL). The mixture was heated to 45°C in an oil bath and stirred continuously for 15 hours. The reaction mixture was concentrated under reduced pressure at 40°C. The residue was purified by flash chromatography and eluted with PE / EA (15:1-8:1) to give the product INT-3 (0.72 g, 44.3%). LC / MS: retention time: 1.309 min, MS (ESI) m / z: 549.2, [2M+Na] + .

[0207] Preparation of INT-D

[0208] A mixture of INT-3 (800 mg) and 10% Pd / C (258.7 mg) in MeOH (10 mL) was stirred at 25° C. under a hydrogen balloon for 5 hours. The solution was filtered and the filtrate was concentrated in vacuo to give the product INT-D. LC / MS: retention time: 1.258 min, MS (ESI) m / z: 256.1, [M+Na] + .

[0209] 5. Synthesis of intermediate INT-E

[0210] Synthesis route of INT-E

[0211] Preparation of intermediate INT-E

[0212] To a solution of NaIO4 (9844.69 mg, 46.03 mmol) in water (70 mL) and EtOAc (70 mL) was added compound SM-5 (5000.00 mg, 16.44 mmol). After 5 minutes, RuCl3 (511.47 mg, 2.47 mmol) was added, and the final reaction was stirred at room temperature under nitrogen for 5 hours. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE:EA from 10:1 to 1:1 in 30 minutes) to give intermediate INT-E (3900 mg, 74.57%).

[0213] LC / MS: retention time: 1.231 min, MS (ESI) m / z: 217.9, [M-Boc] + .

[0214] Example 1

[0215] Synthesis route of compound 1:

[0216] Preparation of intermediate 1-2

[0217] To a solution of compound 1-1 (5 g, 41.0 mmol) and triethylamine (17.0 mL, 123 mmol) in THF (25 mL), tetrahydropyrrole (5.02 mL, 61.4 mmol) was added dropwise at 0 ° C. The mixture was stirred for 0.5 hours at 0 ° C. under nitrogen protection, and then the reaction mixture was heated to 25 ° C. and stirred for 16 hours. The reaction mixture was concentrated to dryness, and the crude product was purified by silica gel chromatography (eluent: PE: EA = 50: 1 to 10: 1) to obtain intermediate 1-2 (5.90 g, 34.1 mmol) with a yield of 83%. MS m / z (ESI): 173.9 [M + H]+ .

[0218] Preparation of intermediate 1-3

[0219] To a mixture of 1-2 (1.00 g, 5.77 mmol) in MeOH (50 mL) was added Raney nickel (0.0400 mL, 5.77 mmol), the resulting mixture was degassed and purged with hydrogen three times, and stirred for 16 hours at 25 ° C under hydrogen (15 psi). After the reaction was completed, the reaction mixture was allowed to stand for 10 minutes, the supernatant was filtered through diatomaceous earth, and the filter cake was washed three times with MeOH (20 mL). The filtrate was concentrated to dryness under reduced pressure to give a crude product 1-3 (1.00 g, 5.64 mmol) with a yield of 98%. MS m / z (ESI): 178.0 [M + H] + .

[0220] Preparation of compound 1

[0221] To a THF (1 mL) solution of intermediate INT-A (100 mg, 0.370 mmol) and DIEA (180 μL, 1.11 mmol) was added intermediate 1-3 (97.9 mg, 0.550 mmol), and the resulting mixture was stirred at 80 ° C for 16 hours. After the reaction was completed, it was cooled to room temperature and the reaction mixture was concentrated to dryness. The crude product was purified by preparative HPLC to give compound 1 (134.0 mg, 0.130 mmol) with a yield of 58%. MS m / z (ESI): 413.2 [M + H] + .

[0222] 1 H NMR (400MHz, DMSO-d6) δ10.67(s,1H),9.31(s,1H),8.89(s,1H),8.73(s,1H),7.89(dd,J=35.7,6.2H z,2H),7.37–7.15(m,4H),6.98–6.65(m,1H),4.83(dd,J=60.6,4.1Hz,4H),3.70(s,4H),1.96(s,4H).

[0223] Example 2

[0224] Synthesis route of compound 2:

[0225] Preparation of intermediate 2-1

[0226] INT-A (200 mg, 0.74 mmol) was dissolved in aqueous ammonia (2 mL). The mixture was heated to 110°C under microwave conditions and stirred for 1 hour. After the reaction was complete, the mixture was filtered and concentrated to afford Intermediate 2-1 (60 mg) in a 32% yield. MS m / z (ESI): 253.1 [M+H] + .

[0227] Preparation of intermediate 2-3

[0228] To a mixed solution of Intermediate 2-1 (60 mg, 0.24 mmol), DIEA (92 mg, 0.71 mmol), and THF (2 mL) was added Intermediate 2-2 (201 mg, 0.24 mmol) at 0°C and stirred for 1 hour. After completion of the reaction, the mixture was concentrated to afford the crude product of Intermediate 2-3. The crude product was used directly in the next step.

[0229] Preparation of compound 2

[0230] To a mixture of intermediate 2-3 and THF (2 mL) were added DIEA (37 mg, 0.29 mmol) and compound 2-4 (16 mg, 0.14 mmol), respectively. The temperature was gradually raised to 80°C and stirred for 2 hours. After completion of the reaction, the mixture was concentrated to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 2 (3.5 mg) in a yield of 5.4%. MS m / z (ESI): 387.0 [M+H] + .

[0231] 1 H NMR(400MHz,Chloroform-d)δ10.02(s,1H),8.91(d,J=2.0Hz,1H),8.80–8.64(m,2H),8.39(s,2H),8.20 (d,J=8.1Hz,1H),7.82(d,J=6.7Hz,1H),7.56–7.33(m,4H),5.22(d,J=5.9Hz,2H),5.02(d,J=5.8Hz,2H).

[0232] Example 3

[0233] Synthesis route of compound 3:

[0234] Preparation of intermediate 3-1

[0235] To a mixed solution of INT-B (200 mg, 0.74 mmol) and DMF (5 mL) were added intermediate INT-A (247.5 mg, 0.91 mmol), t-BuOK (165 mg, 1.47 mmol), Sphos (30 mg, 0.07 mmol) and Pd(OAc)2 (16.5 mg, 0.07 mmol), the atmosphere was replaced with nitrogen three times, and the mixture was stirred at 110°C for 18 hours. After the reaction was completed, the mixture was cooled to room temperature and poured into 20 mL of water. The mixture was extracted with EtOAc (20 mL×3), and the organic phases were combined, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated to obtain the crude product. The crude product was separated and purified by column chromatography (eluent: PE:EA = 100:0 to 1:1) to obtain intermediate 3-1 (100 mg, 27.24%). MS m / z (ESI): 499.2 [M+H] + .

[0236] Preparation of compound 3

[0237] To a mixed solution of intermediate 3-1 (100 mg, 0.2 mmol) and DCM (2 mL) was added TFA (1 mL, 13.42 mmol) and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated to give a crude product, which was then purified by preparative HPLC to afford compound 3 (30.8 mg) in a 41.69% yield. MS m / z (ESI): 369.1 [M+H] + .

[0238] 1 H NMR(400MHz, DMSO-d6)δ13.04(s,1H),10.57(d,J=78.6Hz,2H),9.02–8.93(m,1H),8.75( s,1H),8.21(s,1H),7.77(d,J=8.0Hz,1H),7.44(s,1H),7.28–6.69(m,4H),4.33(s,3H).

[0239] Example 4

[0240] Synthesis route of compound 4:

[0241] Preparation of compound 4

[0242] To a solution of INT-C (50 mg, 0.15 mmol) and DIEA (57 mg, 0.44 mmol) in THF (1.0 mL) was slowly added dropwise 4-1 (0.02 mL, 0.22 mmol). After the addition was complete, the temperature was raised to 110°C and the reaction was allowed to proceed for 1.5 hours. After completion of the reaction, the crude product was concentrated to obtain the product. The crude product was purified by preparative HPLC to afford compound 4 (42.6 mg, 0.1 mmol) in a 63% yield. MS m / z (ESI): 410.0 [M+H] + .

[0243] 1 H NMR (400MHz, DMSO-d6) δ10.64(d,J=7.3Hz,1H),9.21(t,J=6.1,1H),8.94(d,J=2 .3Hz,1H),8.79(dd,J=8.2,6.1Hz,3H),8.33(d,J=8.1Hz,1H),7.90(dd,J=8.0,5. 7Hz,1H),7.56(dd,J=8.6,6.2Hz,1H),7.21-7.08(m,2H),5.56(p,J=7.0Hz,1H),4 .99(dd,J=16.5,6.5Hz,1H), 4.79(dd,J=16.6,5.7Hz,1H), 1.50(d,J=7.0Hz,3H).

[0244] Example 5

[0245] Synthesis route of compound 5:

[0246] Preparation of intermediate 2-1

[0247] INT-A (200 mg, 0.74 mmol) was dissolved in aqueous ammonia (2 mL). The mixture was heated to 110°C under microwave conditions and stirred for 1 hour. After the reaction was complete, the mixture was filtered and concentrated to afford Intermediate 2-1 (60 mg) in a 32% yield. MS m / z (ESI): 253.1 [M+H] + .

[0248] Preparation of intermediate 2-3

[0249] To a mixed solution of intermediate 2-1 (60 mg, 0.24 mmol), DIEA (92 mg, 0.71 mmol), and THF (2 mL) was added compound 2-2 (201 mg, 0.24 mmol) at 0°C and stirred for 1 hour. After completion of the reaction, the mixture was concentrated to afford the crude product, which was used directly in the next step.

[0250] Preparation of compound 5

[0251] To a mixture of intermediate 2-3 and THF (2 mL) were added DIEA (104 mg, 0.81 mmol) and compound 5-1 (15 mg, 0.27 mmol), respectively. The temperature was gradually raised to 100°C and stirred for 16 hours. After completion of the reaction, the mixture was concentrated to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 5 (6.8 mg) in a yield of 7.5%. MS m / z (ESI): 358.1 [M+Na] + .

[0252] 1 H NMR(400MHz, DMSO-d6)δ8.95(d,J=2.1Hz,1H),8.70(d,J=2.1Hz,1H),7.52–7.41(m,2H),7.36–7 .24(m,3H),4.74(d,J=6.4Hz,2H),2.68(d,J=1.8Hz,1H),0.75–0.64(m,2H),0.53–0.36(m,2H).

[0253] Example 6

[0254] Synthesis route of compound 6:

[0255] Preparation of intermediate 6-2

[0256] To a mixed solution of INT-1 (500 mg, 1.24 mmol), compound 6-1 (160.00 μL, 1.24 mmol) and THF (3 mL) was added DIEA (2050.00 μL, 12.40 mmol), and the reaction was stirred at 25 ° C for 16 hours. After the reaction was completed, the mixture was poured into water (20 mL) and extracted with DCM (50 mL x 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by column chromatography (eluent: PE: EA = 3: 1 to 1: 1, Rf = 0.2) to give intermediate 6-2 (100 mg, 28.14%). MS m / z (ESI): 287.0 [M + H] + .

[0257] Preparation of compound 6

[0258] To a mixed solution of intermediate 6-2 (100 mg, 0.35 mmol), compound 4-1 (42.84 μL, 0.42 mmol) and DMF (1 mL) was added DIEA (115.98 μL, 0.70 mmol), gradually heated to 80°C, and stirred for 3 hours. After the reaction was completed, it was cooled to room temperature, poured into water (5 mL) and extracted with EtOAc (15 mL x 2). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*25mm*10μm column (eluent: 30%-60% (v / v) CH3CN and water and 0.025% NH4HCO3) to give compound 6 (80 mg, 63.95%). MS m / z (ESI): 358.1 [M+H] + . 1 H NMR (400MHz, DMSO) δ9.58 (s, 1H), 8.88–8.30 (m, 5H), 7.90 (s, 1H), 7.71 (dd, J = 53.6, 7.3Hz, 1H), 7. 56–7.14(m,5H),5.45(dd,J=17.0,7.6Hz,1H),4.65(dt,J=28.9,9.7Hz,2H),1.58(d,J=7.2Hz,3H).

[0259] Example 7

[0260] Synthesis route of compound 7:

[0261] Preparation of intermediate 7-2

[0262] Compound 7-1 (159 mg, 0.99 mmol) was added to a mixed solution of INT-1 (200 mg, 0.990 mmol), DIEA (1.98 mL, 11.9 mmol), and THF (5 mL), and the mixture was stirred at 25°C for 16 hours. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was then separated and purified by column chromatography (eluent: PE:EA = 10:1 to 1:1) to obtain intermediate 7-2 (90.0 mg, 28%). MS m / z (ESI): 324.0 [M+H] + .

[0263] Preparation of compound 7

[0264] Compound 4-1 (0.0600 mL, 0.560 mmol) was added to a mixed solution of 7-2 (90.0 mg, 0.280 mmol), DIEA (0.140 mL, 0.830 mmol), and THF (1 mL). The mixture was heated to 80°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 7 (30.4 mg) in a yield of 27%. MS m / z (ESI): 395.1 [M+H] + .

[0265] 1 H NMR (400MHz, DMSO) δ9.86(s,1H),8.99(s,1H),8.78(dd,J=31.7,1.2Hz,1H),8.64-8.37(m,3H),7.79(d,J=7.3Hz,1H ),7.58-7.43(m,1H),7.31(dd,J=21.2,13.3Hz,2H),7.23-6.98(m,1H),4.73(d,J=3.9Hz,2H),4.56(d,J=5.4Hz,2H).

[0266] Example 8

[0267] Synthesis route of compound 8:

[0268] Preparation of intermediate 8-2

[0269] To a mixed solution of compound 8-1 (3.73 g, 25.4 mmol), K2CO3 (10.52 g, 76.1 mmol), and DMF (50 mL) was added SEM-Cl (5.40 mL, 30.4 mmol) at 0°C, and the mixture was stirred at 15°C for 3 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, which was then extracted with EtOAc (100 mL). The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to obtain the crude product. The crude product was isolated and purified by column chromatography (eluent: PE:EA = 10:1 to 5:1) to obtain intermediate 8-2 (5.68 g) in an 81% yield. MS m / z (ESI): 278.9 [M+H] + .

[0270] Preparation of intermediate 8-4

[0271] To a mixed solution of intermediate 8-2 (7.00 g, 38.4 mmol), compound 8-3 (7.00 g, 38.4 mmol), 1,4-dioxane (10 mL), and water (2 mL) were added Pd(PPh3)4 (10.3 g, 57.6 mmol) and K2CO3 (10.3 g, 57.6 mmol), respectively. The mixture was purged with nitrogen three times, gradually heated to 110°C, and stirred for 8 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated to obtain a crude product. The crude product was isolated and purified by column chromatography (eluent: PE:EA = 10:1 to EA:anhydrous MeOH = 8:1) to obtain intermediate 8-4 (560 mg) in an 83% yield. MS m / z (ESI): 304.0 [M+H] + .

[0272] Preparation of intermediate 8-5

[0273] To a mixed solution of Intermediate 8-4 (140 mg, 0.46 mmol), INT-1 (111 mg, 0.55 mmol), and THF (3 mL) was added DIEA (0.15 mL, 0.92 mmol) and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated to obtain a crude product. The crude product was isolated and purified by column chromatography (eluent: PE:EA = 10:1 to 1:1) to obtain Intermediate 8-5 (152 mg) in a 70% yield. MS m / z (ESI): 468.2 [M+H] + .

[0274] Preparation of intermediate 8-6

[0275] To a mixed solution (3 mL) of intermediate 8-5 (133 mg, 0.28 mmol), compound 4-1 (61 mg, 0.57 mmol), and THF was added DIEA (0.14 mL, 0.985 mmol). The temperature was gradually raised to 80°C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated to obtain a crude product. The crude product was isolated and purified by column chromatography (eluent: PE:EA = 10:1 to 1:1) to obtain intermediate 8-6 (150 mg) in a 98% yield. MS m / z (ESI): 541.2 [M+H] + .

[0276] Preparation of compound 8

[0277] To a mixed solution of intermediate 8-6 (150 mg, 0.28 mmol) and EtOH (1 mL) was added HCl / 1,4-dioxane solution (1 mL, 4 mmol), the temperature was gradually raised to 60°C, and the mixture was stirred for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 8 (35 mg) in a 31% yield. MS m / z (ESI): 410.0 [M+H] + .

[0278] 1 H NMR (400MHz, DMSO) δ12.49 (s, 1H), 9.25-8.91 (m, 1H), 8.71 (d, J = 2.0Hz, 1H), 8.63-8.46 (m, 1H), 8.45-8.25 (m, 2H), 8.02- 7.84(m,2H),7.82-7.48(m,2H),7.43-7.26(m,2H),7.25-7.08(m,2H),6.99(s,1H),4.82-4.64(m,2H),4.62-4.43(m,2H).

[0279] Example 9

[0280] Synthesis route of compound 9:

[0281] Preparation of intermediate 9-2

[0282] To a mixed solution of compound 9-1 (100 mg, 0.750 mmol) and DCM (1 mL) were added INT-1 (553 mg, 0.830 mmol) and DIEA (746 μL, 4.50 mmol), respectively, and the mixture was stirred at 25°C for 16 hours. After completion of the reaction, the mixture was concentrated to obtain a crude product, which was then purified by column chromatography (eluent: PE:EA = 5:1 to 3:1) to afford intermediate 9-2 (100 mg) in a 46% yield. MS m / z (ESI): 298.8 [M+H] + .

[0283] Preparation of compound 9

[0284] To a mixed solution of intermediate 9-2 (100 mg, 0.340 mmol) and DMF (2 mL) were added compound 4-1 (40 mg, 0.37 mmol) and DIEA (167 μL, 1.01 mmol), respectively. The temperature was gradually raised to 110°C and stirred for 1.5 hours. After completion of the reaction, the mixture was concentrated to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 9 (27 mg) in a 22% yield. MS m / z (ESI): 370.5 [M+H]+ .

[0285] 1 H-NMR(400MHz,DMSO)δ,8.89(s,1H),8.71(d,J=11.1Hz,1H),8.54(dd,J=22.4,2 1.9Hz,1H),8.45(d,J=16.4Hz,1H),8.32(d,J=12.4Hz,1H),,8.02(d,J=70.2Hz, 1H),7.75(dd,J=34.5,7.3Hz,1H),7.37-7.04(m,5H),5.84(dd,J=23.1,7.9Hz,1 H),4.69-4.47(m,2H),3.11-2.79(m,2H),2.45-2.34(m,1H),2.28-2.15(m,1H).

[0286] Example 10

[0287] Synthesis route of compound 10

[0288] Preparation of intermediate 10-2

[0289] Compound 10-1 (1.0 g, 3.82 mmol), phthalimide (0.68 g, 4.59 mmol), and K2CO3 (1.32 g, 9.56 mmol) were dissolved in CH3CN (20 ml) and reacted at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated to dryness to obtain a crude product, which was then purified by column chromatography (PE:EA = 10:1–2:1) to afford intermediate 10-2 (1.1 g, 71.9%). MS m / z (ESI): 329.9 [M+H] + .

[0290] Preparation of intermediate 10-3

[0291] To a solution of intermediate 10-2 (400 mg, 1.22 mmol) in EtOH (10 mL) was added hydrazine hydrate (763 mg, 12.2 mmol), and the resulting mixture was stirred at 80° C. for 30 minutes. The reaction mixture was concentrated to dryness and used in the next step without further manipulation. MS m / z (ESI): 197.0 [M+H] + .

[0292] Preparation of intermediate 10-4

[0293] Compound INT-1 (488 mg, 2.43 mmol) was added to a solution of the crude product from the previous step and DIEA (2.01 mL, 12.1 mmol) in DCM (16 mL). The resulting mixture was stirred at 25°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated to dryness. The crude product was isolated and purified by preparative TLC (developing solvent: PE:EA = 10:1 to 1:1) to obtain intermediate 10-4 (170 mg, 0.470 mmol) in a 39% yield. MS m / z (ESI): 361.9 [M+H] + .

[0294] Preparation of compound 10

[0295] To a DMF (3 mL) solution of intermediate 10-4 (170 mg, 0.470 mmol) and compound 4-1 (95.8 μL, 0.940 mmol) was added DIEA (233 μL, 1.41 mmol) and stirred at 80 ° C for 2 hours to obtain a mixed solution. After the reaction was completed, it was cooled to room temperature. The mixture was poured into water (10 mL) and extracted with EtOAc (10 mL) three times. The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 10 (25.6 mg, 0.0600 mmol) in a yield of 13%. MS m / z (ESI): 434.0 [M+H] + .

[0296] 1 H NMR (400MHz, DMSO) δ9.12 (d, J=66.7Hz, 1H), 8.74-8.35 (m, 3H), 8.35-8.19 (m, 2H), 8.06–7.89 (m,2H),7.87-7.72(m,1H),7.65-7.02(m,3H),4.86(d,J=5.3Hz,2H),,4.59(d,J=5.8Hz,2H).

[0297] Example 11

[0298] Synthesis route of compound 11:

[0299] Preparation of Intermediate 11-1

[0300] A mixture of INT-C (250 mg, 0.74 mmol) and NH 3 in MeOH (4 mL) was added to a round-bottom flask and heated to 90 ° C in a microwave. The mixture was stirred continuously for 1 hour. The reaction mixture was concentrated under reduced pressure at 40 ° C. The residue was purified by flash chromatography and eluted with DCM / MeOH (30: 1-10: 1) to give intermediate 11-1 (180 mg, 76.3%). LC / MS: retention time: 1.004 min, MS (ESI) m / z: 319.0, [M + H] + .

[0301] Preparation of Intermediate 11-3

[0302] Intermediate 11-1 (180 mg, 0.57 mmol, 1 eq) and compound 11-2 (178 mg, 1.14 mmol, 2 eq) were dissolved in THF (6 mL), and DIEA (221 mg, 1.71 mmol, 3 eq) was added at 25 ° C under nitrogen protection. The reaction mixture was stirred at 25 ° C for 4 hours. The reaction mixture was concentrated at 30 ° C. The residue was purified by flash chromatography and eluted with PE / EA (3:1-1:1) to obtain 11-3 (40 mg, 16.1%). LC / MS: retention time: 1.310 min, MS (ESI) m / z: 439.0, [M+H] + .

[0303] Preparation of compound 11

[0304] A mixture of intermediate 11-3 (40 mg, 0.09 mmol, 1 eq) and compound 11-4 (35 mg, 0.27 mmol, 3 eq) was dissolved in CH3CN (3 mL) and stirred at 60°C under nitrogen for 3 hours. The reaction mixture was concentrated under reduced pressure at 40°C. The crude product was purified by Genal-Prep-HPLC to give the product compound 11 (1.9 mg, 4.4%). LC / MS: retention time: 1.268 min, MS (ESI) m / z: 474.2, [M+H] + .

[0305] 1H NMR (400MHz, CDCl3) δ9.54(s,1H),8.87(d,J=4.0Hz,1H),8.48(s,1H),7.46(d,J=4.0Hz,1H),7.37–7.34(m,1H),7.24(s,1H),7.15(d,J=8.0Hz, 1H),7.00–6.95(m,1H),5.61(t,J=8.0Hz,1H),3.95(d,J=12.0Hz,2H),3 .43–3.36(m,4H),1.68(d,J=8.0Hz,3H),1.65(s,1H),1.35–1.26(s,6H).

[0306] Example 12

[0307] Synthesis route of compound 12:

[0308] Preparation of compound 12

[0309] A solution of INT-C (55 mg, 0.16 mmol, 1 eq) and 12-1 (32 mg, 0.21 mmol, 1.3 eq) in toluene (3 mL) was placed in a round-bottom flask and heated to 150°C under microwave. The mixture was stirred continuously for 25 minutes. The reaction mixture was concentrated under reduced pressure at 40°C. The crude product was purified by Genal-Prep-HPLC to afford product 12 (64.3 mg, 86.8%). LC / MS: retention time: 1.188 min, MS (ESI) m / z: 455.1, [M+H] + .

[0310] 1 H NMR(400MHz,DMSO-d6)δ9.31–8.99(m,3H),8.81(s,1H),8.44(s,1H),7.66(s,1H),7.46(d,J=8.0Hz,1H),7.3 5(s,1H),7.20(t,J=8.0Hz,1H),6.84(d,J=8.0Hz,1H),5.74(s,1H),3.73–3.72(m,6H),1.60(d,J=8.0Hz,3H).

[0311] Example 13

[0312] Synthesis route of compound 13:

[0313] A DMSO (4 mL) solution containing INT-C (45 mg, 0.13 mmol, 1 eq), 13-1 (36 mg, 0.17 mmol, 1.3 eq) and DIEA (50.4 mg, 0.39 mmol, 3 eq) was placed in a round-bottom flask and placed in an oil bath heated to 150°C with continuous stirring for 3 hours. After the reaction was complete, 15 mL of water was added, the residue was extracted with EA (3 x 20 mL), and the organic phase was washed with saturated brine (50 mL). The reaction mixture was concentrated under reduced pressure at 40°C. The crude product was purified by Genal-Prep-HPLC to give product 13 (23.2 mg, 42.4%). LC / MS: retention time: 1.035 min, MS (ESI) m / z: 411.0, [M+H] + .

[0314] 1 H NMR(400MHz,DMSO-d6)δ9.39(s,1H),9.03(s,2H),8.78(s,1H),8.41(s,1H),7.89(s,1H),7.62 (s,1H),7.42(d,J=12.0Hz,1H),7.19(s,1H),6.45(s,1H),5.78(s,3H),1.56(d,J=4.0Hz,3H).

[0315] Example 14

[0316] Synthesis route of compound 14

[0317] Preparation of intermediate 14-2

[0318] To a solution of INT-1 (40 mg, 0.20 mmol) in THF (5 mL) was added compound 14-1 (36.1 mg, 0.20 mmol) and DIEA (77.2 mg, 0.60 mmol). The reaction mixture was stirred at 15 ° C for 16 hours. LC / MS showed the desired MS. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE: EA from 100: 0 to 0: 100 in 30 minutes) to give 14-2 (60 mg, 78.6%). LC / MS: retention time: 1.203 min, MS (ESI) m / z: 346.1, [M + H] + .

[0319] Preparation of compound 14

[0320] To a solution of intermediate 14-2 (60 mg, 0.17 mmol) in toluene (2 mL) was added compound INT-D (121.42 mg, 0.52 mmol) and the reaction was stirred at 150 ° C for 0.5 hours under microwave conditions. LC / MS showed that the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC and eluted with CH 3 CN aqueous solution (CH 3 CN increased from 15% to 45% in 30 minutes) to give compound 14 (40.6 mg, 52.9%). LC / MS: retention time: 1.092 min, MS (ESI) m / z: 443.2, [M + H] + .

[0321] 1 H NMR (400MHz, DMSO) δ12.93(s,1H),9.50(s,1H),8.90(d,J=8.2Hz,1H),8.82(d,J=2.0Hz,1H),8.46(d,J=2.1Hz,1H),8.09(s,1H),7.89(d, J=7.2Hz,1H),7.48(d,J=8.0Hz,1H),7.11(t,J=7.8Hz,2H),6.86(t,J=15.1Hz,2H),5.38(s,1H),3.68(d,J=4.2Hz,6H),1.66–1.57(m,3H).

[0322] Example 15

[0323] Synthesis route of compound 15

[0324] Preparation of intermediate 15-3

[0325] To a solution of compound 15-1 (5.0 g, 29.7 mmol) in THF (100 mL) was added compound 15-2 (3.96 g, 32.6 mmol) and Ti(OEt) 4 (20.31 g, 89.1 mmol). The reaction mixture was stirred at 80 ° C for 16 hours. LC / MS showed that the desired MS was detected. The reaction mixture was poured into water. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE / EA from 100:0 to 50:50 in 30 minutes) to give compound 15-3 (6.3 g, 82%).

[0326] LC / MS: retention time: 1.26 min, MS (ESI) m / z: 272.0, [M+H] + .

[0327] Preparation of intermediate 15-4

[0328] To a mixed solution of intermediate 15-3 (6.0 g, 22.1 mmol) in THF (100 mL) and water (5 mL) was added NaBH4 (1.25 g, 33.1 mmol) at -30 ° C. The reaction was warmed to 25 ° C and then stirred at 25 ° C for 12 h. LC / MS showed that the desired MS was detected. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE: EA from 100:0 to 0:100 in 30 minutes) to give intermediate 15-4 (3.0 g, 49.6%). LC / MS: retention time: 1.234 min, MS (ESI) m / z: 274.1, [M + H] + .

[0329] Preparation of intermediate 15-5

[0330] A solution of intermediate 15-4 (1.0 g, 3.7 mmol) in HCl / 1,4-dioxane (10 mL) was stirred at 25 ° C for 2 h. The mixture was adjusted to pH = 8 with solid NaHCO 3. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE: EA from 100:0 to 0:100 in 30 minutes) to give intermediate 15-5 (580 mg, 93.7%). LC / MS: retention time: 0.618 min, MS (ESI) m / z: 153.1, [M–NH 2] + .

[0331] Preparation of intermediate 15-6

[0332] To a solution of intermediate 15-5 (80 mg, 0.47 mmol) in THF (5 mL) was added intermediate INT-1 (105 mg, 0.52 mmol) and DIEA (183 mg, 1.42 mmol). The reaction mixture was stirred at 25 ° C for 16 h. LC / MS showed that the desired MS was detected. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE: EA from 100: 0 to 0: 100 in 30 minutes) to give intermediate 15-6 (120 mg, 76%). LC / MS: retention time: 1.25 min, MS (ESI) m / z: 334.0, [M + H] + .

[0333] Preparation of Example 15

[0334] To a solution of intermediate 15-6 (60 mg, 0.18 mmol) in toluene (2 mL) was added compound INT-D (168 mg, 0.72 mmol). The reaction was stirred at 150 ° C for 0.5 hours. LC / MS showed that the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using a CH 3 CN aqueous solution (CH 3 CN increased from 15% to 45% in 30 minutes) to give compound 15 (40 mg, 51.7%).

[0335] LC / MS: retention time: 1.135 min, MS (ESI) m / z: 431.2, [M+H] + .

[0336] 1 H NMR (400MHz, DMSO) δ12.92(s,1H),9.59(s,1H),9.09(s,1H),8.84(d,J=2.0Hz,1H),8.50(d,J=1.7Hz,1H),8.10(s,1H),7.79(s, 1H),7.52(d,J=7.9Hz,1H),7.25(s,1H),7.11(t,J=7.8Hz,1H),7.03(m,2H),5.30(s,1H),3.80–3.74(m,3H),1.63–1.51(m,3H).

[0337] Example 16

[0338] Synthesis route of compound 16

[0339] Preparation of intermediate 16-2

[0340] To a solution of compound 16-1 (5.0 g, 29.7 mmol) in THF (100 mL) was added 15-2 (3.96 g, 32.6 mmol) and Ti(OEt) 4 (20.3 g, 89.1 mmol). The reaction mixture was stirred at 80 ° C for 16 hours. LC / MS showed that the desired MS was detected. The reaction mixture was poured into water. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE / EA from 100:0 to 50:50 in 30 minutes) to give intermediate 16-2 (7.0 g, 86.7%).

[0341] LC / MS: retention time: 1.291 min, MS (ESI) m / z: 272.1, [M+H] + .

[0342] Preparation of intermediate 16-3

[0343] To a mixed solution of intermediate 16-2 (7.0 g, 25.8 mmol) with THF (100 mL) and water (5 mL), NaBH 4 (1.46 g, 38.7 mmol) was added at -30 ° C. The reaction was warmed to 25 ° C and then stirred at 25 ° C for 12 h. LC / MS showed that the desired MS was detected. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE: EA from 100: 0 to 0: 100 in 30 minutes) to give intermediate 16-2 (1.0 g, 14.34%).

[0344] LC / MS: retention time: 1.256 min, MS (ESI) m / z: 274.1, [M+H] + .

[0345] Preparation of intermediate 16-4

[0346] A solution of intermediate 16-3 (1 g, 3.7 mmol) in HCl / 1,4-dioxane (10 mL) was stirred at 25 ° C for 2 h. The mixture was adjusted to pH = 8 with solid NaHCO 3. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE: EA from 100:0 to 0:100 in 30 minutes) to give intermediate 16-4 (0.4 g, yield: 64.6%). LC / MS: retention time: 0.559 min, MS (ESI) m / z: 153.1, [M–NH 2] + .

[0347] Preparation of intermediate 16-5

[0348] To a THF (5 mL) solution of intermediate 16-4 (60 mg, 0.36 mmol) was added intermediate INT-D (85.5 mg, 0.43 mmol) and DIEA (137 mg, 1.06 mmol). The reaction mixture was stirred at 25 ° C for 16 hours. LC / MS showed that the required MS was detected. The reaction mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE: EA from 100: 0 to 0: 100 in 30 minutes) to give intermediate 16-5 (80 mg, 67.6%).

[0349] LC / MS: retention time: 1.274 min, MS (ESI) m / z: 334.1, [M+H] + .

[0350] Preparation of compound 16

[0351] To a solution of intermediate 16-5 (40 mg, 0.12 mmol) in toluene (2 mL) was added intermediate INT-D (83.9 mg, 0.36 mmol) and the reaction was stirred at 150 ° C for 0.5 hours under microwave. LC / MS showed that the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using a CH 3 CN aqueous solution (CH 3 CN increased from 15% to 45% in 30 minutes) to give compound 16 (28.3 mg, 54.8% yield). LC / MS: retention time: 1.181 min, MS (ESI) m / z: 431.2, [M + H] + .

[0352] 1 H NMR(400MHz,)δ12.89(s,1H),9.48(s,1H),8.94(s,1H),8.84(d,J=2.0Hz,1H),8.49(d,J=2.0Hz,1H),8.07(s,1H),7.88(d,J=7.2Hz,1H),7.44(dd ,J=15.3,8.5Hz,2H),7.07(t,J=7.7Hz,1H),6.82(dd,J=12.5,2.4Hz,1H) ,6.72(d,J=8.5Hz,1H),5.67(s,1H),3.72(s,3H),1.59(d,J=7.0Hz,3H).

[0353] Example 17

[0354] Synthesis route of compound 17

[0355] Preparation of intermediate 17-3

[0356] To a solution of compound 17-1 (1.2 g, 7.1 mmol, 1 eq), compound 17-2 (749 mg, 8.5 mmol, 1.2 eq) and PPh3 (2.2 g, 8.5 mmol, 1.2 eq) in THF (20 mL), DIAD (1.7 g, 8.5 mmol, 1.2 eq) was added under nitrogen at 0 ° C with stirring. The reaction mixture was warmed to 25 ° C and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure at 40 ° C. The residue was purified by flash chromatography and eluted with PE / EA (15: 1-5: 1) to give the product intermediate 17-3 (350 mg, yield: 20.6%). LC / MS: retention time: 1.183 min, MS (ESI) m / z: 240.1, [M+H] + .

[0357] Preparation of intermediate 17-4

[0358] A mixture of Intermediate 17-3 (120 mg), 10% Pd / C (30 mg), and MeOH (7 mL) was stirred at 25°C under a hydrogen balloon for 5 hours. The solution was filtered, and the filtrate was concentrated in vacuo to afford Intermediate 17-4 (65 mg, 61.9%). The residue was used directly in the next step without further purification. LC / MS: Retention time: 0.512 min, MS (ESI) m / z: 210.1, [M+H] + .

[0359] Preparation of compound 17

[0360] A round-bottom flask containing a mixed solution of intermediate INT-C (45 mg, 0.13 mmol, 1 eq) and intermediate 17-4 (42 mg, 0.20 mmol, 1.5 eq) in toluene (4 mL) was heated to 150°C under microwave. The mixture was stirred continuously for 1 hour. The reaction mixture was concentrated under reduced pressure at 40°C. The crude product was purified by Genal-Prep-HPLC to obtain the product compound 17 (22.8 mg, 33.5%). LC / MS: retention time: 1.183 min, MS (ESI) m / z: 511.0, [M+H] + .

[0361] 1H NMR(400MHz,DMSO-d6)δ9.34–9.01(m,3H),8.82(s,1H),8.44(d,J=4.0Hz,1H ),7.65(s,1H),7.45(d,J=12.0Hz,1H),7.23(s,1H),7.19(d,J=8.0Hz,1H),6. 81(d,J=8.0Hz,1H),5.74(s,1H),4.92(t,J=4.0Hz,1H),3.87–3.81(m,4H),3. 78–3.73(m,3H),2.18–2.11(m,1H),2.01–1.95(m,1H),1.60(d,J=8.0Hz,3H).

[0362] Example 18

[0363] Synthesis route of compound 18

[0364] Preparation of intermediate 18-3

[0365] To a solution of compound 18-1 (1.2, 7.1 mmol, 1 eq), compound 17-2 (749 mg, 8.5 mmol, 1.2 eq), PPh3 (2.2 g, 8.5 mmol, 1.2 eq) in THF (20 mL), DIAD (1.7 g, 8.5 mmol, 1.2 eq) was added under nitrogen at 0 ° C with stirring. The reaction mixture was warmed to 25 ° C and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure at 40 ° C. The residue was purified by flash chromatography and eluted with PE / EA (15: 1-5: 1) to give the product intermediate 18-3 (350 mg, yield: 20.6%). LC / MS: retention time: 1.177 min, MS (ESI) m / z: 240.0, [M+H] + .

[0366] Preparation of intermediate 18-4

[0367] A mixture of Intermediate 18-3 (200 mg) and 10% Pd / C (50 mg) in MeOH (10 mL) was stirred at 25°C under hydrogen for 5 hours. The solution was filtered and the filtrate was concentrated in vacuo to afford the product, Intermediate 18-4 (85 mg, 48.6%). The residue was used directly in the next step without further purification. LC / MS: Retention time: 0.506 min, MS (ESI) m / z: 210.1, [M+H] + .

[0368] Preparation of compound 18

[0369] A round-bottom flask containing a mixed solution of intermediate INT-C (30 mg, 0.09 mmol, 1 eq) and intermediate 18-4 (29 mg, 0.14 mmol, 1.5 eq) in toluene (3 mL) was heated to 150°C under microwave. The mixture was stirred continuously for 30 minutes. The reaction mixture was concentrated under reduced pressure at 40°C. The crude product was purified by Genal-Prep-HPLC to obtain the product compound 18 (19.1 mg, 42.1%). LC / MS: retention time: 1.191 min, MS (ESI) m / z: 511.2, [M+H] + .

[0370] 1 H NMR (400MHz, DMSO-d6) δ9.01 (s, 3H), 8.81 (d, J = 4.0Hz, 1H), 8.44 (s, 1H), 7.66 (s, 1H), 7.47 (d, J = 8. 0Hz,1H),7.39(s,1H),7.21(t,J=8.0Hz,1H),6.86(d,J=8.0Hz,1H),5.74(s,1H),4.87(s,1H),3.89–

[0371] 3.80(m,4H),3.79–3.73(m,3H),2.18(s,1H),1.99–1.97(m,1H),1.60(d,J=4.0Hz,3H).

[0372] Example 19

[0373] Synthesis route of compound 19

[0374] Preparation of intermediate 19-2

[0375] To a solution of compound 19-1 (60 mg, 0.275 mmol) in CH 3 CN (5 mL) was added compound SM-2 (35.4 mg, 0.33 mmol) and Et 3 N (83.5 mg, 0.826 mmol). The reaction mixture was stirred at 25 ° C for 2 hours. LC / MS showed that the desired MS was detected. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE: EA from 100: 0 to 0: 100 in 30 minutes) to give intermediate 19-2 (70 mg, 88%).

[0376] LC / MS: retention time: 1.11 min, MS (ESI) m / z: 289.1, [M+H] + .

[0377] Preparation of compound 19

[0378] To a solution of intermediate 19-2 (70 mg, 0.24 mmol) in o-DCB (2 mL) was added intermediate INT-D (226 mg, 0.97 mmol) and the reaction was stirred at 180 ° C for 0.5 h under microwave. LC / MS showed that the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC using a CH CN aqueous solution (CH CN increased from 15% to 45% in 30 minutes) to give compound 19 (37.5 mg, 40%).

[0379] LC / MS: retention time: 1.052 min, MS (ESI) m / z: 386.2, [M+H] + .

[0380] 1 H NMR (400MHz, DMSO) δ13.75(s,1H),9.16(s,1H),8.16(s,1H),7.99(s,1H),7.81(t,J=5.8Hz,1H),7.63(d,J=7.4Hz,1H),7.29(d dt,J=26.7,14.1,7.0Hz,6H),6.91(t,J=7.8Hz,1H),4.69(d,J=5.8Hz,2H),3.42(td,J=6.7,2.7Hz,2H),2.69(t,J=6.7Hz,2H).

[0381] Example 20

[0382] Synthesis route of compound 20

[0383] Preparation of intermediate 20-2

[0384] A round-bottom flask containing a mixed solution of compound 20-1 (10 g, 58 mmol, 1 eq), compound 15-2 (14 g, 116 mmol, 2 eq), and Ti(OEt)4 (26.4 g, 116 mmol, 2 eq) in THF (200 ml) was placed in an oil bath and heated to 80°C. The mixture was stirred continuously for 15 hours. The reaction mixture was concentrated under reduced pressure at 40°C. The residue was purified by flash chromatography and eluted with PE / EA (20:1-10:1) to give the product intermediate 20-2 (10 g, 62.0%). LC / MS: retention time: 1.317 min, MS (ESI) m / z: 276.0, [M+H] + .

[0385] Preparation of intermediate 20-3

[0386] A solution of intermediate 20-2 (3.5 g, 12.7 mmol, 1 eq) in THF (50 mL) was stirred at -50 ° C under nitrogen protection and NaBH4 (1.44 g, 38.1 mmol, 3 eq) was added. The reaction mixture was warmed to 25 ° C and stirred for 5 hours. Saturated NH4Cl aqueous solution (30 mL) was added. The residue was extracted with EA (30 mL×3). The reaction mixture was concentrated under reduced pressure at 40 ° C. The residue was purified by flash chromatography and eluted with PE / EA (15:1-5:1) to obtain the product intermediate 20-3 (1.4 g, 40.2%). LC / MS: retention time: 1.302 min, MS (ESI) m / z: 278.1, [M+H] + .

[0387] Preparation of intermediate SM-4

[0388] To a solution of intermediate 20-3 (2.5 g) in 1,4-dioxane (10 mL) was added a solution of HCl in 1,4-dioxane (15 mL). The reaction mixture was stirred at 25 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure at 40 ° C. The mixture was adjusted to pH = 7-8 with Na2CO3. The residue was extracted with THF (3x30 mL). The reaction mixture was concentrated in vacuo to give the product intermediate SM-4 (1.4 g, 82.2%). The residue was used directly in the next step without further purification. LC / MS: retention time: 0.869 min, MS (ESI) m / z: 174.1, [M+H] + .

[0389] Preparation of intermediate INT-C

[0390] Intermediate INT-1 (206 mg, 1 mmol, 1 eq) and intermediate SM-4 (196 mg, 1.1 mmol, 1.1 eq) were dissolved in THF (6 mL) and DIEA (397 mg, 3 mmol, 3 eq) was added at 25 ° C under nitrogen. The reaction mixture was stirred at 25 ° C for 5 hours. The reaction mixture was concentrated under reduced pressure at 40 ° C. The residue was purified by flash chromatography and eluted with PE / EA (5: 1-2: 1) to give the product intermediate INT-C (180 mg, 52.1%). LC / MS of 6: retention time: 1.322 min, MS (ESI) m / z: 338.0, [M+H] + .

[0391] Preparation of compound 20

[0392] A round-bottom flask containing a mixed solution of intermediate INT-C (125 mg, 0.37 mmol, 1 eq), intermediate INT-D (112 mg, 0.48 mmol, 1.3 eq) and toluene (4 mL) was placed in a microwave and heated to 150°C. The mixture was stirred continuously for 30 minutes. The reaction mixture was concentrated under reduced pressure at 40°C. The crude product was purified by Genal-Prep-HPLC to obtain the product compound 20 (53.9 mg, 33.1%). LC / MS: retention time: 1.202 min, MS (ESI) m / z: 435.0, [M+H] + .

[0393] 1 H NMR (400MHz, DMSO-d6) δ12.84(s,1H),9.46(s,1H),9.19(s,1H),8.86(s,1H),8.51(s,1H),8.06(s,1H),7.73(d,J=4 Hz, 1H), 7.63 (s, 1H), 7.42 (d, J = 12Hz, 2H), 7.2 (t, J = 8Hz, 1H), 7.05 (t, J = 8Hz, 1H), 5.68 (s, 1H), 4.59 (d, J = 8Hz, 3H).

[0394] Example 21

[0395] Synthesis route of compound 21

[0396] Preparation of Intermediate 21-2

[0397] To a solution of intermediate 21-1 (1.0 g, 4.7 mmol) in CH3CN (20 mL) was added TCFH (1.58 g, 5.6 mmol), NMI (0.77 g, 9.4 mmol) and methylamine (0.29 g, 9.4 mmol). The reaction mixture was stirred at 25 ° C for 16 hours. LC / MS showed that the desired MS was detected. The reaction mixture was poured into water. The layers were separated and the aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE / EA from 100:0 to 50:50 in 30 minutes) to give intermediate 21-2 (0.65 g, yield: 59.57%). LC / MS: retention time: 1.138 min, MS (ESI) m / z: 228.0, 230.0, [M + H] + .

[0398] Preparation of Intermediate 21-3

[0399] To a solution of intermediate 21-2 (650 mg, 2.85 mmol) in 1,4-dioxane (20 mL) was added compound 21-6 (1235 mg, 3.42 mmol) and Pd(PPh3)4 (326 mg, 0.285 mmol). The reaction mixture was stirred at 110 ° C for 2 hours under argon. The reaction was cooled to room temperature, and then HCl (5 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE:EA from 100:0 to 0:100 in 30 minutes) to give intermediate 21-3 (400 mg, yield: 73.4%). LC / MS: retention time: 0.971 min, MS (ESI) m / z: 192.1, [M+H] + .

[0400] Preparation of Intermediate 21-4

[0401] To a solution of intermediate 21-3 (400 mg, 2.09 mmol) in MeOH (20 mL) was added NH4OAc (1612 mg, 20.9 mmol) and NaBH3CN (263 mg, 4.18 mmol). The reaction mixture was stirred at 60 ° C for 16 hours. The mixture was adjusted to pH = 8 with solid NaHCO3. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE:EA from 100:0 to 0:100 in 30 minutes) to give intermediate 21-4 (100 mg, 24.9%). LC / MS: retention time: 0.363 min, MS (ESI) m / z: 176.2, [M–NH2] + .

[0402] Preparation of Intermediate 21-5

[0403] To a solution of intermediate 21-4 (100 mg, 0.52 mmol) in THF (5 mL) was added INT-1 (125 mg, 0.624 mmol) and DIEA (202 mg, 1.56 mmol). The reaction mixture was stirred at 25 ° C for 16 hours. LC / MS showed that the desired MS was detected. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE: EA from 100: 0 to 0: 100 in 30 minutes) to give intermediate 21-5 (80 mg, 43%). LC / MS: retention time: 1.115 min, MS (ESI) m / z: 357.2, [M + H]+ .

[0404] Preparation of compound 21

[0405] To a solution of intermediate 21-5 (80 mg, 0.22 mmol) in toluene (2 mL) was added INT-D (157 mg, 0.67 mmol). The reaction was stirred at 150 ° C for 0.5 hours under microwave. LC / MS showed that the desired MS was detected. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC and eluted with CH 3 CN aqueous solution (CH 3 CN increased from 15% to 45% in 30 minutes) to give compound 21 (26.7 mg, 26.3% yield). LC / MS: retention time: 1.036 min, MS (ESI) m / z: 454.3, [M + H] + .

[0406] 1 H NMR (400MHz, DMSO) δ12.91 (s, 1H), 9.48 (s, 1H), 9.00 (d, J = 8.4Hz, 1H), 8.82 ( d,J=2.0Hz,1H),8.47(d,J=2.1Hz,1H),8.09(d,J=5.6Hz,2H),7.85(d,J=5.3 Hz,1H),7.48(d,J=8.0Hz,1H),7.41(s,1H),7.28(s,1H),7.10(t,J=7.8Hz,2 H), 5.40 (s, 1H), 2.72 (d, J = 4.6Hz, 3H), 2.25 (s, 3H), 1.60 (t, J = 13.9Hz, 3H).

[0407] Example 22

[0408] Synthesis route of compound 22

[0409] Preparation of Intermediate 22-2

[0410] To a solution of compound 22-1 (2.0 g, 9.6 mmol) in 1,4-dioxane (50 mL) was added compound 21-6 (4.16 g, 11.5 mmol) and Pd(PPh3)4 (0.55 g, 0.4 mmol). The reaction was cooled to room temperature under argon, and then HCl (5 mL) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE:EA from 100:0 to 0:100 in 30 minutes) to give intermediate 22-2 (0.85 g, 52%).

[0411] LC / MS: retention time: 0.755 min, MS (ESI) m / z: 172.1, [M+H] + .

[0412] Preparation of intermediate 22-3

[0413] To a solution of intermediate 22-2 (850 mg, 4.97 mmol) in AcOH (5 mL) and EA (5 mL) was added PtO2 (113 mg, 0.497 mmol) at 0°C. The reaction mixture was stirred under hydrogen for 2 hours. LC / MS showed that the desired MS was detected. The mixture was adjusted to pH = 8 with aqueous NaHCO3 solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE:EA from 100:0 to 0:100 in 30 minutes) to give intermediate 22-3 (700 mg, 80.5%). LC / MS: retention time: 0.394 min, MS (ESI) m / z: 176.1, [M+H] + .

[0414] Preparation of Intermediate 22-4

[0415] To a solution of intermediate 22-3 (700 mg, 4.0 mmol) in DCM (10 mL) was added Et3N (808 mg, 8.0 mmol) and (Boc)2O (959 mg, 4.39 mmol). The reaction mixture was stirred at 25 ° C for 1 hour. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE: EA from 100: 0 to 0: 100 in 30 minutes) to give intermediate 22-4 (800 mg, yield: 72.7%). LC / MS: retention time: 1.347 min, MS (ESI) m / z: 298.1, [M + Na] + .

[0416] Preparation of Intermediate 22-5

[0417] To a solution of intermediate 22-4 (400 mg, 1.45 mmol) in MeOH (20 mL) was added NH4OAc (1120 mg, 14.5 mmol) and NaBH3CN (183 mg, 2.91 mmol). The reactants were stirred at 60 ° C for 16 h. The mixture was adjusted to pH = 8 with solid NaHCO3. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE:EA from 100:0 to 0:100 in 30 minutes) to give intermediate 22-5 (300 mg, 74.7%). LC / MS: retention time: 1.062 min, MS (ESI) m / z: 552.9, [2M+H] + .

[0418] Preparation of Intermediate 22-6

[0419] To a solution of intermediate 22-5 (70 mg, 0.253 mmol) in THF (5 mL) was added INT-1 (61.1 mg, 0.304 mmol) and DIEA (98.2 mg, 0.76 mmol). The reaction mixture was stirred at 25 ° C for 16 hours. LC / MS showed that the desired MS was detected. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluted with PE: EA from 100: 0 to 0: 100 in 30 minutes) to give intermediate 22-6 (100 mg, 89.5%). LC / MS: retention time: 1.383 min, MS (ESI) m / z: 441.3, [M + H] + .

[0420] Preparation of compound 22

[0421] To a toluene solution (2 mL) of intermediate 22-6 (50 mg, 0.113 mmol) was added INT-D (79.4 mg, 0.34 mmol). The reaction was stirred at 150 ° C for 0.5 hours under microwave. The mixture was concentrated under reduced pressure, and then HCl / 1,4-dioxane (3 mL) was added and the mixture was stirred at 25 ° C for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC using aqueous CH 3 CN (CH 3 CN increased from 15% to 45% in 30 minutes) to give compound 22 (21.6 mg, 43.6% yield). LC / MS: retention time: 0.925 min, MS (ESI) m / z: 438.3, [M+H] + . 1H NMR (400MHz, DMSO) δ12.95(s,1H),9.50(s,1H),8.96(d,J=7.5Hz,1H),8.82(d,J =2.0Hz,1H),8.47(d,J=2.0Hz,1H),8.31(s,1H),8.09(s,1H),7.85(s,1H),7.49( d,J=7.9Hz,1H),7.18(s,1H),7.11(t,J=7.8Hz,2H),6.99(d,J=8.0Hz,1H),5.32 (s,1H),3.93(s,2H),3.06(s,2H),2.69(d,J=17.8Hz,2H),1.57(d,J=6.8Hz,3H).

[0422] Example 23

[0423] Synthesis route of compound 23

[0424] Preparation of Intermediate 23-2

[0425] To a solution of compound 23-1 (270 mg, 2.31 mmol, 3 eq), TCFH (862 mg, 3.08 mmol, 4 eq), and NMI (505 mg, 6.16 mmol, 8 eq) in CH3CN (15 mL) was added intermediate 11-1 (245 mg, 0.77 mmol, 1 eq) at 25°C under nitrogen. The reaction mixture was stirred at 25°C for 15 hours. The reaction mixture was concentrated under reduced pressure at 40°C. The residue was purified by flash chromatography and eluted with DCM / MeOH (30:1 to 10:1) to give product 23-2 (160 mg, 49.8%). LC / MS: retention time: 1.087 min, MS (ESI) m / z: 418.2, [M+H] + .

[0426] Preparation of compound 23

[0427] To a solution of intermediate 23-2 (160 mg) in DCM (2 mL) were added TFAA (2 mL) and TFA (1 mL). The reaction mixture was stirred at 25 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure at 40 ° C, and the pH of the mixture was adjusted to 7-8 with a saturated aqueous solution of Na2CO3. The residue was extracted with THF (3×15 mL) and concentrated in vacuo to give a crude product. The crude product was purified by Genal-Prep-HPLC to give the product compound 23 (22.9 mg, 15.2%). LC / MS: retention time: 1.177 min, MS (ESI) m / z: 400.0, [M+H] + .

[0428] 1 H NMR(400MHz, DMSO-d6)δ9.19(br,1H),8.86(s,1H),8.53(s,1H),7.73–7.63(m,2H),7.41(dd,J=8.8 ,2.4Hz,1H),7.18(t,J=8.0Hz,1H),6.67(br,1H),5.67(br,1H),2.32(s,3H),1.57(d,J=8.0Hz,3H).

[0429] Example 25

[0430] Synthesis route of compound 25

[0431] Preparation of intermediate 25-2

[0432] At 0 ° C, under nitrogen protection, NBS (15.77 g, 88.61 mmol) was added to a TFA (90 mL) solution of compound 25-1 (10 g, 80.55 mmol). The reaction mixture was stirred at room temperature under nitrogen for 12 hours. The reaction mixture was adjusted to pH = 7 with a saturated aqueous solution. NaHCO3 and extracted with EtOAc (100 mL * 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography (PE: EA = 10: 1 to 1: 3) to give intermediate 25-2 (7.2 g, 44.01%). LC / MS: retention time: 0.608 min, MS (ESI) m / z: 203.0 / 205.0, [M + H] + .

[0433] Preparation of intermediate 25-3

[0434] Intermediate 25-2 (1500.00 mg, 7.39 mmol), a stirring bar, Zn(CN)2 (867.46 mg, 7.39 mmol), Xantphos (427.47 mg, 0.74 mmol) and NMP (15 mL) were added to a 30 mL microwave tube, and the resulting mixture was purged with nitrogen for 5 minutes. The resulting mixture was treated with Pd2(dba)3 (338.26 mg, 0.37 mmol), and then the resulting mixture was purged with nitrogen again for 5 minutes. The resulting mixture was stirred at 150 ° C in a microwave for 1 hour and then cooled to room temperature. The reaction mixture was extracted with EtOAc (50 mL * 2). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated. The crude product / mixture was purified by silica gel chromatography (eluent: PE: EA = 10: 1 to 1: 1) to give intermediate 25-3 (800 mg, 72.73%). LC / MS: retention time: 0.788 min, MS (ESI) m / z: 150.0, [M+H] + .

[0435] Preparation of intermediate 25-4

[0436] To a solution of intermediate 25-3 (3000 mg, 20.11 mmol) in 1,4-dioxane (5 mL) was added KOH (10 mL). The reaction mixture was stirred at 110 ° C for 2 hours under nitrogen. The mixture was filtered, the solid was washed with 1,4-dioxane (20 mL × 3), and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate 25-4 (1.6 g, 47.58%). The crude product was used in the next step without further post-treatment. LC / MS: retention time: 0.71 min, MS (ESI) m / z: 168.0, [M+H] + .

[0437] Preparation of intermediate 25-5

[0438] Intermediate 25-4 (600 mg, 3.59 mmol) and triphosgene (1065.01 mg, 3.59 mmol) were dissolved in 1,4-dioxane (6 mL). The reaction mixture was stirred at 100 ° C for 1 hour under nitrogen. The mixture was filtered and the filtered solid was washed with 1,4-dioxane (10 mL x 3). The solid was concentrated to dryness under reduced pressure to give intermediate 25-5 (550 mg, 63.47%). LC / MS: retention time: 0.355 min, MS (ESI) m / z: 194.0, [M+H] + .

[0439] Preparation of intermediate 25-6

[0440] To a solution of intermediate 25-5 (550 mg, 2.85 mmol) in POCl3 (10 mL) was added PCl5 (2371.53 mg, 11.39 mmol), and the reaction mixture was stirred at 100°C under nitrogen for 0.5 hours. The reaction mixture was concentrated to dryness under reduced pressure to give intermediate 25-6 (600 mg, 91.60%). The crude product was used in the next step without further workup. LC / MS: retention time: 0.954 min, MS (ESI) m / z: 230.0 / 232.0, [M+H] + .

[0441] Preparation of intermediate 25-7

[0442] To a solution of intermediate 25-6 (600 mg, 2.61 mmol) in THF (10 mL) at 0°C was added DIEA (4.54 mL, 26.08 mmol) and SM-2 (0.29 mL, 2.61 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was extracted with EtOAc (30 mL*2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography (eluent: PE:EA=10:1 to 1:1) to give intermediate 25-7 (300 mg, 38.25%). LC / MS: retention time: 1.255 min, MS (ESI) m / z: 301.0, [M+H] + .

[0443] Preparation of intermediate 25-8

[0444] Intermediate 25-7 (140 mg, 0.47 mmol) and INT-B (245.25 mg, 0.93 mmol) were dissolved in EtOH (2 mL) and HCl (1 mol / L) (0.2 mL). The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to give Intermediate 25-8 (230 mg, 68.37%). The crude product was used in the next step without further post-treatment. LC / MS: retention time: 0.914 min, MS (ESI) m / z: 398.2, [M+H] + .

[0445] Preparation of compound 25

[0446] Intermediate 25-8 (185 mg, 0.47 mmol) and (2-aminophenyl)phenylmethanone (0.18 mL, 1.02 mmol) were dissolved in HBr / HOAc (5 mL) solution. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150 mm*25 mm*10 μm column (eluent: 30% to 60% (v / v) CH3CN and water, containing 0.025% NH4HCO3) to obtain compound 25 (29.3 mg, 16.26%). LC / MS: retention time: 0.875 min, MS (ESI) m / z: 384.2, [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.69(s,1H),9.14(s,1H),8.78(s,1H),8.21(d,1H),8.04(s,1H),7.86(d, J=6.6Hz,1H),7.44–7.28(m,6H),7.26–7.19(m,1H),7.00(t,J=7.8Hz,2H),4.76(d,J=6.4iHz,2H).

[0447] Example 26

[0448] Synthesis route of compound 26

[0449] Preparation of Intermediate 26-2

[0450] To a solution of compound 26-1 (2000 mg, 7.72 mmol) and compound 21-6 (3.13 mL, 9.27 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh3)2Cl (572.81 mg, 0.77 mmol). The mixture was evacuated and purged with nitrogen three times and stirred at 100°C under nitrogen for 18 hours. A black solution formed. 1M HCl (20 ml) was added, and the resulting mixture was stirred at 25°C for 1 hour to obtain a black solution. The mixture was poured into KF solution (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (eluent: PE:EA=20:1 to 10:1) to give Intermediate 26-2 (1100 mg, 64.13%). 1H NMR (400MHz, DMSO-d6) δ7.97 (t, J = 8.6 Hz, 1H), 7.61–7.48 (m, 1H), 7.35 (d, J = 8.8 Hz, 1H), 2.59 (d, J = 4.2 Hz, 3H).

[0451] Preparation of intermediate 26-3

[0452] To a solution of intermediate 26-2 (1100 mg, 4.95 mmol) and compound 15-2 (1200.32 mg, 9.90 mmol) in THF (10 mL) was added Ti(OEt)4 (4.40 mL, 14.86 mmol), and the resulting mixture was stirred at 65°C for 18 hours to give a yellow solution. The mixture was poured into EA (20 mL) and water (5 mL), filtered, and the filter solid was washed with EtOAc (10 mL x 2). The filtrate was concentrated to dryness under reduced pressure to give the crude product 26-3. LC / MS: retention time: 1.411 min, MS (ESI) m / z: 326.0, [M+H] + .

[0453] Preparation of intermediate 26-4

[0454] To a solution of intermediate 26-3 (1470 mg, 4.52 mmol) in THF (20 mL) was added NaBH4 (205.13 mg, 5.42 mmol) at a rate such that the temperature did not exceed -40 ° C, and the resulting mixture was stirred at -40 ° C for 2 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent: PE: EA = 10: 1 to 5: 1) to give intermediate 26-4 (1290 mg, 87.21%). LC / MS: retention time: 1.309 min, MS (ESI) m / z: 328.0, [M + H] + .

[0455] Preparation of intermediate 26-5

[0456] To a solution of intermediate 26-4 (1200 mg, 3.67 mmol) in 1,4-dioxane (12 mL) was added HCl (12 mL, 48.00 mmol), and the resulting mixture was stirred at 25°C for 0.5 hours to obtain a yellow solution. The mixture was concentrated to dryness under reduced pressure to obtain the crude product 26-5. LC / MS: retention time: 1.161 min, MS (ESI) m / z: 224.0, [M+H] + .

[0457] Preparation of intermediate 26-6

[0458] To a solution of intermediate INT-1 (540 mg, 2.69 mmol) and DIEA (2.35 mL, 13.43 mmol) in THF (20 mL) was added intermediate 26-5 (528.01 mg, 2.49 mmol), and the resulting mixture was stirred at room temperature for 16 hours to give a yellow solution. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent: PE: EA = 1: 1 to 0: 1) to give intermediate 26-6 (135 mg, 12.96%). LC / MS: retention time: 1.366 min, MS (ESI) m / z: 388.0, [M+H] + .

[0459] Preparation of compound 26

[0460] To a solution of intermediate 26-6 (40 mg, 0.10 mmol) and compound 12-1 (15.80 mg, 0.10 mmol) in EtOH (1 mL) was added HCl (0.1 mL), and the resulting mixture was stirred at 90°C for 2 hours to give a yellow solution. The mixture was concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150 mm*25 mm*10 μm column (eluent: 30% to 60% (v / v) CH3CN and water, containing 0.05% NH4HCO3) to give compound 26 (21.93 mg, 42.14%). LC / MS: retention time: 1.394 min, MS (ESI) m / z: 505.1, [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ9.49–9.18(m,1H),9.06–8.90(m,1H),8.81(d,J=2.2Hz,1H),8.44(d,J=1.8Hz, 1H),7.85–7.08(m,5H),6.94–6.71(m,1H),5.91–5.62(m,1H),3.76–3.71(m,6H),1.61(d,J=7.0Hz,3H).

[0461] Example 27

[0462] Synthesis route of compound 27

[0463] Preparation of Intermediate 27-2

[0464] To a solution of compound INT-E (250 mg, 0.79 mmol) in THF (3 mL) were added DIEA (0.41 mL, 2.36 mmol) and SM-4 (136.43 mg, 0.79 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain intermediate 27-2 (400 mg). The reaction mixture was used in the next step without further post-treatment. LC / MS: retention time: 1.303 min, MS (ESI) m / z: 453.0, [MH] - .

[0465] Preparation of compound 27

[0466] Intermediate 27-2 (190 mg, 0.42 mmol) and compound 12-1 (63.92 mg, 0.42 mmol) were dissolved in EtOH (3 mL) and HCl (1 mol / L) (0.3 mL). The reaction mixture was stirred at 80° C. for 1 hour. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by preparative HPLC (Phenomenex Gemini 150 mm*25 mm*10 μm column (eluent: 30% to 60% (v / v) CH 3 CN and water, containing 0.025% NH 4 HCO 3 ) to give compound 27 (61.14 mg, 30.85%). LC / MS: retention time: 1.178 min, MS (ESI) m / z: 471.9, [M+H] + .

[0467] 1 H NMR(400MHz,DMSO-d6)δ8.97–8.87(m,1H),8.00(s,1H),7.55–7.50(m,1H),7.48–7.44(m,1H),7.26–7.15(m,4H),6 .73(d,J=9.0Hz,1H),5.61–5.52(m,1H),3.70(s,3H),3.68(s,3H),3.37(s,2H),2.81–2.67(m,2H),1.50(d,J=6.8i Hz,3H).

[0468] Example 28

[0469] Synthesis route of compound 28

[0470] Preparation of compound 28

[0471] HCl (0.1 mL) was added to a solution of intermediate INT-C (25 mg, 0.07 mmol) and compound 28-1 (11.10 mg, 0.07 mmol) in EtOH (1 mL), and the resulting mixture was stirred at 80 ° C for 18 hours to obtain a yellow solution. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (eluent: 30% to 60% (v / v) CH3CN and water, containing 0.5% NH4HCO3) to obtain compound 28 (4.13 mg, 12.36%). MS (ESI) m / z: 452.1, [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ8.99(d,J=8.0Hz,1H),8.78(d,J=2.2Hz,1H),8.42(d, J=2.2Hz,1H),8.38(s,1H),7.75–7.54(m,1H),7.40(dd,J=8.8,2.8Hz,1H),7.2 6–7.07(m,1H),7.04–6.80(m,1H),6.64–6.34(m,2H),5.86–5.51(m,1H),5.24 –5.04(m,1H),4.06(t,J=4.4Hz,2H),3.28–3.18(m,2H),1.55(d,J=6.8Hz,3H).

[0472] Example 29

[0473] Synthesis route of compound 29

[0474] Preparation of intermediate 29-2

[0475] To a solution of compound INT-E (220 mg, 0.69 mmol) and compound 29-1 (142.21 mg, 0.69 mmol) in THF (3 mL) was added DIEA (0.36 mL, 2.07 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain intermediate 29-2 (400 mg). The reaction mixture was used in the next step without further post-treatment. LC / MS: retention time: 1.259 min, MS (ESI) m / z: 451.2, [M+H] + .

[0476] Preparation of compound 29

[0477] Intermediate 29-2 (160 mg, 0.35 mmol) and intermediate INT-B (93.47 mg, 0.35 mmol) were dissolved in EtOH (2 mL) and HCl (1 mol / L) (0.2 mL). The reaction mixture was stirred at 80 ° C for 1 hour. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um column (eluent: 30% to 60% (v / v) CH3CN and water, containing 0.025% NH4HCO3) to obtain compound 29 (17.15 mg, 10.80%). LC / MS: retention time: 1.185 min, MS (ESI) m / z: 448.0, [M+H] + .

[0478] 1 H NMR(400MHz,DMSO-d6)δ13.51(s,1H),9.13(s,1H),8.19–8.13(m,1H),7.99(s,1H),7 .74(t,J=8.8Hz,1H),7.39(d,J=7.4Hz,1H),7.34(t,J=8.8Hz,1H),7.28(d,J=8.0Hz, 1H),6.95(t,J=7.8Hz,1H),6.83(d,J=12.4Hz,1H),6.72(d,J=8.6Hz,1H),5.67–5.49 (m,1H),3.71(s,3H),3.45–3.38(m,2H),2.77(d,J=6.6Hz,2H),1.51(d,J=7.0Hz,3H).

[0479] Example 30

[0480] Synthesis route of compound 30

[0481] Preparation of intermediate 30-1

[0482] To a solution of intermediate INT-E (250 mg, 0.79 mmol) in THF (3 mL) were added DIEA (0.41 mL, 2.36 mmol) and compound SM-4 (136.43 mg, 0.79 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain intermediate 30-1 (400 mg). The reaction mixture was used in the next step without further post-treatment. LC / MS: retention time: 1.303 min, MS (ESI) m / z: 453.0, [MH] - .

[0483] Preparation of compound 30

[0484] Intermediate 30-1 (190 mg, 0.42 mmol) and intermediate INT-B (165.95 mg, 0.63 mmol) were dissolved in EtOH (3 mL) and HCl (1 mol / L) (0.3 mL). The reaction mixture was stirred at 80 ° C for 1 hour. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by preparative HPLC (Phenomenex Gemini 150mm*25mm*10um column (eluent: 30% to 60% (v / v) CH3CN and water, containing 0.025% NH4HCO3) to obtain compound 30 (32.47 mg, 17.11%). LC / MS: retention time: 1.248 min, MS (ESI) m / z: 451.9, [M+H] + .

[0485] 1 H NMR(400MHz,DMSO-d6)δ13.32(s,1H),9.09(s,1H),8.15(s,1H),7.99(s,1 H),7.67(s,1H),7.56–7.51(m,1H),7.50–7.46(m,1H),7.44(d,J=7.4Hz,1 H),7.26(d,J=7.8Hz,1H),7.22–7.15(m,1H),6.96(t,J=7.8Hz,1H),5.64– 5.52(m,1H),3.46–3.39(m,2H),2.89–2.72(m,2H),1.54(d,J=6.8Hz,3H).

[0486] Example 31

[0487] Synthesis route of compound 31

[0488] Preparation of Intermediate 31-1

[0489] To a solution of intermediate INT-E (96.94 mg, 0.30 mmol) and intermediate 26-5 (68 mg, 0.30 mmol) in THF (2 mL) was added DIEA (0.27 mL, 1.52 mmol), and the resulting mixture was stirred at room temperature for 2 hours to give a yellow solution. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give a crude product.

[0490] LC / MS: retention time: 1.441 min, MS (ESI) m / z: 505.1, [M+H] + .

[0491] Preparation of compound 31

[0492] To a solution of intermediate 31-1 (154 mg, 0.31 mmol) and intermediate INT-B (80.35 mg, 0.31 mmol) in ethanol (2 mL) was added HCl (0.2 mL), and the resulting mixture was stirred at 90 ° C for 2 hours to obtain a yellow solution. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150 mm * 25 mm * 10 μm column (eluent: 30% to 60% (v / v) CH 3 CN and water, containing 0.05% NH 4 HCO 3) to obtain compound 31 (15.86 mg, 10.37%). LC / MS: retention time: 1.308 min, MS (ESI) m / z: 502.2, [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ13.44(s,1H),9.14(s,1H),8.24–8.10(m,1H),8.04–7.95(m,1H),7.68–7.46(m,3H),7.42(d,J=10.8Hz,1H),7.28(d ,J=8.0Hz,1H),7.19(d,J=8.6Hz,1H),6.91(t,J=7.8Hz,1H),5.71–5.52(m,1H),3.49–3.37(m,2H),2.91–2.70(m,2H),1.54(d,J=7.0Hz,3H).

[0493] Example 32

[0494] Synthesis route of compound 32

[0495] Preparation of Intermediate 32-1

[0496] To a solution of intermediate INT-E (220 mg, 0.69 mmol) and compound 29-1 (142.21 mg, 0.69 mmol) in THF (3 mL) was added DIEA (0.36 mL, 2.07 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to obtain intermediate 32-1 (400 mg). The reaction mixture was used in the next step without further post-treatment. LC / MS: retention time: 1.259 min, MS (ESI) m / z: 451.2, [M+H]+ .

[0497] Preparation of compound 32

[0498] Intermediate 32-1 (140 mg, 0.31 mmol) and compound 12-1 (47.56 mg, 0.31 mmol) were dissolved in EtOH (2 mL) and HCl (1 mol / L) (0.2 mL). The reaction mixture was stirred at 80° C. for 1 hour. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , and concentrated. The crude product was purified by preparative HPLC (Phenomenex Gemini 150 mm*25 mm*10 μm column (eluent: 30% to 60% (v / v) CH 3 CN and water, containing 0.025% NH 4 HCO 3 ) to give compound 32 (37.01 mg, 26.64%).

[0499] LC / MS: retention time: 1.123 min, MS (ESI) m / z: 468.0, [M+H] + .

[0500] 1 H NMR(400MHz, DMSO-d6)δ8.95(s,1H),8.03–7.98(m,1H),7.46–7.38(m,1H),7.34(t,J=8.8Hz,1H),7.24(s,1H),7.16(d,J=7.8Hz,1H),6.84– 6.78(m,1H),6.76–6.70(m,2H),5.65–5.55(m,1H),3.71(d,J=10.8Hz,9H),3.35(d,J=2.8Hz,2H),2.75–2.64(m,2H),1.48(d,J=7.0Hz,3H).

[0501] Example 33

[0502] Synthesis route of compound 33

[0503] Preparation of compound 33

[0504] Intermediate INT-C (44 mg, 0.13 mmol), compound 33-1 (14.99 mg, 0.13 mmol), DIEA (67.99 μL, 0.39 mmol), and NMP (5 mL) were added to a 10 mL microwave tube with a stirrer. The resulting mixture was stirred at 100°C for 2 hours. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150 mm*25 mm*10 μm column (eluent: 30% to 60% (v / v) CH3CN and water containing 0.025% NH4HCO3) to obtain compound 33 (30.04 mg, 55.38%). LC / MS: retention time: 1.14 min, MS (ESI) m / z: 417.1, [M+H] + .

[0505] 1 H NMR(400MHz,DMSO-d6)δ8.68(d,J=2.2Hz,1H),8.61–8.38(m,1H),8.28(d,J =2.0Hz,1H),7.74–7.49(m,1H),7.41–7.27(m,1H),7.23–7.07(m,1H),6.98 –6.56(m,1H),5.75–5.49(m,1H),4.49–4.09(m,1H),3.87–3.49(m,1H),3.5 2–3.23(m,1H),1.94–1.70(m,3H),1.58(d,J=7.0Hz,3H),1.43–1.12(m,4H).

[0506] Example 34

[0507] Synthesis route of compound 34

[0508] Preparation of compound 34

[0509] Intermediate INT-C (100 mg, 0.30 mmol), compound 5-1 (20.49 μL, 0.30 mmol), DIEA (154.95 μL, 0.89 mmol) and NMP (2 mL) were added to a 10 mL microwave tube, a stirrer was added, and the resulting mixture was stirred at 100°C under microwave conditions for 2 hours, then cooled to room temperature. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150 mm*25 mm*10 μm column (eluent: 30% to 60% (v / v) CH3CN and water, containing 0.025% NH4HCO3) to obtain compound 34 (10.13 mg, 9.55%). LC / MS: retention time: 1.30 min, MS (ESI) m / z: 359.1, [M+H] + .

[0510] 1 H NMR(500MHz,DMSO-d6)δ9.13–8.61(m,2H),8.44–8.23(m,1H),7.73–7.08(m,4H) ,5.87–5.53(m,1H),2.90–2.66(m,1H),1.55(d,J=6.8Hz,3H),0.75–0.19(m,4H).

[0511] Example 35

[0512] Synthesis route of compound 35

[0513] Preparation of intermediate 35-3

[0514] At -78 ° C, n-butyl lithium (1.17 g, 18.23 mmol) was added dropwise to a solution of compound 35-1 (4.5 g, 15.19 mmol) in THF (40 mL). The reaction mixture was stirred at -78 ° C for 1 hour, and then compound 35-2 (2.35 g, 22.79 mmol) was added. The reaction mixture was warmed to 25 ° C and stirred for 1 hour to obtain a yellow suspension. The mixture was poured into water (150 mL) and extracted with EtOAc (150 mL × 3). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The residue was purified by silica gel chromatography (eluent: PE: EA = 100: 1 to 10: 1) to obtain compound 35-3 (680 mg, 17.26%).

[0515] 1H NMR (400MHz, DMSO-d6) δ8.36(d,J=8.4Hz,1H),7.96(d,J=7.6Hz,1H),7.84(d,J=3 .8Hz,1H),7.47(t,J=8.0Hz,1H),7.32(d,J=3.2Hz,1H),2.67(s,3H),1.64(s,9H).

[0516] Preparation of intermediate 35-4

[0517] To a solution of intermediate 35-3 (580 mg, 2.24 mmol) and (NH4)2OAc (1724.05 mg, 22.37 mmol) in EtOH (5 mL) was added NaBH3CN (267.60 mg, 4.47 mmol), and the resulting mixture was stirred at 120°C under microwave for 20 minutes to give a yellow solution. The reaction was concentrated to dryness under reduced pressure to give the crude product. LC / MS: retention time: 0.872 min, MS (ESI) m / z: 244.0, [M-NH2] + .

[0518] Preparation of intermediate 35-5

[0519] To a solution of INT-1 (300 mg, 1.49 mmol) and DIEA (2.61 mL, 14.92 mmol) in THF (10 mL) was added intermediate 35-4 (388.55 mg, 1.49 mmol), and the resulting mixture was stirred at room temperature for 2 hours to give a yellow solution. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent: PE: EA = 1: 1 to 0: 1) to give intermediate 35-5 (120 mg, 18.92%). LC / MS: retention time: 1.480 min, MS (ESI) m / z: 425.1, [M+H] + .

[0520] Preparation of intermediate 35-6

[0521] Intermediate 35-5 (120 mg, 0.28 mmol), compound 5-1 (98.33 μL, 1.41 mmol), DIEA (147.99 μL, 0.85 mmol), and NMP (2 mL) were added to a 10 mL microwave tube and a stirrer was added. The resulting mixture was stirred in a microwave at 100°C for 2 hours and then cooled to room temperature. The reaction mixture was used in the next step without further post-treatment. LC / MS: retention time: 1.492 min, MS (ESI) m / z: 446.2, [M+H] + .

[0522] Preparation of compound 35

[0523] Intermediate 35-6 (100 mg, 0.22 mmol) was dissolved in HCl / 1,4-dioxane (1 mL, 4.00 mmol) solution, and the mixture was stirred at 80°C for 1 hour to obtain a yellow solution. The mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (Phenomenex Gemini 150 mm*25 mm*10 μm column (eluent: 30% to 60% (v / v) CH3CN and water containing 0.5% NH4HCO3) to obtain compound 35 (2.07 mg, 2.67%). LC / MS: retention time: 0.847 min, MS (ESI) m / z: 346.2, [M+H] + .

[0524] 1 H NMR: (400MHz, DMSO-d6) δ10.96(s,1H),8.68(d,J=2.2Hz,1H),8.26(d,J=2.2Hz,1H),8.12–7.89(m,1H),7.33–7.27(m,2H),7.20–7 .09(m,2H),6.76–6.50(m,1H),5.98–5.71(m,1H),2.93–2.83(m,1H),2.07–1.97(m,1H),1.72(d,J=6.8Hz,3H),0.77–0.41(m,4H).

[0525] Example 36

[0526] Synthesis route of compound 36

[0527] Preparation of intermediate 36-2

[0528] At -70 ° C, n-butyl lithium (9.60 mL, 23.99 mmol) was added dropwise to a solution of compound 36-1 (4.06 g, 20.00 mmol) in THF (80 mL), stirred for 2 h, and then DMF (3.21 mL, 39.99 mmol) was added dropwise while maintaining at -70 ° C. The reaction mixture was warmed to 25 ° C. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (eluent: PE: EA = 20: 1 to 10: 1) to give intermediate 36-2 (1.84 g, 60.46%). 1 H NMR (400MHz, DMSO-d6) δ 10.42 (s, 1H), 7.06 (d, J = 5.4Hz, 1H), 7.04 (s, 1H), 2.56 (s, 6H).

[0529] Preparation of intermediate 36-4

[0530] To a solution of Intermediate 36-2 (1.84 g, 12.09 mmol) and Intermediate 36-3 (2.93 g, 24.18 mmol) in THF (20 mL) was added Ti(OEt)4 (7.61 mL, 36.28 mmol), and the resulting mixture was stirred at 80°C for 18 hours. Water (30 mL) was added to the reaction mixture, which was filtered and the filter cake was washed with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent: PE:EA = 20:1 to 10:1) to give Intermediate 36-4 (3 g, 97.09%).

[0531] LC / MS: retention time: 1.451 min, MS (ESI) m / z: 256.1, [M+H] + .

[0532] Preparation of intermediate 36-5

[0533] To a solution of intermediate 36-4 (1.84 g, 7.21 mmol) in DCM (40 mL) was added methylmagnesium bromide (28.82 mL, 28.82 mmol) dropwise at -70°C. After the addition was complete, the reaction mixture was warmed to 25°C and stirred for 18 hours. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (eluent: PE:EA = 20:1 to 8:1) to give intermediate 36-5 (1.3 g, 66.33%). LC / MS: retention time: 1.249 min, MS (ESI) m / z: 272.2, [M+H] + .

[0534] Preparation of intermediate 36-6

[0535] To intermediate 36-5 (1.9 g, 7.00 mmol) was added HCl (20 mL, 2 M) and the resulting mixture was stirred at 25 ° C for 2 h. The reaction mixture was adjusted to pH = 7 with saturated NaHCO 3 solution and then extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated to dryness under reduced pressure to give a crude product. The residue was purified by silica gel chromatography (eluent: PE: EA = 10: 1 to 5: 1) to give intermediate 36-6 (800 mg, 68.33%).

[0536] Preparation of intermediate 36-7

[0537] To a solution of intermediate INT-1 (200 mg, 0.99 mmol) in THF (6 mL) was added intermediate 36-6 (166.39 mg, 0.99 mmol), and the resulting mixture was stirred at 25°C for 18 hours. The mixture was concentrated to dryness under reduced pressure to give intermediate 36-7 (crude, 200 mg). LC / MS: retention time: 1.305 min, MS (ESI) m / z: 332.0, [M+H] + .

[0538] Preparation of compound 36

[0539] Intermediate 36-7 (100 mg, 0.30 mmol), compound 5-1 (731.56 μL, 0.60 mmol), and isopropanol were added to a 10 mL microwave tube, and the resulting mixture was purged with nitrogen for 2 minutes. The resulting mixture was treated with DIEA (1218.62 μL, 0.90 mmol), and then the mixture was purged with nitrogen for another 5 minutes. The reaction solution was stirred in a microwave at 110°C for 2 hours and then cooled to room temperature. The resulting mixture was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-10um-19*250mm column (eluent: 44% to 56% (v / v) CH3CN and water, containing 10mNH4HCO3) to give compound 36 (33.67 mg, 31.70%). LC / MS: retention time: 1.328 min, MS (ESI) m / z: 353.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.68(d,J=2.1Hz,1H),8.20(d,J=2.0Hz,1H),7.36(s,1H),6.70(s,1H),6.68(s,1H ),5.70(s,1H),5.3-5.1(m,1H),2.88(s,1H),2.52(s,6H),1.65(d,J=7.2Hz,3H),0.81(s,2H),0.67–0.31(m,2H).

[0540] Control compound 1-2

[0541] The structural formula of reference compound 1 is: CAS No.1144470-00-7.

[0542] The structural formula of reference compound 2 is: CAS No.1144474-00-9.

[0543] Part II Biological Tests

[0544] Test Example 1BRD4(D1)&BRD4(D2) enzyme inhibition experiment

[0545] Experimental reagents and materials

[0546] BRD4 (D1) and BRD4 (D2) proteins were purchased from RBC, Cat. No. RD-11-157 and RD-11-158;

[0547] Yangshen molecule (+)-JQ1 was purchased from BPS, Cat. No. 27402;

[0548] 384-well OptiPlate was purchased from Perkin Elmer, Cat. No. 6007299.

[0549] Experimental procedures

[0550] 1. Serially dilute the compound in an Echo plate according to the plate map. The final DMSO concentration is 0.1%.

[0551] 2. Transfer compound / DMSO to 384-well assay plate by Echo.

[0552] 3. Add 2x protein and peptide mix to the assay plate.

[0553] 4. Add 2x detection mix to the assay plate and shake for 30 seconds.

[0554] 5. Incubate at room temperature for 1 hour.

[0555] 6. Read the HTRF signal on EnVision (Ex at 340 nm, Em at 615 nm and 665 nm).

[0556] 7. Curve Fitting

[0557] Fit the data in Excel using equation (1) to obtain inhibition values

[0558] Equation (1): Inh% = (Max-Signal) / (Max-Min)*100

[0559] The data were fitted in XL-Fit using equation (2) to obtain IC50 values.

[0560] Equation (2): Y = Bottom + (Top - Bottom) / (1 + (IC50 / X) * Hill Slope)

[0561] Y is % inhibition and X is compound concentration.

[0562] Experimental results

[0563] The experimental results are shown in Table 1, where the activity classification is: IC50<0.1μM:****,0.1μM <IC50<1μM:***,1μM<IC50<10μM:**,10μM<IC50:*

[0564] Table 1

[0565] Test Example 2 Fluorescence cell viability assay

[0566] Experimental reagents and materials

[0567] Cells: HGC27, SNU16, COLO320DM, COLO320HSR, and SNU-1 were purchased from ATCC. The drug-resistant strain HGC27 was induced to resist drug by BRD4 inhibitor.

[0568] Culture medium and serum: from Sigma-Aldrich, RPMI-1640

[0569] CellTiter-Glo luminescent assay: from Promega, G7573

[0570] 96-well plate: from Thermo, 1371362;

[0571] DMSO: from Beyotime, ST038

[0572] Microplate reader: from BioTek, Synergy

[0573] Experimental procedures

[0574] 1. Plate the cells to be tested in a 96-well plate, with 2000 cells per well in a volume of 100ul (treatment for 3 days, detection of CTG); plate the cells to be tested in a 96-well plate, with 1000 cells per well in a volume of 70ul (treatment for 7 days, detection of CTG, and drug supplementation after 3 days of culture).

[0575] 2. Prepare drug solutions of various concentration gradients using a culture medium compatible with the cells

[0576] The drug concentration gradient was prepared as follows: 0, 2, 6.6, 20, 66, 200, 666, 2000, 6666, 20000 (nM). According to the plate layout plan, equal volumes (100 μl / 70 μl) of drug solutions of corresponding concentrations were added to each well to achieve the following final drug concentrations: 0, 1, 3.3, 10, 33, 100, 333, 1000, 3333, 10000 (nM).

[0577] The method for preparing each drug concentration gradient is as follows: Prepare a 10mM drug stock solution. For a 96-well plate, add 998µl of complete medium to a sterile EP tube, then add 2µl of the drug stock solution and mix thoroughly. This creates the highest concentration of the drug solution in the experimental protocol, 20,000nM. Then, add 100µl of this solution to another tube containing 900µl of complete medium, add 1.8µl of DMSO, and mix thoroughly. This creates a 2000nM drug solution. Repeat this process by gradient dilution to create solutions of lower concentrations.

[0578] Prepare 6666nM drug solution: Take 666.6ul complete culture medium and add it to a sterile EP tube. Take 333.3ul of the prepared 20000nM drug solution and add it. Add 1.33ul of DMSO and mix thoroughly. At this time, a 6666nM drug solution is obtained. The same as the above method is used to gradient dilute to concentrations of 666, 66, and 6.6nM (DMSO content in each well is 0.1%).

[0579] When 7-day data is required, add an equal volume of drug after 3 days of culture. At this time, prepare a solution with 3 times the drug concentration and add it.

[0580] 3. Incubate the 96-well plate for 3 or 7 days (for the 7-day test, an equal volume of drug solution needs to be added midway). For the 3-day test, remove the cell plate and place it at room temperature for 20-30 minutes. At the same time, allow the CTG solution to equilibrate to room temperature (CTG needs to be protected from light). Use a dispenser to take 22ul of CTG solution and add it to all wells to be tested (protect from light). Avoid bubbles, then place on a shaker at 150rpm and incubate at room temperature for 10 minutes.

[0581] 4. Protect from light and use the enzyme labeler to set the corresponding CTG detection program and detect the reading.

[0582] 5. Calculate IC50 curve using GraphPad software

[0583] Experimental results

[0584] The experimental results of the control compounds are shown in Table 2.

[0585] Table 2

[0586] The test results of the example compounds are shown in Table 3, where the activity rating is: IC50<0.1μM: ****, 0.1μM <IC50<1μM:***,1μM<IC50<10μM:**,10μM<IC50:*

[0587] Table 3

[0588] Therefore, it can be seen that the compounds provided in the present application have high activity and BD2 selectivity in enzyme inhibition experiments, and have inhibitory effects on cell proliferation of multiple gastric cancer and colorectal cancer cell lines at the cellular level.

[0589] It should be noted that the embodiments described above are only used to explain the present invention and do not constitute any limitation of the present invention. The present invention has been described with reference to typical embodiments, but it should be understood that the words used therein are descriptive and explanatory words, rather than restrictive words. The present invention may be modified as specified within the scope of the claims of the present invention, and the present invention may be revised without departing from the scope and spirit of the present invention. Although the present invention described therein relates to specific methods, materials and embodiments, it does not mean that the present invention is limited to the specific examples disclosed therein. On the contrary, the present invention can be extended to all other methods and applications with the same function.

Claims

1. A compound of formula I, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof, Ring C is absent, 3-6 membered cycloalkyl, 6-10 membered aryl, 5-6 membered heterocyclyl containing N, O or S, 5-6 membered heteroaryl containing N, O or S, or 7-10 membered fused bicyclic ring containing N, O or S, and the 3-6 membered cycloalkyl, 6-10 membered aryl, 5-6 membered heterocyclyl containing N, O or S, 5-6 membered heteroaryl containing N, O or S, or 7-10 membered fused bicyclic ring containing N, O or S is optionally substituted with one or more substituents Rs; A is selected from the group consisting of: phenyl, 5-10 membered heteroaryl, 3-6 membered cycloalkyl, 4-10 membered heterocyclyl, -NHSO2NH2, -SO2NH2, -NHSO2NH-C1-C6 alkyl, -NHSO2-C1-C6 alkyl, -SO2NH-C1-C6 alkyl, wherein the phenyl, 5-10 membered heteroaryl, 3-6 membered cycloalkyl, 4-10 membered heterocyclyl is optionally substituted with one or more substituents Rs; Ring B is selected from: phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the phenyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl is optionally substituted with one or more substituents Rs; X1 and X2 are each independently CR3 or N; L1 is -N(R a1 )-, -O-, -O-R b1 -, -N(R a1 )-R b1 -, -NHC(O)N(R a1 )-, -NHC(O)(R a1 )- or -NHC(O)N(R a1 )-R b1 -; L2 key, -N(R a2 )-, -C(R b2 )-, -O-, -OR b2 -, -N(R a2 )-R b2 -, -NHC(O)N(R a2 )-or-NHC(O)N(R a2 )-R b2 -; R1 is selected from H, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, nitro, alkyl-NH2-, such as C1-C3 alkyl-NH2, 6-10 membered aryl with or without substituent Rs, 5-10 membered heteroaryl with or without substituent Rs, 4-10 membered heterocyclyl with or without substituent Rs; R2 is selected from H, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, nitro, phenoxy, alkyl-NH2 such as C1-C3 alkyl-NH2, 6-10 membered aryl with or without substituents Rs, 5-10 membered heteroaryl with or without substituents Rs, 4-10 membered heterocyclyl with or without substituents Rs, the phenoxy is optionally substituted with a substituent selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxy, carboxyl, nitro, halogen, amino, cyano; R3 is selected from H and Rs; R a1 and R a2 Selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered oxacycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered oxacycloalkyl are optionally substituted with one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, carboxyl, hydroxy, hydroxy-substituted C1-C6 alkyl, nitro, halogen, amino, and cyano; R b1 and R b2 Each is independently selected from C1-C6 alkylene, wherein the C1-C6 alkylene is optionally substituted with one or more substituents selected from C1-C6 alkoxy, hydroxy, halogen, amino, and cyano; Rs is selected from deuterium, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxy, nitro, carboxyl, aldehyde such as -C(=O)-(C1-C6 alkyl), ester such as -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-3-6 membered cycloalkyl, -O-5-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), said C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, hydroxy, nitro, carboxyl, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-3-6 membered cycloalkyl, -O-4-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl) are optionally substituted with one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxy, nitro, halogen, amino, cyano; When ring C is absent, at least one of X1 and X2 is N, and R1 is a 5- to 10-membered heteroaryl group which may contain a substituent Rs, or a 4- to 10-membered heterocycloalkyl group which may contain a substituent Rs.

2. The compound according to claim 1, wherein the compound is represented by formula II, III, IV or V: in, A, ring B, ring C, R1, R2, R3, L1 and L2 are as defined in claim 1.

3. The compound according to claim 1, wherein The compound is represented by any one of Formula I-1 to Formula I-12: wherein n1 is 0 or 1; n2 is 0, 1 or 2; n3 is selected from an integer of 0-3; n4 is selected from an integer of 0-4; n5 is 0, 1 or 2; n6 is 0 or 1; n7 is 0, 1 or 2; n8 is selected from an integer of 0-3; n9 is 0 or 1; n10 is selected from an integer of 0-5; n11 is 0, 1 or 2; n12 is 0, 1 or 2; A, ring B, R1, R2, Rs, L1 and L2 are as defined in claim 1.

4. The compound according to claim 1, wherein The compound is represented by any one of the following formulas: Optionally, any of the above general formulas may be further substituted by one or more substituents Rs; Wherein, A, ring B, R2, Rs, L1 and L2 are as defined in claim 1.

5. The compound according to any one of claims 1 to 4, wherein A is selected from phenyl which may be substituted, pyridyl which may be substituted, benzopyrazolyl which may be substituted, C3-C6 cycloalkyl which may be substituted, pyranyl which may be substituted, tetrahydropyranyl which may be substituted, tetrahydrofuranyl which may be substituted, oxazolyl which may be substituted, and benzoxazinyl which may be substituted; The substituent is selected from deuterium, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, carboxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-4-10 membered heterocycloalkyl, 5-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); Preferably, the substituent is selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -C(=O)-(C1-C4 alkyl), -C(=O)O-(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -O-5-6 membered azacycloalkyl, 5-6 membered azacycloalkyl, -O-5-6 membered oxacycloalkyl, 5-6 membered oxacycloalkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl).

6. The compound according to any one of claims 1 to 4, wherein A is selected from the following groups:

7. The compound according to any one of claims 1 to 4, wherein Ring B is selected from phenyl which may be substituted, pyridyl which may be substituted, imidazolyl which may be substituted, pyrazolyl which may be substituted, triazolyl which may be substituted, indanyl which may be substituted, benzofuranyl which may be substituted, benzothiophenyl which may be substituted, tetrahydroisoquinolinyl which may be substituted, and benzopyrrolyl which may be substituted; The substituent is selected from deuterium, halogen, hydroxy, oxo, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-4-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl); Preferably, the substituent is selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -C(=O)-(C1-C4 alkyl), -C(=O)O-(C1-C4 alkyl), -C(=O)NH(C1-C4 alkyl), -O-5-6 membered nitrogen heterocycloalkyl, -O-5-6 membered oxygen heterocycloalkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl).

8. The compound according to any one of claims 1 to 4, wherein Ring B is selected from the following groups:

9. The compound according to any one of claims 1 to 4, wherein L1 is -NH-, -O-, or -NHR b1 -、-NHC(O)NH-、-NHC(O)(R a1 )-or-NHC(O)NHR b1 -; and / or L2 is a bond, -NH-, or -NHR b2 、-C(R b2 )-OR-OR b2 -; Preferably, R b1 and R b2 is C1-C6 straight chain alkylene or C2-C6 branched chain alkylene; for example, C1-C3 straight chain alkylene; C3-C4 branched chain alkylene.

10. The compound according to any one of claims 1 to 9, wherein The compound is shown in formula I-1: Wherein, A, Ring B, R1, R2, Rs, L1 and L2 are as defined in claims 1-9, and n1 is 0 or 1; Preferably, A is selected from phenyl which may be substituted, 5-10 membered heteroaryl which may be substituted, 3-6 membered cycloalkyl which may be substituted, 4-10 membered heterocyclyl which may be substituted, and the substituent is selected from deuterium, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, carboxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-4-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), Preferably, the substituent is selected from phenyl which may be substituted, pyridyl which may be substituted, benzopyrazolyl which may be substituted, cyclopropyl which may be substituted, pyranyl which may be substituted, tetrahydropyranyl which may be substituted, tetrahydrofuranyl which may be substituted, oxazolyl which may be substituted, cyclohexyl which may be substituted, and benzoxazinyl which may be substituted, wherein the substituent is selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -O-5-6 membered azacycloalkyl, 5-6 membered azacycloalkyl, -O-5-6 membered oxacycloalkyl, and 5-6 membered oxacycloalkyl; Preferably, ring B is selected from phenyl which may be substituted, 5-10 membered heterocycloalkyl which may be substituted, or 5-10 membered heteroaryl which may be substituted, wherein the substituent is selected from deuterium, halogen, hydroxy, oxo, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-4-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)(C1-C6 alkyl). Preferably selected from phenyl which may be substituted, pyridyl which may be substituted, imidazolyl which may be substituted, pyrazolyl which may be substituted, triazolyl which may be substituted, indanyl which may be substituted, benzofuranyl which may be substituted, benzothiophenyl which may be substituted, benzopyrrolyl which may be substituted, tetrahydroisoquinolinyl which may be substituted, wherein the substituent is selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl); Preferably, R1 is selected from H, halogen, hydroxy, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, nitro or C1-C3 alkyl-NH2; Preferably, R2 is selected from H, halogen, hydroxy, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, nitro, phenoxy, imidazolyl; Preferably, Rs is selected from deuterium, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, hydroxy, nitro, halogen, amino, cyano, aldehyde, ester, and carboxyl; Preferably, L1 is -NH-, -O-, or -NHR b1 -, -NHC(O)NH- or -NHC(O)NHR b1 -; L2 is a bond, -NH- or -NHR b2 -; Preferably, R b1 and R b2 is C1-C6 straight chain alkylene or C2-C6 branched chain alkylene; for example, C1-C3 straight chain alkylene; C3-C4 branched chain alkylene.

11. The compound according to any one of claims 1 to 9, wherein The compound is shown in formula I-4 or I-13: wherein, A, Ring B, R1, R2, Rs, L1 and L2 are as defined in claims 1-9, n4 is 0, 1, 2, 3 or 4; n13 is 0, 1, 2 or 3; Preferably, A is selected from phenyl which may be substituted, 5-10 membered heteroaryl which may be substituted, 3-6 membered cycloalkyl which may be substituted, 4-10 membered heterocyclyl which may be substituted, and the substituent is selected from deuterium, halogen, hydroxy, oxo, amino, cyano, C1-C6 alkyl, carboxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-4-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), Preferably, the substituent is selected from phenyl which may be substituted, pyridyl which may be substituted, benzopyrazolyl which may be substituted, cyclopropyl which may be substituted, pyranyl which may be substituted, tetrahydropyranyl which may be substituted, tetrahydrofuranyl which may be substituted, and oxazolyl which may be substituted, wherein the substituent is selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, -O-5-6 membered azacycloalkyl, 5-6 membered azacycloalkyl, -O-5-6 membered oxacycloalkyl, and 5-6 membered oxacycloalkyl; Preferably, ring B is selected from phenyl which may be substituted, 4-10 membered heterocycloalkyl which may be substituted, or 5-10 membered heteroaryl which may be substituted, wherein the substituent is selected from deuterium, halogen, hydroxy, oxo, amino, cyano, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, nitro, -C(=O)-(C1-C6 alkyl), -C(=O)O-(C1-C6 alkyl), -C(=O)NH(C1-C6 alkyl), -O-4-10 membered heterocycloalkyl, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), Preferably selected from phenyl which may be substituted, pyridyl which may be substituted, imidazolyl which may be substituted, pyrazolyl which may be substituted, triazolyl which may be substituted, indanyl which may be substituted, benzofuranyl which may be substituted, benzothiophenyl which may be substituted, tetrahydroisoquinolinyl which may be substituted, wherein the substituent is selected from deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH(C1-C4 alkyl), -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl); Preferably, R1 is selected from H, halogen, hydroxy, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, nitro or C1-C3 alkyl-NH2; Preferably, R2 is selected from H, halogen, hydroxy, oxo, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy, nitro, phenoxy, imidazolyl; Preferably, Rs is selected from deuterium, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, hydroxy, nitro, halogen, amino, cyano, aldehyde, ester, and carboxyl; Preferably, L1 is -NH-, -O-, or -NHR b1 -, -NHC(O)NH- or -NHC(O)NHR b1 -; L2 is a bond, -NH- or -NHR b2 -; Preferably, R b1 and R b2 is C1-C6 straight chain alkylene or C2-C6 branched chain alkylene; for example, C1-C3 straight chain alkylene; C3-C4 branched chain alkylene.

12. The compound according to claim 1, wherein The compound is selected from the following compounds:

13. A pharmaceutical composition comprising the compound of any one of claims 1 to 12 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.

14. A method for regulating gene transcription in a cell, comprising exposing a protein comprising a bromodomain to a compound of any one of claims 1 to 12 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 or the pharmaceutical composition of claim 13.

15. A method for inhibiting bromodomain-mediated recognition of the acetyl lysine region of a protein, comprising exposing the bromodomain to a compound of any one of claims 1-12 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 claim 13.

16. A method for treating cancer, comprising administering to a patient a compound according to any one of claims 1 to 12 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 13.

17. The method according to claim 16, wherein The cancer is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplastic changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, tumor), fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphocytic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma , myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (epithelial cancers and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

18. Use of the compound of any one of claims 1 to 12 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 claim 13 in the preparation of a medicament for regulating gene transcription in a cell.

19. Use of the compound of any one of claims 1-12 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 claim 13 in the preparation of a drug for inhibiting bromodomain-mediated recognition of the acetyl lysine region of a protein.

20. Use of the compound of any one of claims 1 to 12 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 claim 13 in the preparation of a medicament for treating cancer.

21. The use according to claim 20, wherein The cancer is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysplastic changes (dysplasia and metaplasia), embryonal carcinoma, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, tumor), fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphocytic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin, and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple Myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, solid tumors (epithelial cancers and sarcomas), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

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