Compound for targeting SMARCA protein degradation and application thereof

Abstract

The invention provides a compound for targeting SMARCA protein degradation and application thereof, and belongs to the field of chemical medicines. The compound for targeting SMARCA protein degradation has a structure as shown in a formula I in the specification. The compound for targeting SMARCA protein degradation can effectively inhibit proliferation of acute myelogenous leukemia cells, and meanwhile, induces degradation of SMRACA2 / 4 protein. The compound provided by the invention has a wide application prospect in preparation of SMARCA2 / 4 degradation agents and antitumor drugs. And the formula I of the # imgabs0 # is shown in the specification.

Description

Technical Field

[0001] The present invention relates to the field of chemical medicine technology, and in particular to a compound targeting SMARCA protein degradation and an application thereof, and in particular to a compound targeting SMARCA2 / 4 protein degradation, 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 an application thereof. Background Art

[0002] Switch defective / sucrose non-fermentable is a highly conserved ATP-dependent chromatin remodeling factor that uses the energy generated by hydrolyzing ATP to maintain the open state of chromatin, mediate the sliding or dissociation of nucleosomes associated with active transcription, and thus regulate the expression of downstream signals. SMARCA2 and SMARCA4 are two homologous and mutually exclusive catalytic subunits of the SWI / SNF complex. The two have high protein sequence homology and both contain an ATPase domain and a bromodomain in their structures. SMARCA4 often undergoes deletion mutations in solid tumors, such as non-small cell lung cancer, colon cancer, and melanoma, and the survival of cancer cells with SMARCA4 deletion is highly dependent on its paralogous gene SMARCA2. In hematological tumors, SMARCA4 acts as the main catalytic subunit and participates in the continuous activation of oncogene expression.

[0003] Small molecule inhibitors developed for different binding sites of SMARCA2 / 4 have limitations, such as competition between ATPase inhibitors and endogenous ATP in cells, and the high homology between SMARCA2 and SMARCA4, which limits the therapeutic window. Bromodomain inhibitors cannot play an anti-cancer role because the bromodomain function does not participate in the tumor development process.

[0004] Protein degradation targeted chimera (PROTAC) technology is an emerging strategy to induce target protein degradation. PROTAC is a class of heterobifunctional molecules that induce target protein degradation. It is composed of three types of chemical fragments: target protein ligand, E3 ubiquitin ligase ligand and linker. This type of compound can bind to the target protein and 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 proposed. Summary of the invention

[0006] The object of the present invention is to provide a compound targeting SMARCA protein degradation and its application. The compound targeting SMARCA protein degradation of the present invention can effectively inhibit the proliferation of acute myeloid leukemia cells and induce the degradation of SMRACA2 / 4 protein.

[0007] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are particularly adopted:

[0008] In a first aspect, the present invention provides a compound targeting SMARCA protein degradation, 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, wherein the compound targeting SMARCA protein degradation has a structure as shown in the following formula I:

[0009]

[0010] in,

[0011] R1 is selected from hydrogen or amino;

[0012] Ring A is selected from an unsubstituted aryl group or a 5- to 6-membered unsaturated heterocyclic group;

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

[0014]

[0015] in, represents the connection position of the group, and the left side of the connecting group is connected to X; n is an integer selected from 1 to 5, R a is 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, represents the attachment position of the group, and R2 and R3 are each independently selected from hydrogen or alkyl.

[0019] Preferably, the compound targeting SMARCA protein degradation has a structure as shown in the following formula II:

[0020]

[0021] in,

[0022] R1 is selected from hydrogen or amino;

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

[0024]

[0025] in, represents the connection position of the group, and the left side of the connecting group is connected to X; n is an integer selected from 1 to 5, R a is 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, represents the attachment position of the group, and R2 and R3 are each independently selected from hydrogen or alkyl.

[0029] Preferably, the compound targeting SMARCA protein degradation has a structure as shown in the following formula III:

[0030]

[0031] in,

[0032] R1 is selected from hydrogen or amino;

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

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

[0035]

[0036] in, represents the connection position of the 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 a structure as shown in the following 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 a structure as shown in the following 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 SMARCA protein degradation as described in the first aspect, wherein the preparation method comprises method 1 and method 2:

[0056] Wherein, method 1 specifically comprises the following steps:

[0057] (i) In the presence of a palladium catalyst and a base, compound 1 and compound 2 react to obtain an intermediate 3, and the reaction formula is as follows:

[0058]

[0059] (ii) In the presence of a palladium catalyst and a base, intermediate 3 reacts with compound 4 to obtain intermediate 5. The reaction formula is shown below:

[0060]

[0061] (iii) Intermediate 5 is first subjected to a hydrolysis reaction in the presence of a base or an acid; and then subjected to 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-C6 straight 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;

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

[0069] Wherein, method 2 specifically includes the following steps:

[0070] (1) In the presence of an iodine reagent and a base, compound 6 and compound 7 react to obtain an intermediate 8. The reaction formula is shown below:

[0071]

[0072] (2) In the presence of a palladium catalyst and a base, intermediate 8 reacts with compound 2 to obtain intermediate 9. The reaction formula is as follows:

[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, and the reaction formula is as follows:

[0075]

[0076] in,

[0077] R1 is selected from hydrogen or amino;

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

[0079] In the third aspect, the present invention provides a compound targeting SMARCA protein degradation 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 isotope substitute thereof, for use in the preparation of a SMARCA2 / 4 degrader.

[0080] In a fourth aspect, the present invention provides a compound targeting SMARCA protein degradation 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 isotope substitute thereof, for use in the preparation of a drug for preventing and / or treating 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] In a fifth aspect, the present invention provides a drug for targeted degradation of SMARCA2 / 4 protein, wherein the drug for targeted degradation of SMARCA2 / 4 protein comprises an active ingredient and a pharmaceutically acceptable excipient;

[0083] Wherein, the active ingredient includes any one or a combination of at least two of the compound targeting SMARCA protein degradation 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 isotope substitute thereof.

[0084] [Term explanation]

[0085] Various aspects and features of the present invention are further described below.

[0086] The various terms and phrases used in the present invention have the general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases. If the terms and phrases mentioned are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail. Below are the definitions of various terms used in the present invention, which apply to the terms used throughout the specification of this application, unless otherwise specified in specific circumstances. The following provides definitions of various groups of the compounds of the present invention, which are used uniformly in the specification unless otherwise defined.

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

[0088] As used herein, the term "aryl" refers to monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) aromatic hydrocarbons, such as phenyl, naphthyl, anthracenyl, phenanthrenyl, indenyl, and the like, and particularly refers to phenyl.

[0089] As mentioned in the present invention, the term "5-6 membered unsaturated heterocyclic group" refers to an aromatic heterocycle (containing 5 to 6 atoms in the ring) having at least one heteroatom ring member such as O, N or S, and specific groups include furanyl, pyrrolyl, thienyl, imidazolyl, pyridyl, pyrimidinyl, thiazolyl, isothiazolyl, and the like.

[0090] As mentioned in the present 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, the "C1-C6 straight-chain or branched alkyl group" refers to a straight-chain alkyl group or a branched alkyl group having 1 to 20 carbon atoms, and specific groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc., and similar groups.

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

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

[0093] As mentioned in the present invention, the term "halogen atom" means fluorine, chlorine, bromine or iodine, and particularly means fluorine or chlorine.

[0094] As mentioned in the present invention, the term "compound", as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, isotopes.

[0095] The compounds of the present invention may be asymmetric, for example, having one or more stereocenters. Unless otherwise specified, all stereoisomers, enantiomers and diastereomers, are possible. Compounds of the present invention containing asymmetrically substituted carbon atoms may be separated into optically pure or racemic forms. Optically pure forms may be prepared by resolution of racemates, or by using chiral synthons or chiral reagents.

[0096] The compounds of the present invention may also include tautomeric forms. Tautomeric forms are generated by the interchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0097] The compounds of the present invention may also include all isotopic forms of atoms present in the intermediates or final compounds. 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 the present invention, the term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or salt formed is generally chemically or physically compatible with other ingredients constituting a pharmaceutical dosage form and physiologically compatible with the receptor.

[0099] As mentioned in the present 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 use value, such as a salt formed as an intermediate when performing chiral separation. Although the salt of this intermediate cannot be directly administered to the subject, the salt can play a role in obtaining the final product of the present invention. The term "pharmaceutically acceptable salt" has two forms: one is a salt formed with an acid; the other is a salt formed with an alkali or an alkali metal, also including zwitterionic salts (inner salts), and also including quaternary ammonium salts, such as alkylammonium salts. These salts can be directly obtained in the final separation and purification of the compound. It can also be obtained by mixing the compound with a certain amount of acid or base appropriately (for example, equivalent amount). These salts may form a precipitate in the solution and be collected by filtration, or be recovered after the solvent is evaporated, or be obtained by freeze-drying after reaction in an aqueous medium. The acid that forms a pharmaceutically acceptable salt with the compound shown in Formula I includes an inorganic acid and an organic acid. The salt can be a hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, 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 the present invention, the term "prodrug" refers to some derivatives of the compound shown in Formula I that are converted into the compound shown in Formula I in vivo by means of in vivo metabolism (e.g., hydrolysis, reduction or oxidation), and these derivatives are called prodrugs. For example, the compound shown in Formula I and containing a hydroxyl group can be reacted with an acid to prepare a corresponding ester, and the prepared ester is a prodrug that can hydrolyze the parent drug in vivo.

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

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

[0103] (2) The compounds targeting SMARCA protein degradation described in the present invention have broad application prospects in the preparation of SMARCA2 / 4 degraders, anti-tumor drugs and drugs targeting protein degradation. BRIEF DESCRIPTION OF THE DRAWINGS

[0104] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0105] Figure 1 This is a graph showing the degradation ability of compound A11 on SMARCA2 / 4 protein at different treatment concentrations.

[0106] Figure 2 This is a graph showing the degradation ability of compound A11 on SMARCA2 / 4 protein at different treatment times.

[0107] Figure 3 This is a diagram of the genetic regulation study on compound A11-induced SMARCA2 / 4 protein degradation.

[0108] Figure 4 Diagram for studying the protein level pathway of compound A11-induced SMARCA2 / 4 protein degradation.

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

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

[0111] It should be noted that specific details are described in the following description to facilitate a full understanding of the present invention. However, the present invention can be implemented in a variety of other ways different from those described herein, and those skilled in the art can make similar generalizations without violating the connotation of the present invention. Therefore, the present 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 in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0113] In a first aspect, the present invention provides a compound targeting SMARCA protein degradation, 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, wherein the compound targeting SMARCA protein degradation has a structure as shown in the following formula I:

[0114]

[0115] in,

[0116] R1 is selected from hydrogen or amino;

[0117] Ring A is selected from an unsubstituted aryl group or a 5- to 6-membered unsaturated heterocyclic group;

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

[0119]

[0120] in, represents the connection position of the group, and the left side of the connecting group is connected to X; n is an integer selected from 1 to 5, R a is 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, represents the attachment position of the group, and R2 and R3 are each independently selected from hydrogen or alkyl.

[0124] In the present invention, a class of compounds targeting SMARCA2 / 4 protein degradation and their uses are provided. The compounds provided by the present invention can effectively inhibit the proliferation of acute myeloid leukemia (IC 50 <50 nM), and simultaneously induces the degradation of SMARCA2 and SMARCA4 proteins. The compounds provided by the present invention have broad application prospects in the preparation of SMARCA2 / 4 degradation agents and anti-tumor drugs.

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

[0126] As an optional embodiment, ring A is selected from an unsubstituted aryl group or a 5-6-membered unsaturated heterocyclic group, for example, it can be any one of phenyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyridyl, pyrimidyl, thiazolyl, isothiazolyl, preferably phenyl. Preferably

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

[0128] As an optional embodiment, R2 is selected from hydrogen or a C1-C6 linear or branched alkyl group, for example, it can be any one of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

[0129] As an optional embodiment, R3 is selected from hydrogen or a C1-C6 linear or branched alkyl group, for example, it can be any one of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

[0130] As an optional embodiment, the compound targeting SMARCA protein degradation has a structure as shown in the following formula II:

[0131]

[0132] in,

[0133] R1 is selected from hydrogen or amino;

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

[0135]

[0136] in, represents the connection position of the group, and the left side of the connecting group is connected to X; n is an integer selected from 1 to 5, R a is 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, represents the attachment position of the group, and R2 and R3 are each independently selected from hydrogen or alkyl.

[0140] As an optional embodiment, the compound targeting SMARCA protein degradation has a structure as shown in the following formula III:

[0141]

[0142] in,

[0143] R1 is selected from hydrogen or amino;

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

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

[0146]

[0147] in, represents the connection position of the 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 embodiment, the compound targeting SMARCA protein degradation has a structure as shown in the following 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 embodiment, the compound targeting SMARCA protein degradation has a structure as shown in the following 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 embodiment, 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 SMARCA protein degradation as described in the first aspect, the preparation method comprising the following steps:

[0167] The preparation method includes method one and method two.

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

[0169] (i) In the presence of a palladium catalyst and a base, compound 1 and compound 2 react to obtain an intermediate 3, and the reaction formula is as follows:

[0170]

[0171] (ii) In the presence of a palladium catalyst and a base, intermediate 3 reacts with compound 4 to obtain intermediate 5. The reaction formula is shown below:

[0172]

[0173] (iii) Intermediate 5 is first subjected to a hydrolysis reaction in the presence of a base or an acid; and then subjected to 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-C6 straight 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;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0200] As an optional embodiment, in step (iii), the hydrolysis reaction temperature is 20 to 30° C., and the time is 0.5 to 24 h.

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

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

[0203] As an optional embodiment, in step (iii), the condensation reaction temperature is 0 to 30° C., and the reaction time is 1 to 3 hours.

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

[0205] As an optional implementation, method 2 specifically includes the following steps:

[0206] (1) In the presence of an iodine reagent and a base, compound 6 and compound 7 react to obtain an intermediate 8. The reaction formula is shown below:

[0207]

[0208] (2) In the presence of a palladium catalyst and a base, intermediate 8 reacts with compound 2 to obtain intermediate 9. The reaction formula is as follows:

[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, and the reaction formula is as follows:

[0211]

[0212] in,

[0213] R1 is selected from hydrogen or amino;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0233] In the third aspect, the present invention provides a compound targeting SMARCA protein degradation 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 isotope substitute thereof, for use in the preparation of a SMARCA2 / 4 degrader.

[0234] In a fourth aspect, the present invention provides a compound targeting SMARCA protein degradation 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 isotope substitute thereof, for use in the preparation of a drug for preventing and / or treating tumors.

[0235] As an optional embodiment, 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] In a fifth aspect, the present invention provides a drug for targeted degradation of SMARCA2 / 4 protein, wherein the drug for targeted degradation of SMARCA2 / 4 protein comprises an active ingredient and a pharmaceutically acceptable excipient;

[0237] Wherein, the active ingredient includes any one or a combination of at least two of the compound targeting SMARCA protein degradation 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 isotope substitute thereof.

[0238] The present invention is further described below by way of examples. Unless otherwise specified, the materials in the examples are prepared according to existing methods or directly purchased from the market.

[0239] Example 1

[0240] This embodiment provides compound A1 for targeting SMARCA protein degradation, and compound A1 is named: (2S, 4R)-1-((S)-2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0241] The synthetic route of the compound A1 targeting SMARCA protein degradation is as follows:

[0242]

[0243] The compound A1 targeting 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.), sodium carbonate (318 mg, 3 mmol, 2 equiv.) were dissolved in a mixed system (25 mL, 1,4-dioxane: water = 4:1), nitrogen was protected, and refluxed at 100°C for 4 hours. When the reaction was completed, the solvent was removed by rotary evaporation, and palladium dichloride and some inorganic salts were removed by diatomaceous earth filtration. After purification by thin layer chromatography, intermediate 3a was obtained.

[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.), potassium carbonate (332 mg, 2.4 mmol, 2 equiv.) were dissolved in a mixed system (25 mL, 1,4-dioxane: water = 4:1), nitrogen was protected, and the reaction was refluxed at 90°C for 3 hours. When the reaction was completed, the solvent was distilled off under reduced pressure, and palladium and inorganic salts were removed by diatomaceous earth filtration. The intermediate 5a was separated and purified by thin layer chromatography.

[0246] (iii) 5a (0.56 mmol, 1 equiv.) and lithium hydroxide (95 mg, 2.24 mmol, 4 equiv.) were dissolved in a mixture (10 mL, methanol: water = 4:1) and allowed to stand overnight at room temperature. When the reaction was complete, the solvent was removed by distillation under reduced pressure. Water was added to dissolve the compound, and the pH was adjusted to weak acidity with 1N hydrochloric acid. The precipitate was filtered and dried. The solid obtained by hydrolysis (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 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 was complete, the organic phase was repeatedly extracted three times with a system of ethyl acetate and water and backwashed once with a saturated sodium chloride solution. The organic phases from the three extractions were combined, and the solvent was removed by using a neutral salt drying agent and a rotary evaporator to obtain the final product A1, a light 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 compound A2 that targets SMARCA protein degradation. Compound A2 is named: (2S, 4R)-1-((S)-2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)benzamido)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0250] The synthetic route of the compound A2 targeting SMARCA protein degradation is as follows:

[0251]

[0252] The compound A2 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0254] Light 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 SMARCA protein degradation. Compound A3 is named: (2S, 4R)-1-((S)-2-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)benzyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0258] The synthetic route of the compound A3 targeting SMARCA protein degradation is as follows:

[0259]

[0260] The compound A3 targeting SMARCA protein degradation 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.), 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 completed, the organic phase was repeatedly extracted three times with a system of ethyl acetate and water and backwashed once with a saturated sodium chloride solution. The organic phases extracted three times were combined and the solvent was removed by a neutral salt drying agent 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.), sodium carbonate (68 mg, 0.64 mmol, 2 equiv.) were dissolved in a mixed system (10 mL, 1,4-dioxane: water = 4:1), protected by nitrogen, and refluxed at 100°C for 4 hours. When the reaction was completed, the solvent was removed by rotary evaporation, and palladium dichloride and inorganic salts were removed by diatomaceous earth filtration. Intermediate 9a was separated and purified by thin layer chromatography.

[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.), potassium carbonate (56 mg, 0.4 mmol, 2 equiv.) were dissolved in a mixed system (10 mL, 1,4-dioxane: water = 4:1), protected by nitrogen, and refluxed at 90°C for 3 hours. When the reaction was completed, the solvent was distilled off under reduced pressure, and palladium and inorganic salts were removed by diatomaceous earth filtration. The final product A3 was obtained by separation and purification by thin layer chromatography.

[0264] Light 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 that targets SMARCA protein degradation. Compound A4 is named: (2S, 4R)-1-((S)-2-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)benzyl)amino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0267] The synthetic route of the compound A4 targeting SMARCA protein degradation is as follows:

[0268]

[0269] The compound A4 targeting SMARCA protein degradation is prepared by the following steps:

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

[0271] Light 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] + : 706.3170, found: 706.3160 (1.42 ppm).

[0273] Example 5

[0274] This embodiment provides compound A5 that targets SMARCA protein degradation. Compound A5 is named: (2S, 4R)-1-((S)-2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)acetylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0275] The synthetic route of the compound A5 targeting SMARCA protein degradation is as follows:

[0276]

[0277] The compound A5 targeting 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 respectively, following the preparation conditions of A1.

[0279] Light 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 compound A6 that targets SMARCA protein degradation. Compound A6 is named: (2S, 4R)-1-((S)-2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)acetylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0283] The synthetic route of the compound A6 targeting SMARCA protein degradation is as follows:

[0284]

[0285] The compound A6 targeting SMARCA protein degradation is prepared by the following steps:

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

[0287] Light 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 that targets SMARCA protein degradation. Compound A7 is named: (2S, 4R)-1-((S)-2-(3-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)propylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0291] The synthetic route of the compound A7 targeting SMARCA protein degradation is as follows:

[0292]

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

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

[0295] Light 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 compound A8 targeting SMARCA protein degradation, and compound A8 is named: (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-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0299] The synthetic route of the compound A8 targeting SMARCA protein degradation is as follows:

[0300]

[0301] The compound A8 targeting 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, respectively, following the preparation conditions of A1.

[0303] Light 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 that targets SMARCA protein degradation. Compound A9 is named: (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-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0307] The synthetic route of the compound A9 targeting SMARCA protein degradation is as follows:

[0308]

[0309] The compound A9 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0311] Light 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 example provides a compound A10 targeting SMARCA protein degradation. 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-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0315] The synthetic route of the compound A10 targeting SMARCA protein degradation is as follows:

[0316]

[0317] The compound A10 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0319] Light 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 compound A11 targeting SMARCA protein degradation, and compound A11 is named: (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-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0323] The synthetic route of the compound A11 targeting SMARCA protein degradation is as follows:

[0324]

[0325] The compound A11 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0327] Light 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 compound A12 that targets SMARCA protein degradation. Compound A12 is named: (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-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0331] The synthetic route of the compound A12 targeting SMARCA protein degradation is as follows:

[0332]

[0333] The compound A12 targeting SMARCA protein degradation is prepared by the following steps:

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

[0335] Light 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, 30.61, 26.62, 16.39, 16.01, 15.06. HRMS m / z calculated for C 42 H 45 N7O5S [M + H] + : 760.3276, found: 760.3252 (3.16 ppm)

[0337] Example 13

[0338] This embodiment provides compound A13 targeting SMARCA protein degradation, and compound A13 is named: (2S, 4R)-1-((S)-2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0339] The synthetic route of the compound A13 targeting SMARCA protein degradation is as follows:

[0340]

[0341] The compound A13 targeting SMARCA protein degradation is specifically 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.), sodium carbonate (102 mg, 0.96 mmol, 2 equiv.) were dissolved in a mixed system (25 mL, 1,4-dioxane: water = 4:1), nitrogen was protected, and refluxed at 100 ° C for 4 hours. When the reaction was completed, the solvent was removed by rotary evaporation, and palladium dichloride and inorganic salts were removed by diatomaceous earth filtration. After purification by thin layer chromatography, intermediate 3f was obtained.

[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.), potassium carbonate (100 mg, 0.72 mmol, 2 equiv.) were dissolved in a mixed system (10 mL, 1,4-dioxane: water = 4:1), nitrogen was protected, and refluxed at 90°C for 3 hours. When the reaction was completed, the solvent was distilled off under reduced pressure, and palladium and inorganic salts were removed by diatomaceous earth filtration. After separation and purification by thin layer chromatography, intermediate 5f was obtained.

[0344] (iii) 5f (0.2 mmol, 1 equiv.) and trifluoroacetic acid (5 mL) were dissolved in 5 mL of dichloromethane and reacted at room temperature overnight. When the reaction was complete, the solvent was removed by distillation under reduced pressure. The solid obtained after oil pump drying was directly subjected to the next step of the reaction. The solid obtained after oil pump drying (0.2 mmol, 1 equiv.), 6a (0.2 mmol, 1 equiv.), HATU (114 mg, 0.3 mmol, 1.5 equiv.), N,N-diisopropylethylamine (78 mg, 0.6 mmol, 3 equiv.) were 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 was complete, the organic phase was repeatedly extracted three times with a system of ethyl acetate and water and backwashed once with a saturated sodium chloride solution. The organic phases extracted three times were combined, and the solvent was removed by a neutral salt drying agent and a rotary evaporator to obtain the final product A13.

[0345] Light 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] Embodiment 14

[0348] This embodiment provides compound A14 targeting SMARCA protein degradation, and compound A14 is named: (2S, 4R)-1-((S)-2-(2-(4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0349] The synthetic route of the compound A14 targeting SMARCA protein degradation is as follows:

[0350]

[0351] The compound A14 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0353] Light 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] Embodiment 15

[0356] This embodiment provides compound A15 targeting SMARCA protein degradation, and compound A15 is named: (2S,4R)-1-((S)-2-(2-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)thio)acetylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0357] The synthetic route of the compound A15 targeting SMARCA protein degradation is as follows:

[0358]

[0359] The compound A15 targeting SMARCA protein degradation is specifically 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] Light 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 compound A16 targeting SMARCA protein degradation, and compound A16 is named: (2S, 4R)-1-((S)-2-(2-((4-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)thio)acetylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0365] The synthetic route of the compound A16 targeting SMARCA protein degradation is as follows:

[0366]

[0367] The compound A16 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0369] Light 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 compound A17 that targets SMARCA protein degradation. Compound A17 is named: (2S, 4R)-4-hydroxy-1-((S)-2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)benzamido)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0373] The synthetic route of the compound A17 targeting SMARCA protein degradation is as follows:

[0374]

[0375] The compound A17 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0377] Light 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] Embodiment 18

[0380] This example provides a compound A18 targeting SMARCA protein degradation. The compound A18 is named as: (2S, 4R)-4-hydroxy-1-((S)-2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)benzamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0381] The synthetic route of the compound A18 targeting SMARCA protein degradation is as follows:

[0382]

[0383] The compound A18 targeting SMARCA protein degradation is prepared by the following steps:

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

[0385] Light 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, 169.82, 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 compound A19 targeting SMARCA protein degradation, and compound A19 is named: (2S, 4R)-4-hydroxy-1-((S)-2-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)benzyl)amino)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0389] The synthetic route of the compound A19 targeting SMARCA protein degradation is as follows:

[0390]

[0391] The compound A19 targeting SMARCA protein degradation 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] Light 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] Embodiment 20

[0396] This embodiment provides compound A20 targeting SMARCA protein degradation, and compound A20 is named: (2S, 4R)-4-hydroxy-1-((S)-2-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)benzyl)amino)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0397] The synthetic route of the compound A20 targeting SMARCA protein degradation is as follows:

[0398]

[0399] The compound A20 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0401] Light 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, 131.18, 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 39 C 42 H + N6O4S [M + H]

[0403] Example 21

[0404] This embodiment provides compound A21 targeting SMARCA protein degradation, and compound A21 is named: (2S, 4R)-4-hydroxy-1-((S)-2-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)acetylamino)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0405] The synthetic route of the compound A21 targeting SMARCA protein degradation is as follows:

[0406]

[0407] The compound A21 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0409] Light 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] Embodiment 22

[0412] This embodiment provides compound A22 targeting SMARCA protein degradation. Compound A22 is named: (2S, 4R)-4-hydroxy-1-((S)-2-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)acetylamino)-3,3-dimethylbutyryl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0413] The synthetic route of the compound A22 targeting SMARCA protein degradation is as follows:

[0414]

[0415] The compound A22 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0417] Light 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] Embodiment 23

[0420] This embodiment provides compound A23 targeting SMARCA protein degradation, and compound A23 is named: (2S, 4R)-4-hydroxy-1-((S)-2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)propionamido)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0421] The synthetic route of the compound A23 targeting SMARCA protein degradation is as follows:

[0422]

[0423] The compound A23 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0425] Light 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] Embodiment 24

[0428] This embodiment provides compound A24 targeting SMARCA protein degradation, and compound A24 is named: (2S, 4R)-4-hydroxy-1-((S)-2-(3-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)propylamino)-3,3-dimethylbutyryl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0429] The synthetic route of the compound A24 targeting SMARCA protein degradation is as follows:

[0430]

[0431] The compound A24 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0433] Light 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 compound A25 targeting SMARCA protein degradation, and compound A25 is named: (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-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0437] The synthetic route of the compound A25 targeting SMARCA protein degradation is as follows:

[0438]

[0439] The compound A25 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0441] Light 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] Embodiment 26

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

[0445] The synthetic route of the compound A26 targeting SMARCA protein degradation is as follows:

[0446]

[0447] The compound A26 targeting 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, respectively, following the preparation conditions of A1.

[0449] Light 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 compound A27 that targets SMARCA protein degradation. Compound A27 is named: (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-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0453] The synthetic route of the compound A27 targeting SMARCA protein degradation is as follows:

[0454]

[0455] The compound A27 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0457] Light 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] Embodiment 28

[0460] This embodiment provides compound A28 targeting SMARCA protein degradation, and compound A28 is named: (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-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0461] The synthetic route of the compound A28 targeting SMARCA protein degradation is as follows:

[0462]

[0463] The compound A28 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0465] Light 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 that targets SMARCA protein degradation. Compound A29 is named: (2S, 4R)-4-hydroxy-1-((S)-2-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetylamino)-3,3-dimethylbutyryl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0469] The synthetic route of the compound A29 targeting SMARCA protein degradation is as follows:

[0470]

[0471] The compound A29 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0473] Light 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] Embodiment 30

[0476] This embodiment provides compound A30 targeting SMARCA protein degradation, and compound A30 is named: (2S, 4R)-4-hydroxy-1-((S)-2-(2-(4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenoxy)acetylamino)-3,3-dimethylbutyryl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0477] The synthetic route of the compound A30 targeting SMARCA protein degradation is as follows:

[0478]

[0479] The compound A30 targeting SMARCA protein degradation is specifically prepared by the following steps:

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

[0481] Light 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, 130.17, 129.63, 129.14, 128.79, 127.94, 126.69, 120.44, 119.64, 118.38, 118.23, 115.94, 69.37, 67.01, 59.27, 57.03, 56.71, 42.18, 38.42, 36.20, 26.76, 16.40. HRMS m / z calculated for C 40 H 42 N6O6S [M + H] + : 735.2959, found: 735.2944 (2.04 ppm).

[0483] Example 31

[0484] This embodiment provides compound A31 targeting SMARCA protein degradation, and compound A31 is named: (2S, 4R)-4-hydroxy-1-((S)-2-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)thio)acetylamino)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide.

[0485] The synthetic route of the compound A31 targeting SMARCA protein degradation is as follows:

[0486]

[0487] The compound A31 targeting SMARCA protein degradation is specifically 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] Light 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] Embodiment 32

[0492] This embodiment provides compound A32 targeting SMARCA protein degradation, and compound A32 is named: (2S, 4R)-4-hydroxy-1-((S)-2-(2-((4-(6-(2-hydroxyphenyl)pyridazin-4-yl)phenyl)thio)acetylamino)-3,3-dimethylbutyryl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide.

[0493] The synthetic route of the compound A32 targeting SMARCA protein degradation is as follows:

[0494]

[0495] The compound A32 targeting SMARCA protein degradation is specifically 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] Light 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 compounds against MV-4-11 cells

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

[0502] Test method: Cells of appropriate density were inoculated in a 96-well plate, and 100 μL of culture medium containing different concentrations of compounds and 20 μL of 5 mg / mL MTT solution were added to each well. Incubate in an incubator for 2-4 hours, then add 50 μL of 10% SDS solution to each well overnight, and measure the absorbance at a wavelength of 570 nm the next day. The measured results were calculated using GraphPad Prism software to calculate the IC 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 of the present invention have certain proliferation inhibition activity on acute myeloid leukemia MV-4-11 cells, and their IC 50 The values ​​ranged from 0.0049 to 10 μM. Among them, compound 10, compound 11, and compound 12 had the most significant inhibitory effects on the proliferation of MV-4-11 cells of acute myeloid leukemia. Their IC 50 The value can drop below 0.0049 μM.

[0509] Test Example 2

[0510] Efficiency of compounds inducing target protein degradation in MV-4-11 cells

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

[0512] Test method: Cells of appropriate density were inoculated in 6-well plates, and different concentrations of compounds were added for corresponding treatment time and then the cells were collected. The cells were washed with phosphate buffered saline (PBS), and then resuspended and lysed with RIPA buffer. The cell lysate denatured the protein in a high temperature environment to prepare the sample. The sample was quantitatively loaded into sodium dodecyl sulfate polyacrylamide gel (SDS-PAGE), and the protein was separated by electrophoresis and transferred to polyvinylidene fluoride (PVDF) membrane. The bands were blocked, incubated with primary and secondary antibodies, washed, and finally developed with luminescent solution. The results were analyzed by Image J 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, and the values ​​in the table represent the average value. DR: drgratation rate.

[0520] As shown in Table 2, the compounds targeting SMARCA protein degradation of the present invention can induce the degradation of SMARCA2 and SMARCA4 in MV-4-11 cells; among them, compound 5, compound 7, compound 9, compound 11 and compound 13 have the most obvious effect on the degradation of SMARCA2 and SMARCA4 in MV-4-11 cells of acute myeloid leukemia, with DR of SMARCA2 degradation ≥ 75%, and DR of SMARCA4 degradation ≥ 75%.

[0521] Test Example 3

[0522] Ability of compound A11 to induce SMARCA2 / 4 degradation

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

[0524] Test method: Cells of appropriate density were inoculated in 6-well plates, and different concentrations of compounds were added for corresponding treatment time and then the cells were collected. The cells were washed with phosphate buffered saline (PBS), and then resuspended and lysed with RIPA buffer. The cell lysate denatured the protein in a high temperature environment to prepare the sample. The sample was quantitatively loaded into sodium dodecyl sulfate polyacrylamide gel (SDS-PAGE), and the protein was separated by electrophoresis and transferred to polyvinylidene fluoride (PVDF) membrane. The bands were blocked, incubated with primary and secondary antibodies, washed, and finally developed with luminescent solution. The results were analyzed by Image J and GraphPad Prism software.

[0525] Test results:

[0526] like Figure 1As shown, compound A11 can significantly degrade SMARCA2 / 4 at a relatively low concentration (11.1 nM). And as the concentration of A11 increases, the level of SMARCA2 / 4 protein decreases significantly. This indicates that the effect of A11 in degrading SMARCA2 / 4 is concentration-dependent.

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

[0528] like Figure 3 As shown, when the A11 concentration increased from 11.1nM to 1000nM to treat cells for 24 hours, it did not interfere with the mRNA expression level encoding SMARCA2 / 4, indicating that A11 induced SMARCA2 / 4 degradation not through the regulatory gene level.

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

[0530] Test Example 4

[0531] Ability of compound A11 to inhibit proliferation of acute myeloid leukemia cells

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

[0533] Test method: Inoculate the cell suspension in the logarithmic growth phase into a 60mm culture dish, add different concentrations of drug-containing culture medium for treatment, and at the same time, treat a group of cells with a culture medium containing 0.1% DMSO alone as a blank control. Culture the cells in an incubator at 37°C and 5% CO2. Take photos of the cells on days 0, 3, 5, and 7 using the IncuCyte S3 live cell dynamic imaging and analysis system. The counting results were analyzed using image J and GraphPad Prism software.

[0534] Test results:

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

[0536] In summary, the present invention provides a compound targeting SMARCA2 / 4 protein degradation and its use. The compound provided by the present invention can effectively inhibit the proliferation of acute myeloid leukemia (IC 50 <50 nM), and simultaneously induces the degradation of SMARCA2 and SMARCA4 proteins. The compounds provided by the present invention have broad application prospects in the preparation of SMARCA2 / 4 degradation agents and anti-tumor drugs.

[0537] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements 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 targeting SMARCA protein degradation, 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, characterized in that: The compound targeting SMARCA protein degradation has a structure as shown in the following formula I: in, R1 is selected from hydrogen or amino; Ring A is selected from an unsubstituted aryl group or a 5- to 6-membered unsaturated heterocyclic group; L is a linking group selected from any one or a combination of at least two of the following groups: in, represents the connection position of the group, and the left side of the connecting group is connected to X; n is an integer selected from 1 to 5, R a is selected from oxygen or sulfur; X is an E3 ligase ligand selected from any one or a combination of two of the following groups: in, represents the attachment position of the group, and R2 and R3 are each independently selected from hydrogen or alkyl.

2. The compound targeting SMARCA protein degradation according to claim 1, 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, characterized in that: The compound targeting SMARCA protein degradation has a structure shown in the following formula II: in, R1 is selected from hydrogen or amino; L is a linking group selected from any one or a combination of at least two of the following groups: in, represents the connection position of the group, and the left side of the connecting group is connected to X; n is an integer selected from 1 to 5, R a is selected from oxygen or sulfur; X is an E3 ligase ligand selected from any one or a combination of two of the following groups: in, represents the attachment position of the group, and R2 and R3 are each independently selected from hydrogen or alkyl.

3. The compound targeting SMARCA protein degradation according to claim 1 or 2, 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, characterized in that: The compound targeting SMARCA protein degradation has a structure as shown in the following formula III: in, R1 is selected from hydrogen or amino; R2 and R3 are each independently selected from hydrogen or alkyl; L is a linking group selected from any one or a combination of at least two of the following groups: in, represents the connection position of the 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.

4. The compound targeting SMARCA protein degradation according to claim 3, 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, characterized in that: The compound targeting SMARCA protein degradation has a structure as shown in the following formula IV-1: in, R2 is selected from hydrogen or alkyl; L is a linking group selected from any one or a combination of at least two of the following groups:

5. The compound targeting SMARCA protein degradation according to claim 3, 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, characterized in that: The compound targeting SMARCA protein degradation has a structure as shown in the following formula IV-2: in, R2 is selected from hydrogen or alkyl; L is a linking group selected from any one or a combination of at least two of the following groups:

6. The compound targeting SMARCA protein degradation according to claim 1, 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, characterized in that: The compound targeting SMARCA protein degradation is selected from any one of the following compounds A1 to A32:

7. Use of a compound targeting SMARCA protein degradation according to any one of claims 1 to 6, 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 in the preparation of a SMARCA2 / 4 degrader.

8. Use of a compound targeting SMARCA protein degradation according to any one of claims 1 to 6, 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 in the preparation of a drug for preventing and / or treating tumors.

9. The use according to claim 8, characterized in that: The tumor includes any one of acute myeloid leukemia, non-small cell lung cancer, melanoma, prostate cancer or colon cancer.

10. A drug for targeted degradation of SMARCA2 / 4 protein, characterized in that: The drug for targeted degradation of SMARCA2 / 4 protein comprises an active ingredient and a pharmaceutically acceptable excipient; Wherein, the active ingredient includes any one or a combination of at least two of the compound targeting SMARCA protein degradation according to any one of claims 1 to 6, 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.

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