Tricyclic compound and application thereof

Abstract

The invention provides a compound which has a structure as shown in a formula I, or an enantiomer, a diastereoisomer, a racemate, a tautomer, a stereoisomer, a geometric isomer, nitrogen oxide, a metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope labeled compound or prodrug of the compound. The invention also provides medical application of the compound or the enantiomer, diastereoisomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope labeled compound or prodrug thereof.

Description

Technical Field

[0001] This application relates to the pharmaceutical field, specifically to a substituted tricyclic compound and its pharmaceutical uses. Background Technology

[0002] Werner syndrome protein is a RecQ family DNA helicase. RecQ helicases are widely found in prokaryotes, eukaryotes, and viruses, and play a crucial role in DNA replication, recombination, repair, and maintaining telomere stability.

[0003] WRN (Werner syndrome ATP-dependent helicase gene) is synthetically lethal in microsatellite-unstable cancers. WRN depletion leads to antiproliferative effects and activation of multiple DNA damage signaling markers, induces cell cycle arrest and apoptosis in MMR cancer models, but does not induce cell cycle arrest and apoptosis in cancer cells with intact MMR pathways. This finding suggests that WRN provides a DNA repair and maintenance function crucial for cell survival in MSI cancers. Recently, the mechanism of WRN dependence has been elucidated. It has been proposed that dinucleotide TA repeat sequences are selectively unstable and undergo massive amplification in MSI cells. These amplified TA repeat sequences form secondary DNA structures that require WRN helicase unwinding (van Wietmarschen, N. et al., Repeat expansions confer WRN dependence in microsatellite-unstable cancers. Nature, 586, 292-298, 2020). In the absence of WRN or under inhibition of WRN helicase, the amplified TA repeat sequences in MSI cells undergo nuclease cleavage and chromosome breakage. Therefore, inhibiting WRN helicase is a potential strategy for treating mismatch repair defective cancers.

[0004] Therefore, there is a need to develop WRN inhibitors to treat MSI cancer. Summary of the Invention

[0005] On the one hand, this application provides a compound having the structure shown in Formula I, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof. in, A is selected from R, which may or may not contain substituents.S1 C1-C10 alkyl, with or without substituents R S1 3-12 membered heterocyclic groups, with or without substituents R S1 C3-C20 cycloalkyl groups R' and R" are each independently selected from R with or without substituents. S2 C1-C10 alkyl, with or without substituents R S2 C3-C20 cycloalkyl groups; L is selected from bonds, with or without substituents. R S1 C1-C10 alkylene groups, with or without substituents R S1 C3-C20 cycloalkylene compounds, with or without substituents R S1 3-12 membered subheterocyclic groups; R2 and R3 are each independently selected from hydrogen, deuterium, and R with or without substituents. S1 C1-C6 alkyl C(=O)-, with or without substituents R S1 C1-C6 alkyl-OC(=O)-, with or without substituents R S1 C1-C10 alkyl, with or without substituents R S1 C3-C20 cycloalkyl, with or without substituents R S1 3-12 membered heterocyclic groups, with or without substituents R S1 6-10 aryl (e.g., phenyl) or with or without substituents R S1 3-10 heteroaryl groups (e.g., pyridyl); R4 and R5 are each independently selected from R4 with or without substituents. S1 C6-C10 aryl, with or without substituents R S1 5-10 aryl heteroaryl groups, with or without substituents R S1 3-12 membered heterocyclic groups; R a Selected from deuterium, halogen, oxo, hydroxyl, cyano, carboxyl, SF5, amino, C1-C6 alkyl-substituted amino, with or without substituents R S2 C1-C6 alkyl, with or without substituents R S2 C1-C6 alkoxy groups, with or without substituents R S2 C2-C6 alkenyl, with or without substituents R S2 C2-C6 alkynyl, with or without substituents R S2 C3-C6 cycloalkyl, with or without substituents R S2 3-6 membered oxygen heterocyclic group, with or without substituent R S2 -S(=O)2-C1-C6 alkyl or with or without substituents R S2-C1-C6 alkylene-S(=O)2-C1-C6 alkyl; a is an integer selected from 0 to 8. When a ≥ 2, two adjacent R a The carbon atoms that can be attached to them can form R with or without substituents. S1 3-12 membered carbon rings or heterocycles; X, Y, and Z satisfy the following conditions (1), (2), or (3): Condition (1) X is CH or N, and Y is selected from hydrogen, deuterium, and R with or without substituents. S2 C1-C10 alkyl, with or without substituents R S1 C3-C6 cycloalkyl, with or without substituents R S1 The C3-C10 heterocyclic group, Z is selected from hydrogen, with or without substituents R. S2 C1-C10 alkyl, with or without substituents R S1 C3-C6 cycloalkyl, with or without substituents R S1 3-10 membered heterocyclic groups; Condition (2) X is CH or N, and Y and Z and the atoms they are connected to form R with or without substituents. S1 5-10 membered carbon rings or heterocycles; Condition (3) X is C, and forms R with or without substituents with Y and the atoms they are connected to. S1 A 5-10 membered carbon ring or heterocycle, Z selected from hydrogen, deuterium, with or without substituents R. S2 C1-C10 alkyl, with or without substituents R S1 C3-C20 cycloalkyl, with or without substituents R S1 3-12 membered heterocyclic groups; The substituent R S1 Selected from deuterium, halogen, oxo, hydroxyl, cyano, carboxyl, SF5, amino, C1-C6 alkyl-substituted amino, with or without substituents R S2 C1-C6 alkyl, with or without substituents R S2 C1-C6 alkoxy groups, with or without substituents R S2 C2-C6 alkenyl, with or without substituents R S2 C2-C6 alkynyl, with or without substituents R S2 C3-C6 cycloalkyl, with or without substituents R S2 C3-C6 oxoheterocyclic group, with or without substituents R S2 C3-C6 thioheterocyclic group, with or without substituents R S2 -S(=O)2-C1-C6 alkyl, with or without substituents R S2 -C1-C6 alkylene-S(=O)2-C1-C6 alkyl or ; or two Rs S1 Together with the carbon atoms attached to them, they form 3-6 membered oxoheterocyclic groups or 3-6 membered thioheterocyclic groups, with or without substituents R. S2 phenyl R b and R c Each is independently selected from hydrogen, deuterium, halogen, oxo, hydroxyl, cyano, C1-C4 alkyl, or fluorinated C1-C4 alkyl; R w Selected from hydrogen, deuterium, or C1-C6 alkyl groups; The substituent R S2 Selected from deuterium, halogen, oxo, hydroxyl, cyano, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, and SF5.

[0006] On the other hand, this application provides a pharmaceutical composition comprising the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs and at least one pharmaceutically acceptable carrier.

[0007] On the other hand, this application provides the compounds described herein or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or their pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs, or combinations thereof, which treat diseases or conditions by inhibiting WRN activity.

[0008] On the other hand, this application provides the use of the compound described herein or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs or combinations thereof in the preparation of a medicament that treats a disease or condition by inhibiting WRN activity.

[0009] On the other hand, this application provides a method for treating a disease or condition by inhibiting WRN activity, comprising administering to a person in need a therapeutically effective amount of the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs or combinations thereof.

[0010] Another aspect of this application relates to methods for the preparation, separation, and purification of compounds represented by the general formula in this application.

[0011] Any embodiment of any aspect of this application may be combined with other embodiments, provided that they do not contradict each other. Furthermore, any technical feature in any embodiment of any aspect of this application may be applied to the same technical feature in other embodiments, provided that they do not contradict each other.

[0012] The foregoing description only outlines certain aspects of this application, but is not limited to them. These and other aspects will be described in more detail and in full below. All references in this specification are incorporated herein by reference in their entirety. Detailed Implementation

[0013] To make the objectives, technical solutions, and advantages of this application clearer, the following detailed description is provided in conjunction with embodiments. The specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of this application. Furthermore, descriptions of well-known structures and technologies are omitted in the following description to avoid unnecessarily obscuring the concepts of this disclosure. Such structures and technologies have also been described in numerous publications.

[0014] definition Certain embodiments of this application will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. This application is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of this application as defined in the claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to practice this application. This application is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), this application shall prevail.

[0015] It should be further appreciated that some features of this application, for clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of this application, for brevity, have been described in a single embodiment, but may also be provided individually or in any suitable sub-combination.

[0016] Unless otherwise stated, all technical terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. All patents and publications related to this application are incorporated herein by reference in their entirety.

[0017] Unless otherwise stated, the following definitions shall apply as used herein. For the purposes of this application, chemical elements are consistent with the CAS edition of the periodic table and the Handbook of Chemistry and Physics, 75th edition, 1994. Furthermore, general principles of organic chemistry can 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.

[0018] Unless otherwise stated or there is a clear conflict in the context, the articles “a,” “an,” and “described” as used herein are intended to include “at least one” or “one or more.” Therefore, these articles as used herein refer to articles for one or more (i.e., at least one) objects. For example, “a component” refers to one or more components, meaning that more than one component may be considered for use or adoption in the implementation of the described embodiments.

[0019] The term "test subject" refers to an animal. Typically, the animal is a mammal. Test subjects also include, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the test subject is a primate. In other embodiments, the test subject is a human.

[0020] The terms "patient" or "subject" refer to a person (including adults and children) or other animal. In some implementations, "patient" refers to a person.

[0021] The terms “comprising” or “including” are open-ended expressions, meaning they include the contents specified in this application but do not exclude other contents.

[0022] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0023] The term "enantiomer" refers to two non-overlapping but mirror-image isomers of a compound.

[0024] The term "diastereomer" refers to a stereoisomer that has two or more chiral neutral molecules that are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical techniques such as electrophoresis and chromatography, for example, HPLC.

[0025] The terms “racemate,” “racemic mixture,” or “racemic mixture” refer to an equimolar mixture of two enantiomers that lack optical activity.

[0026] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridin-4-ol and pyridin-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds in this application are within the scope of this application.

[0027] The term "stereoisomer" refers to compounds that have the same chemical structure but whose atoms or groups are arranged differently in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), and hindered isomers, etc.

[0028] The term "geometric isomers," also known as "cis-trans isomers," refers to isomers that cannot rotate freely due to the double bond (including the double bond, C=N double bond, and N=N double bond in alkenes) or the single bond of a cyclic carbon atom.

[0029] The stereochemical definitions and rules used in this application generally follow those of S.P. 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 an optically active form, meaning they have the ability to rotate the plane of 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 with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols used to specify the rotation of plane-polarized light caused by the compound, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0030] Any asymmetric atom (e.g., carbon, etc.) in the compounds disclosed in this application may exist in a racemic or enantiomerically enriched form, such as in (R)-, (S)-, or (R,S)- configurations. In some 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 the (R)- or (S)- configuration.

[0031] Depending on the choice of starting materials and methods, the compounds of this application may exist as one or a mixture of possible isomers, such as racemic mixtures and 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 E or Z configurations; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be cis or trans configurations.

[0032] Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0033] Racemic mixtures of any resulting end product or intermediate can be separated into optical enantiomers using known methods, such as by separating their diastereomeric salts. Racemic products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. 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-VCHVerlag GmbH&Co.KGaA, Weinheim, Germany, 2007).

[0034] The term "nitrogen oxide" refers to the oxidation of one or more nitrogen atoms to form N-oxides when a compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th ed., Jerry March, pages). In particular, N-oxides can be prepared using the LWDeady method (Syn. Comm. 1977, 7, 509-514), in which the amine compound is reacted with m-chloroperbenzoic acid (MCPBA) in an inert solvent, such as dichloromethane.

[0035] The term "metabolite" refers to the product obtained in vivo through the metabolism of a specific compound or its salt. A compound's metabolite can be identified using techniques known in the art, and its activity can be characterized by experimental methods as described in this application. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this application includes metabolites of compounds, including metabolites produced by sufficient contact of the compound of this application with mammals for a period of time.

[0036] The term "pharmaceutical acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals to which it is treated. Preferably, "pharmaceutical acceptable" as used herein means approved by a federal regulatory agency or national government, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, particularly in humans.

[0037] The term "pharmaceutically acceptable salt" refers to both organic and inorganic salts of the compounds of this application. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts include salts formed by the compound with an acid, including, but not limited to, inorganic acid salts (such as hydrochlorides, hydrobromic acids, phosphates, sulfates, nitrates, and perchlorates) and organic acid salts (such as acetates, glycolic acids, oxalates, maleates, tartrates, citrates, succinates, fumarates, mandelates, and sulfosalicylates), or salts obtained by other methods described in the literature, such as ion exchange. More pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, gluconate, glycerophosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Pharmaceutically acceptable salts also include salts formed by compounds with bases, including but not limited to inorganic base salts (such as alkali metal salts, alkaline earth metal salts, ammonium salts, and N+(C1-C4 alkyl)4 salts), alkali metal or alkaline earth metal salts including sodium, lithium, potassium, calcium, magnesium, etc. This application also contemplates quaternary ammonium salts formed by any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations resistant to the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C... 1-8 Sulfonates and aromatic sulfonates. Organic base salts (such as primary, secondary, and tertiary amine salts, substituted amine salts (including naturally occurring substituted amines, cyclic amines, and basic ion exchange resin salts)). 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.

[0038] Pharmaceutically acceptable acid addition salts can be formed by the reaction of the compounds of this application with inorganic or organic acids, and pharmaceutically acceptable base addition salts can be formed by the reaction of the compounds of this application with inorganic or organic bases. The pharmaceutically acceptable salts of this application can be synthesized using conventional chemical methods from a parent compound and its basic or acidic components. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water or an organic solvent or a mixture thereof. Generally, in suitable cases, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is required. Other lists of suitable salts can be found in, for example, “Remington’s Pharmaceutical Sciences”, 20th edition, Mack Publishing Company, Easton, Pa. (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, Stahland Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0039] The term "solvent" refers to an association formed by one or more solvent molecules with the compound of this application. The solvent may be water, acetic acid, diethyl ether, isopropyl ether, petroleum ether, ethyl formate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl tert-butyl ether (MTBE), n-heptane, a mixture 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, or tert-butanol. Sec-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, n-hexane, cyclohexane, n-heptane, a mixture of n-heptane and ethyl acetate in a volume ratio of 1:5 to 5:1, isopropanol, methanol, butanone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, n-propanol, isopropanol, 2-propanone, 4-methyl-2-pentanone, pyridine, tetrahydrofuran, methyl ethyl ketone, toluene, xylene, cumene, or mixtures thereof, etc.

[0040] The term "hydrate" refers to an associative compound formed by one or more water molecules and the compound of this application.

[0041] Furthermore, the compounds disclosed in this application, including their salts, can also be obtained in their hydrated form or in the form of a solvent containing them (e.g., ethanol, DMSO, etc.) for crystallization. The compounds disclosed in this application can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, this application is intended to include both solvated and unsolvated forms.

[0042] The term "ester" is represented by the formula -OC(O)R' or -C(O)OR', where R' can be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described in this application.

[0043] The term "isotope-labeled compound" refers to compounds in this application that are labeled with isotopes. They are identical to those compounds described in this application except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Exemplary isotopes may also be introduced in the compounds of this application, including 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.

[0044] Other isotopically labeled compounds of this application containing the aforementioned isotopic label and / or other atoms, as well as pharmaceutically acceptable salts of said compounds, are included within the scope of this application. Isotopically labeled compounds of this application, such as radioisotopically labeled compounds, are also included. 3 H and 14 The incorporation of tritium into the compounds of this application can be used for drug and / or substrate tissue distribution analysis. Due to its ease of preparation and detection, tritium-substituted compounds, i.e., 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred. Additionally, isotopes with higher mass numbers, such as deuterium, are used. 2 H substitution can offer therapeutic advantages such as greater metabolic stability, including increased in vivo half-life or reduced dose requirements. Therefore, it may be preferred in some situations.

[0045] Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), can provide certain therapeutic advantages due to increased metabolic stability. These advantages include, for example, an increased half-life in vivo, a reduced dose requirement, or an improved therapeutic index. It should be understood that deuterium in this application is considered a substituent. The concentration of such heavier isotopes, particularly deuterium, can be defined using an isotope enrichment factor. As used in this application, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of the specified isotope and its native abundance. If the substituents of the compounds in this application are designated as deuterium, the compounds have an isotopic enrichment factor of at least 3500 (52.5% deuterium doping at each designated deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping) with respect to each designated deuterium atom. The pharmaceutically usable solvates of this application include those in which the crystallization solvent may be isotopically substituted, such as D2O, acetone-d6, DMSO-d6.

[0046] As used in this application, the term "prodrug" refers to the conversion of a compound into the compound represented by Formula I in vivo. Such conversion is influenced by the hydrolysis of the prodrug in the blood or its enzymatic conversion into the parent structure in the blood or tissues. The prodrug compounds in this application can be esters; among existing inventions, esters that can serve as prodrugs include phenyl esters and aliphatic (C14) esters. 1-24Esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one compound in this application contains a hydroxyl group, meaning it can be acylated to yield a prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a parent hydroxyl group. A complete discussion of prodrugs can be found in 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 DrugDiscovery, 2008, 7, 255-270; and Hecker et al., Prodrugs of Phosphates and Phosphonates, J.Med.Chem., 2008, 51, 2328-2345.

[0047] Unless otherwise expressly indicated, the descriptive terms “each…independently”, “…each…independently”, and “…independently” used in this application are interchangeable and should be interpreted broadly. They can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0048] The terms “optional,” “optionally,” or “arbitrarily” mean that the event or situation described below may, but is not necessarily, occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, “optionally replaced by…” means that the replacement may or may not occur.

[0049] When the terms “independent” and “arbitrarily” are used together, for example, “independently and arbitrarily replaced by…”, it means that specific options are replaced by or not replaced by each other without affecting each other.

[0050] The term "unsaturated" or "unsaturated" means that a portion contains one or more degrees of unsaturation.

[0051] In various parts of this specification, the substituents of the compounds disclosed in this application are disclosed according to the type or range of groups. In particular, this application includes each independent sub-combination of the members of these types and ranges of groups. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

[0052] Linking substituents are described in various parts of this application. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the 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 "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0053] The term "heteroatom" refers to O, S, N, P, B, and Si, including S, N, and P in any oxidation state; primary, secondary, tertiary amines, and quaternary ammonium salts; or forms in which the hydrogen atom on the nitrogen atom of a heterocycle is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrole), NH (like NH in pyrrolidinyl), or NRT (like NRT in N-substituted pyrrolidinyl, where RT is a substituent on N). In the compounds involved in this application, when multiple heteroatoms are contained, the resulting compounds conform to the covalent and compositional rules of organic compounds; that is, compounds containing multiple heteroatoms should exclude those that do not conform to the covalent and compositional rules of organic compounds.

[0054] The term "heterocyclic group" or "heterocycle" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic system containing a carbon atom and a heteroatom. The heteroatom has the meaning as described in this application. A heterocyclic group can be fully saturated or contain one or more degrees of unsaturation, wherein at least one ring is not an aromatic ring and the group as a whole is not aromatic; when the heterocyclic group is a polycyclic system, at least one ring is a non-aromatic ring. In one embodiment, the heterocyclic group is a 4-12 membered ring, such as a 4-12 membered saturated or partially unsaturated heterocyclic group (a carbon atom and a heteroatom selected from N, O, P, S, B, Si, where S or P is optionally substituted by one or more oxygen atoms to obtain a group like SO, SO2, PO, PO2). In one embodiment, the saturated or partially unsaturated heterocyclic group is selected from: saturated monocyclic heterocyclic groups, saturated bicyclic heterocyclic groups, saturated tricyclic heterocyclic groups, partially unsaturated monocyclic heterocyclic groups, partially unsaturated bicyclic heterocyclic groups, and partially unsaturated tricyclic heterocyclic groups. Bicyclic heterocyclic groups refer to heterocyclic groups in bicyclic systems. Monocyclic heterocyclic groups refer to heterocyclic groups in monocyclic systems. 5-12 membered heterocyclic groups refer to heterocyclic groups with 5-12 ring atoms. 6-12 membered heterocyclic groups refer to heterocyclic groups with 6-12 ring atoms. 7-8 membered heterocyclic groups refer to heterocyclic groups with 7-8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl, or morpholinyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azircyclopropane, oxacyclopropane, and thiohexane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azircyclobutane, oxacyclobutane, and thiohexane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxacyclopentane, oxothiophenyl, dithiophenyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiohexane. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiohexane, and dioxane. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxaheptanyl, and thioheptanyl.

[0055] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein the ring atoms are selected from N, O, and S(O). m The ring may contain B (where m is an integer from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. One or more rings may contain one or more double bonds, but the ring as a whole is not aromatic. The rings are preferably 6 to 12-membered. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic spirocyclic groups, with bicyclic being preferred. Based on the number of non-shared atoms on the rings, examples of spirobicyclic rings include, but are not limited to: spiro[3.2]bicyclic, spiro[3.3]bicyclic, spiro[3.4]bicyclic, spiro[3.5]bicyclic, spiro[4.4]bicyclic, spiro[4.5]bicyclic, spiro[5.5]bicyclic, spiro[6.3]bicyclic, spiro[6.4]bicyclic, and spiro[6.5]bicyclic.

[0056] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein at least one ring is not an aromatic ring and the whole is not aromatic, and one or more ring atoms are selected from N, O, and S(O). m The heteroatom is B (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it consists of 6 to 12 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, with bicyclic being preferred. Based on the number of non-shared atoms on the rings, examples of fused bicyclic heterocycles include, but are not limited to: fused [2.2.0] bicyclic, fused [3.2.0] bicyclic, fused [3.3.0] bicyclic, fused [4.2.0] bicyclic, fused [4.3.0] bicyclic, fused [4.4.0] bicyclic, fused [5.2.0] bicyclic, fused [5.3.0] bicyclic, fused [5.4.0] bicyclic, fused [5.5.0] bicyclic, fused [6.2.0] bicyclic, fused [6.3.0] bicyclic, and fused [6.4.0] bicyclic.

[0057] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. One or more rings may contain one or more double bonds, at least one of which is not an aromatic ring and the group as a whole is not aromatic. One or more ring atoms are selected from N, O, and S(O). mThe heteroatom is B (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it consists of 6 to 12 rings. Depending on the number of rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, with bicyclic being preferred. Based on the number of non-shared atoms on the ring, examples of bridged bicyclic rings include, but are not limited to: bridged [2.1.1] bicyclic ring, bridged [2.2.1] bicyclic ring, bridged [2.2.2] bicyclic ring, bridged [3.1.1] bicyclic ring, bridged [3.2.1] bicyclic ring, bridged [3.2.2] bicyclic ring, bridged [3.3.1] bicyclic ring, bridged [3.3.2] bicyclic ring, bridged [3.3.3] bicyclic ring, bridged [4.1.1] bicyclic ring, bridged [4.2.1] bicyclic ring, bridged [4.2.2] bicyclic ring, bridged [4.3.1] bicyclic ring, bridged [4.3.2] bicyclic ring, bridged [4.4.1] bicyclic ring, or bridged [4.4.2] bicyclic ring.

[0058] The term "cycloalkyl" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic system containing carbon atoms. A cycloalkyl group can be fully saturated or contain one or more degrees of unsaturation, wherein at least one ring is not an aromatic ring and the whole is not aromatic. 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, etc. In one embodiment, the saturated or partially unsaturated cycloalkyl group is selected from: saturated monocyclic cycloalkyl, saturated bicyclic cycloalkyl, saturated tricyclic cycloalkyl, partially unsaturated monocyclic cycloalkyl, partially unsaturated bicyclic cycloalkyl, and partially unsaturated tricyclic cycloalkyl. 4-7 Cycloalkyl refers to cycloalkyl groups with 4-7 ring atoms. C3-C6 cycloalkyl refers to cycloalkyl groups with 3-6 ring atoms.

[0059] The terms "heteroaryl" or "heteroaromatic ring" refer to aromatic systems containing heteroatoms, including monocyclic, bicyclic, and tricyclic rings. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." Heteroatoms are defined as described in this application. In some embodiments, a heteroaryl is a heteroaryl comprising 5-10 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-10-membered heteroaryl; a heteroaryl is a heteroaryl comprising 5-8 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-8-membered heteroaryl; in some embodiments, a heteroaryl is a heteroaryl comprising 5-7 atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 5-7-membered heteroaryl. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms 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 heteroaryl group consisting of 5 atoms 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 heteroaryl group consisting of 6 atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, i.e., a 6 membered heteroaryl group.

[0060] The term "aryl" or "aromatic ring" refers to aromatic carbocyclic systems that are monocyclic, bicyclic, or tricyclic. The term "aryl" can be used interchangeably with "aromatic ring" or "aromatic ring". A 6-10 membered aryl group indicates an aryl group containing 6-10 ring atoms. Examples include, but are not limited to, phenyl and naphthyl groups.

[0061] The term "alkyl" or "alkyl group" refers to a carbon-containing, saturated, straight-chain or branched hydrocarbon group. In one embodiment, the alkyl group contains 1-6 carbon atoms, i.e., C1-C6 alkyl; in another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., C1-C4 alkyl; and in yet another embodiment, the alkyl group contains 1-3 carbon atoms, i.e., C1-C4 alkyl. 1-3 Alkyl groups. 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 similar alkyl groups; in another embodiment, C1-C6 alkyl groups further include heteroalkyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0062] The term "alkenyl" refers to a straight-chain or branched monovalent or polyvalent hydrocarbon group containing carbon atoms, wherein there is at least one unsaturated site, i.e., a carbon-carbon sp2 double bond, including "cis" and "tans" orientation, or "E" and "Z" orientation. In one embodiment, the alkenyl group comprises 2-6 carbon atoms, i.e., a C2-C6 alkenyl group; in another embodiment, the alkenyl group comprises 2-4 carbon atoms, i.e., a C2-C4 alkenyl group. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), etc.; in yet another embodiment, the C2-C6 alkenyl group further includes a heteroalkenyl group, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may optionally be substituted by one or more substituents, for example, substituted by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0063] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing a carbon atom, wherein there is at least one unsaturated site, i.e., a carbon-carbon sp triple bond. In one embodiment, the alkynyl group comprises 2-6 carbon atoms, i.e., a C2-C6 alkynyl; in another embodiment, the alkynyl group comprises 2-4 carbon atoms, i.e., a C2-C4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc.; in yet another embodiment, the C2-C6 alkynyl group further includes a heteroalkynyl group, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may optionally be substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0064] The term "alkoxy group" indicates that an alkyl group is attached to the remainder of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described in this application. In one embodiment, the alkoxy group contains 1-6 carbon atoms, i.e., C1-C6 alkoxy; in another embodiment, the alkoxy group contains 1-4 carbon atoms, i.e., C1-C4 alkoxy; and in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, i.e., C1-C4 alkoxy. 1-3 Alkyl group.

[0065] The term "alkylamino" indicates that an alkyl group is attached to the remainder of the molecule via a nitrogen atom, wherein the alkyl group has the meaning as described in this application. 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; and in yet another embodiment, the alkylamino group contains 1-3 carbon atoms, i.e., C1-C4 alkylamino. 1-3 Alkylamino.

[0066] The term "hydrogen" refers to 1 H; "deuterium" refers to 2 H.

[0067] The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Thus, "C 1-6 haloalkyl" refers to "C 1-6 alkyl" which is substituted by one or more halogen groups. In some embodiments, C 1-4 haloalkyl is particularly preferred. Exemplary haloalkyls include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group can be substituted at any available attachment point, for example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0068] The term "amino" refers to -NH2.

[0069] The term "hydroxy" refers to -OH.

[0070] The term "cyano" refers to -CN.

[0071] The term "nitro" refers to -NO2.

[0072] The term "carboxy" refers to HO(C=O)-.

[0073] The term "oxo" refers to O=, that is, when the substituent is O=, O is connected to the substituted group by a double bond.

[0074] In this application document, when it is mentioned that a group is substituted by a substituent, it means that the appropriate group is substituted at a reasonable position. For example, for oxo, when there is a description: R is alkyl, aryl, and the alkyl and aryl are each optionally independently substituted by 0, 1, 2, 3 substituents selected from halogens, hydroxy, oxo, it can be reasonably understood that oxo only occurs at the appropriate position on the alkyl.

[0075] The term "comprising" is synonymous with "including", "containing" or "characterized by", and it is inclusive or open-ended and does not exclude additional unmentioned elements or ingredients from the drug (or in the case of a method, steps). The phrase "consisting of" does not include any element, step or ingredient not specified in the drug (or in the case of a method, steps). The phrase "consisting essentially of" means the specified materials and those materials that do not substantially affect the basic and novel properties of the drug (or in the case of a method, steps).

[0076] As described in this paper, a ring system formed by a substituent R being bonded to a central ring (as shown in the figure below) represents the substitution of substituent R at any substituted or reasonable position on ring A or ring B. For example, formula f represents any possible substituted position on ring A or B, as shown in formulas f1-f8: As described in this paper, a ring system is formed by a substituent being linked by a single bond to a central ring, such as (R x ) n , representing n substituents R x It can be substituted at any substituted position on the ring. For example, formula a represents that the benzene ring can be substituted by n R groups. x replace.

[0077] When the substituent is a ring, and the bond connecting the substituted part to the molecule is attached to the center of the ring of the substituent (as shown below), the ring system represents any reasonable position on the substituent connected to the substituted part. For example, formula b is represented as formulas b1-b5: The term "substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is either the substituent described above or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position, i.e., the various substitutions are independent of each other. Those skilled in the art will understand that the combinations of substituents contemplated in this application are those that are stable or chemically feasible.

[0078] Description of the compounds in this application This application provides a compound or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or their pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs that treat diseases or conditions by inhibiting WRN activity.

[0079] On the one hand, this application provides a compound having the structure shown in Formula I, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotope-labeled compound, or prodrug thereof. in, A is selected from R, which may or may not contain substituents. S1C1-C10 alkyl, with or without substituents R S1 3-12 membered heterocyclic groups, with or without substituents R S1 C3-C20 cycloalkyl groups R' and R" are each independently selected from R with or without substituents. S2 C1-C10 alkyl, with or without substituents R S2 C3-C20 cycloalkyl groups; L is selected from bonds, with or without substituents. R S1 C1-C10 alkylene groups, with or without substituents R S1 C3-C20 cycloalkylene compounds, with or without substituents R S1 3-12 membered subheterocyclic groups; R2 and R3 are each independently selected from hydrogen, deuterium, and R with or without substituents. S1 C1-C6 alkyl C(=O)-, with or without substituents R S1 C1-C6 alkyl-OC(=O)-, with or without substituents R S1 C1-C10 alkyl, with or without substituents R S1 C3-C20 cycloalkyl, with or without substituents R S1 3-12 membered heterocyclic groups, with or without substituents R S1 6-10 aryl groups with or without substituents R S1 3-10 aryl compounds; R4 and R5 are each independently selected from R4 with or without substituents. S1 C6-C10 aryl, with or without substituents R S1 5-10 aryl heteroaryl groups, with or without substituents R S1 3-12 membered heterocyclic groups; R a Selected from deuterium, halogen, oxo, hydroxyl, cyano, carboxyl, SF5, amino, C1-C6 alkyl-substituted amino, with or without substituents R S2 C1-C6 alkyl, with or without substituents R S2 C1-C6 alkoxy groups, with or without substituents R S2 C2-C6 alkenyl, with or without substituents R S2 C2-C6 alkynyl, with or without substituents R S2 C3-C6 cycloalkyl, with or without substituents R S2 3-6 membered oxygen heterocyclic group, with or without substituent R S2 -S(=O)2-C1-C6 alkyl or with or without substituents R S2 -C1-C6 alkylene-S(=O)2-C1-C6 alkyl; a is an integer selected from 0 to 8. When a ≥ 2, two adjacent R a The carbon atoms that can be attached to them can form R with or without substituents. S1 3-12 membered carbon rings or heterocycles; X, Y, and Z satisfy the following conditions (1), (2), or (3): Condition (1) X is CH or N, and Y is selected from hydrogen, deuterium, and R with or without substituents. S2 C1-C10 alkyl, with or without substituents R S1 C3-C6 cycloalkyl, with or without substituents R S1 The C3-C10 heterocyclic group, Z is selected from hydrogen, with or without substituents R. S2 C1-C10 alkyl, with or without substituents R S1 C3-C6 cycloalkyl, with or without substituents R S1 3-10 membered heterocyclic groups; Condition (2) X is CH or N, and Y and Z and the atoms they are connected to form R with or without substituents. S1 5-10 membered carbon rings or heterocycles; Condition (3) X is C, and forms R with or without substituents with Y and the atoms they are connected to. S1 A 5-10 membered carbon ring or heterocycle, Z selected from hydrogen, deuterium, with or without substituents R. S2 C1-C10 alkyl, with or without substituents R S1 C3-C20 cycloalkyl, with or without substituents R S1 3-12 membered heterocyclic groups; The substituent R S1 Selected from deuterium, halogen, oxo, hydroxyl, cyano, carboxyl, SF5, amino, C1-C6 alkyl-substituted amino, with or without substituents R S2 C1-C6 alkyl, with or without substituents R S2 C1-C6 alkoxy groups, with or without substituents R S2 C2-C6 alkenyl, with or without substituents R S2 C2-C6 alkynyl, with or without substituents R S2 C3-C6 cycloalkyl, with or without substituents R S2 C3-C6 oxoheterocyclic group, with or without substituents R S2 C3-C6 thioheterocyclic group, with or without substituents R S2 -S(=O)2-C1-C6 alkyl, with or without substituents R S2 -C1-C6 alkylene-S(=O)2-C1-C6 alkyl or ; or two Rs S1Together with the carbon atoms attached to them, they form 3-6 membered oxygen heterocyclic groups or 3-6 membered sulfur heterocyclic groups. R b and R c Each is independently selected from hydrogen, deuterium, halogen, oxo, hydroxyl, cyano, C1-C4 alkyl, or fluorinated C1-C4 alkyl; R w Selected from hydrogen, deuterium, or C1-C6 alkyl groups; The substituent R S2 Selected from deuterium, halogen, oxo, hydroxyl, cyano, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, SF5, with or without substituents R S2 phenyl.

[0080] In some embodiments, the compound is as shown in Formula I-1. In Equation I-1, A, L, R2, R3, R a a, Y, Z, R4, and R5 are the same as defined in this application; In some embodiments, R2 is hydrogen, deuterium, or C1-C6 alkyl; R3 is hydrogen, deuterium, C1-C6 alkyl, or C1-C6 alkoxy; preferably, R2 is hydrogen and R3 is hydrogen.

[0081] In some implementations, R a It is a C1-C6 alkyl group, preferably methyl.

[0082] In some implementations, a is 0, 1, 2, or 3.

[0083] In some implementations, a≥2, two adjacent R a The carbon atoms bonded to them together form R with or without substituents. S1 The 3-6 membered carbon rings preferably form with or without substituents R. S1 4-5 quinary carbon rings.

[0084] In some embodiments, Y and Z, along with the atoms they are connected to, form a substituent R, with or without substituents. S1 5-6 member nitrogen-containing heterocycles.

[0085] In some embodiments, the substituent R S1 Selected from deuterium and C1-C6 alkyl groups.

[0086] In some embodiments, the compound is as shown in Formula I-2. In Equation I-2, R cSelected from deuterium or C1-C6 alkyl, preferably methyl, where c is 0, 1, 2, 3 or 4, and A, L, R2, R3, R a a, Z, R4, and R5 are the same as defined in this application.

[0087] In some implementations, R c Selected from C1-C3 alkyl groups, where c is 0 or 1; in some embodiments R c It is a methyl group.

[0088] In some embodiments, the compound is as shown in I-3 or I-4: In equations I-3 and I-4, R b Selected from deuterium or C1-C6 alkyl, preferably methyl, b is 0, 1, 2, 3 or 4, A, L, R2, R3, R a a, R4, and R5 are the same as defined in claim 1 or 2; In some implementations, in Equation I-3, a is 0 or 1, and R a It is methyl; In some implementations, in equations I-3 and I-4, b is 0 or 1, and R b It is a methyl group.

[0089] In some embodiments, the compound is represented by any of the following formulas: Where m is 0 or 1, n is 0 or 1, and the other symbols are the same as those defined in this application.

[0090] In some embodiments, R2 is selected from hydrogen or C1-C5 alkyl groups, preferably hydrogen.

[0091] In some embodiments, R3 is selected from hydrogen or C1-C5 alkyl groups, preferably hydrogen.

[0092] In some implementations, R a It is selected from C1-C5 alkyl groups, preferably methyl or ethyl.

[0093] In some implementations, R b It is selected from C1-C5 alkyl groups, preferably methyl or ethyl.

[0094] In some implementations, R c It is selected from C1-C5 alkyl groups, preferably methyl or ethyl.

[0095] In some embodiments, R4 is selected from R4 with or without substituents. S1 The 6-7 member oxygen-containing heterocyclic alkenyl group, preferably, the substituent R S1 Selected from fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, isopropyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, isopropoxy, and trifluoromethoxy, with R4 being preferred. or .

[0096] In some embodiments, R5 is selected from those containing or not containing substituents R. S1 The phenyl group, preferably, wherein the substituent R S1 Selected from fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, isopropyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, isopropoxy, and trifluoromethoxy; R5 is preferably... .

[0097] In some implementations, L is a bond or may or may not contain substituents R. S1 C1-C5 alkylene groups, with or without substituents R S1 C3-C10 cycloalkylene compounds, with or without substituents R S1 The 3-6 membered subheterocyclic group, preferably, the substituent R S1 Selected from fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, isopropyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, isopropoxy, and trifluoromethoxy.

[0098] In some embodiments, A is selected from R with or without substituents. S1 C1-C6 alkyl, with or without substituents R S1 C3-C10 membered cycloalkyl, with or without substituents R S1 4-12 membered heterocyclic groups, with or without substituents R S1 of R' and R" are each independently selected from R with or without substituents. S2 C1-C5 alkyl groups.

[0099] In some implementations, R S1 Selected from deuterium, halogen, oxo, hydroxyl, cyano, carboxyl, oxo, SF5, amino, C1-C6 alkyl-substituted amino, with or without substituents R S2 C1-C6 alkyl, with or without substituents R S2 C1-C6 alkoxy groups, with or without substituents R S2 C2-C6 alkenyl, with or without substituents R S2C2-C6 alkynyl, with or without substituents R S2 C3-C6 cycloalkyl, with or without substituents R S2 3-6 membered oxygen heterocyclic group, with or without substituent R S2 -S(=O)2-C1-C6 alkyl, with or without substituents R S2 -C1-C6 alkylene-S(=O)2-C1-C6 alkyl or Optional, both R S1 Together with the carbon atoms attached to them, they form a C2-C6 alkenyl group, a 3-6 oxoheterocyclic group, or a 3-6 thioheterocyclic group, wherein the C2-C6 alkenyl group or the 3-6 oxoheterocyclic group is optionally substituted with a substituent R. S2 replace.

[0100] In some implementations, R S2 Selected from deuterium, halogen, oxo, hydroxyl, cyano, amino, carboxyl, C1-C6 alkoxy, SF5, CF3.

[0101] In some implementations, R S1 Selected from deuterium, halogen, oxo, hydroxyl, cyano, carboxyl, oxo, SF5, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, halo-C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C2-C6 alkenyl, halo-C2-C6 alkyl. 6-alkynyl, halogenated C3-C6 cycloalkyl, amino-substituted C3-C6 cycloalkyl, hydroxyl-substituted C3-C6 cycloalkyl, cyano-substituted C3-C6 cycloalkyl, C1-C6 alkoxy-substituted C3-C6 cycloalkyl, amino-substituted 3-6-membered oxetane, hydroxyl-substituted 3-6-membered oxetane, cyano-substituted 3-6-membered oxetane, -S(=O)2-C1-C6 alkyl, -C1-C6 alkylene-S(=O)2-C1-C6 alkyl or R W Selected from hydrogen, deuterium, or C1-C6 alkyl, preferably, R W Selected from hydrogen, deuterium, methyl or ethyl.

[0102] In some embodiments, A is selected from R with or without substituents. S1 4-10 member monoheterocyclic groups, with or without substituents R S1 5-12 bridging biheterocyclic groups with or without substituents R S1 5-12 spirobicyclic groups.

[0103] In some embodiments, A is selected from R with or without substituents. S1The following groups are included: 3-6 membered cycloalkyl, 4-membered mono-heterocyclic, 5-membered mono-heterocyclic, 6-membered mono-heterocyclic, bridged[2.1.1]bi-heterocyclic, bridged[2.2.1]bi-heterocyclic, bridged[2.2.2]bi-heterocyclic, bridged[3.1.1]bi-heterocyclic, bridged[3.2.1]bi-heterocyclic, bridged[3.2.2]bi-heterocyclic, bridged[3.3.1]bi-heterocyclic, bridged[3.3.2]bi-heterocyclic, bridged[3.3.3]bi-heterocyclic, bridged[4.1.1]bi-heterocyclic, bridged[4.2.1]bi-heterocyclic Ring, bridge [4.2.2] double heterocyclic ring, bridge [4.3.1] double heterocyclic ring, bridge [4.3.2] double heterocyclic ring, bridge [4.4.1] double heterocyclic ring, bridge [4.4.2] double heterocyclic ring, screw [3.2] double heterocyclic ring, screw [3.3] double heterocyclic ring, screw [3.4] double heterocyclic ring, screw [3.5] double heterocyclic ring, screw [4.4] double heterocyclic ring, screw [4.5] double heterocyclic ring, screw [5.5] double heterocyclic ring, screw [6.3] double heterocyclic ring, screw [6.4] double heterocyclic ring or screw [6.5] double heterocyclic ring; In some embodiments, the heteroatom in the heterocycle is selected from oxygen, sulfur, or nitrogen.

[0104] In some embodiments, A is selected from R with or without substituents. S1 The following groups, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; In some embodiments, A is a substituent R. S1of , or ; In some implementations, A is , , , or .

[0105] In some implementations, A is .

[0106] In some implementations, R S1 Selected from: halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and C3-C6 cycloalkyl optionally substituted with a substituent selected from halogen, cyano, hydroxy, amino, C1-C4 alkyl, and C1-C4 alkoxy.

[0107] In some implementations, R S1 The radical is independently selected from deuterium, halogen, oxo, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, fluoroC1-C4 alkyl, C1-C4 hydroxy-substituted alkyl, C1-C4 cyano-substituted alkyl, C1-C4 alkoxy-substituted C1-C4 alkyl, fluoroC1-C4 alkoxy, fluoroC2-C4 alkenyl, fluoroC2-C4 alkynyl, C3-C6 cycloalkyl, and 3-6 member alkyl groups. Oxycyclic groups, hydroxyl-substituted C3-C6 cycloalkyl groups, amino-substituted C3-C6 cycloalkyl groups, cyano-substituted C3-C6 cycloalkyl groups, C1-C4 alkoxy-substituted C3-C6 cycloalkyl groups, hydroxyl-substituted 3-6 membered oxycyclic groups, amino-substituted 3-6 membered oxycyclic groups, cyano-substituted 3-6 membered oxycyclic groups, -S(=O)2-C1-C4 alkyl groups, -C1-C4 alkylene groups -S(=O)2-C1-C4 alkyl groups, Or two Rs s1 Together they form oxetine propyl, oxetine butyl, oxetine pentyl, R b and R c Each is independently selected from hydrogen, deuterium, halogen, oxo, hydroxyl, cyano, C1-C4 alkyl or fluorinated C1-C4 alkyl, preferably selected from hydrogen, fluorine, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl, R W Selected from hydrogen, deuterium, or C1-C4 alkyl groups, Indicates the connection point with the ring.

[0108] In some implementations, R S1Each is independently selected from deuterium, fluorine, hydroxyl, cyano, methyl, ethyl, methoxy, ethoxy, vinyl, propenyl, ethynyl, propynyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, ethoxy-substituted methyl, ethoxy-substituted ethyl, ethoxy-substituted propyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, monofluorovinyl, difluorovinyl, trifluorovinyl, -S(=O)2-methyl, -S(=O)2-ethyl, -methylene-S(=O)2-methyl, -methylene-S(=O)2-ethyl. , , , , , , , Cyclopropyl, cyclobutyl, amino-substituted cyclopropyl, amino-substituted cyclobutyl, hydroxy-substituted cyclopropyl, cyano-substituted cyclopropyl, hydroxy-substituted cyclobutyl, methoxy-substituted cyclopropyl, methoxy-substituted cyclobutyl, ethoxy-substituted cyclopropyl, ethoxy-substituted cyclobutyl, propoxy-substituted cyclopropyl, propoxy-substituted cyclobutyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, hydroxy-substituted oxacyclopropyl, hydroxy-substituted oxacyclobutyl, hydroxy-substituted oxacyclopentyl, cyano-substituted oxacyclopropyl, cyano-substituted oxacyclobutyl, or cyano-substituted oxacyclopentyl.

[0109] In some embodiments, AL- or A is selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ... , , , , , , , , , , , , , , , , .

[0110] In some embodiments, the compound is as shown in formula II, II-1, III, or III-1: In formulas II, II-1, III, or III-1, R S1 R4 is as defined above; Preferably, R4 is selected from 6-7 member oxygen-containing heterocyclic alkenyl groups, and more preferably... or ; The definition of R1 and R S1 Or R S2 The same, preferably selected from cyano, hydroxy, amino, and methoxy groups; Preferably, R S1 Selected from deuterium or C1-C5 alkyl, preferably methyl.

[0111] In some embodiments, the compounds of this application have the following structures or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds, or prodrugs:

[0112] Pharmaceutical Compositions and Administration This application relates to a pharmaceutical composition comprising the compound described in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds, labeled compounds or prodrugs or pharmaceutically acceptable carriers; and a pharmaceutically acceptable carrier.

[0113] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or their physiologically / pharmaceutical acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutical acceptable carriers, diluents, and further excipients such as excipients, binders, fillers, etc., 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 the administration of the compound to a living organism.

[0114] As used herein, the term “pharmaceutically acceptable carrier” means a substance that can be used in the preparation or use of a pharmaceutical composition, and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delay agents, salts, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, 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).

[0115] This application also relates to pharmaceutical compositions comprising, as active ingredients, compounds having the general formula shown herein or pharmaceutically acceptable salts thereof, which may be used, in particular, to treat neoplastic diseases, especially cancer, as described herein. The compositions may be formulated for non-parenteral administration, such as nasal, oral, rectal, lung, vaginal, sublingual, topical, transdermal, ocular, or especially for oral administration, for example in oral solid dosage forms such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules and soft capsules or hydroxypropyl methylcellulose (HPMC) capsules (suitably coated), 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, particularly humans, for example in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. These compositions may contain a single active ingredient, or preferably, together with a pharmaceutically acceptable carrier.

[0116] Compounds having the general formula shown in this application, or pharmaceutically acceptable salts thereof, can be processed with pharmaceutically inert inorganic or organic excipients for the production of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or orally disintegrating tablets. Fillers such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or derivatives thereof, binders such as cellulose, starch, polyvinylpyrrolidone or derivatives thereof, flow aids such as talc, stearic acid or salts thereof, and flow agents such as calcined silica can be used as such excipients for the formulation and manufacture of oral solid dosage forms, such as granules, pills, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or orally disintegrating tablets. Suitable excipients for soft capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols.

[0117] Suitable excipients for manufacturing oral solutions, lipid emulsions or suspensions include, for example, water, alcohol, polyol, sucrose, invert sugar, glucose, etc.

[0118] Suitable excipients for parenteral preparations include water, alcohol, polyol, glycerin, vegetable oil, lecithin, surfactant, etc.

[0119] In addition, pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for altering osmotic pressure, buffers, masking agents, or antioxidants. Pharmaceutical preparations may also contain other substances of therapeutic value.

[0120] Dosage can vary over a wide range, and of course, it is individualized in each specific case. Generally, in the case of oral administration, a dose of about 1 to 1000 mg of a compound of general formula I per person per day should be appropriate, although it may be necessary to exceed the lower or upper limits mentioned above.

[0121] Compounds having the general formula shown in this application 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 to reduce or prevent potential undesirable side effects of compounds having the general formula shown in this application. Combination partners may be administered simultaneously in such treatment, for example, by incorporating them into a single pharmaceutical formulation, or by administering two or more different dosage forms (each containing one or more combination partners) sequentially.

[0122] Other pharmacologically active compounds can be other anticancer agents, selected from: anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukera) n®, cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytarabine (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazin (DTIC-Dome®), actinomycin (actinomycin D, Cosmegan), daunomycin hydrochloride (Cerubidine®), daunomycin citrate liposome injection (DaunoXome®), dexamethasone Doxotere®, Doxorubicin®, Adriamycin®, Rubex®, Vepesid®, Fludarabine®, Adrucil®, Efudex®, Eulexin®, Tezacitibine, Gemcitabine (Difluorodeoxycytidine), Hydroxyurea®, Idamycin®, Ifosfamide®, Efoxitin® (Camptosar®), L-aspartate aminotransferase (ELSPAR®), calcium leucovorin, Alkeran®, 6-mercaptopurine (Purinethol®), methopterin (Folex®), mitoxantrone (Novantrone®), mylotarg, taxol (Taxol®), phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 cocarmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0123] Other pharmacologically active compounds can also be PD-1 inhibitors. PD-1 inhibitors are selected from: PDR001 (Novartis), nivolumab (Bristol-Myers Squibb), pembrolizumab (Merck), pildizumab (CureTech), MEDI0680 (Mediamuse), cimiprimab (REGN2810, Regeneron), dotalimab (TSR-042, Tesalo), and PF-0680. 1591 (Pfizer), tislelizumab (BGB-A317, BeiGene), BGB-108 (BeiGene), INCSHR1210 (IncSHR), baritelizumab (AGEN2035, Agencia), sintilimab (Innovent Biologics), toripalimab (Shanghai Junshi Biosciences Co., Ltd.), camrelizumab (Jiangsu Hengrui Medicine Co., Ltd.), and AMP-224 (Amplimmune).

[0124] The term "therapeutic effective amount" for the compound of this application refers to the amount of the compound of this application that will elicit a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement of symptoms, relief of symptoms, slowing or delaying disease progression, or prevention of disease).

[0125] As used herein in the context of treating a disease or disorder, the term "treatment" generally refers to the treatment and therapy of humans or animals (e.g., in veterinary applications) in which some desired therapeutic effect is achieved, such as inhibiting the progression of the disease or disorder, and includes reducing the rate of progression, stopping the rate of progression, alleviating the symptoms of the disease or disorder, improving the disease or disorder, and curing the disease or disorder. It also includes treatment as a preventative measure (i.e., prevention). For example, treatment for patients who have not yet developed the disease or disorder but are at risk of developing it is covered by the term "treatment." For example, treatment includes cancer prevention, reducing cancer incidence, alleviating cancer symptoms, etc.

[0126] On the other hand, this application provides compounds represented by the general formula in this application or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or their pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs or combinations thereof, which treat diseases or conditions by inhibiting WRN activity.

[0127] On the other hand, this application provides the use of the compound represented by the general formula in this application or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs or combinations thereof in the preparation of a medicament that treats a disease or condition by inhibiting WRN activity.

[0128] On the other hand, this application provides a method for treating a disease or condition by inhibiting WRN activity, comprising administering to a person in need a therapeutically effective amount of a compound of the general formula shown in this application or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug or a combination thereof.

[0129] In some implementations, diseases or conditions such as cancer are treated by inhibiting WRN activity.

[0130] In some embodiments, this application provides a method for treating cancer characterized by high microsatellite instability (MSI-H) or mismatch repair defect (dMMR); it includes administering to a person in need a therapeutically effective amount of a compound of the formula shown in this application or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug or a combination thereof.

[0131] In some implementations, the cancer is selected from colorectal cancer, stomach cancer, endometrial cancer, adrenocortical cancer, uterine cancer, cervical cancer, esophageal cancer, breast cancer, kidney cancer, prostate cancer, and ovarian cancer.

[0132] In some implementation schemes, the compounds of this application can be used to treat cancers including: breast cancer, pancreatic cancer, lung cancer, colon cancer, colorectal cancer, brain cancer, kidney cancer, testicular cancer, urethral cancer, rectal cancer, fallopian tube cancer, penile cancer, vaginal cancer, gastric cancer, skin cancer, melanoma, liver cancer, gastrointestinal stromal tumor, urothelial carcinoma, thyroid cancer, parathyroid cancer, adrenal cancer, bone cancer, oral cancer, ovarian cancer, uterine cancer, squamous cell carcinoma of the head and neck, endometrial cancer, gallbladder cancer, bladder cancer, oropharyngeal cancer, lymph node cancer, glioblastoma, astrocytoma, glioblastoma multiforme or soft tissue sarcoma, fibrosarcoma, chondrosarcoma, hemangioma, teratoma, lipoma, myxoma, fibroma, rhabdomyosarcoma, teratoma, bile duct cancer, and Ewing's sarcoma.Examples of leukemias that can be treated with the compounds of this application may include or exclude: lymphoblastic T-cell leukemia, chronic myelogenous leukemia, acute lymphoblastic T-cell leukemia, acute myeloid leukemia, hairy-cell leukemia, chronic neutrophilic leukemia, mantle cell leukemia, acute megakaryocytic leukemia, multiple myeloma, megakaryoblastic leukemia, erythroleukemia, plasmacytoma, and promyelocytic leukemia. Leukemia, chronic myelomonocytic leukemia, myelodysplastic syndrome, myelofibrosis, chronic myeloid leukemia, polycythemia vera, thrombocythemia, chronic lymphocytic leukemia, prolymphocytic leukemia, hairy cell leukemia, Waldenstrom's macroglobulinemia, Castleman's disease, chronic neutrophilic leukemia, immunoblastic large cell leukemia, plasmacytoma, and leukemia in any other part of the body.Examples of lymphomas that can be treated with the compounds of this application may include or exclude: Hodgkin's disease, non-Hodgkin's lymphoma, follicular lymphoma, mantle cell lymphoma, Burkitt's lymphoma, lymphoblastic T-cell lymphoma, marginal zone lymphoma, cutaneous T-cell lymphoma, CNS lymphoma, small phocytic lymphoma, lymphoplasmic lymphoma, diffuse large B-cell lymphoma (DLBCL), and peripheral T-cell lymphoma. Solid tumors include anaplastic large cell lymphoma, primary mediastinal lymphoma, mycosis fungal infections, small non-cleaved cell lymphoma, lymphoblastic lymphoma, immunoblastic lymphoma, primary effusion lymphoma, and HIV-related (or AIDS-related) lymphomas. The methods and cell lines described in the examples can be used to model these solid tumors.

[0133] Synthesis method Compounds having the general formula shown in this application can be synthesized by the methods given below, by the methods given in the experimental section below, or by similar methods. The schemes described herein are not intended to present an exhaustive list of methods for preparing compounds having the general formula shown in this application; rather, other techniques known to a skilled chemist may also be used for compound synthesis.

[0134] The structure of the compound was determined by nuclear magnetic resonance (NMR). 1 H-NMR, 13 C-NMR or / and19 It was determined by F-NMR. 1 H-NMR, 13 C-NMR, 19 F-NMR chemical shifts (δ) are given in parts per million (ppm). 1 H-NMR, 13 C-NMR, 19 F-NMR measurements were performed using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer. The solvents used were deuterated chloroform (CDCl3), deuterated methanol (CD3OD or MeOH-d4), or deuterated dimethyl sulfoxide (DMSO-d6). TMS (0 ppm) or chloroform (7.25 ppm) was used as the reference standard. When multiplets are observed, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), and brs (broadened singlet). The coupling constant J is expressed in Hertz (Hz).

[0135] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1260 mass spectrometer. HPLC determinations were performed using an Agilent 1100 high-performance chromatograph (Microsorb 5micron C18 100 x 3.0 mm column).

[0136] Thin-layer chromatography (TLC) uses Qingdao GF254 silica gel plates, with a thickness of 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative TLC. Column chromatography typically uses Qingdao 200-300 mesh silica gel as the support.

[0137] The starting materials used in the embodiments of this application are all known and commercially available, or can be synthesized using or in accordance with literature reported in the field.

[0138] Unless otherwise specified, all reactions in this application are carried out under the protection of a dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperature is [degrees Celsius].

[0139] Those skilled in the art of organic synthesis will understand that optimal reaction conditions can vary depending on the specific reactants or solvents used, but these conditions can be determined through conventional optimization procedures. In some cases, the order of the reaction scheme and / or reaction steps can be altered to promote the reaction or avoid the formation of unwanted byproducts. Furthermore, functional groups present at various positions in the molecule must be compatible with the proposed reagents and reactions. This limitation on substituents compatible with the reaction conditions will be apparent to those skilled in the art, and alternative methods must then be employed. Additionally, in some of the reactions mentioned herein, it may be necessary or desirable to protect any sensitive groups in the compound, and it is assumed that such protecting groups (PGs) are in the appropriate positions if necessary. Conventional protecting groups can be used according to standard practices well known in the art (for details, see Greene TW, Wuts PGM, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons, 2014). Protecting groups can be removed at any convenient stage of the synthesis using conventional techniques well known in the art, or they can be removed in subsequent reaction steps or post-treatments.

[0140] The following abbreviations are used throughout this application. LCMS: Liquid chromatography-mass spectrometry M, mol / L: moles per liter ml, mL: milliliters g: grams mmol: millimole ℃: degrees Celsius TCFH: Tetramethylchlorourea hexafluorophosphate The following embodiments are provided to aid in understanding this application. However, it should be understood that these embodiments are for illustrative purposes only and do not constitute any limitation. The actual scope of protection of this application is set forth in the claims. It should be understood that any modifications and changes can be made without departing from the spirit of this application.

[0141] Example 1: Synthesis of Compound 1 (7 R 9 R )- N -[2-chloro-4-(trifluoromethyl)phenyl]-6-[(3 R )-4-({6-[3-(2-cyanopropyl-2-yl)azacyclobut-1-yl]-5-hydroxypyrimidin-4-yl}carbonyl)-3-methylpiperazin-1-yl]-2-(3,6-dihydro-2 H -pyran-4-yl)-7-methyl-5-oxoylide-8,9-dihydro-7 H-[1,2,4]triazacyclopentanone[1,5- a ]pyrrolo[1,2- c Pyrimidine-9-carboxamide (1) Preparation of compound 1b in step one Compound 1a (30 mg, 0.102 mmol) and N,N-diisopropylethylamine (72 μL, 0.410 mmol) were dissolved in acetonitrile (1 mL). 2-(azacyclobutane-3-yl)-2-methylpropionitrile 2,2,2-trifluoroacetate (48.83 mg, 0.205 mmol) was slowly added, and the reaction was carried out at 80 °C for 0.5 h. After the reaction was complete, 10 mL of water was added to quench the reaction, and ethyl acetate was added for extraction (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent system (petroleum ether:ethyl acetate = 3:1) to give compound 1b (32 mg, yield: 82%). MS m / z(ESI): 381.3 [M+1] + .

[0142] Step 2: Preparation of compound 1c Compound 1b (32 mg, 0.084 mmol) was dissolved in tetrahydrofuran (0.5 mL) and methanol (0.5 mL), and 500 μL (1.000 mmol) of 2M sodium hydroxide aqueous solution was added. The reaction mixture was reacted at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure to approximately 0.3 mL, and the pH was adjusted to 5 by adding 2M hydrochloric acid aqueous solution. A white solid precipitated out, which was filtered and washed with water to give compound 1c (26 mg, yield: 88%).

[0143] MS m / z(ESI): 353.2 [M+1] + .

[0144] Step 3: Preparation of compound 1d Compound 1c (23.35 mg, 0.066 mmol), EDCI (16.94 mg, 0.088 mmol), and HOBt (11.94 mg, 0.088 mmol) were dissolved in dimethylformamide (1 mL). A solution of compound Int_A (26 mg, 0.044 mmol) and N,N-diisopropylethylamine (38 μL, 0.221 mmol) in dimethylformamide (1 mL) was added, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, 3 mL of water was added to quench the reaction, followed by extraction with ethyl acetate (6 mL). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure to give compound 1d (31 mg, yield: 75%).

[0145] MS m / z(ESI): 926.3 [M+1].

[0146] Step 4: Preparation of Compound 1 Compound 1d (31 mg, 0.033 mmol) was dissolved in trifluoroacetic acid (1500 μL), and the reaction solution was stirred overnight at 60 °C. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Gilson 306, column: Waters-Xbridge-C18-10µm-19*250mm; mobile phase: water (containing 10mM NH4HCO3) and acetonitrile, gradient ratio: acetonitrile 30%-60%, flow rate: 25mL / min) to obtain compound 1 (1.8 mg, yield: 6.60%).

[0147] MS m / z (ESI): 834.3 [M-1] - .

[0148] Example 2: Synthesis of compounds 2-A and 2-B (compounds 2-A and 2-B are isomers, and the carbon atoms in * are in a single configuration) (7R or S,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5-hydroxy-6-(3-(1-hydroxycyclopropyl)-3-methylazacyclobutane-1-yl)pyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]octane-2-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-9-carboxamide(2-A) (7S or R,9R)-N-(2-chloro-4-(trifluoromethyl)phenyl)-2-(3,6-dihydro-2H-pyran-4-yl)-6-((1S,6S)-5-(5-hydroxy-6-(3-(1-hydroxycyclopropyl)-3-methylazacyclobutane-1-yl)pyrimidin-4-carbonyl)-2,5-diazabicyclo[4.2.0]octane-2-yl)-7-methyl-5-oxo-5,7,8,9-tetrahydropyrrolo[1,2-c][1,2,4]triazolo[1,5-a]pyrimidin-9-carboxamide(2-B) Preparation of compounds 2-A and 2-B in the first step Compound Int_B (80 mg, 0.119 mmol) and compound 2a (100 mg, 0.188 mmol) were dissolved in acetonitrile (2 mL), and N-methylimidazole (472.955 μL, 5.933 mmol) and TCFH (99.88 mg, 0.356 mmol) were added. The mixture was reacted overnight at room temperature. After the reaction was completed, 3 mL of water was added to quench the reaction, and ethyl acetate was added for extraction (5 mL). The organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was analyzed by high performance liquid chromatography (LAIPU_LP3050_UV2000, column: Waters-SunFire-C18-10µm-19*250mm; mobile phase: water (containing 10 mM... The compounds 2-A (7.76 mg, yield: 7.08%) and 2-B (23.00 mg, yield: 20.67%) were purified by NH4HCO3 and acetonitrile in a gradient ratio of 30%-60% acetonitrile at a flow rate of 25 mL / min.

[0149] Compound 2-A: MS m / z (ESI): 851.3 [M+1] + .

[0150] 11H NMR (400 MHz, DMSO-d6): δ 10.50 (br s, 1H), 8.03 (s, 1H), 8.00 - 7.92 (m, 2H), 7.75 (br d, J = 8.8 Hz, 1H), 6.78 (br s, 1H), 5.62 (br dd, J = 5.1, 7.9 Hz, 1H), 5.35 (br s, 1H), 4.24 (br s, 2H), 3.99 (br s, 2H), 3.80 (br s, 4H), 3.68 (br d, J = 7.5 Hz, 1H), 2.66 - 2.52 (m, 5H), 2.47 - 2.36 (m, 2H), 1.56 (br d, J = 6.5 Hz, 3H), 1.32 (s, 3H), 1.27 - 1.24 (m, 4H), 0.82 (br s, 3H), 0.60 (br s, 4H) 19 19F NMR (376 MHz, DMSO-d6 ): δ -60.84 (s, 1F) Compound 2-B: MS m / z (ESI): 851.3 [M+1] + .

[0151] 1H NMR(400 MHz, DMSO-d6): δ 10.65 - 10.39 (m, 1H), 8.03 (s, 1H), 7.98(s, 1H), 7.94 (br d, J = 8.8 Hz, 1H), 7.75 (br d, J = 8.0 Hz, 1H), 6.80 (brs, 1H), 5.55 (br d, J = 9.0 Hz, 1H), 5.39 - 5.31 (m, 1H), 4.30 - 4.22 (m,2H), 4.05 - 3.95 (m, 2H), 3.83 - 3.73 (m, 5H), 3.59 - 3.41 (m, 5H), 3.08 -2.97 (m, 1H), 2.57 - 2.53 (m, 2H), 2.11 (br d, J = 13.8 Hz, 1H), 1.75 - 1.50(m, 4H), 1.43 (br d, J = 7.0 Hz, 3H), 1.32 (s, 3H), 0.77 - 0.72 (m, 1H), 0.65- 0.56 (m, 4H) 19 F NMR (376 MHz, DMSO-d6): δ -60.87 (s, 1F) Example 3: Synthesis of compounds 3-A and 3-B (compounds 3-A and 3-B are isomers, and the carbon atoms in * are in a single configuration) ( 7R or S 9 R )- N -[2-chloro-4-(trifluoromethyl)phenyl]-2-(3,6-dihydro-2- H -pyran-4-yl)-6-[(4a S ,6a S )-4-({5-hydroxy-6-[(1 R ,3 S )-3-(hydroxycyclopropyl)-3-methylcyclobutyl]pyrimidin-4-yl}carbonyl)octahydrocyclobutano[1,2- b ]pyrazin-1-yl]-7-methyl-5-oxoyl-8,9-dihydro-7 H -[1,2,4]triazacyclopentanone[1,5- a ]pyrrolo[1,2- c Pyrimidine-9-carboxamide (3-A) ( 7R or S 9 R)- N -[2-chloro-4-(trifluoromethyl)phenyl]-2-(3,6-dihydro-2- H -pyran-4-yl)-6-[(4a S ,6a S )-4-({5-hydroxy-6-[(1 R ,3 S )-3-(hydroxycyclopropyl)-3-methylcyclobutyl]pyrimidin-4-yl}carbonyl)octahydrocyclobutano[1,2- b ]pyrazin-1-yl]-7-methyl-5-oxoyl-8,9-dihydro-7 H -[1,2,4]triazacyclopentanone[1,5- a ]pyrrolo[1,2- c Pyrimidine-9-carboxamide (3-B) Preparation of compound 3b in step one Compound 3a (1226 mg, 5.921 mmol) was dissolved in tetrahydrofuran (30 mL), and tetraisopropyl titanate (2.454 mL, 8.289 mmol) and ethyl magnesium bromide (20.722 mL, 20.722 mmol) were slowly added dropwise at -10 °C. The reaction was allowed to proceed to room temperature for 18 hours. After the reaction was complete, water (30 mL) was added, and the solid was removed by filtration. The filtrate was extracted with ethyl acetate (30 mL), the organic phase was washed with water (20 mL × 2), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B (petroleum ether: ethyl acetate = 5:1) to give compound 3b (884 mg, yield: 72.80%).

[0152] Step 2: Preparation of compound 3d The reactor was purged with nitrogen, and compound 3c (300 mg, 1.025 mmol), compound 3b (210.19 mg, 1.025 mmol), tris(trimethylsilyl)silane (254.84 mg, 1.025 mmol), [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel dichloride (407.90 mg, 1.025 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl-KN)phenylKC]IRID (CAS: 870987-63-6, 1149.81 mg, 1.025 mmol), sodium carbonate (108.63 mg, 1.025 mmol), and ethylene glycol dimethyl ether (16 mL) were added. The reaction mixture was irradiated overnight with a blue LED lamp. The reaction solution was purified by column chromatography (washing with petroleum ether: ethyl acetate). 3d (237 mg, yield 51.65%) and 3e (160 mg, yield 34.57%) were given.

[0153] MS m / z(ESI): 383.1 [M+1]+.

[0154] The third step involves the preparation of compound 3f. Compound 3d (53 mg, 0.118 mmol) was added to methanol (0.2 mL) and tetrahydrofuran (0.2 mL). A 2N aqueous solution of sodium hydroxide (200 μL, 0.400 mmol) was then added, and the mixture was stirred at 25 °C for 10 min. The tetrahydrofuran and methanol were removed by concentration under reduced pressure. The resulting aqueous phase was then adjusted to pH 5 with 2N hydrochloric acid, and the mixture was filtered to obtain compound 3f.

[0155] MS m / z(ESI): 355.1 [M+1]+.

[0156] Step 4: Preparation of 3g of compound Compound 3f (40 mg, 0.073 mmol) and 10% palladium on carbon (20 mg, 0.189 mmol) were added to tetrahydrofuran (5 mL), and the mixture was stirred at 25 °C under a hydrogen atmosphere for 4 hours. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with tetrahydrofuran (2 mL × 3). The filtrates were combined and concentrated to give 3 g (23 mg) of compound.

[0157] MS m / z(ESI): 265.1 [M+1]+.

[0158] Step 5: Preparation of compounds 3-A and 3-B Compound Int_B (100 mg, 0.166 mmol) and 3 g of compound (50 mg, 0.568 mmol) were dissolved in acetonitrile (2 mL). N-methylimidazole (472.955 μL, 5.933 mmol) and TCFH (99.88 mg, 0.356 mmol) were added, and the mixture was reacted overnight at room temperature. After the reaction was completed, 3 mL of water was added to quench the reaction, and ethyl acetate was added for extraction (5 mL). The organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was analyzed by high performance liquid chromatography (LAIPU_LP3050_UV2000, column: Waters-SunFire-C18-10µm-19*250mm; mobile phase: water (containing 10 mM... The compounds 3-A (7.67 mg) and 3-B (13.61 mg) were purified by using NH4HCO3 and acetonitrile in a gradient ratio of 30%-60% acetonitrile at a flow rate of 25 mL / min. Compound 3-A: MS m / z (ESI): 850.3 [M+1] + .

[0159] Compound 3-B: MS m / z (ESI): 850.3 [M+1] + .

[0160] Biological tests: Experimental Example 1: WRN Helicase Activity Assay Assay buffer working solution was prepared using RNase-free water: 25 mM Tris (pH 7.5), 2 mM MgCl2, 50 mM NaCl, 0.02% BSA, 0.01% Tween, and 1 mM DTT. WRN protein (AAN517-P1238, ICE, Cat. S2212T-H56HZ) was obtained through in vitro protein expression and purification. Two single-stranded DNA molecules were synthesized: TTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCGTACCCGATGTGTTCGTTC-BHQ2 (quencher group) and (fluorescent group) TAMRA-GAACGAACACATCGGGTACGTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT. The single strands were annealed to obtain dsDNA (FORKF). Upon binding of WRN to FORKF, the dsDNA unwinds, exposing the fluorescent group and producing fluorescence. Take 2 μL of different concentrations of the compound and 4 μL of WRN protein, add them to a 384-well black plate (Greiner, Cat#784075), and pre-incubate at room temperature for 20 minutes. Add 2 μL each of ATP and FORKF substrate to make the working concentrations of WRN protein, FORKF, and ATP 10 nM, 10 nM, and 2 mM, respectively. Incubate at room temperature for 20 minutes. After incubation, detect the Ex540 / Em590nm fluorescence value using a BMG microplate reader (PHERAstarFSX).

[0161] The inhibition rate is calculated according to Equation 1, where RLU sample RLU is the compound well read value. max For DMSO reference well readings, RLU min The readings were from control wells without WRN protein. Using GraphPad Prism software, a four-parameter curve was fitted to calculate the IC50 concentration of the compound at a 50% inhibition rate. 50 value.

[0162] Inhibition% = (1-(RLUsampl-RLU) min ) / (RLUmax-RLU min )×100% (Formula 1) The results of the test compounds' inhibitory activity against WRN helicase ATPase activity are shown in Table 1. Table 1

[0163] The structural formulas of the control compounds HRO761, Ref-1, and Ref-2 are as follows: Experimental Example 2: CellTiter-Glo® Chemiluminescence Assay for the Effect of WRN Inhibitors on SW48 and DLD1 Cell Viability 1. Materials and Instruments 96-well black transparent bottom cell plate (Corning, #3603); CellTiter-Glo® assay kit (Promega, G7570); SpectraMax® iD3 microplate reader (Molecular Devices); TC20 cell counter (BIO-RAD).

[0164] SW48 cells were derived from ATCC, catalog number CCL-231; DLD1 cells were derived from ATCC, catalog number CCL-221.

[0165] 2. Cell Culture 2.1 SW48 cells were cultured in 89% RPMI-1640 + 10% FBS + 1% penicillin antibiotics and incubated in a 37 ℃ constant temperature incubator with 5% CO2. HCT116 and DLD1 cells were cultured using the same method.

[0166] 2.2 Cell passage Once the cell density reaches 80%, passage the cells. Discard the old culture medium, wash the adherent cells with PBS, discard the PBS, add 1 mL of trypsin, digest in an incubator for 3 min, add 3 mL of 1640 complete culture medium to stop digestion, gently agitate the bottom of the culture dish, collect the cell suspension in a 15 mL centrifuge tube, centrifuge at 1000 rpm for 3 min, resuspend the cell pellet with an appropriate amount of culture medium, and expand the culture at a ratio of 1:4. 2.3 After two generations of stable cell culture, experimental studies can be conducted. 3. Cell seeding 3.1 When the confluence of SW48 and DLD1 cells reached 80%, the cells were passaged according to the procedure in 2.2. 3.2. Cell Count Resuspend the cell pellet in 5 mL of 1640 complete culture medium, and take 10 μL of the cell suspension and drop it onto a cell counting chamber for counting.

[0167] 3.3. Add 200 μL of PBS solution to the wells around the perimeter of a 96-well black transparent bottom cell plate. Seed cells in each of the remaining 60 wells (1500 cells per well for HCT116, 2000 cells per well for SW48, and 1500 cells per well for DLD1), with a culture volume of 100 μL per well. Incubate overnight in an incubator. 4. Cell-based drug delivery 4.1. Prepare a stock solution of 60 mg / mL of the drug with DMSO according to its purity and quality, dilute it with DMSO to prepare a working solution of 30 mM, and store it at -20℃ for a short time for later use. 4.2. Take out the working solution of the candidate compound and melt it with DMSO, and vortex mix. 4.3. The highest dosing concentration for each candidate compound was 30 μM. The compounds were then 3-fold diluted to nine different concentrations: Dilution tubes were placed in a tube rack. 600 μL of 1640 complete medium was added to the first well, and 400 μL of medium was added to the remaining nine wells. 1.2 μL of 30 mM stock was added to the 600 μL of 1640 complete medium. After mixing with a pipette, 200 μL was transferred to the next dilution tube and mixed. The remaining eight dilution tubes were then 3-fold diluted. 0.8 μL of DMSO was added to the 400 μL of medium in the last dilution tube and mixed.

[0168] 4.4. Take out the 96-well plate inoculated with cells the day before, label each well with the drug number and corresponding drug concentration, and use a multi-channel pipette to take 100 μL of the drug concentration from the dilution tube and add it to the 96-well plate. Add other drugs in the same way.

[0169] 4.5. Gently shake the well plate to mix the drug thoroughly, record the time, and incubate in a cell culture incubator for 96 h. 5. CTG detection 5.1 Collecting CTG Data After the cells were treated with the drug for 96 h, the old culture medium was discarded. Following the instructions of the CellTiter-Glo® kit, 100 μL of premixed detection solution was added to each well and incubated at room temperature for 10 min. The detection program of CellTiter-Glo was selected on the microplate reader, and the luminescence value was read.

[0170] 5.2 Data Processing Cell viability value = 100 * (luminescence value of drug-treated wells - luminescence value of blank wells) / (luminescence value of solvent-treated wells - luminescence value of blank wells); IC50 calculation: The cell viability value and the corresponding drug concentration value are calculated using the (log(inhibitor) vs. normalized response -- Variable slope) algorithm in Curvefit of Prism 8 software.

[0171] The selectivity results are shown in Table 2 below, with the SW48 IC50 of the compounds being... 50 Value level: A: IC 50 ≤50nM; B: 50nM <IC 50 ≤500nM; C:IC 50 >500 nM; DLD1 IC50 of the compound 50 Value level: A: IC 50 ≤1μM; B: 1 μM <IC 50 ≤10 μM; C:IC 50 >10 μM.

[0172] Table 2

[0173] Experimental results show that the compound of this application can effectively inhibit the proliferation of target-sensitive tumor cells SW48, while it has no inhibitory effect on the proliferation of target-insensitive tumor cells DLD1. It can be seen that the compound of this application has good target selectivity.

[0174] Test Example 3. In vivo PK test 1. Laboratory animals Six female ICR mice were divided into two groups: one receiving oral administration and the other receiving intravenous administration, with three mice in each group. The mice were fasted for 10-14 hours before administration, but had free access to water.

[0175] 2. Preparation of drug formulations Weigh the test compound according to the dosage, and prepare an appropriate concentration of the drug preparation with a solvent (commonly 5% DMSO + 10% Solutol + 85% physiological saline) (for mice, administer intravenous and oral doses at volumes of 5 mL / kg and 10 mL / kg, respectively). For intravenous injection, use a clear solution; for oral administration, use a clear solution or a homogeneous suspension.

[0176] 3. Animal drug administration and blood sample collection Animals were administered the drug via intravenous injection and oral gavage. Blood samples were collected at 0.033h, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h after intravenous injection, and at the same time after oral administration. Whole blood was centrifuged at 6800g for 6 min at 4°C, and the supernatant plasma was collected and stored at -80°C for analysis.

[0177] 4. Plasma sample testing Dilute the analyte DMSO stock solution with methanol or acetonitrile to prepare a series of working solutions, add them to blank plasma matrix, and prepare standard curves and quality control samples. Take an appropriate volume of plasma sample and add an appropriate amount of methanol or acetonitrile containing internal standard according to the response to precipitate proteins. Centrifuge all samples at 18000 g for 10 min at 4℃, and take an appropriate amount of supernatant for LC-MS / MS analysis.

[0178] 5. Parameter Calculation Based on the tested concentration, a blood drug concentration-time curve was plotted. Using WinNonlin software and a non-compartmental model, the curve was calculated, including the area under the curve (AUC). 0-t ), maximum blood concentration (C max ), half-life (T) 1 / 2 Pharmacokinetic parameters such as pharmacokinetic parameters were obtained. Results are shown in Table 3.

[0179] Table 3

[0180] Experimental results show that the compounds of this application have excellent pharmacokinetic properties, and at the same oral gavage dose, the exposure is better than that of the control compounds HRO761, Ref-1, and Ref-2.

[0181] The technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made in accordance with the technical solutions of the present invention fall within the protection scope of the present invention.

Claims

1. A compound having the structure shown in Formula I, or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug thereof, in, A is selected from R, which may or may not contain substituents. S1 C1-C10 alkyl, with or without substituents R S1 3-12 membered heterocyclic groups, with or without substituents R S1 C3-C20 cycloalkyl groups R' and R" are each independently selected from R with or without substituents. S2 C1-C10 alkyl, with or without substituents R S2 C3-C20 cycloalkyl groups; L is selected from bonds, with or without substituents. R S1 C1-C10 alkylene groups, with or without substituents R S1 C3-C20 cycloalkylene compounds, with or without substituents R S1 3-12 membered subheterocyclic groups; R2 and R3 are each independently selected from hydrogen, deuterium, and R with or without substituents. S1 C1-C6 alkyl C(=O)-, with or without substituents R S1 C1-C6 alkyl-OC(=O)-, with or without substituents R S1 C1-C10 alkyl, with or without substituents R S1 C3-C20 cycloalkyl, with or without substituents R S1 3-12 membered heterocyclic groups, with or without substituents R S1 6-10 aryl groups with or without substituents R S1 3-10 aryl compounds; R4 and R5 are each independently selected from R4 with or without substituents. S1 C6-C10 aryl, with or without substituents R S1 5-10 aryl heteroaryl groups, with or without substituents R S1 3-12 membered heterocyclic groups; R a Selected from deuterium, halogen, oxo, hydroxyl, cyano, carboxyl, SF5, amino, C1-C6 alkyl-substituted amino, with or without substituents R S2 C1-C6 alkyl, with or without substituents R S2 C1-C6 alkoxy groups, with or without substituents R S2 C2-C6 alkenyl, with or without substituents R S2 C2-C6 alkynyl, with or without substituents R S2 C3-C6 cycloalkyl, with or without substituents R S2 3-6 membered oxygen heterocyclic group, with or without substituent R S2 -S(=O)2-C1-C6 alkyl or with or without substituents R S2 -C1-C6 alkylene-S(=O)2-C1-C6 alkyl; a is an integer selected from 0 to 8. When a ≥ 2, two adjacent R a The carbon atoms that can be attached to them can form R with or without substituents. S1 3-12 membered carbon rings or heterocycles; X, Y, and Z satisfy the following conditions (1), (2), or (3): Condition (1) X is CH or N, and Y is selected from hydrogen, deuterium, and R with or without substituents. S2 C1-C10 alkyl, with or without substituents R S1 C3-C6 cycloalkyl, with or without substituents R S1 The C3-C10 heterocyclic group, Z is selected from hydrogen, with or without substituents R. S2 C1-C10 alkyl, with or without substituents R S1 C3-C6 cycloalkyl, with or without substituents R S1 3-10 membered heterocyclic groups; Condition (2) X is CH or N, and Y and Z and the atoms they are connected to form R with or without substituents. S1 5-10 membered carbon rings or heterocycles; Condition (3) X is C, and forms R with or without substituents with Y and the atoms they are connected to. S1 A 5-10 membered carbon ring or heterocycle, Z selected from hydrogen, deuterium, with or without substituents R. S2 C1-C10 alkyl, with or without substituents R S1 C3-C20 cycloalkyl, with or without substituents R S1 3-12 membered heterocyclic groups; The substituent R S1 Selected from deuterium, halogen, oxo, hydroxyl, cyano, carboxyl, SF5, amino, C1-C6 alkyl-substituted amino, with or without substituents R S2 C1-C6 alkyl, with or without substituents R S2 C1-C6 alkoxy groups, with or without substituents R S2 C2-C6 alkenyl, with or without substituents R S2 C2-C6 alkynyl, with or without substituents R S2 C3-C6 cycloalkyl, with or without substituents R S2 C3-C6 oxoheterocyclic group, with or without substituents R S2 C3-C6 thioheterocyclic group, with or without substituents R S2 -S(=O)2-C1-C6 alkyl, with or without substituents R S2 -C1-C6 alkylene-S(=O)2-C1-C6 alkyl, with or without substituents R S2 phenyl or ; or two Rs S1 Together with the carbon atoms attached to them, they form 3-6 membered oxygen heterocyclic groups or 3-6 membered sulfur heterocyclic groups. R b and R c Each is independently selected from hydrogen, deuterium, halogen, oxo, hydroxyl, cyano, C1-C4 alkyl, or fluorinated C1-C4 alkyl; R w Selected from hydrogen, deuterium, or C1-C6 alkyl groups; The substituent R S2 Selected from deuterium, halogen, oxo, hydroxyl, cyano, amino, carboxyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, SF5, with or without substituents R S2 phenyl.

2. The compound according to the preceding claims, wherein, The compound is shown in formula I-1 or I-2: In Equation I-1, A, L, R2, R3, R a a, Y, Z, R4, and R5 are the same as defined in claim 1; Preferably, R2 is hydrogen, deuterium, or C1-C6 alkyl; R3 is hydrogen, deuterium, C1-C6 alkyl, or C1-C6 alkoxy; preferably, R2 is hydrogen and R3 is hydrogen. Preferably, R a It is a C1-C6 alkyl group, preferably methyl; Preferably, a is 0, 1, 2 or 3; Preferably, a≥2, two adjacent R a The carbon atoms bonded to them together form R with or without substituents. S1 The 3-6 membered carbon rings preferably form with or without substituents R. S1 4-5 membered carbon rings; Preferably, Y and Z, along with the atoms they are connected to, form a substituent-containing or non-substituent-containing R. S1 5-6 member nitrogen-containing heterocycles; Preferably, the substituent R S1 Selected from deuterium and C1-C6 alkyl groups; In Equation I-2, R c Selected from deuterium or C1-C6 alkyl, preferably methyl, where c is 0, 1, 2, 3 or 4, and A, L, R2, R3, R a a, Z, R4, and R5 are the same as defined in claim 1; Preferably, R c Selected from C1-C3 alkyl groups, where c is 0 or 1; Preferably, R2 is hydrogen, deuterium, or C1-C6 alkyl; R3 is hydrogen, deuterium, C1-C6 alkyl, or C1-C6 alkoxy; preferably, R2 is hydrogen and R3 is hydrogen. Preferably, R a It is a C1-C6 alkyl group, preferably methyl or ethyl; Preferably, a is 0, 1, 2 or 3; Preferably, Z is hydrogen.

3. The compound according to any one of the preceding claims, wherein, The compounds are as shown in I-3 or I-4: In equations I-3 and I-4, R b Selected from deuterium or C1-C6 alkyl, preferably methyl, b is 0, 1, 2, 3 or 4, A, L, R2, R3, R a a, R4, and R5 are the same as defined in claim 1 or 2; Preferably, in formula I-3, a is 0 or 1, and R a It is methyl; Preferably, in formulas I-3 and I-4, b is 0 or 1, and R b It is a methyl group.

4. The compound according to any one of the preceding claims, wherein, The compound is represented by any of the following formulas: Where m is 0 or 1, n is 0 or 1, and the definitions of other symbols are the same as those in any of claims 1-3.

5. The compound according to any one of the preceding claims, wherein, R2 is selected from hydrogen or C1-C5 alkyl groups, preferably hydrogen; and / or R3 is selected from hydrogen or C1-C5 alkyl groups, preferably hydrogen; and / or R a Selected from C1-C5 alkyl groups, preferably methyl or ethyl; and / or R b Selected from C1-C5 alkyl groups, preferably methyl or ethyl; and / or R c It is selected from C1-C5 alkyl groups, preferably methyl or ethyl.

6. The compound according to any one of the preceding claims, wherein, R4 is selected from R4 with or without substituents. S1 The 6-7 member oxygen-containing heterocyclic alkenyl group, preferably, the substituent R S1 Selected from fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, isopropyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, isopropoxy, and trifluoromethoxy, with R4 being preferred. or ; and / or R5 is selected from R5 with or without substituents. S1 The phenyl group, preferably, wherein the substituent R S1 Selected from fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, isopropyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, isopropoxy, and trifluoromethoxy; R5 is preferably... ; and / or L is a bond or may or may not contain substituents. R is... S1 C1-C5 alkylene groups, with or without substituents R S1 C3-C10 cycloalkylene compounds, with or without substituents R S1 The 3-6 membered subheterocyclic group, preferably, the substituent R S1 Selected from fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, isopropyl, trifluoromethyl, methoxy, ethoxy, tert-butoxy, isopropoxy, and trifluoromethoxy.

7. The compound according to any one of the preceding claims, wherein, A is selected from R, which may or may not contain substituents. S1 C1-C6 alkyl, with or without substituents R S1 C3-C10 membered cycloalkyl, with or without substituents R S1 4-12 membered heterocyclic groups, with or without substituents R S1 of R' and R" are each independently selected from R with or without substituents. S2 C1-C5 alkyl groups; and / or R S1 Selected from deuterium, halogen, oxo, hydroxyl, cyano, carboxyl, oxo, SF5, amino, C1-C6 alkyl-substituted amino, with or without substituents R S2 C1-C6 alkyl, with or without substituents R S2 C1-C6 alkoxy groups, with or without substituents R S2 C2-C6 alkenyl, with or without substituents R S2 C2-C6 alkynyl, with or without substituents R S2 C3-C6 cycloalkyl, with or without substituents R S2 3-6 membered oxygen heterocyclic group, with or without substituent R S2 -S(=O)2-C1-C6 alkyl, with or without substituents R S2 -C1-C6 alkylene-S(=O)2-C1-C6 alkyl or Optional, both R S1 Together with the carbon atoms attached to them, they form a C2-C6 alkenyl group, a 3-6 oxoheterocyclic group, or a 3-6 thioheterocyclic group, wherein the C2-C6 alkenyl group or the 3-6 oxoheterocyclic group is optionally substituted with a substituent R. S2 Replace; and / or R S2 Selected from deuterium, halogen, oxo, hydroxyl, cyano, amino, carboxyl, C1-C6 alkoxy, SF5, CF3; Preferably, R S1 Selected from deuterium, halogen, oxo, hydroxyl, cyano, carboxyl, oxo, SF5, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, halo-C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, cyano-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C2-C6 alkenyl, halo-C2-C6 alkyl. 6-alkynyl, halogenated C3-C6 cycloalkyl, amino-substituted C3-C6 cycloalkyl, hydroxyl-substituted C3-C6 cycloalkyl, cyano-substituted C3-C6 cycloalkyl, C1-C6 alkoxy-substituted C3-C6 cycloalkyl, amino-substituted 3-6-membered oxetane, hydroxyl-substituted 3-6-membered oxetane, cyano-substituted 3-6-membered oxetane, -S(=O)2-C1-C6 alkyl, -C1-C6 alkylene-S(=O)2-C1-C6 alkyl or R W Selected from hydrogen, deuterium, or C1-C6 alkyl, preferably, R W Selected from hydrogen, deuterium, methyl or ethyl.

8. The compound according to any one of the preceding claims, wherein, A is selected from R, which may or may not contain substituents. S1 4-10 member monoheterocyclic groups, with or without substituents R S1 5-12 bridging biheterocyclic groups with or without substituents R S1 5-12 spirobiheterocyclic groups, Preferably, A is selected from R with or without substituents. S1 The following groups are included: 3-6 membered cycloalkyl, 4-membered mono-heterocyclic, 5-membered mono-heterocyclic, 6-membered mono-heterocyclic, bridged[2.1.1]bi-heterocyclic, bridged[2.2.1]bi-heterocyclic, bridged[2.2.2]bi-heterocyclic, bridged[3.1.1]bi-heterocyclic, bridged[3.2.1]bi-heterocyclic, bridged[3.2.2]bi-heterocyclic, bridged[3.3.1]bi-heterocyclic, bridged[3.3.2]bi-heterocyclic, bridged[3.3.3]bi-heterocyclic, bridged[4.1.1]bi-heterocyclic, bridged[4.2.1]bi-heterocyclic Ring, bridge [4.2.2] double heterocyclic ring, bridge [4.3.1] double heterocyclic ring, bridge [4.3.2] double heterocyclic ring, bridge [4.4.1] double heterocyclic ring, bridge [4.4.2] double heterocyclic ring, screw [3.2] double heterocyclic ring, screw [3.3] double heterocyclic ring, screw [3.4] double heterocyclic ring, screw [3.5] double heterocyclic ring, screw [4.4] double heterocyclic ring, screw [4.5] double heterocyclic ring, screw [5.5] double heterocyclic ring, screw [6.3] double heterocyclic ring, screw [6.4] double heterocyclic ring or screw [6.5] double heterocyclic ring; Preferably, the heteroatom in the heterocycle is selected from oxygen, sulfur, or nitrogen; Preferably, A is selected from R with or without substituents. S1 The following groups, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Preferably, A is a substituent R. S1 of , or ; Preferably, A is , , , or ; Preferably, R S1 Selected from: halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, and C3-C6 cycloalkyl optionally substituted with a substituent selected from halogen, cyano, hydroxy, amino, C1-C4 alkyl, and C1-C4 alkoxy.

9. The compound according to any one of the preceding claims, wherein, R S1 The radical is independently selected from deuterium, halogen, oxo, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, fluoroC1-C4 alkyl, C1-C4 hydroxy-substituted alkyl, C1-C4 cyano-substituted alkyl, C1-C4 alkoxy-substituted C1-C4 alkyl, fluoroC1-C4 alkoxy, fluoroC2-C4 alkenyl, fluoroC2-C4 alkynyl, C3-C6 cycloalkyl, and 3-6 member alkyl groups. Oxycyclic groups, hydroxyl-substituted C3-C6 cycloalkyl groups, amino-substituted C3-C6 cycloalkyl groups, cyano-substituted C3-C6 cycloalkyl groups, C1-C4 alkoxy-substituted C3-C6 cycloalkyl groups, hydroxyl-substituted 3-6 membered oxycyclic groups, amino-substituted 3-6 membered oxycyclic groups, cyano-substituted 3-6 membered oxycyclic groups, -S(=O)2-C1-C4 alkyl groups, -C1-C4 alkylene groups -S(=O)2-C1-C4 alkyl groups, Or two Rs s1 Together they form oxetine propyl, oxetine butyl, oxetine pentyl, R b and R c Each is independently selected from hydrogen, deuterium, halogen, oxo, hydroxyl, cyano, C1-C4 alkyl or fluorinated C1-C4 alkyl, preferably selected from hydrogen, fluorine, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl or trifluoroethyl, R W Selected from hydrogen, deuterium, or C1-C4 alkyl groups. Indicates the connection point with the loop; Preferably, R S1 Each is independently selected from deuterium, fluorine, hydroxyl, cyano, methyl, ethyl, methoxy, ethoxy, vinyl, propenyl, ethynyl, propynyl, monofluoromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, methoxy-substituted methyl, methoxy-substituted ethyl, methoxy-substituted propyl, ethoxy-substituted methyl, ethoxy-substituted ethyl, ethoxy-substituted propyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy, trifluoroethoxy, monofluorovinyl, difluorovinyl, trifluorovinyl, -S(=O)2-methyl, -S(=O)2-ethyl, -methylene-S(=O)2-methyl, -methylene-S(=O)2-ethyl. , , , , , , , Cyclopropyl, cyclobutyl, amino-substituted cyclopropyl, amino-substituted cyclobutyl, hydroxy-substituted cyclopropyl, cyano-substituted cyclopropyl, hydroxy-substituted cyclobutyl, methoxy-substituted cyclopropyl, methoxy-substituted cyclobutyl, ethoxy-substituted cyclopropyl, ethoxy-substituted cyclobutyl, propoxy-substituted cyclopropyl, propoxy-substituted cyclobutyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, hydroxy-substituted oxacyclopropyl, hydroxy-substituted oxacyclobutyl, hydroxy-substituted oxacyclopentyl, cyano-substituted oxacyclopropyl, cyano-substituted oxacyclobutyl, or cyano-substituted oxacyclopentyl.

10. The compound of claim 1, wherein, AL- or A is selected from the following groups: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 11. The compound according to any one of claims 1-10, wherein, The compounds are shown as those of formula II, II-1, III, or III-1: In formulas II, II-1, III, or III-1, R S1 R4 is as defined in any of the preceding claims; Preferably, R4 is selected from 6-7 member oxygen-containing heterocyclic alkenyl groups, and more preferably... or ; The definition of R1 and R S1 Or R S2 The same, preferably selected from cyano, hydroxyl, amino, and methoxy groups; Preferably, R S1 Selected from deuterium or C1-C5 alkyl, preferably methyl.

12. The compound according to any one of claims 1-11, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites, or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds, or prodrugs, wherein, The compound is selected from the following compounds: 。 13. A pharmaceutical composition comprising a compound as claimed in any one of claims 1-12 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug or at least one pharmaceutically acceptable carrier.

14. The compound of any one of claims 1-12 or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrides, metabolites or pharmaceutically acceptable salts, esters, solvates, hydrates, isotopically labeled compounds or prodrugs, or the composition of claim 13, which treats a disease or condition by inhibiting WRN activity.

15. Use of the compound of any one of claims 1-12 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug or composition of claim 13 in the preparation of a medicament, said medicament treating a disease or condition by inhibiting WRN activity.

16. A method of treating a disease or condition by inhibiting WRN activity, comprising administering to a person in need a therapeutically effective amount of the compound of any one of claims 1-8 or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitride, metabolite or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug or composition of claim 13.

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