Compounds targeting smarca protein degradation and uses thereof

Abstract

The application provides a compound targeting SMARCA protein degradation and an application thereof, and belongs to the field of chemical medicines.The compound targeting SMARCA protein degradation has the structure shown in the following formula I.The compound targeting SMARCA protein degradation of the application can effectively inhibit the proliferation of acute myeloid leukemia cells, and simultaneously induce the degradation of SMRACA2 / 4 proteins.The compound provided by the application has a wide application prospect in the preparation of SMARCA2 / 4 degradation agents and antitumor drugs.Formula I.

Description

Technical Field

[0001] This invention relates to the field of chemical and pharmaceutical technology, and in particular to a compound that targets the degradation of SMARCA protein and its application. Specifically, it relates to a compound that targets the degradation of SMARCA2 / 4 protein, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or an active metabolite thereof, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an isotope substitute thereof and its application. Background Technology

[0002] Switch-defective (SDE) / sucrose-nonfermentable (SNF) proteins are a class of highly conserved ATP-dependent chromatin remodeling factors. They utilize energy from ATP hydrolysis to maintain chromatin in an open state, mediating the sliding or dissociation of nucleosomes associated with active transcription, thereby regulating the expression of downstream signals. SMARCA2 and SMARCA4 are two homologous mutually exclusive catalytic subunits of the SWI / SNF complex. They share high protein sequence homology and both contain an ATPase domain and a bromine domain. SMARCA4 is frequently mutated in solid tumors, such as non-small cell lung cancer, colon cancer, and melanoma, and the survival of SMARCA4-deficient cancer cells is highly dependent on its paralog, SMARCA2. In hematologic malignancies, SMARCA4 acts as a major catalytic subunit involved in the sustained activation of oncogene expression.

[0003] Small molecule inhibitors developed targeting different binding sites of SMARCA2 / 4 have limitations. For example, ATPase inhibitors compete with endogenous ATP, and the high homology between SMARCA2 and SMARCA4 limits the therapeutic window. Bromodomain inhibitors cannot exert their anticancer effect because the bromodomain function is not involved in tumor development.

[0004] Protein degradation-targeting chimeras (PROTACs) are an emerging strategy for inducing the degradation of target proteins. PROTACs are a class of heterobifunctional molecules that induce the degradation of target proteins, composed of three chemical fragments: a target protein ligand, an E3 ubiquitin ligase ligand, and a linker. These compounds can bind to the target protein and the E3 ubiquitin ligase to form a ternary complex, which is then recognized and degraded by the ubiquitin-proteasome system.

[0005] In view of this, the present invention is hereby proposed. Summary of the Invention

[0006] The purpose of this invention is to provide a compound that targets the degradation of SMARCA protein and its application. The compound described in this invention can effectively inhibit the proliferation of acute myeloid leukemia cells while inducing the degradation of SMARCA2 / 4 proteins.

[0007] In order to achieve the above-mentioned objectives of the present invention, the following technical solution is adopted:

[0008] In a first aspect, the present invention provides a compound targeting the degradation of SMARCA protein, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or an active metabolite thereof, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an isotopic substitute thereof, wherein the compound targeting the degradation of SMARCA protein has the structure shown in Formula I:

[0009]

[0010] in,

[0011] R1 is selected from hydrogen or amino groups;

[0012] Ring A is selected from unsubstituted aryl groups or 5-6 membered unsaturated heterocyclic groups;

[0013] L is a linking group, selected from any one or a combination of at least two of the following groups:

[0014]

[0015] in, The connection position of the representative group, and the left side of the connecting group is connected to X; n is an integer selected from 1 to 5, R a Selected from oxygen or sulfur;

[0016] X is an E3 ligase ligand, selected from any one or a combination of two of the following groups:

[0017]

[0018] in, The positions of the groups are represented by R2 and R3, which are each independently selected from hydrogen or alkyl groups.

[0019] Preferably, the compound targeting SMARCA protein degradation has the structure shown in Formula II:

[0020]

[0021] in,

[0022] R1 is selected from hydrogen or amino groups;

[0023] L is a linking group, selected from any one or a combination of at least two of the following groups:

[0024]

[0025] in, The connection position of the representative group, and the left side of the connecting group is connected to X; n is an integer selected from 1 to 5, R a Selected from oxygen or sulfur;

[0026] X is an E3 ligase ligand, selected from any one or a combination of two of the following groups:

[0027]

[0028] in, The positions of the groups are represented by R2 and R3, which are each independently selected from hydrogen or alkyl groups.

[0029] Preferably, the compound targeting SMARCA protein degradation has the structure shown in Formula III:

[0030]

[0031] in,

[0032] R1 is selected from hydrogen or amino groups;

[0033] R2 and R3 are each independently selected from hydrogen or alkyl groups;

[0034] L is a linking group, selected from any one or a combination of at least two of the following groups:

[0035]

[0036] in, The connection position of the representative group, and the left side of the connecting group is connected to X; n is an integer selected from 1 to 5, R a Selected from oxygen or sulfur.

[0037] Preferably, the compound targeting SMARCA protein degradation has the structure shown in Formula IV-1:

[0038]

[0039] in,

[0040] R2 is selected from hydrogen or alkyl;

[0041] L is a linking group, selected from any one or a combination of at least two of the following groups:

[0042]

[0043] Preferably, the compound targeting SMARCA protein degradation has the structure shown in Formula IV-2:

[0044]

[0045] in,

[0046] R2 is selected from hydrogen or alkyl;

[0047] L is a linking group, selected from any one or a combination of at least two of the following groups:

[0048]

[0049] Preferably, the compound targeting SMARCA protein degradation is selected from any one of the following compounds A1 to A32:

[0050]

[0051]

[0052]

[0053]

[0054]

[0055] In a second aspect, the present invention provides a method for preparing a compound targeting the degradation of SMARCA protein as described in the first aspect, the preparation method comprising method one and method two:

[0056] Method 1 specifically includes the following steps:

[0057] (i) Compound 1 and compound 2 react in the presence of a palladium catalyst and a base to give intermediate 3, as shown in the following reaction formula:

[0058]

[0059] (ii) In the presence of a palladium catalyst and a base, intermediate 3 and compound 4 react to give intermediate 5, as shown in the following reaction formula:

[0060]

[0061] (iii) Intermediate 5 is first hydrolyzed in the presence of a base or acid; then it undergoes a condensation reaction with compound 6 in the presence of a condensing agent and a base to obtain the compound targeting SMARCA protein degradation, as shown in the following reaction formula:

[0062]

[0063] in,

[0064] Z is selected from C1 to C6 straight-chain or branched alkyl groups, including but not limited to methyl, ethyl, tert-butyl, etc.

[0065] Y is a linking group, selected from any one or a combination of at least two of the following groups:

[0066]

[0067] R1 is selected from hydrogen or amino groups;

[0068] R2 is selected from hydrogen or C1-C6 straight or branched alkyl groups.

[0069] Method 2 specifically includes the following steps:

[0070] (1) In the presence of iodine reagent and base, compound 6 and compound 7 react to give intermediate 8, as shown in the following reaction formula:

[0071]

[0072] (2) In the presence of a palladium catalyst and a base, intermediate 8 and compound 2 react to give intermediate 9, as shown in the following reaction formula:

[0073]

[0074] (3) In the presence of a palladium catalyst and a base, intermediate 9 and compound 4 react to obtain the compound targeting SMARCA protein degradation, as shown in the following reaction formula:

[0075]

[0076] in,

[0077] R1 is selected from hydrogen or amino groups;

[0078] R2 is selected from hydrogen or C1-C6 straight or branched alkyl groups.

[0079] Thirdly, the present invention provides the use of a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an active metabolite thereof, a stereoisomer thereof, a tautomer thereof, a geometric isomer thereof, or an isotopic substitute thereof, as described in the first aspect, in the preparation of a SMARCA2 / 4 degrading agent.

[0080] Fourthly, the present invention provides the use of a compound that targets the degradation of SMARCA protein as described in the first aspect, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or an active metabolite thereof, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an isotopic substitute thereof, in the preparation of a medicament for the prevention and / or treatment of tumors.

[0081] Preferably, the tumor includes any one of acute myeloid leukemia, non-small cell lung cancer, melanoma, prostate cancer, or colon cancer, and more preferably acute myeloid leukemia.

[0082] Fifthly, the present invention provides a drug for targeting the degradation of SMARCA2 / 4 protein, the drug comprising an active ingredient and pharmaceutically acceptable excipients;

[0083] The active ingredient comprises any one or a combination of at least two of the following: a compound that targets the degradation of SMARCA protein as described in the first aspect, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or an active metabolite thereof, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an isotopic substitute thereof.

[0084] [Terminology Explanation]

[0085] The various aspects and features of the present invention will be further described below.

[0086] The various terms and phrases used in this invention have their general meanings known to those skilled in the art. Nevertheless, this invention still aims to provide a more detailed explanation and interpretation of these terms and phrases. In the event of any inconsistency between the mentioned terms and their known meanings and those of the present invention, the meaning expressed in this invention shall prevail. Below are definitions of various terms used in this invention. These definitions apply to all terms used throughout this specification, unless otherwise specified in the specific context. The following provides definitions of various groups in the compounds of this invention, which, unless otherwise defined, are used consistently throughout the specification.

[0087] As mentioned in this invention, the term "amino" refers to a primary amino group consisting of one nitrogen atom and two hydrogen atoms, -NH2.

[0088] As mentioned in this invention, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon (e.g., having 2, 3, or 4 fused rings), such as phenyl, naphthyl, anthracene, phenanthryl, indene, and similar groups, particularly phenyl.

[0089] As mentioned in this invention, the term "5-6 member unsaturated heterocyclic group" refers to an aromatic heterocycle (containing 5-6 atoms) having at least one heteroatom ring member such as O, N or S, specifically groups such as furanyl, pyrroleyl, thiopheneyl, imidazolyl, pyridinyl, pyrimidinyl, thiazolyl, isothiazolyl, and similar groups.

[0090] As mentioned in this invention, the term "alkyl" refers to an alkyl group having a specified number of carbon atoms, which can be a straight-chain alkyl group or a branched alkyl group. For example, when "C1 to C6 straight-chain or branched alkyl group" is mentioned, it refers to a straight-chain alkyl group or a branched alkyl group having 1 to 20 carbon atoms. Specific groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc., and similar groups.

[0091] As mentioned in this invention, the term "cycloalkyl" refers to a cyclic alkyl group having a specified number of cyclic carbon atoms. For example, when "C3-C6 cycloalkyl" is mentioned, it refers to a cycloalkyl group having 3 to 6 carbon atoms. Specific groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and similar groups.

[0092] As mentioned in this invention, the term "azacycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing at least one nitrogen atom. For example, when "C3-C6 azacycloalkyl" is mentioned, it refers to an azacycloalkyl group having 3 to 6 carbon atoms, such as azacyclobutane and similar groups.

[0093] As mentioned in this invention, the term "halogen atom" refers to fluorine, chlorine, bromine, or iodine, particularly fluorine or chlorine.

[0094] As used herein, the term "compound" means, as is used herein, all stereoisomers, geometric isomers, tautomers, and isotopes.

[0095] The compounds of this invention can be asymmetric, for example, having one or more stereocenters. Unless otherwise specified, all stereoisomers can be enantiomers and diastereomers. Compounds of this invention containing asymmetrically substituted carbon atoms can be isolated into optically pure or racemic forms. The optically pure form can be prepared by resolving the racemic mixture or by using a chiral synthon or a chiral reagent.

[0096] The compounds of this invention may also include tautomer forms. New tautomer forms are generated by the exchange of single bonds and adjacent double bonds along with proton migration.

[0097] The compounds of this invention may also include all isotopic forms of atoms present in the intermediates or the final compound. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.

[0098] As mentioned in this invention, the term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with the receptor.

[0099] As used in this invention, the term "pharmaceutically acceptable salt" means that the salt is not only physiologically acceptable to the subject, but also refers to a synthetic substance with pharmaceutical value, such as a salt formed as an intermediate during chiral resolution, although such intermediate salts cannot be directly administered to the subject, but can play a role in obtaining the end product of this invention. The term "pharmaceutically acceptable salt" has two forms: one is a salt formed with an acid; the other is a salt formed with a base or alkali metal, including zwitterionic salts (internal salts), and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final separation and purification of the compound. They can also be obtained by mixing the compound with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may form a precipitate in solution and be collected by filtration, or be recovered after solvent evaporation, or be prepared by freeze-drying after reaction in an aqueous medium. Acids that form pharmaceutically acceptable salts with the compounds shown in Formula I include inorganic acids and organic acids. The salt may be a hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric acid, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate, or trifluoroacetate of the compound. Alkali metals that form pharmaceutically acceptable salts with the compound shown in Formula I include lithium, sodium, potassium, magnesium, calcium, aluminum, zinc, etc.; bases that form pharmaceutically acceptable salts with the compound shown in Formula I include choline, diethanolamine, morpholine, etc.

[0100] As mentioned in this invention, the term "prodrug" refers to derivatives of compounds of Formula I that are converted in vivo (e.g., hydrolyzed, reduced, or oxidized) into compounds of Formula I through in vivo metabolism. For example, compounds of Formula I containing hydroxyl groups can be reacted with acids to prepare the corresponding esters, which are prodrugs that can be used to hydrolyze the parent drug in vivo.

[0101] Compared with the prior art, the present invention has the following beneficial effects:

[0102] (1) The compound targeting SMARCA protein degradation described in this invention can effectively induce SMARCA2 (DC) degradation. 50 =6nM) and SMARCA4 (DC 50 The degradation of SMARCA protein (=8nM) is achieved; at the same time, the compound targeting the degradation of SMARCA protein provided by the present invention can also effectively inhibit the proliferation of tumor cells.

[0103] (2) The compounds targeting SMARCA protein degradation described in this invention have broad application prospects in the preparation of SMARCA2 / 4 degrading agents, anti-tumor drugs and drugs targeting protein degradation. Attached Figure Description

[0104] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0105] Figure 1 The graph shows the degradation ability of compound A11 on SMARCA2 / 4 protein at different treatment concentrations.

[0106] Figure 2 The graph shows the degradation ability of compound A11 on SMARCA2 / 4 protein at different treatment times.

[0107] Figure 3 This diagram illustrates the gene-level regulation of SMARCA2 / 4 protein degradation induced by compound A11.

[0108] Figure 4 This diagram illustrates the protein-level pathway of SMARCA2 / 4 protein degradation induced by compound A11.

[0109] Figure 5 The graph shows the ability of compound A11 to inhibit the proliferation of acute myeloid leukemia cells. Detailed Implementation

[0110] Unless otherwise defined herein, scientific and process terms used in conjunction with this invention should have the meanings commonly understood by one of ordinary skill in the art. The meaning and scope of terms should be clear; however, in any case of potential ambiguity, the definitions provided herein take precedence over any dictionary or foreign definitions. In this application, unless otherwise stated, the use of "or" means "and / or". Furthermore, the use of the term "comprising" and other forms is non-limiting.

[0111] It should be noted that specific details are set forth in the following description to provide a full understanding of the invention. However, the invention can be practiced in many ways other than those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0112] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0113] In a first aspect, the present invention provides a compound targeting the degradation of SMARCA protein, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or an active metabolite thereof, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an isotopic substitute thereof, wherein the compound targeting the degradation of SMARCA protein has the structure shown in Formula I:

[0114]

[0115] in,

[0116] R1 is selected from hydrogen or amino groups;

[0117] Ring A is selected from unsubstituted aryl groups or 5-6 membered unsaturated heterocyclic groups;

[0118] L is a linking group, selected from any one or a combination of at least two of the following groups:

[0119]

[0120] in, The connection position of the representative group, and the left side of the connecting group is connected to X; n is an integer selected from 1 to 5, R a Selected from oxygen or sulfur;

[0121] X is an E3 ligase ligand, selected from any one or a combination of two of the following groups:

[0122]

[0123] in, The positions of the groups are represented by R2 and R3, which are each independently selected from hydrogen or alkyl groups.

[0124] This invention provides a class of compounds targeting the degradation of SMARCA2 / 4 protein and their uses. The compounds provided by this invention can effectively inhibit the proliferation of acute myeloid leukemia (ICL). 50 The compounds (<50 nM) simultaneously induce the degradation of SMARCA2 and SMARCA4 proteins. The compounds provided by this invention have broad application prospects in the preparation of SMARCA2 / 4 degrading agents and antitumor drugs.

[0125] As an optional implementation, the R1 group is selected from hydrogen (-H) or amino (-NH2).

[0126] As an optional implementation, ring A is selected from unsubstituted aryl or 5-6 membered unsaturated heterocyclic groups, such as any one of phenyl, furanyl, pyrroleyl, thiopheneyl, imidazolyl, pyridyl, pyrimidinyl, thiazolyl, and isothiazolyl, preferably phenyl. Preferred

[0127] As an optional implementation, Ra is selected from any one of methyl, ethyl, isopropyl, cyclopropyl, aziridine, fluorine, or chlorine.

[0128] As an optional implementation, R2 is selected from hydrogen or a C1-C6 straight or branched alkyl group, such as any one of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

[0129] As an optional implementation, R3 is selected from hydrogen or a C1-C6 straight or branched alkyl group, such as any one of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

[0130] As an optional implementation, the compound targeting SMARCA protein degradation has the structure shown in Formula II:

[0131]

[0132] in,

[0133] R1 is selected from hydrogen or amino groups;

[0134] L is a linking group, selected from any one or a combination of at least two of the following groups:

[0135]

[0136] in, The connection position of the representative group, and the left side of the connecting group is connected to X; n is an integer selected from 1 to 5, R a Selected from oxygen or sulfur;

[0137] X is an E3 ligase ligand, selected from any one or a combination of two of the following groups:

[0138]

[0139] in, The positions of the groups are represented by R2 and R3, which are each independently selected from hydrogen or alkyl groups.

[0140] As an optional implementation, the compound targeting SMARCA protein degradation has the structure shown in Formula III:

[0141]

[0142] in,

[0143] R1 is selected from hydrogen or amino groups;

[0144] R2 and R3 are each independently selected from hydrogen or alkyl groups;

[0145] L is a linking group, selected from any one or a combination of at least two of the following groups:

[0146]

[0147] in, The connection position of the representative group, and the left side of the connecting group is connected to X; n is an integer selected from 1 to 5, R a Selected from oxygen or sulfur.

[0148] As an optional implementation, the compound targeting SMARCA protein degradation has the structure shown in Formula IV-1:

[0149]

[0150] in,

[0151] R2 is selected from hydrogen or alkyl;

[0152] L is a linking group, selected from any one or a combination of at least two of the following groups:

[0153]

[0154] As an optional implementation, the compound targeting SMARCA protein degradation has the structure shown in Formula IV-2:

[0155]

[0156] in,

[0157] R2 is selected from hydrogen or alkyl;

[0158] L is a linking group, selected from any one or a combination of at least two of the following groups:

[0159]

[0160] As an optional implementation, the compound targeting SMARCA protein degradation is selected from any one of the following compounds A1 to A32:

[0161]

[0162]

[0163]

[0164]

[0165]

[0166] In a second aspect, the present invention provides a method for preparing a compound targeting the degradation of SMARCA protein as described in the first aspect, the preparation method comprising the following steps:

[0167] The preparation methods include Method 1 and Method 2.

[0168] As an optional implementation method, Method 1 specifically includes the following steps:

[0169] (i) Compound 1 and compound 2 react in the presence of a palladium catalyst and a base to give intermediate 3, as shown in the following reaction formula:

[0170]

[0171] (ii) In the presence of a palladium catalyst and a base, intermediate 3 and compound 4 react to give intermediate 5, as shown in the following reaction formula:

[0172]

[0173] (iii) Intermediate 5 is first hydrolyzed in the presence of a base or acid; then it undergoes a condensation reaction with compound 6 in the presence of a condensing agent and a base to obtain the compound targeting SMARCA protein degradation, as shown in the following reaction formula:

[0174]

[0175] in,

[0176] Z is selected from C1 to C6 straight-chain or branched alkyl groups, including but not limited to methyl, ethyl, tert-butyl, etc.

[0177] Y is a linking group, selected from any one or a combination of at least two of the following groups:

[0178]

[0179] R1 is selected from hydrogen or amino groups;

[0180] R2 is selected from hydrogen or C1-C6 straight or branched alkyl groups.

[0181] As an optional implementation, in step (i), the palladium catalyst is Pd(dppf)Cl2.

[0182] As an optional implementation, in step (i), the alkali is sodium carbonate.

[0183] As an optional implementation, in step (i), the reaction is carried out in a mixed solvent of 1,4-dioxane and water.

[0184] As an optional implementation, in step (i), the volume ratio of 1,4-dioxane to water is (3-5):1.

[0185] As an optional implementation, in step (i), the reaction is carried out in the presence of a protective gas.

[0186] As an optional implementation, in step (i), the protective gas includes nitrogen.

[0187] As an optional implementation, in step (i), the reaction temperature is 95–105°C and the time is 3–5 h.

[0188] As an optional implementation, in step (ii), the palladium catalyst includes BrettPhos Pd G3 and Pd(PPh3)4.

[0189] As an optional implementation, in step (ii), the alkali is potassium carbonate.

[0190] As an optional implementation, in step (ii), the reaction is carried out in a mixed solvent of 1,4-dioxane and water.

[0191] As an optional implementation, in step (ii), the volume ratio of 1,4-dioxane to water is (3-5):1.

[0192] As an optional implementation, in step (ii), the reaction is carried out in the presence of a protective gas.

[0193] As an optional implementation, in step (ii), the protective gas includes nitrogen.

[0194] As an optional implementation, in step (ii), the reaction temperature is 85–95°C and the time is 2–4 hours.

[0195] As an optional implementation, in step (iii), the alkali used in the hydrolysis reaction is lithium hydroxide.

[0196] As an optional implementation, in step (iii), when alkaline hydrolysis is used, the reaction solvent is a mixture of methanol and water.

[0197] As an optional implementation, in step (iii), the volume ratio of methanol to water is (3-5):1.

[0198] As an optional implementation, in step (iii), the acid used in the hydrolysis reaction is trifluoroacetic acid.

[0199] As an optional implementation, in step (iii), when acid hydrolysis is used, the reaction solvent is dichloromethane.

[0200] As an optional implementation, in step (iii), the hydrolysis reaction is carried out at a temperature of 20–30°C for a time of 0.5–24 h.

[0201] As an optional implementation, in step (iii), the condensing agent is HATU.

[0202] As an optional implementation, in step (iii), the base used for the condensation reaction is N,N-diisopropylethylamine.

[0203] As an optional implementation, in step (iii), the temperature of the condensation reaction is 0–30°C and the time is 1–3 h.

[0204] As an optional implementation, in step (iii), the compound targeting SMARCA protein degradation includes any one of compounds A1 to A2 and A5 to A16.

[0205] As an optional implementation method, method two specifically includes the following steps:

[0206] (1) In the presence of iodine reagent and base, compound 6 and compound 7 react to give intermediate 8, as shown in the following reaction formula:

[0207]

[0208] (2) In the presence of a palladium catalyst and a base, intermediate 8 and compound 2 react to give intermediate 9, as shown in the following reaction formula:

[0209]

[0210] (3) In the presence of a palladium catalyst and a base, intermediate 9 and compound 4 react to obtain the compound targeting SMARCA protein degradation, as shown in the following reaction formula:

[0211]

[0212] in,

[0213] R1 is selected from hydrogen or amino groups;

[0214] R2 is selected from hydrogen or C1-C6 straight or branched alkyl groups.

[0215] As an optional implementation, in step (1), the iodine reagent is potassium iodide.

[0216] As an optional implementation, in step (1), the alkali is sodium carbonate.

[0217] As an optional implementation, in step (1), the reaction solvent is N,N-dimethylformamide.

[0218] As an optional implementation, in step (1), the reaction temperature is 55-65°C and the time is 3-5 hours.

[0219] As an optional implementation, in step (2), the palladium catalyst is Pd(dppf)Cl2.

[0220] As an optional implementation, in step (2), the alkali is sodium carbonate.

[0221] As an optional implementation, in step (2), the reaction is carried out in a mixed solvent of 1,4-dioxane and water.

[0222] As an optional implementation, in step (2), the volume ratio of 1,4-dioxane to water is (3-5):1.

[0223] As an optional implementation, in step (2), the reaction is carried out in the presence of a protective gas.

[0224] As an optional implementation, in step (2), the protective gas includes nitrogen.

[0225] As an optional implementation, in step (2), the reaction temperature is 95-105°C and the time is 3-5 hours.

[0226] As an optional implementation, in step (3), the palladium catalyst includes BrettPhos Pd G3 and Pd(PPh3)4.

[0227] As an optional implementation, in step (3), the alkali is potassium carbonate.

[0228] As an optional implementation, in step (3), the reaction is carried out in a mixed solvent of 1,4-dioxane and water.

[0229] As an optional implementation, in step (3), the volume ratio of 1,4-dioxane to water is (3-5):1.

[0230] As an optional implementation, in step (3), the reaction is carried out in the presence of a protective gas.

[0231] As an optional implementation, in step (3), the protective gas includes nitrogen.

[0232] As an optional implementation, in step (3), the reaction temperature is 85-95°C and the time is 2-4 hours.

[0233] Thirdly, the present invention provides the use of a compound, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, an active metabolite thereof, a stereoisomer thereof, a tautomer thereof, a geometric isomer thereof, or an isotopic substitute thereof, as described in the first aspect, in the preparation of a SMARCA2 / 4 degrading agent.

[0234] Fourthly, the present invention provides the use of a compound that targets the degradation of SMARCA protein as described in the first aspect, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or an active metabolite thereof, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an isotopic substitute thereof, in the preparation of a medicament for the prevention and / or treatment of tumors.

[0235] As an optional implementation, the tumor includes any one of acute myeloid leukemia, non-small cell lung cancer, melanoma, prostate cancer, or colon cancer, and is more preferably acute myeloid leukemia.

[0236] Fifthly, the present invention provides a drug for targeting the degradation of SMARCA2 / 4 protein, the drug comprising an active ingredient and pharmaceutically acceptable excipients;

[0237] The active ingredient comprises any one or a combination of at least two of the following: a compound that targets the degradation of SMARCA protein as described in the first aspect, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or an active metabolite thereof, or a stereoisomer thereof, or a tautomer thereof, or a geometric isomer thereof, or an isotopic substitute thereof.

[0238] The present invention will be further illustrated by the following examples. Unless otherwise specified, the materials in the examples are prepared according to existing methods or purchased directly from the market.

[0239] Example 1

[0240] This embodiment provides a compound A1 that targets the degradation of SMARCA protein. The name of compound A1 is: (2S,4R)-1-((S)-2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)benzamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0241] The synthetic route for compound A1, which targets SMARCA protein degradation, is shown below:

[0242]

[0243] The compound A1, which targets SMARCA protein degradation, is prepared by the following steps:

[0244] (i) 1a (472 mg, 1.8 mmol, 1.2 equiv.), 2a (1.5 mmol, 1 equiv.), Pd(dppf)Cl2 (123 mg, 0.15 mmol, 10% equiv.), and sodium carbonate (318 mg, 3 mmol, 2 equiv.) were dissolved in a mixed system (25 mL, 1,4-dioxane:water = 4:1). The mixture was refluxed at 100 °C for 4 hours under nitrogen protection. After the reaction was complete, the solvent was removed by rotary evaporation, and palladium dichloride and some inorganic salts were removed by diatomaceous earth filtration. Thin-layer chromatography was used to purify the mixture, yielding intermediate 3a.

[0245] (ii) 3a (1.2 mmol, 1 equiv.), 4a (198 mg, 1.44 mmol, 1.2 equiv.), BrettPhos Pd G3 (32 mg, 0.036 mmol, 3% equiv.), Pd(PPh3)4 (41 mg, 0.036 mmol, 3% equiv.), and potassium carbonate (332 mg, 2.4 mmol, 2 equiv.) were dissolved in a mixed system (25 mL, 1,4-dioxane:water = 4:1). The mixture was refluxed at 90 °C for 3 hours under nitrogen protection. After the reaction was complete, the solvent was removed by vacuum distillation, and palladium and inorganic salts were removed by diatomaceous earth filtration. The mixture was purified by thin-layer chromatography to obtain intermediate 5a.

[0246] (iii) 5a (0.56 mmol, 1 equiv.) and lithium hydroxide (95 mg, 2.24 mmol, 4 equiv.) were dissolved in a mixed system (10 mL, methanol:water = 4:1) and incubated overnight at room temperature. When the reaction was complete, the solvent was removed by vacuum distillation. The compound was dissolved in water, and the pH was adjusted to weakly acidic with 1 N hydrochloric acid. The precipitate was collected and filtered to dryness. The hydrolyzed solid (0.19 mmol, 1 equiv.), 6a (0.21 mmol, 1.1 equiv.), HATU (112 mg, 0.29 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (76 mg, 0.58 mmol, 3 equiv.) were dissolved in 2 mL of ultradry N,N-dimethylformamide. The mixture was reacted in an ice bath for 1 hour, then transferred to room temperature and stirred for 1 hour. When the reaction was complete, the organic phase was extracted three times with a system of ethyl acetate and water and backwashed once with saturated sodium chloride solution. The organic phases from the three extractions were combined, and the solvent was removed by passing a neutral salt desiccant and a rotary evaporator to obtain the final product A1, a pale yellow solid (78 mg, 56% yield).

[0247] 1H NMR (400MHz, DMSO-d6): δ13.49(s,1H),8.99(s,1H),8.43(d,J=7.8Hz,1H),8.09(d,J=8.2Hz,2H),8.06-8.03(m,2H),7.95 (dd,J=8.0,1.7Hz,1H),7.72(d,J=8.2Hz,2H),7.45(d,J=8.3Hz,2H),7.40(d,J=8.3Hz,2H),7.26(t,J=6.9Hz,1H),6.95-6 .89(m,2H),6.52(s,2H),5.16(d,J=3.5Hz,1H),4.95(t,J=7.2Hz,1H),4.82(d,J=9.1Hz,1H),4.48(t,J=8.1Hz,1H),4.33( s,1H),3.70(d,J=3.1Hz,2H),2.46(s,3H),2.06(dd,J=12.0,8.8Hz,1H),1.83(m,1H),1.39(d,J=7.0Hz,3H),1.06(s,9H). 13 C NMR (101MHz, DMSO-d6): δ170.62,169.30,165.76,157.95,157.07,152.48 ,151.55,147.79,144.70,137.61,134.29,131.15,130.25,129.73,128.8 7,128.54,128.37,127.58,126.49,126.42,124.88,118.88,118.04,117. 39,68.85,58.75,57.41,56.43,47.73,37.80,35.77,26.63,22.52,16.03. HRMS m / z calculated for C 40 H 43 N7O5S[M+H] + :734.3119,found:734.3108(1.50ppm).

[0248] Example 2

[0249] This embodiment provides a compound A2 that targets the degradation of SMARCA protein. The name of compound A2 is: (2S,4R)-1-((S)-2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)benzamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0250] The synthetic route for compound A2, which targets SMARCA protein degradation, is shown below:

[0251]

[0252] The compound A2, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0253] The final product A2 was prepared using 1a, 2a, 4a and 6b as starting materials, following the preparation conditions of A1.

[0254] Pale yellow solid (22 mg, 18% yield).

[0255] 1 H NMR (400MHz, DMSO-d6) δ13.50(s,1H),8.99(s,1H),8.61(t,J=6.1Hz,1H),8.11(t,J=4.5Hz,2H),8.07(d,J=16.1Hz,2H),7 .95(dd,J=8.1,1.6Hz,1H),7.73(d,J=8.0Hz,2H),7.44(d,J=8.5Hz,2H),7.41(d,J=8.4Hz,2H),7.29-7.25(m,1H),6.96-6 .89(m,2H),6.53(s,2H),5.20(d,J=3.5Hz,1H),4.85(d,J=9.1Hz,1H),4.49(d,J=8.5Hz,1H),4.42(t,J=6.2Hz,2H),4.27( dd,J=15.8,5.5Hz,1H),3.76(d,J=2.9Hz,2H),2.46(s,3H),2.09(dd,J=11.8,6.9Hz,1H),1.99-1.92(m,1H),1.07(s,9H). 13 C NMR(101MHz,DMSO-d6)δ171.96,169.43,165.90,157.96,157.08,152.49 ,151.53,147.78,139.52,137.61,134.33,131.21,130.26,129.72,128.7 4,128.53,128.44,127.62,127.51,126.48,124.88,118.89,118.04,117 .41,68.98,58.91,57.42,56.53,41.73,38.02,35.75,26.58,16.00.HRMS m / z calculated for C 39 H 41N7O5S[M+H] + :720.2963,found:720.2949(1.94ppm).

[0256] Example 3

[0257] This embodiment provides compound A3 that targets the degradation of SMARCA protein. The name of compound A3 is: (2S,4R)-1-((S)-2-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)benzyl)amino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0258] The synthetic route for compound A3, which targets SMARCA protein degradation, is shown below:

[0259]

[0260] The compound A3, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0261] (1) 6a (0.5 mmol, 1 equiv.), 7a (297 mg, 0.6 mmol, 1.2 equiv.), sodium carbonate (106 mg, 1 mmol, 2 equiv.), and potassium iodide (9 mg, 0.05 mmol, 0.1 equiv.) were dissolved in 3 mL of N,N-dimethylformamide and heated at 60 °C for 3 hours. After the reaction was complete, the organic phase was extracted three times with ethyl acetate and water and backwashed once with saturated sodium chloride solution. The organic phases from the three extractions were combined, and the solvent was removed by using a neutral salt desiccant and a rotary evaporator to obtain intermediate 8a.

[0262] (2) 8a (0.35 mmol, 1.1 equiv.), 2a (0.32 mmol, 1 equiv.), Pd(dppf)Cl2 (0.035 mmol, 10% equiv.), and sodium carbonate (68 mg, 0.64 mmol, 2 equiv.) were dissolved in a mixed system (10 mL, 1,4-dioxane:water = 4:1). The mixture was refluxed at 100 °C for 4 hours under nitrogen protection. After the reaction was complete, the solvent was removed by rotary evaporation, and palladium dichloride and inorganic salts were removed by diatomaceous earth filtration. Intermediate 9a was obtained by thin-layer chromatography for separation and purification.

[0263] (3) 9a (0.2 mmol, 1 equiv.), 4a (33 mg, 0.24 mmol, 1.2 equiv.), BrettPhos Pd G3 (6 mg, 0.006 mmol, 3% equiv.), Pd(PPh3)4 (7 mg, 0.006 mmol, 3% equiv.), and potassium carbonate (56 mg, 0.4 mmol, 2 equiv.) were dissolved in a mixed system (10 mL, 1,4-dioxane:water = 4:1). The mixture was refluxed at 90 °C for 3 hours under nitrogen protection. After the reaction was complete, the solvent was removed by vacuum distillation, and palladium and inorganic salts were removed by diatomaceous earth filtration. The final product A3 was obtained by thin-layer chromatography.

[0264] Pale yellow solid (23 mg, 16% yield). 1 H NMR (400MHz, DMSO-d6) δ13.63(s,1H),8.99(s,1H),8.42(d,J=7.7Hz,1H),8.02(s,1H),7.95(dd,J=8.1,1.6Hz,1H),7.60(d,J=8.1Hz,2H),7. 51(d,J=7.8Hz,2H),7.48(d,J=2.8Hz,1H),7.45(d,J=8.0Hz,2H),7.39(d,J=8.2Hz,2H),7.26(t,J=6.9Hz,1H),6.95-6.88(m,2H),6.46(s,2H ),5.13(d,J=3.5Hz,1H),4.93(t,J=7.2Hz,1H),4.59(t,J=7.9Hz,1H),4.29(s,1H),3.75(d,J=13.5Hz,1H),3.54(d,J=13.8Hz,1H),3.47(dd, J=10.7,4.0Hz,1H),3.39(d,J=10.8Hz,1H),3.08(s,1H),2.46(s,3H),2.05(d,J=9.6Hz,1H),1.82(m,1H),1.40(d,J=7.0Hz,3H),0.97(s,9H). 13CNMR(101MHz,DMSO-d6)δ172.84,170.79,158.05,157.26,153.01,152.61,1 51.52,147.77,144.80,133.05,131.14,130.20,129.99,129.71,128.98,128 .87,128.77,128.36,126.39,126.35,124.59,118.83,117.96,117.39,68.79 ,65.59,63.88,58.35,55.86,47.75,37.53,35.02,26.69,22.57,16.02.HRMS m / z calculated for C 40 H 45 N7O4S[M+H] + :720.3327,found:720.3315(1.67ppm).

[0265] Example 4

[0266] This embodiment provides compound A4, which targets the degradation of SMARCA protein. The name of compound A4 is: (2S,4R)-1-((S)-2-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)benzyl)amino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0267] The synthetic route for compound A4, which targets SMARCA protein degradation, is shown below:

[0268]

[0269] The compound A4, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0270] The final product A4 was prepared using 6b, 7a, 2a and 4a as starting materials, following the preparation conditions of A3.

[0271] Pale yellow solid (31 mg, 15% yield).

[0272] 11H NMR (400 MHz, DMSO-d6) δ 13.62 (s, 1H), 8.98 (s, 1H), 8.60 (t, J = 6.0 Hz, 1H), 8.01 (s, 1H), 7.95 (dd, J = 8.1, 1.6 Hz, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 7.8 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.38 - 7.32 (m, 1H), 7.28 - 7.23 (m, 1H), 6.94 - 6.87 (m, 2H), 6.45 (s, 2H), 5.17 (d, J = 3.5 Hz, 1H), 4.59 (t, J = 8.0 Hz, 1H), 4.42 (dd, J = 15.8, 6.4 Hz, 1H), 4.36 (s, 1H), 4.27 (dd, J = 15.9, 5.5 Hz, 1H), 3.76 (d, J = 13.6 Hz, 1H), 3.55 (d, J = 6.7 Hz, 1H), 3.51 (d, J = 7.8 Hz, 1H), 3.43 (d, J = 10.8 Hz, 1H), 3.08 (s, 1H), 2.45 (s, 3H), 2.06 (t, J = 10.7 Hz, 1H), 1.94 (m, 1H), 0.96 (s, 9H). 13 13C NMR (101 MHz, DMSO-d6) δ 173.38, 172.64, 158.54, 157.76, 153.10, 152.00, 148.26, 142.39, 140.04, 133.53, 131.69, 130.69, 130.19, 129.37, 129.25, 129.22, 128.85, 128.42, 127.99, 126.90, 125.09, 119.33, 118.47, 117.88, 69.43, 67.40, 66.06, 59.07, 51.99, 42.17, 38.27, 35.56, 27.15, 16.47. HRMS m / z calculated for C 39 H 43 N7O4S [M + H] + [[ID=⑧]]: 706.3170, found: 706.3160 (1.42 ppm).

[0273] Example 5

[0274] It should be noted that in the translation of the chemical data in and , the Chinese character "⑧" in the original text seems to be an incorrect character. I have translated it as "8" according to common sense. If this is not what you intended, please provide more accurate information.This embodiment provides compound A5, which targets the degradation of SMARCA protein. The name of compound A5 is: (2S,4R)-1-((S)-2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0275] The synthetic route for compound A5, which targets SMARCA protein degradation, is shown below:

[0276]

[0277] The compound A5, which targets SMARCA protein degradation, is prepared by the following steps:

[0278] The final product A5 was prepared using 1b, 2a, 4a and 6a as starting materials, following the preparation conditions of A1.

[0279] Pale yellow solid (32 mg, 17% yield).

[0280] 1 H NMR (400MHz, DMSO-d6) δ13.64(s,1H),8.98(s,1H),8.41(d,J=7.8Hz,1H),8.21(d,J=9.2Hz,1H),8.02(s,1H),7.96(dd,J=8.2,1.6Hz, 1H),7.58(d,J=7.9Hz,2H),7.48(s,1H),7.47-7.44(m,2H),7.43(s,1H),7.39(d,J=8.0Hz,2H),7.28-7.24(m,1H),6.95-6.88(m,2H), 6.45(s,2H),5.13(d,J=3.4Hz,1H),4.94(t,J=7.2Hz,1H),4.54(d,J=9.1Hz,1H),4.45(t,J=8.1Hz,1H),4.29(s,1H),3.73(d,J=13.9H z,1H),3.64(s,1H),3.61(d,J=4.9Hz,2H),2.46(s,3H),2.02(t,J=9.8Hz,1H),1.84-1.77(m,1H),1.40(d,J=7.0Hz,3H),0.98(s,9H). 13C NMR(101MHz,DMSO-d6)δ171.07,170.05,169.88,158.49,157.66,153.08, 151.94,148.22,145.08,138.22,133.09,131.57,130.63,130.32,130.17, 129.29,128.79,128.73,126.85,125.09,119.26,118.38,117.81,69.25,5 9.08,57.17,56.83,48.18,41.93,38.22,35.90,26.94,22.90,16.44.HRMS m / z calculated for C 41 H 45 N7O5S[M+H] + :748.3276,found:748.3254(2.94ppm).

[0281] Example 6

[0282] This embodiment provides a compound A6 that targets the degradation of SMARCA protein. The name of compound A6 is: (2S,4R)-1-((S)-2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0283] The synthetic route for compound A6, which targets SMARCA protein degradation, is shown below:

[0284]

[0285] The compound A6, which targets SMARCA protein degradation, is specifically prepared by the following steps:

[0286] The final product A6 was prepared using 1b, 2a, 4a and 6b as starting materials, following the preparation conditions of A1.

[0287] Pale yellow solid (42 mg, 35% yield).

[0288] 11H NMR (400 MHz, DMSO-d6) δ 13.64 (s, 1H), 8.99 (s, 1H), 8.60 (t, J = 6.0 Hz, 1H), 8.28 (d, J = 9.2 Hz, 1H), 8.02 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.28 - 7.23 (m, 1H), 6.94 - 6.86 (m, 2H), 6.45 (s, 2H), 5.15 (d, J = 3.4 Hz, 1H), 4.57 (d, J = 9.3 Hz, 1H), 4.49 - 4.43 (m, 2H), 4.36 (s, 1H), 4.23 (dd, J = 15.9, 5.5 Hz, 1H), 3.75 (d, J = 13.8 Hz, 1H), 3.68 (dd, J = 12.2, 8.6 Hz, 2H), 3.62 (d, J = 13.6 Hz, 1H), 2.46 (s, 3H), 2.05 (t, J = 10.5 Hz, 1H), 1.92 (m, 1H), 0.98 (s, 9H). 13 13C NMR (101 MHz, DMSO-d6) δ 172.48, 170.18, 170.05, 158.55, 157.73, 153.13, 152.01, 148.24, 140.03, 138.31, 133.14, 131.70, 130.70, 130.38, 130.17, 129.17, 128.84, 128.80, 127.94, 126.90, 125.15, 119.32, 118.43, 117.87, 69.41, 59.27, 57.16, 57.01, 42.18, 41.93, 38.51, 35.98, 26.93, 16.49. HRMS m / z calculated for C 40 H 43 N7O5S [M + H] + : 734.3119, found: 734.3111 (1.09 ppm).

[0289] Example 7

[0290] This embodiment provides compound A7, which targets the degradation of SMARCA protein. The name of compound A7 is: (2S,4R)-1-((S)-2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)propylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0291] The synthetic route for compound A7, which targets SMARCA protein degradation, is shown below:

[0292]

[0293] The compound A7, which targets SMARCA protein degradation, is specifically prepared by the following steps:

[0294] The final product A7 was prepared using 1c, 2a, 4a and 6a as starting materials, following the preparation conditions of A1.

[0295] Pale yellow solid (48 mg, 36% yield).

[0296] 1 H NMR (400MHz, DMSO-d6) δ13.62(s,1H),8.99(s,1H),8.38(d,J=7.8Hz,1H),7.99(s,1H),7.98-7.95(m,1H),7.95-7.93(m,1H),7.57-7.54 (m,2H),7.45(d,J=1.9Hz,1H),7.43(d,J=1.6Hz,2H),7.41(s,1H),7.39(d,J=8.4Hz,2H),7.28-7.24(m,1H),6.95-6.87(m,2H),6.41(s, 2H),5.14(d,J=3.5Hz,1H),4.96-4.91(m,1H),4.58(d,J=9.4Hz,1H),4.45(t,J=8.1Hz,1H),4.31(q,J=3.5Hz,1H),3.64(d,J=3.1Hz,2H) ,2.91(t,J=7.8Hz,2H),2.69-2.62(m,1H),2.56-2.52(m,1H),2.46(s,3H),2.04(m,1H),1.82(m,1H),1.39(d,J=7.0Hz,3H),0.94(s,9H). 13C NMR (101MHz, DMSO-D6) δ171.20,170.63,169.55,158.06,157.27,152.62,151. 55,147.79,144.70,142.57,132.26,131.15,130.21,129.73,129.11,128.87, 128.44,128.40,126.42,126.39,124.59,118.85,117.98,117.40,68.82,58.6 0,56.44,47.75,37.81,36.35,36.09,35.31,31.18,26.47,22.49,16.03.HRMS m / zcalculated for C 42 H 47 N7O5S[M+H] + :762.3432,found:762.3409(3.02ppm).

[0297] Example 8

[0298] This embodiment provides a compound A8 that targets the degradation of SMARCA protein. The name of compound A8 is: (2S,4R)-1-((S)-2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)propylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0299] The synthetic route for compound A8, which targets SMARCA protein degradation, is shown below:

[0300]

[0301] The compound A8, which targets SMARCA protein degradation, is specifically prepared by the following steps:

[0302] The final product A8 was prepared using 1c, 2a, 4a and 6b as starting materials, following the preparation conditions of A1.

[0303] Pale yellow solid (35 mg, 26% yield).

[0304] 11H NMR (400 MHz, DMSO-d6) δ 13.63 (s, 1H), 8.98 (s, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.03 (d, J = 9.4 Hz, 1H), 7.99 (s, 1H), 7.94 (dd, J = 8.1, 1.6 Hz, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 3.9 Hz, 2H), 7.42 (d, J = 3.6 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.26 (t, J = 7.0 Hz, 1H), 6.95 - 6.87 (m, 2H), 6.41 (s, 2H), 5.18 (d, J = 3.4 Hz, 1H), 4.61 (d, J = 9.4 Hz, 1H), 4.49 - 4.43 (m, 2H), 4.40 - 4.37 (m, 1H), 4.24 (dd, J = 15.9, 5.4 Hz, 1H), 3.70 (d, J = 2.9 Hz, 2H), 2.92 (t, J = 7.8 Hz, 2H), 2.71 - 2.63 (m, 1H), 2.55 (d, J = 7.5 Hz, 1H), 2.45 (s, 3H), 2.10 - 2.05 (m, 1H), 1.93 (m, 1H), 0.94 (s, 9H).<> 13 13C NMR (101 MHz, DMSO-d6) δ 171.99, 171.27, 169.69, 158.06, 157.26, 152.64, 151.50, 147.75, 142.59, 139.54, 132.25, 131.21, 130.21, 129.68, 129.12, 128.68, 128.45, 128.39, 127.46, 126.38, 124.58, 118.84, 117.98, 117.40, 68.94, 58.76, 56.53, 56.41, 41.70, 38.03, 36.33, 35.34, 31.19, 26.41, 15.99. HRMS m / z calculated for C<> 41 H<> 45 N7O5S [M + H]<> + : 748.3276, found: 748.3253 (3.07 ppm).<> <>

[0305] Example 9<> <>

[0306] This embodiment provides compound A9, which targets the degradation of SMARCA protein. The name of compound A9 is: (2S,4R)-1-((S)-2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)butyrylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0307] The synthetic route for compound A9, which targets SMARCA protein degradation, is shown below:

[0308]

[0309] The compound A9, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0310] The final product A9 was prepared using 1d, 2a, 4a and 6a as starting materials, following the preparation conditions of A1.

[0311] Pale yellow solid (42 mg, 45% yield).

[0312] 1 H NMR(400MHz,DMSO-d6)δ13.65(s,1H),8.98(s,1H),8.39(d,J=7.8Hz,1H),8 .01(s,1H),7.95(dd,J=8.0,1.7Hz,1H),7.88(d,J=9.2Hz,1H),7.57(d,J=7 .9Hz,2H),7.44(d,J=8.3Hz,2H),7.40(d,J=2.8Hz,2H),7.37(d,J=2.5Hz,2 H),7.26(t,J=6.9Hz,1H),6.95-6.87(m,2H),6.45(s,2H),5.13(d,J=3.5Hz, 1H), 4.93 (t, J = 7.2Hz, 1H), 4.58 (d, J = 9.3Hz, 1H), 4.45 (t, J = 8.1Hz, 1H), 4. 31(q,J=3.6Hz,1H),3.64(d,J=3.1Hz,2H),2.66(m,2H),2.46(s,3H),2.37- 2.31(m,1H),2.26-2.21(m,1H),2.07-2.01(m,1H),1.88(d,J=7.6Hz,1H),1 .85-1.83(m,1H),1.81(d,J=8.1Hz,1H),1.39(d,J=7.0Hz,3H),0.97(s,9H). 13C NMR(101MHz,DMSO-d6)δ171.86,170.67,169.65,158.08,157.31,152.63,151.5 3,147.79,144.71,143.13,132.15,131.16,130.20,129.73,129.15,128.87,128 .46,128.45,126.42,126.39,124.57,118.84,117.97,117.40,68.82,58.59,56 .46,56.37,47.75,37.82,35.27,34.58,27.38,26.55,26.51,22.50,16.03.HRMS m / z calculated forC 43 H 49 N7O5S[M+H] + :776.3589,found:776.3569(2.58ppm).

[0313] Example 10

[0314] This embodiment provides a compound A10 that targets the degradation of SMARCA protein. The compound A10 is named as: (2S,4R)-1-((S)-2-(4-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)butyrylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0315] The synthetic route for compound A10, which targets SMARCA protein degradation, is shown below:

[0316]

[0317] The compound A10, which targets SMARCA protein degradation, is prepared by the following steps:

[0318] The final product A10 was prepared using 1d, 2a, 4a and 6b as starting materials, following the preparation conditions of A1.

[0319] Pale yellow solid (54 mg, 38% yield).

[0320] 11H NMR (400 MHz, DMSO-d6) δ 13.65 (s, 1H), 8.98 (s, 1H), 8.58 (t, J = 6.1 Hz, 1H), 8.00 (s, 1H), 7.96 - 7.92 (m, 2H), 7.58 - 7.55 (m, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 2.7 Hz, 2H), 7.37 (d, J = 2.4 Hz, 2H), 7.28 - 7.23 (m, 1H), 6.95 - 6.87 (m, 2H), 6.45 (s, 2H), 5.15 (d, J = 3.5 Hz, 1H), 4.60 (d, J = 9.4 Hz, 1H), 4.45 (m, 2H), 4.37 (q, J = 3.6, 3.0 Hz, 1H), 4.23 (dd, J = 15.9, 5.4 Hz, 1H), 3.69 (d, J = 3.1 Hz, 2H), 2.66 (q, J = 8.9, 6.8 Hz, 2H), 2.45 (s, 3H), 2.37 - 2.31 (m, 1H), 2.27 - 2.21 (m, 1H), 2.06 (dd, J = 11.4, 8.1 Hz, 1H), 1.96 - 1.91 (m, 1H), 1.88 (d, J = 7.6 Hz, 1H), 1.84 (d, J = 8.0 Hz, 1H), 0.97 (s, 9H). 13 13C NMR (101 MHz, DMSO-d6) δ 172.01, 171.91, 169.76, 158.08, 157.31, 152.62, 151.51, 147.75, 143.13, 139.55, 132.14, 131.21, 130.20, 129.67, 129.16, 128.68, 128.46, 128.45, 127.50 - 127.41 (m), 126.39, 124.57, 118.84, 117.96, 117.39, 68.93, 58.75, 56.48, 56.40, 41.68, 38.04, 35.29, 34.58, 34.55, 27.39, 26.45, 16.00. HRMS m / z calculated for C 42 H 47 N7O5S [M + H] + : 762.3432, found: 762.3408 (3.15 ppm).

[0321] Example 11

[0322] This embodiment provides a compound A11 that targets the degradation of SMARCA protein. The compound A11 is named as: (2S,4R)-1-((S)-2-(1-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)cyclopropane-1-carboxamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0323] The synthetic route for compound A11, which targets SMARCA protein degradation, is shown below:

[0324]

[0325] The compound A11, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0326] The final product A11 was prepared using 1e, 2a, 4a and 6a as starting materials, following the preparation conditions of A1.

[0327] Pale yellow solid (52 mg, 51% yield).

[0328] 1 H NMR (400MHz, DMSO-d6) δ13.55(s,1H),8.97(s,1H),8.42(d,J=7.6Hz,1H),8.08(s,1H),7.98(dd,J=8.1,1.6Hz,1H),7.73(d,J=8.0Hz,2H),7.61(d, J=8.1Hz,2H),7.42(d,J=8.1Hz,2H),7.34(d,J=8.1Hz,2H),7.27(t,J=6.9 Hz,1H),6.95-6.89(m,2H),6.44(s,2H),6.15(d,J=9.3Hz,1H),5.17(d,J= 3.4Hz,1H),4.85(t,J=7.2Hz,1H),4.55(d,J=9.3Hz,1H),4.43(d,J=8.2Hz ,1H),4.29(s,1H),3.57(d,J=2.7Hz,2H),2.45(s,3H),2.10-2.04(m,1H), 1.75(td,J=8.8,4.5Hz,1H),1.50(d,J=6.9Hz,1H),1.42-1.38(m,1H),1.3 3(d,J=7.0Hz,3H),1.18(d,J=6.5Hz,1H),1.04-1.00(m,1H),0.86(s,9H). 13CNMR(101MHz,DMSO-d6)δ171.85,170.88,169.39,158.49,157.64,153.17,152.00,14 8.25,145.30,140.85,134.55,131.80,131.63,130.74,130.18,129.56,129.34,128. 28,127.04,126.77,125.22,119.37,118.50,117.87,69.33,59.12-59.02(m),57.20- 57.12(m),48.28,38.27,37.01,36.75,30.57,26.66,23.01,16.51,16.07,15.09.HRMS m / z calculated forC 43 H 47 N7O5S[M+H] + :774.3432,found:774.3411(2.71ppm).

[0329] Example 12

[0330] This embodiment provides a compound A12 that targets the degradation of SMARCA protein. The name of compound A12 is: (2S,4R)-1-((S)-2-(1-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)cyclopropane-1-carboxamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0331] The synthetic route for compound A12, which targets SMARCA protein degradation, is shown below:

[0332]

[0333] The compound A12, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0334] The final product A12 was prepared using 1e, 2a, 4a and 6b as starting materials, following the preparation conditions of A1.

[0335] Pale yellow solid (46 mg, 33% yield).

[0336] 11H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 8.89 (s, 1H), 8.58 (t, J = 6.1 Hz, 1H), 8.02 (s, 1H), 7.88 (dd, J = 8.1, 1.6 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.34 (s, 2H), 7.33 (d, J = 8.5 Hz, 2H), 7.27 - 7.23 (m, 1H), 6.94 (dd, J = 8.2, 1.2 Hz, 1H), 6.84 (t, J = 7.8 Hz, 1H), 6.43 (s, 2H), 6.20 (d, J = 9.3 Hz, 1H), 5.20 (d, J = 3.3 Hz, 1H), 4.55 (d, J = 9.3 Hz, 1H), 4.43 (t, J = 8.2 Hz, 1H), 4.36 (s, 1H), 4.29 (d, J = 5.9 Hz, 2H), 3.63 (d, J = 4.9 Hz, 2H), 2.37 (s, 3H), 2.07 (dd, J = 12.9, 7.8 Hz, 1H), 1.90 (m, 1H), 1.51 (m, 1H), 1.40 (t, J = 6.3 Hz, 1H), 1.18 (t, J = 6.2 Hz, 1H), 1.03 (dd, J = 8.2, 5.1 Hz, 1H), 0.86 (s, 9H). 13 13C NMR (101 MHz, DMSO-d6) δ 172.17, 171.89, 169.52, 158.51, 157.61, 153.12, 151.81, 148.18, 140.90, 139.81, 134.55, 131.78, 131.57, 130.71, 130.22, 129.51, 129.15, 128.64, 128.00, 126.88, 125.10, 119.30, 118.41, 117.87, 69.45, 59.30, 57.20, 57.15, 42.19, 38.38, 36.82, 3 {0} 61, 26.62, 16.39, 16.01, 15.06. HRMS m / z calculated for C 42 1H 45 + N7O5S [M + H]

[0337] Example 13

[0338] This embodiment provides a compound A13 that targets the degradation of SMARCA protein. The name of compound A13 is: (2S,4R)-1-((S)-2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0339] The synthetic route for compound A13, which targets SMARCA protein degradation, is shown below:

[0340]

[0341] The compound A13, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0342] (i) 1f (0.576 mmol, 1.2 equiv.), 2a (0.48 mmol, 1 equiv.), Pd(dppf)Cl2 (0.048 mmol, 10% equiv.), and sodium carbonate (102 mg, 0.96 mmol, 2 equiv.) were dissolved in a mixed system (25 mL, 1,4-dioxane:water = 4:1). The mixture was refluxed at 100 °C for 4 hours under nitrogen protection. After the reaction was complete, the solvent was removed by rotary evaporation, and palladium dichloride and inorganic salts were removed by diatomaceous earth filtration. The intermediate 3f was obtained by thin-layer chromatography.

[0343] (ii) 3f (0.36 mmol, 1 equiv.), 4a (60 mg, 0.432 mmol, 1.2 equiv.), BrettPhos Pd G3 (10 mg, 0.01 mmol, 3% equiv.), Pd(PPh3)4 (12 mg, 0.01 mmol, 3% equiv.), and potassium carbonate (100 mg, 0.72 mmol, 2 equiv.) were dissolved in a mixed system (10 mL, 1,4-dioxane:water = 4:1). The mixture was refluxed at 90 °C for 3 hours under nitrogen protection. After the reaction was complete, the solvent was removed by vacuum distillation, and palladium and inorganic salts were removed by diatomaceous earth filtration. The intermediate 5f was obtained by thin-layer chromatography.

[0344] (iii) Dissolve 5f (0.2 mmol, 1 equiv.) and trifluoroacetic acid (5 mL) in 5 mL of dichloromethane and react overnight at room temperature. When the reaction is complete, remove the solvent by vacuum distillation. The solid obtained after oil pump drying is directly used for the next reaction. The solid obtained by oil pump drying (0.2 mmol, 1 equiv.), 6a (0.2 mmol, 1 equiv.), HATU (114 mg, 0.3 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (78 mg, 0.6 mmol, 3 equiv.) are dissolved in 2 mL of ultra-dry N,N-dimethylformamide, reacted in an ice bath for 1 hour, and then transferred to room temperature and stirred for 1 hour. When the reaction is complete, the organic phase is extracted three times with an ethyl acetate and water system and backwashed once with saturated sodium chloride solution. The organic phases from the three extractions are combined, and the solvent is removed by a neutral salt desiccant and a rotary evaporator to obtain the final product A13.

[0345] Pale yellow solid (66 mg, 43% yield).

[0346] 1 H NMR (400MHz, DMSO-d6) δ13.67(s,1H),8.99(s,1H),8.46(d,J=7.7Hz,1H),7.99(s,1H),7.97-7.93(m,2H),7.62-7.6 0(m,2H),7.44(d,J=8.3Hz,2H),7.39(d,J=8.3Hz,2H),7.27-7.24(m,1H),7.15-7.12(m,2H),6.95-6.89(m,2H),6.43 (s,2H),5.17(d,J=3.4Hz,1H),4.93(t,J=7.2Hz,1H),4.73(s,2H),4.61(d,J=9.4Hz,1H),4.48(t,J=8.3Hz,1H),4.31 (s,1H),3.61(t,J=9.0Hz,2H),2.46(s,3H),2.07(t,J=10.5Hz,1H),1.80(m,1H),1.39(d,J=7.0Hz,3H),0.98(s,9H). 13C NMR(101MHz,DMSO-d6)δ170.53,169.03,166.98,158.46,158.08,157.37,15 2.65,151.53,147.78,144.73,131.15,130.19,129.98,129.73,128.87,128. 81,128.16,127.41,126.39,124.39,118.81,117.96,117.38,115.25,68.82 ,66.56,58.66,56.55,56.25,47.79,37.80,35.80,26.38,22.51,16.03.HRMS m / zcalculated for C 41 H 45 N7O6S[M+H] + :764.3225,found:764.3202(3.01ppm).

[0347] Example 14

[0348] This embodiment provides a compound A14 that targets the degradation of SMARCA protein. The compound A14 is named as: (2S,4R)-1-((S)-2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0349] The synthetic route for compound A14, which targets SMARCA protein degradation, is shown below:

[0350]

[0351] The compound A14, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0352] The final product A14 was prepared using 1f, 2a, 4a and 6b as starting materials, following the preparation conditions of A13.

[0353] Pale yellow solid (53 mg, 30% yield).

[0354] 1H NMR (400MHz, DMSO-d6) δ13.67(s,1H),8.98(s,1H),8.63(t,J=6.1Hz,1H),8.03(d,J=9.3Hz,1H),7.98(s,1H),7.95(dd,J=8. 1,1.6Hz,1H),7.62-7.59(m,2H),7.43(d,J=8.5Hz,2H),7.40(d,J=8.4Hz,2H),7.28-7.24(m,1H),7.14-7.11(m,2H),6.95-6. 89(m,2H),6.42(s,2H),5.20(d,J=3.4Hz,1H),4.74(s,2H),4.63(d,J=9.3Hz,1H),4.47(d,J=7.8Hz,1H),4.45-4.40(m,1H), 4.38(s,1H),4.29-4.23(m,1H),3.69(dd,J=11.7,7.9Hz,2H),2.45(s,3H),2.08(t,J=10.4Hz,1H),1.93(m,1H),0.98(s,9H). 13 C NMR(101MHz,DMSO-d6)δ171.89,169.19,167.10,158.54,158.10,157.39,1 52.67,151.53,147.78,139.52,131.21,130.21,129.98,129.73,128.73,1 28.19,127.51,127.37,126.40,124.40,118.84,117.97,117.41,115.25,6 8.95,66.53,58.85,56.65,56.28,41.72,38.01,35.78,26.35,16.00.HRMS m / z calculated for C 40 H 43 N7O6S[M+H] + :750.3068,found:750.3044(3.20ppm).

[0355] Example 15

[0356] This embodiment provides a compound A15 that targets the degradation of SMARCA protein. The name of compound A15 is: (2S,4R)-1-((S)-2-(2-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)thio)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0357] The synthetic route for compound A15, which targets SMARCA protein degradation, is shown below:

[0358]

[0359] The compound A15, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0360] The final product A15 was prepared using 1g, 2a, 4a and 6a as starting materials, respectively, following the preparation conditions of A13.

[0361] Pale yellow solid (45 mg, 26% yield).

[0362] 1 H NMR (400MHz, DMSO-d6) δ13.57(s,1H),8.98(s,1H),8.41(d,J=7.8Hz,1H),8.23(d,J=9.3Hz,1H),7.99(s,1H),7.94(dd,J=8.1,1.6Hz,1H ),7.58(d,J=8.5Hz,2H),7.54(d,J=8.5Hz,2H),7.44(d,J=8.2Hz,2H),7.38(d,J=8.3Hz,2H),7.26(t,J=6.9Hz,1H),6.94-6.88(m,2H),6. 45(s,2H),5.14(d,J=3.4Hz,1H),4.93(t,J=7.2Hz,1H),4.54(d,J=9.3Hz,1H),4.45(t,J=8.1Hz,1H),4.29(s,1H),3.97(d,J=14.7Hz,1H ),3.82(d,J=14.5Hz,1H),3.63-3.58(m,2H),2.46(s,3H),2.05(d,J=11.7Hz,1H),1.82-1.77(m,1H),1.38(d,J=6.9Hz,3H),0.93(s,9H). 13C NMR(101MHz,DMSO-d6)δ170.99,169.55,168.02,158.44,157.61,153.03 ,151.94,148.21,145.09,138.38,132.17,131.57,130.66,130.16,129. 41,129.29,128.31,128.19,126.84,124.99,119.28,118.43,117.82,69 .23,59.07,57.30,56.92,48.19,38.18,36.06,26.79,22.88,16.46.HRMS m / z calculated forC 41 H 45 N7O5S2[M+H] + :780.2996,found:780.2980(2.05ppm).

[0363] Example 16

[0364] This embodiment provides a compound A16 that targets the degradation of SMARCA protein. The compound A16 is named as: (2S,4R)-1-((S)-2-(2-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)thio)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0365] The synthetic route for compound A16, which targets SMARCA protein degradation, is shown below:

[0366]

[0367] The compound A16, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0368] The final product A16 was prepared using 1f, 2a, 4a and 6b as starting materials, following the preparation conditions of A13.

[0369] Pale yellow solid (48 mg, 39% yield).

[0370] 11H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H), 8.98 (s, 1H), 8.60 (t, J = 6.1 Hz, 1H), 8.30 (d, J = 9.4 Hz, 1H), 7.99 (s, 1H), 7.93 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.26 (t, J = 6.9 Hz, 1H), 6.94 (dd, J = 8.2, 1.2 Hz, 1H), 6.91 - 6.87 (m, 1H), 6.46 (s, 2H), 5.17 (d, J = 3.5 Hz, 1H), 4.57 (d, J = 9.4 Hz, 1H), 4.48 - 4.42 (m, 2H), 4.37 (s, 1H), 4.24 (dd, J = 16.0, 5.5 Hz, 1H), 3.98 (d, J = 14.6 Hz, 1H), 3.84 (d, J = 14.6 Hz, 1H), 3.70 - 3.62 (m, 2H), 2.45 (s, 3H), 2.07 (t, J = 10.4 Hz, 1H), 1.96 - 1.90 (m, 1H), 0.94 (s, 9H). 13 13C NMR (101 MHz, DMSO-d6) δ 172.41, 169.74, 168.17, 158.51, 157.69, 153.08, 151.99, 148.24, 140.01, 138.53, 132.18, 131.69, 130.71, 130.18, 129.47, 129.17, 128.38, 128.17, 127.94, 126.89, 125.05, 119.33, 118.47, 117.88, 69.40, 59.29, 57.32, 57.08, 42.18, 38.47, 36.13, 35.82, 26.79, 16.48. HRMS m / z calculated for C 40 H 43 N7O5S2 [M + H] + : 766.2840, found: 766.2818 (2.87 ppm).

[0371] Example 17

[0372] This embodiment provides a compound A17 that targets the degradation of SMARCA protein. The compound A17 is named as: (2S,4R)-4-hydroxy-1-((S)-2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)benzamido)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0373] The synthetic route for compound A17, which targets SMARCA protein degradation, is shown below:

[0374]

[0375] The compound A17, which targets SMARCA protein degradation, is prepared by the following steps:

[0376] The final product A17 was prepared using 1a, 2b, 4a and 6a as starting materials, following the preparation conditions of A1.

[0377] Pale yellow solid (43 mg, 29% yield).

[0378] 1 H NMR (400MHz, DMSO-d6) δ13.22(s,1H),9.62(s,1H),8.99(s,1H),8.71(s,1H),8.44(d,J=7.7Hz,1H),8.24(t,J= 9.1Hz,2H),8.04(d,J=8.0Hz,2H),7.53(d,J=7.9Hz,2H),7.45(d,J=7.9Hz,2H),7.41(s,2H),7.39(s,1H),7.07- 7.00(m,2H),5.00-4.91(m,1H),4.56(d,J=9.3Hz,1H),4.48(t,J=8.3Hz,1H),4.31(s,1H),3.79(d,J=13.7Hz,1H ),3.63(s,2H),2.47(s,3H),2.05(t,J=10.4Hz,1H),1.84(d,J=11.6Hz,1H),1.41(d,J=7.0Hz,3H),0.97(s,9H). 13C NMR(151MHz,DMSO-d6)δ171.07,169.75,166.27,160.52,158.83,151.91,14 8.42,148.22,145.11,138.37,136.91,136.00,132.71,131.58,130.17,129. 29,129.09,129.08,128.02,126.86,122.20,119.77,118.79,118.16,69.32 ,59.21,58.02,56.88,49.07,48.19,38.24,36.12,27.10,22.90,16.45.HRMS m / z calculated forC 40 H 42 N6O5S[M+H] + :719.3010,found:719.2986(3.34ppm).

[0379] Example 18

[0380] This embodiment provides compound A18, which targets the degradation of SMARCA protein. Compound A18 is named as: (2S,4R)-4-hydroxy-1-((S)-2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)benzamido)-3,3-dimethylbutyryl)-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide

[0381] The synthetic route for compound A18, which targets SMARCA protein degradation, is shown below:

[0382]

[0383] The compound A18, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0384] The final product A18 was prepared using 1a, 2b, 4a and 6b as starting materials, following the preparation conditions of A1.

[0385] Pale yellow solid (54 mg, 38% yield).

[0386] 11H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 9.67 (d, J = 2.1 Hz, 1H), 8.99 (s, 1H), 8.76 (d, J = 2.2 Hz, 1H), 8.61 (t, J = 6.1 Hz, 1H), 8.30 (d, J = 9.0 Hz, 1H), 8.25 - 8.22 (m, 1H), 8.18 (d, J = 8.4 Hz, 2H), 8.10 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.42 - 7.40 (m, 2H), 7.06 (d, J = 2.2 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 5.20 (d, J = 3.6 Hz, 1H), 4.83 (d, J = 9.0 Hz, 1H), 4.49 (d, J = 8.6 Hz, 1H), 4.41 (d, J = 5.3 Hz, 1H), 4.26 (dd, J = 15.9, 5.5 Hz, 1H), 3.77 (d, J = 3.1 Hz, 2H), 3.18 (d, J = 5.0 Hz, 1H), 2.46 (s, 3H), 2.08 (t, J = 9.3, 7.5, 4.4 Hz, 1H), 1.98 - 1.92 (m, 1H), 1.07 (s, 9H). 13 13C NMR (151 MHz, DMSO-d6) δ 172.37, 1's69.82, 166.38, 160.51, 158.81, 151.90, 148.42, 148.20, 139.94, 138.36, 136.90, 136.02, 132.71, 131.63, 130.15, 129.19, 129.15, 129.10, 127.98, 127.94, 122.20, 119.77, 118.80, 118.15, 69.41, 59.34, 58.00, 56.92, 42.18, 38.44, 36.09, 27.05, 16.42. HRMS m / z calculated for C 39 H 40 N6O5S [M + H] + : 705.2854, found: 705.2832 (3.12 ppm).

[0387] Example 19

[0388] This embodiment provides a compound A19 that targets the degradation of SMARCA protein. The name of compound A19 is: (2S,4R)-4-hydroxy-1-((S)-2-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)benzyl)amino)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0389] The synthetic route for compound A19, which targets SMARCA protein degradation, is shown below:

[0390]

[0391] The compound A19, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0392] The final product A19 was prepared using 6a, 7a, 2b and 4a as starting materials, respectively, following the preparation conditions of A3.

[0393] Pale yellow solid (34 mg, 31% yield).

[0394] 1 H NMR (400MHz, DMSO-d6) δ13.17(s,1H),9.62(d,J=2.1Hz,1H),8.98(s,1H),8.71(d,J=2.2Hz,1H),8.41(d,J=7.7Hz,1H),8.25(d ,J=7.9Hz,1H),8.05(d,J=7.9Hz,2H),7.57(d,J=7.9Hz,2H),7.45(s,1H),7.43(s,2H),7.42(s,1H),7.39(d,J=8.1Hz,2H),7.04 (d,J=8.6Hz,2H),5.11(d,J=3.6Hz,1H),4.95-4.91(m,1H),4.59(s,1H),4.27(s,1H),3.81(d,J=13.9Hz,1H),3.51(d,J=13.6Hz ,1H),3.45(d,J=11.2Hz,2H),3.17(d,J=5.2Hz,1H),2.46(s,3H),2.03(s,1H),1.81(s,1H),1.39(d,J=7.0Hz,3H),0.95(s,9H). 13CNMR(101MHz,DMSO-d6)δ173.25,171.28,160.55,159.04,155.69,152.04,1 48.46,148.27,145.30,144.10,132.76,131.64,130.20,129.56,129.44,129 .37,129.00,128.94,128.04,126.85,121.43,119.80,118.63,118.25,69.29 ,65.87,51.70,48.24,46.76,43.48,38.06,35.47,27.19,23.06,16.52.HRMS m / z calculated for C 40 H 44 N6O4S[M+H] + :705.3218,found:705.3203(2.13ppm).

[0395] Example 20

[0396] This embodiment provides a compound A20 that targets the degradation of SMARCA protein. The name of compound A20 is: (2S,4R)-4-hydroxy-1-((S)-2-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)benzyl)amino)-3,3-dimethylbutyryl)-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0397] The synthetic route for compound A20, which targets SMARCA protein degradation, is shown below:

[0398]

[0399] The compound A20, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0400] The final product A20 was prepared using 6b, 7a, 2b and 4a as starting materials, following the preparation conditions of A3.

[0401] Pale yellow solid (38 mg, 21% yield).

[0402] 11H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.62 (d, J = 2.1 Hz, 1H), 8.98 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.59 (t, J = 5.6 Hz, 1H), 8.25 (dd, J = 8.0, 1.6 Hz, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 7.9 Hz, 2H), 7.47 - 7.43 (m, 1H), 7.42 (s, 2H), 7.41 (s, 2H), 7.40 - 7.37 (m, 1H), 7.04 (dd, J = 8.0, 2.5 Hz, 2H), 5.15 (d, J = 3.6 Hz, 1H), 4.60 (t, J = 8.0 Hz, 1H), 4.43 (dd, J = 15.8, 6.4 Hz, 1H), 4.35 (s, 1H), 4.27 (dd, J = 15.8, 5.5 Hz, 1H), 3.83 (d, J = 13.9 Hz, 1H), 3.54 - 3.49 (m, 2H), 3.39 (d, J = 11.1 Hz, 1H), 3.03 (s, 1H), 2.45 (s, 3H), 2.05 (d, J = 9.5 Hz, 1H), 1.94 (m, 1H), 0.96 (s, 9H). 13 13C NMR (101 MHz, DMSO-d6) δ 172.83, 172.12, 160.05, 158.56, 151.49, 147.94, 147.76, 143.61, 139.53, 138.73, 132.25, 132.08, 13,1.18, 129.69, 129.05, 128.74, 128.71, 128.48, 127.53, 127.49, 120.89, 119.28, 118.10, 117.76, 68.93, 66.88, 65.35, 58.56, 55.94, 41.67, 37.78, 35.00, 26.65, 15.97. HRMS m / z calculated for C[[ID=...]] 39 H 42 N6O4S [M + H] + : 691.3061, found: 691.3046 (2.17 ppm).

[0403] Example 21

[0404] This embodiment provides a compound A21 that targets the degradation of SMARCA protein. The name of compound A21 is: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)acetamido)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0405] The synthetic route for compound A21, which targets SMARCA protein degradation, is shown below:

[0406]

[0407] The compound A21, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0408] The final product A21 was prepared using 1b, 2b, 4a and 6a as starting materials, following the preparation conditions of A1.

[0409] Pale yellow solid (34 mg, 23% yield).

[0410] 1 H NMR (400MHz, DMSO-d6) δ13.19(s,1H),9.63-9.60(m,1H),8.98(s,1H),8.70(s,1H),8.40(d,J=7.9Hz,1H),8.24(d,J=7.9Hz,1H),8 .20(d,J=9.1Hz,1H),8.03(d,J=8.0Hz,2H),7.52(d,J=7.9Hz,2H),7.44(d,J=7.9Hz,2H),7.42(s,1H),7.39(d,J=8.2Hz,2H),7.04( d,J=8.8Hz,2H),5.11(d,J=3.5Hz,1H),4.96-4.91(m,1H),4.53(d,J=9.3Hz,1H),4.45(t,J=8.2Hz,1H),4.28(s,1H),3.77(d,J=13. 6Hz,1H),3.61(d,J=6.9Hz,2H),3.57(s,1H),2.46(s,3H),2.01(d,J=10.6Hz,1H),1.80(s,1H),1.39(d,J=7.1Hz,3H),0.95(s,9H). 13C NMR(101MHz,DMSO-d6)δ171.13,170.02,169.89,160.55,159.07,152.03,14 8.45,148.28,145.17,139.95,139.22,132.76,132.20,131.64,130.63,130. 22,129.36,128.97,128.01,126.91,121.41,119.79,118.59,118.27,69.30 ,59.11,57.14,56.88,48.24,42.12,38.28,36.03,26.95,22.98,16.52.HRMS m / z calculated for C 41 H 44 N6O5S[M+H] + :733.3167,found:733.3152(2.05ppm).

[0411] Example 22

[0412] This embodiment provides compound A22 that targets the degradation of SMARCA protein. The name of compound A22 is: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)acetamido)-3,3-dimethylbutyryl)-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0413] The synthetic route for compound A22, which targets SMARCA protein degradation, is shown below:

[0414]

[0415] The compound A22, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0416] The final product A22 was prepared using 1b, 2b, 4a and 6b as starting materials, following the preparation conditions of A1.

[0417] Pale yellow solid (37 mg, 21% yield).

[0418] 1H NMR (400MHz, DMSO-d6) δ13.20(s,1H),9.61(s,1H),8.99(s,1H),8.70(s,1H),8.60(t,J=6.3Hz,1H),8.27(d,J=9.3Hz,1H),8.2 4(d,J=7.8Hz,1H),8.03(d,J=7.8Hz,2H),7.52(d,J=8.0Hz,2H),7.45(s,1H),7.43(s,2H),7.40(d,J=8.0Hz,2H),7.08-7.01(m ,2H),5.15(d,J=3.6Hz,1H),4.57(d,J=9.2Hz,1H),4.46(q,J=7.0,6.3Hz,2H),4.36(s,1H),4.23(dd,J=16.2,5.3Hz,1H),3.79 (d,J=13.9Hz,1H),3.67(d,J=7.8Hz,2H),3.59(d,J=13.8Hz,1H),2.46(s,3H),2.04(d,J=9.3Hz,1H),1.92(s,1H),0.95(s,9H). 13 CNMR(101MHz,DMSO-d6)δ172.48,170.09,170.02,160.55,159.07,152.01, 148.43,148.24,140.03,139.98,139.22,132.76,132.18,131.70,130.63, 130.17,129.17,128.96,128.00,127.94,121.39,119.78,118.56,118.26, 69.40,59.26,57.09,57.00,49.13,42.18,38.50,36.05,26.88,16.49.HRMS m / z calculated for C 40 H 42 N6O5S[M+H] + :719.3010,found:719.2996(1.95ppm).

[0419] Example 23

[0420] This embodiment provides a compound A23 that targets the degradation of SMARCA protein. The name of compound A23 is: (2S,4R)-4-hydroxy-1-((S)-2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)propamido)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0421] The synthetic route for compound A23, which targets SMARCA protein degradation, is shown below:

[0422]

[0423] The compound A23, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0424] The final product A23 was prepared using 1c, 2b, 4a and 6a as starting materials, following the preparation conditions of A1.

[0425] Pale yellow solid (43 mg, 35% yield).

[0426] 1 H NMR (400MHz, DMSO-d6) δ13.19(s,1H),9.60(d,J=2.2Hz,1H),8.99(s,1H),8.68(d,J=2.3Hz,1H),8.39(d,J=7.8Hz,1H),8.24(dd,J=8.0,1.7 Hz,1H),8.01(d,J=8.2Hz,2H),7.95(d,J=9.3Hz,1H),7.47(d,J=8.2Hz,2H),7.44(d,J=8.2Hz,2H),7.42(s,1H),7.39(d,J=8.1Hz,2H),7.04( dd,J=8.0,3.0Hz,2H),5.15(d,J=3.5Hz,1H),4.94(t,J=7.2Hz,1H),4.56(d,J=9.3Hz,1H),4.46(t,J=8.0Hz,1H),4.31(s,1H),3.64(d,J=3.3 Hz,2H),2.96-2.90(m,2H),2.71-2.64(m,1H),2.52(s,1H),2.46(s,3H ),2.07-2.01(m,1H),1.82(m,1H),1.39(d,J=7.0Hz,3H),0.92(s,9H). 13C NMR (151MHz, DMSO-d6) δ171.00,170.53,169.47,159.94,158.48,151.36,147. 80,147.68,144.54,144.17,138.71,132.13,131.19,131.04,129.64,129.29, 128.75,128.35,127.47,126.32,120.69,119.17,118.01,117.67,68.73,58.5 2,56.40,56.25,47.64,37.68,36.16,35.17,31.00,26.35,22.33,15.91.HRMS m / z calculated for C 42 H 46 N6O5S[M+H] + :747.3323,found:747.3311(1.61ppm).

[0427] Example 24

[0428] This embodiment provides a compound A24 that targets the degradation of SMARCA protein. The name of compound A24 is: (2S,4R)-4-hydroxy-1-((S)-2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)propylamino)-3,3-dimethylbutyryl)-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0429] The synthetic route for compound A24, which targets SMARCA protein degradation, is shown below:

[0430]

[0431] The compound A24, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0432] The final product A23 was prepared using 1c, 2b, 4a and 6b as starting materials, following the preparation conditions of A1.

[0433] Pale yellow solid (45 mg, 39% yield).

[0434] 11H NMR (400 MHz, DMSO-d6) δ 13.20 (s, 1H), 9.60 (d, J = 2.1 Hz, 1H), 8.99 (s, 1H), 8.68 (d, J = 2.2 Hz, 1H), 8.58 (t, J = 6.1 Hz, 1H), 8.24 (dd, J = 8.0, 1.6 Hz, 1H), 8.02 (d, J = 4.2 Hz, 1H), 8.01 - 7.98 (m, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 5.6 Hz, 1H), 7.42 (d, J = 4.3 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.06 - 7.00 (m, 2H), 5.19 (d, J = 3.5 Hz, 1H), 4.60 (d, J = 9.4 Hz, 1H), 4.49 - 4.43 (m, 2H), 4.39 (q, J = 3.5 Hz, 1H), 4.23 (dd, J = 15.9, 5.4 Hz, 1H), 3.70 (d, J = 3.3 Hz, 2H), 2.97 - 2.90 (m, 2H), 2.69 (m, 1H), 2.57 - 2.52 (m, 1H), 2.45 (s, 3H), 2.07 (m, 1H), 1.94 (m, 1H), 0.93 (s, 9H). 13 13C NMR (151 MHz, DMSO-d6) δ 171.91, 171.11, 169.63, 159.99, 158.54, 151.38, 147.84, 147.69, 144.22, 139.48, 138.77, 132.17, 131.24, 131.14, 129.63, 129.34, 128.61, 128.38, 127.51, 127.41, 120.71, 119.21, 118.04, 117.72, 68.89, 58.72, 56.40, 54.88, 41.66, 37.97, 36.20, 35.24, 31.07, 26.34, 15.92. HRMS m / z calculated for C 41 H 44 N6O5S [M + H] + : 733.3167, found: 733.3154 (1.77 ppm).

[0435] Example 25

[0436] This embodiment provides a compound A25 that targets the degradation of SMARCA protein. The name of compound A25 is: (2S,4R)-4-hydroxy-1-((S)-2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)butyrylamino)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0437] The synthetic route for compound A25, which targets SMARCA protein degradation, is shown below:

[0438]

[0439] The compound A25, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0440] The final product A25 was prepared using 1d, 2b, 4a and 6a as starting materials, following the preparation conditions of A1.

[0441] Pale yellow solid (41 mg, 34% yield).

[0442] 1 H NMR (400MHz, DMSO-d6) δ13.17(s,1H),9.61(d,J=2.2Hz,1H),8.98(s,1H),8.69( d,J=2.2Hz,1H),8.37(d,J=7.8Hz,1H),8.24(dd,J=8.0,1.7Hz,1H),8.03-8.00( m,2H),7.88(d,J=9.3Hz,1H),7.44(t,J=2.2Hz,2H),7.43(d,J=2.2Hz,1H),7.42 (d,J=2.4Hz,2H),7.38(d,J=8.4Hz,2H),7.03(dd,J=8.4,2.1Hz,2H),5.11(d,J= 3.5Hz,1H),4.92(t,J=7.2Hz,1H),4.56(d,J=9.3Hz,1H),4.44(t,J=8.1Hz,1H), 4.29(s,1H),3.63(d,J=3.2Hz,2H),2.66(q,J=8.8,5.2Hz,2H),2.46(s,3H),2.3 4-2.29(m,1H),2.21(d,J=7.1Hz,1H),2.02(t,J=9.7Hz,1H),1.87(d,J=7.5Hz,1 H),1.83(d,J=5.8Hz,1H),1.81-1.76(m,1H),1.38(d,J=7.0Hz,3H),0.96(s,9H). 13C NMR(151MHz,DMSO-d6)δ172.21,171.07,170.08,160.46,158.99,151.92,148.3 6,148.22,145.27,145.11,139.26,132.66,131.67,131.57,130.16,129.89,129 .28,128.91,128.10,126.84,121.27,119.71,118.58,118.19,69.24,59.02,56 .91,56.75,48.16,38.21,35.65,34.93,34.88,27.64,26.94,22.88,16.45.HRMS m / z calculated for C 43 H 48 N6O5S[M+H] + :761.3480,found:761.3459(2.76ppm).

[0443] Example 26

[0444] This embodiment provides a compound A26 that targets the degradation of SMARCA protein. The name of compound A26 is: (2S,4R)-4-hydroxy-1-((S)-2-(4-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)butyrylamino)-3,3-dimethylbutyryl)-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0445] The synthetic route for compound A26, which targets SMARCA protein degradation, is shown below:

[0446]

[0447] The compound A26, which targets SMARCA protein degradation, is prepared by the following steps:

[0448] The final product A26 was prepared using 1d, 2b, 4a and 6b as starting materials, following the preparation conditions of A1.

[0449] Pale yellow solid (55 mg, 38% yield).

[0450] 11H NMR (400 MHz, DMSO-d6) δ 13.19 (s, 1H), 9.60 (d, J = 2.1 Hz, 1H), 8.98 (s, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.57 (t, J = 6.1 Hz, 1H), 8.24 (dd, J = 8.0, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.95 (d, J = 9.4 Hz, 1H), 7.44 (s, 1H), 7.44 (s, 2H), 7.42 (s, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.04 (dd, J = 8.1, 3.8 Hz, 2H), 5.15 (d, J = 3.5 Hz, 1H), 4.59 (d, J = 9.3 Hz, 1H), 4.45 (m, 2H), 4.37 (d, J = 3.6 Hz, 1H), 4.23 (dd, J = 15.9, 5.4 Hz, 1H), 3.69 (d, J = 3.1 Hz, 2H), 2.68 (d, J = 10.0 Hz, 2H), 2.36 - 2.30 (m, 1H), 2.26 - 2.20 (m, 1H), 2.06 (m, 1H), 1.93 (dd, J = 8.6, 4.4 Hz, 1H), 1.88 (d, J = 6.0 Hz, 1H), 1.86 - 1.81 (m, 1H), 0.97 (s, 9H). 13 13C NMR (151 MHz, DMSO-d6) δ 172.40, 172.26, 170.18, 160.46, 159.01, 151.87, 148.34, 148.18, 145.27, 139.97, 139.27, 132.66, 131.65, 131.62, 130.11, 129.89, 129.10, 128.88, 128.09, 127.89, 121.25, 119.71, 118.55, 118.20, 69.36, 59.18, 56.86, 55.37, 42.13, 38.44, 35.68, 34.93, 34.87, 27.64, 26.88, 16.41. HRMS m / z calculated for C 42 H 46 N6O5S [M + H] + : 747.3323, found: 747.3311 (1.61 ppm).

[0451] Example 27

[0452] This embodiment provides a compound A27 that targets the degradation of SMARCA protein. The name of compound A27 is: (2S,4R)-4-hydroxy-1-((S)-2-(1-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)cyclopropane-1-carboxamido)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0453] The synthetic route for compound A27, which targets SMARCA protein degradation, is shown below:

[0454]

[0455] The compound A27, which targets SMARCA protein degradation, is prepared by the following steps:

[0456] The final product A27 was prepared using 1e, 2b, 4a and 6a as starting materials, following the preparation conditions of A1.

[0457] Pale yellow solid (52 mg, 39% yield).

[0458] 1 H NMR (400MHz, DMSO-d6) δ13.16(s,1H),9.69-9.65(m,1H),8.96(s,1H),8.77(s,1H),8.39(d,J=7.5Hz,1H),8.26(d,J=7.9Hz,1H),8.18(d, J=7.9Hz,2H),7.66(d,J=8.0Hz,2H),7.42(d,J=10.5Hz,2H),7.39(s,1H),7.31(d,J=8.0Hz,2H),7.03(dd,J=8.2,3.0Hz,2H),6.07(d,J=9. 2Hz,1H),5.16(d,J=3.5Hz,1H),4.84-4.77(m,1H),4.52(d,J=9.2Hz,1H),4.39(t,J=8.4Hz,1H),4.27(s,1H),3.54(s,2H),2.43(s,3H),2. 06(dd,J=12.8,7.8Hz,1H),1.72(s,1H),1.49(d,J=7.4Hz,1H),1.40(s,1H),1.29(d,J=7.0Hz,3H),1.19(s,1H),1.04(s,1H),0.82(s,9H). 13C NMR(151MHz,DMSO-d6)δ172.04,171.63,169.40,160.55,159.02,151.67,148.26 ,148.10,142.41,139.72,138.54,133.54,132.72,132.05,131.46,130.14,129. 06,128.94,128.59,127.94,121.51,119.70,118.48,118.21,69.37,59.22,57.1 0,57.05,49.07,42.12,38.30,36.85,30.54,26.51,16.27,15.97,15.07.HRMSm / z calculated for C 43 H 46 N6O5S[M+H] + :759.3323,found:759.3302(2.77ppm).

[0459] Example 28

[0460] This embodiment provides a compound A28 that targets the degradation of SMARCA protein. The name of compound A28 is: (2S,4R)-4-hydroxy-1-((S)-2-(1-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)cyclopropane-1-carboxamido)-3,3-dimethylbutyryl)-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0461] The synthetic route for compound A28, which targets SMARCA protein degradation, is shown below:

[0462]

[0463] The compound A28, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0464] The final product A28 was prepared using 1e, 2b, 4a and 6b as starting materials, following the preparation conditions of A1.

[0465] Pale yellow solid (42 mg, 32% yield).

[0466] 11H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.64 (d, J = 2.2 Hz, 1H), 8.85 (s, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.54 (t, J = 6.0 Hz, 1H), 8.23 (dd, J = 8.1, 1.6 Hz, 1H), 8.18 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.43 - 7.39 (m, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.05 - 6.98 (m, 2H), 6.11 (d, J = 9.3 Hz, 1H), 5.18 (d, J = 3.4 Hz, 1H), 4.53 (d, J = 9.3 Hz, 1H), 4.40 (t, J = 8.4 Hz, 1H), 4.34 (s, 1H), 4.24 (d, J = 6.0 Hz, 2H), 3.64 - 3.55 (m, 2H), 2.34 (s, 3H), 2.06 (dd, J = 12.9, 7.7 Hz, 1H), 1.87 (m, 1H), 1.52 - 1.47 (m, 1H), 1.43 - 1.37 (m, 1H), 1.18 (q, J = 4.9, 3.6 Hz, 1H), 1.05 (m, 1H), 0.83 (s, 9H). 13 13C NMR (151 MHz, DMSO-d6) δ 171.14, 170.29, 168.81, 160.09, 158.51, 151.40, 147.86, 147.70, 144.73, 141.89, 138.06, 133.09, 132.24, 131.59, 131.07, 129.64, 128.78, 128.53, 128.16, 126.21, 121.16, 119.25, 118.07, 117.72, 68.77, 58.48, 56.64, 56.58, 48.59, 47.74, 37.73, 36.32, 30.03, 26.08, 22.41, 15.95. HRMS m / z calculated for C 42 H 44 N6O5S [M + H] + : 745.3167, found: 745.3155 (1.61 ppm).

[0467] Example 29

[0468] This embodiment provides compound A29, which targets the degradation of SMARCA protein. The name of compound A29 is: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetamido)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0469] The synthetic route for compound A29, which targets SMARCA protein degradation, is shown below:

[0470]

[0471] The compound A29, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0472] The final product A29 was prepared using 1f, 2b, 4a and 6a as starting materials, following the preparation conditions of A13.

[0473] Pale yellow solid (35 mg, 20% yield).

[0474] 1 H NMR (400MHz, DMSO-d6) δ13.33(s,1H),9.61(d,J=2.2Hz,1H),8.99(s,1H),8.68(d,J=2.2Hz,1H),8.44(d,J=7.7Hz,1H),8.26(dd,J= 7.9,1.7Hz,1H),8.12-8.09(m,2H),7.94(d,J=9.3Hz,1H),7.44(d,J=8.3Hz,2H),7.41(d,J=6.3Hz,2H),7.38(d,J=1.8Hz,1H),7.19- 7.16(m,2H),7.03(d,J=8.2Hz,2H),5.16(d,J=3.5Hz,1H),4.93(t,J=7.2Hz,1H),4.77(d,J=1.7Hz,2H),4.60(d,J=9.4Hz,1H),4.48 (t,J=8.2Hz,1H),4.30(s,1H),3.65-3.58(m,2H),2.46(s,3H),2.06(t,J=10.4Hz,1H),1.83-1.77(m,1H),1.40(s,3H),0.97(s,9H). 13C NMR(151MHz,DMSO-d6)δ170.46,168.98,166.79,159.94,159.74,158.63,15 1.43,147.73,147.61,144.64,138.34,132.16,131.08,129.69,129.17,128. 81,128.33,126.34,126.26,119.99,119.17,117.93,117.74,115.47,68.77 ,66.56,58.61,56.48,56.22,47.73,37.74,35.74,26.32,22.42,15.96.HRMS m / z calculated for C 41 H 44 N6O6S[M+H] + :749.3116,found:749.3098(2.40ppm).

[0475] Example 30

[0476] This embodiment provides a compound A30 that targets the degradation of SMARCA protein. The name of compound A30 is: (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetamido)-3,3-dimethylbutyryl)-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0477] The synthetic route for compound A30, which targets SMARCA protein degradation, is shown below:

[0478]

[0479] The compound A30, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0480] The final product A30 was prepared using 1f, 2b, 4a and 6b as starting materials, following the preparation conditions of A13.

[0481] Pale yellow solid (49 mg, 31% yield).

[0482] 11H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 9.59 (d, J = 2.1 Hz, 1H), 8.98 (s, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.62 (t, J = 6.0 Hz, 1H), 8.25 (dd, J = 8.0, 1.7 Hz, 1H), 8.11 - 8.08 (m, 2H), 8.03 (d, J = 9.3 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 2.4 Hz, 2H), 7.39 (d, J = 1.5 Hz, 1H), 7.18 - 7.15 (m, 2H), 7.03 (m, 2H), 5.19 (d, J = 3.5 Hz, 1H), 4.78 (d, J = 2.5 Hz, 2H), 4.63 (d, J = 9.4 Hz, 1H), 4.48 (d, J = 8.3 Hz, 1H), 4.46 - 4.40 (m, 1H), 4.38 (s, 1H), 4.26 (dd, J = 15.8, 5.6 Hz, 1H), 3.72 - 3.63 (m, 2H), 2.45 (s, 3H), 2.08 (t, J = 10.5 Hz, 1H), 1.93 (m, 1H), 0.98 (s, 9H). 13 13C NMR (151 MHz, DMSO-d6) δ 172.27, 169.60, 167.36, 160.43, 160.28, 159.14, 151.87, 148.20, 148.08, 139.92, 138.84, 132.64, 131.62, 130.​​​​​​​​​​​This embodiment provides a compound A31 that targets the degradation of SMARCA protein. The name of compound A31 is: (2S,4R)-4-hydroxy-1-((S)-2-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)thio)acetamido)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0485] The synthetic route for compound A31, which targets SMARCA protein degradation, is shown below:

[0486]

[0487] The compound A31, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0488] The final product A31 was prepared using 1g, 2b, 4a and 6a as starting materials, respectively, following the preparation conditions of A13.

[0489] Pale yellow solid (35 mg, 22% yield).

[0490] 1 H NMR (400MHz, DMSO-d6) δ13.19(s,1H),9.61(d,J=2.1Hz,1H),8.99(s,1H),8.70(d,J=2.2Hz,1H),8.42(d,J=7.8Hz,1H),8.26-8.23(m ,2H),8.06-8.03(m,2H),7.60-7.57(m,2H),7.44(d,J=8.2Hz,2H),7.41(d,J=1.3Hz,1H),7.39(d,J=8.3Hz,2H),7.05-7.02(m,2H),5. 15(d,J=3.4Hz,1H),4.96-4.91(m,1H),4.54(d,J=9.3Hz,1H),4.47(t,J=8.1Hz,1H),4.30(s,1H),4.03(d,J=14.7Hz,1H),3.86(d,J=1 4.7Hz,1H),3.62(dd,J=11.3,7.4Hz,2H),2.46(s,3H),2.04(dd,J=11.9,8.4Hz,1H),1.82(m,1H),1.39(d,J=7.0Hz,3H),0.93(s,9H). 13C NMR(151MHz,DMSO-d6)δ170.51,169.07,167.40,159.99,158.52,151.42,14 7.73,147.66,144.59,140.05,138.17,132.19,131.08,130.48,129.69,128. 80,128.43,127.95,127.59,126.36,120.57,119.20,118.05,117.71,68.75 ,58.61,56.84,56.39,47.70,37.71,35.58,35.09,26.28,22.38,15.96.HRMS m / z calculated forC 41 H 44 N6O5S2[M+H] + :765.2887,found:765.2869(2.35ppm).

[0491] Example 32

[0492] This embodiment provides a compound A32 that targets the degradation of SMARCA protein. The name of compound A32 is: (2S,4R)-4-hydroxy-1-((S)-2-(2-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)thio)acetamido)-3,3-dimethylbutyryl)-N-(4-(4-methylthiazolyl-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0493] The synthetic route for compound A32, which targets SMARCA protein degradation, is shown below:

[0494]

[0495] The compound A32, which targets the degradation of SMARCA protein, is prepared by the following steps:

[0496] The final product A32 was prepared using 1g, 2b, 4a and 6b as starting materials, respectively, following the preparation conditions of A13.

[0497] Pale yellow solid (38 mg, 30% yield).

[0498] 1H NMR (400MHz, DMSO-d6) δ13.18(s,1H),9.61(d,J=2.2Hz,1H),8.98(s,1H),8.69(d,J=s 2.2Hz,1H),8.60(t,J=6.1Hz,1H),8.30(d,J=9.3Hz,1H),8.23(dd,J=7.9,1.7Hz,1H),8.05-8.02(m,2H),7.60-7.57(m, 2H),7.43(d,J=8.3Hz,2H),7.41(d,J=1.2Hz,1H),7.39(d,J=8.3Hz,2H),7.03(dd,J=8.6,2.4Hz,2H),5.16(d,J=3.5Hz,1 H),4.56(d,J=9.3Hz,1H),4.49-4.46(m,1H),4.46-4.41(m,1H),4.37(s,1H),4.23(dd,J=15.9,5.5Hz,1H),4.04(d,J=14 .6Hz,1H),3.86(d,J=14.7Hz,1H),3.68(t,J=5.3Hz,2H),2.45(s,3H),2.06(t,J=10.3Hz,1H),1.92(m,1H),0.93(s,9H). 13 C NMR(151MHz,DMSO-d6)δ171.82,169.17,167.46,159.98,158.51,151.39,1 47.69,147.65,140.08,139.46,138.17,132.18,131.12,130.45,129.64,1 28.61,128.42,127.93,127.58,127.40,120.56,119.20,118.05,117.70,6 8.84,58.74,56.79,56.47,41.65,37.93,35.58,35.07,26.22,15.92.HRMS m / z calculated for C 40 H 42 N6O5S2[M+H] + :751.2731,found:751.2706(3.33ppm).

[0499] Test Example 1

[0500] Inhibitory activity of the compound against MV-4-11 cells

[0501] Test samples: Compounds A1 to A32 provided in Examples 1 to 32.

[0502] Assay method: Cells at an appropriate density were seeded into 96-well plates. 100 μL of culture medium containing different concentrations of the compound and 20 μL of 5 mg / mL MTT solution were added to each well. The plates were incubated for 2–4 hours, followed by overnight incubation with 50 μL of 10% SDS solution. The absorbance was measured at 570 nm the next day. The IC50 was calculated using GraphPad Prism software. 50 value.

[0503] The test results are shown in Table 1 below:

[0504] Table 1

[0505]

[0506]

[0507] Note: Each compound was tested twice. SD: Standard Deviation.

[0508] As shown in Table 1, the compounds targeting SMARCA protein degradation described in this invention all exhibit certain inhibitory activity against acute myeloid leukemia MV-4-11 cells, with IC50 values ​​of [missing information]. 50 The values ​​ranged from 0.0049 to 10 μM; among them, compounds 10, 11, and 12 showed the most significant inhibitory effects on the proliferation of MV-4-11 cells in acute myeloid leukemia, with IC50 values ​​ranging from 0.0049 to 10 μM. 50 The value can be reduced to below 0.0049 μM.

[0509] Test Example 2

[0510] The efficiency of compound-induced target protein degradation in MV-4-11 cells

[0511] Test samples: Compounds A1 to A32 provided in Examples 1 to 32.

[0512] Assay Method: Cells at appropriate densities were seeded in 6-well plates. Different concentrations of the compound were added for treatment at appropriate times, and cells were collected afterward. Cells were washed with phosphate-buffered saline (PBS), resuspended in RIPA buffer, and lysed. The cell lysate was denatured at high temperature to obtain the sample. The sample was quantitatively loaded onto a sodium dodecyl sulfate polyacrylamide gel (SDS-PAGE). After protein separation using electrophoresis, the sample was transferred to a polyvinylidene fluoride (PVDF) membrane. The bands were blocked, incubated with primary and secondary antibodies, washed, and finally developed using chemiluminescence. The results were analyzed using ImageJ and GraphPad Prism software.

[0513] The test results are shown in Table 2 below:

[0514] Table 2

[0515]

[0516]

[0517] Note:

[0518] ① “A” represents DR≥75%, “B” represents 50%≤DR<75%, “C” represents 25%≤DR<50%, and “D” represents DR<25%.

[0519] ②a Each compound was tested twice; the values ​​in the table represent the average. DR: drgratation rate.

[0520] As shown in Table 2, all compounds targeting SMARCA protein degradation described in this invention can induce the degradation of SMARCA2 and SMARCA4 in MV-4-11 cells; among them, compounds 5, 7, 9, 11 and 13 have the most significant effects on inducing the degradation of SMARCA2 and SMARCA4 in MV-4-11 cells of acute myeloid leukemia, with a DR of ≥75% for SMARCA2 degradation and a DR of ≥75% for SMARCA4 degradation.

[0521] Test Example 3

[0522] The ability of compound A11 to induce the degradation of SMARCA2 / 4

[0523] Test sample: Compound A11 provided in Example 11.

[0524] Assay Method: Cells at appropriate densities were seeded in 6-well plates. Different concentrations of the compound were added for treatment at appropriate times, and cells were collected afterward. Cells were washed with phosphate-buffered saline (PBS), resuspended in RIPA buffer, and lysed. The cell lysate was denatured at high temperature to obtain the sample. The sample was quantitatively loaded onto a sodium dodecyl sulfate polyacrylamide gel (SDS-PAGE). After protein separation using electrophoresis, the sample was transferred to a polyvinylidene fluoride (PVDF) membrane. The bands were blocked, incubated with primary and secondary antibodies, washed, and finally developed using chemiluminescence. The results were analyzed using ImageJ and GraphPad Prism software.

[0525] Test results:

[0526] like Figure 1As shown, compound A11 significantly degrades SMARCA2 / 4 at a low concentration (11.1 nM). Furthermore, the protein level of SMARCA2 / 4 decreases significantly with increasing A11 concentration, indicating that the degradation of SMARCA2 / 4 by A11 is concentration-dependent.

[0527] like Figure 2 As shown, after treating cells with 100 nM compound A11 for 1 hour, a decrease in SMARCA2 / 4 protein levels was observed. After 4 hours of treatment, SMARCA2 / 4 was almost completely degraded. Furthermore, after 24 hours of A11 treatment, complete degradation of intracellular SMARCA2 / 4 was achieved, indicating that the degradation effect of A11 on SMARCA2 / 4 is time-dependent.

[0528] like Figure 3 As shown, when the concentration of A11 was increased from 11.1 nM to 1000 nM for 24 hours, the expression level of mRNA encoding SMARCA2 / 4 was not interfered, indicating that A11-induced SMARCA2 / 4 degradation does not work at the gene level.

[0529] like Figure 4 As shown, when SMARCA2 / 4 bromodomain inhibitor GNE-064, proteasome inhibitor Bortezomib, or ubiquitination pathway inhibitor MLN4924 were co-incubated with A11, the SMARCA2 / 4 protein level recovered, indicating that A11-induced SMARCA2 / 4 degradation depends on the ubiquitin-proteasome pathway.

[0530] Test Example 4

[0531] The ability of compound A11 to inhibit the proliferation of acute myeloid leukemia cells

[0532] Test sample: Compound A11 provided in Example 11.

[0533] Test Method: Cell suspensions in the logarithmic growth phase were seeded into 60 mm culture dishes and treated with different concentrations of drug-containing medium. Simultaneously, a group of cells was treated separately with medium containing 0.1% DMSO as a blank control. Cells were cultured at 37°C in a 5% CO2 incubator. Cell images were taken on days 0, 3, 5, and 7 using the IncuCyte S3 live-cell dynamic imaging and analysis system. The cell count results were analyzed using ImageJ and GraphPad Prism software.

[0534] Test results:

[0535] like Figure 5As shown, after 3 days of treatment with 100 nM compound A11, the number of colonies of MV-4-11 and MOLM-13 cells was significantly reduced. When the treatment time was extended to the 7th day, almost no residual tumor cells were observed, indicating that compound A11 effectively inhibited the proliferation of acute myeloid leukemia cells.

[0536] In summary, this invention provides a compound targeting the degradation of SMARCA2 / 4 protein and its uses. The compound provided by this invention can effectively inhibit the proliferation of acute myeloid leukemia (ICL). 50 The compounds (<50 nM) simultaneously induce the degradation of SMARCA2 and SMARCA4 proteins. The compounds provided by this invention have broad application prospects in the preparation of SMARCA2 / 4 degrading agents and antitumor drugs.

[0537] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A compound targeted to the degradation of a SMARCA protein, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an isotopically substituted thereof, characterized in that, The compound that targets SMARCA protein degradation has the structure shown in Formula III: Formula III; in, R1 is selected from hydrogen or amino groups; R2 is selected from hydrogen or C1~C6 straight-chain or branched alkyl groups; R3 is selected from hydrogen or C1-C6 straight-chain or branched alkyl groups; L is a linking group, selected from any one or a combination of at least two of the following groups: ； wherein representing the position of attachment of the linking group, and the left side of the linking group is attached to X; n is selected from an integer between 1 and 3, R a is selected from oxygen or sulfur.

2. The compound, or a pharmaceutically acceptable salt, or solvate, or isotopic substitute thereof, targeted to degrade a SMARCA protein according to claim 1, wherein The compound that targets SMARCA protein degradation has the structure shown in Formula IV-1: Ⅳ-1； in, R2 is selected from hydrogen or C1~C6 straight-chain or branched alkyl groups; L is a linking group, selected from any one or a combination of at least two of the following groups: 。 3. The compound targeting SMARCA protein degradation according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an isotopic substitute thereof, characterized in that, The compound that targets SMARCA protein degradation has the structure shown in Formula IV-2: Ⅳ-2； in, R2 is selected from hydrogen or C1~C6 straight-chain or branched alkyl groups; L is a linking group, selected from any one or a combination of at least two of the following groups: 。 4. The compound, or a pharmaceutically acceptable salt, or solvate, or isotopic substitute thereof, of targeting SMARCA protein degradation according to claim 1, characterized in that, The compound targeting SMARCA protein degradation is selected from any one of the following compounds A1 to A32: 。 5. Use of a compound targeting SMARCA protein degradation according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a geometrical isomer thereof, or an isotopic substitute thereof, in the preparation of a SMARCA2 / 4 degrading agent.

6. The use of a compound that targets the degradation of SMARCA protein according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an isotopic substitute thereof, in the preparation of a medicament for the prevention and / or treatment of tumors; The tumor includes any one of acute myeloid leukemia, non-small cell lung cancer, melanoma, prostate cancer, or colon cancer.

7. A medicament for targeted degradation of SMARCA2 / 4 proteins, characterized in that, The drug that targets and degrades SMARCA2 / 4 protein includes an active ingredient and pharmaceutically acceptable excipients; The active ingredient comprises any one or a combination of at least two of the compounds that target the degradation of SMARCA protein according to any one of claims 1 to 4, or pharmaceutically acceptable salts thereof, or geometric isomers thereof, or isotopic substitutes thereof.

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