SMARCA2 degradation agent and application thereof

Abstract

The invention relates to an SMARCA2 degradation agent and application thereof, and provides a compound which is shown in a formula I and has an SMARCA2 protein degradation effect and application of the compound in preparation of medicines for treating diseases related to SMARCA2 activity. X-Y-Z is represented by formula I.

Description

Technical Field

[0001] The present invention relates to a compound with SMARCA2 protein degradation function and use thereof in preparing medicines for diseases related to SMARCA2 activity. Background Art

[0002] The mammalian SWI / SNF chromosome remodeling complex drives nucleosome movement by utilizing the energy released by hydrolyzing ATP, thereby participating in key cellular processes such as chromosome structure regulation and DNA repair. Its function is conferred by two mutually exclusive ATP-dependent helicases, SMARCA2 or SMARCA4, whose protein sequences have a high degree of homology. In recent years, SWI / SNF has attracted great attention in cancer biology. Tumor sequencing studies have shown that about 20% of human cancers have mutations in specific core or auxiliary components of the complex. Loss-of-function mutations in the SMARCA4 gene are common in a variety of malignant tumors, including 10-20% of non-small cell lung cancer, 100% of small cell ovarian cancer, 28% of skin cancer, 16% of gliomas, and 14% of colon cancer. In SMARCA4 mutant cancer cells, due to the loss of the SMARCA4 gene, cancer cells will rely on the paralogous SMARCA2 gene for DNA structure regulation and repair. Therefore, selective SMARCA2 inhibitors can induce the death of SMARCA4-deficient cancer cells.

[0003] However, due to the high similarity of SMARCA2 and SMARCA4 protein sequences, small molecule inhibitors targeting this target currently have problems such as poor selectivity, difficulty in drug development, and high toxicity, and cannot be used in clinical practice. Recently, with the vigorous development of PROTAC technology, selective SMARCA2 protein degraders have become a new direction for drug development. Compared with traditional small molecule inhibitors, PROTAC has the opportunity to avoid off-target effects, reduce some serious adverse reactions caused by traditional small molecule inhibitors, and has the potential to solve drug resistance problems.

[0004] Ubiquitin is a small molecule protein that exists in eukaryotic cells and consists of 76 amino acids with a highly conserved sequence. The main function of ubiquitin is to mark target proteins, which can be recognized and degraded by proteasomes. This process is called the ubiquitin / proteasome system. Among them, E3 ubiquitin-protein ligase directly binds to proteins, determining the specificity of degradation. The degradation process of the ubiquitin / proteasome system mainly includes the following four steps: 1) Ubiquitin activation: the carboxyl residue of ubiquitin combines with the thiol group of the ubiquitin activating enzyme E1; 2) Ubiquitin cross-linking: E1 transfers the activated ubiquitin to the ubiquitin-binding enzyme E2 through the transesterification process; 3) E3 binds the ubiquitin complex to the target protein: the ubiquitin-protein ligase E3 connects the ubiquitin bound to E2 to the target protein. If ubiquitin already exists on the target protein, the ubiquitin bound to E2 can be directly connected to the target protein; 4) Proteasome degradation: the proteasome recognizes the marked target protein, thereby hydrolyzing the target protein into a peptide chain of 7-8 amino acids in length, completing the degradation of the target protein.

[0005] The proteolysis targeting chimeric molecule is a bifunctional molecule that can bind to E3 ubiquitin ligase and target protein at the same time, ubiquitinating the target protein that cannot bind to E3 and selectively degrading it through the ubiquitin / proteasome system, thereby controlling the level of target protein in cells. The current E3 ubiquitin ligases mainly include CRBN, VHL, MDM2 and c IAP1, etc. Summary of the invention

[0006] The present invention provides a compound having a SMARCA2 protein degradation function and use thereof in preparing medicines for diseases related to SMARCA2 activity.

[0007] The technical solution of the present invention is as follows:

[0008] The present invention provides a compound represented by formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof:

[0009] XYZ

[0010] Formula I

[0011] in,

[0012] X is a group that binds to the SMARCA2 protein;

[0013] Y is a linking group;

[0014] Z is a group that binds to E3 ubiquitin ligase.

[0015] According to some embodiments of the present invention, X is selected from

[0016] Wherein, the A ring is selected from 3-10 membered cycloalkanes, 3-10 membered heterocycloalkanes, 6-10 aromatic rings or 5-10 membered aromatic heterocycles; wherein the cycloalkanes, heterocycloalkanes, aromatic rings or aromatic heterocycles may be further replaced by one, two or three R A1 replace;

[0017] Each R A1 is selected from hydrogen, halogen, cyano, nitro, =O, -OH, -C1~6 alkyl, halogen-substituted -C1~6 alkyl, -O(C1~6 alkyl), -O(halogen-substituted C1~6 alkyl), -NH2, -NH(C1~6 alkyl), -N(C1~6 alkyl)(C1~6 alkyl), -C0~2 alkylene-(3~12-membered cycloalkyl), -C0~2 alkylene-(3~12-membered heterocycloalkyl), -C0~2 alkylene-(6~10-membered aromatic ring), -C0~2 alkylene-(5~10-membered aromatic heterocycle); wherein the cycloalkane, heterocycloalkane, aromatic ring, aromatic heterocycle may be further replaced by one, two or three R A2 replace;

[0018] Each R A2 Selected from hydrogen, halogen, cyano, nitro, =O, -OH, -C1~6 alkyl, halogen-substituted -C1~6 alkyl, -O(C1~6 alkyl), -O(halogen-substituted C1~6 alkyl), -NH2, -NH(C1~6 alkyl), -N(C1~6 alkyl)(C1~6 alkyl), -C0~2 alkylene-(3~12 membered cycloalkyl), -C0~2 alkylene-(3~12 membered heterocycloalkyl), -C0~2 alkylene-(6~10 membered aromatic ring), -C0~2 alkylene-(5~10 membered aromatic heterocycle);

[0019] Ring B is selected from 3-10 membered cycloalkanes, 3-10 membered heterocycloalkanes, 6-10 aromatic rings, 5-10 membered aromatic heterocycles, 5-12 membered spiro rings, 5-12 membered spiro heterocycles, 5-12 membered bridged rings, and 5-12 membered bridged heterocycles; wherein the cycloalkanes, heterocycloalkanes, aromatic rings, aromatic heterocycles, spiro rings, spiro heterocycles, bridged rings, and bridged heterocycles may be further substituted by one, two, or three R B1 replace;

[0020] Each R B1 is selected from hydrogen, halogen, cyano, nitro, =O, -OH, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -O(C 1～6Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3- to 12-membered cycloalkyl), -C 0～2 Alkylene-(3- to 12-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocyclic ring);

[0021] The C ring is selected from 3-10 membered cycloalkanes, 3-10 membered heterocycloalkanes, 6-10 aromatic rings or 5-10 membered aromatic heterocycles; wherein the cycloalkanes, heterocycloalkanes, aromatic rings or aromatic heterocycles may be further replaced by one, two or three R C1 replace;

[0022] Each R C1 is selected from hydrogen, halogen, cyano, nitro, =O, -OH, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3- to 12-membered cycloalkyl), -C 0～2 Alkylene-(3- to 12-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5- to 10-membered aromatic heterocycle).

[0023] According to some embodiments of the present invention, the A ring is selected from a 6-membered aromatic heterocycle; the aromatic heterocycle may be further replaced by one, two or three R A1 replace;

[0024] Each R A1 is selected from hydrogen, halogen, -NH2, -(6-membered aromatic ring); wherein the aromatic ring may be further replaced by one, two or three R A2 Replace; each R A2 Selected from hydrogen, -OH.

[0025] More specifically: the A ring is selected from

[0026] According to some embodiments of the invention, the B ring is selected from an 8-membered bridged heterocyclic ring.

[0027] More specifically: the B ring is selected from

[0028] According to some embodiments of the invention, the C ring is selected from a 6-membered aromatic heterocycle.

[0029] More specifically: the C ring is selected from

[0030] Preferably, ring A is selected from Ring B is selected from The C ring is selected from

[0031] Further: the X is selected from

[0032] According to some embodiments of the present invention, said Y is selected from -(L Y ) q -;

[0033] q is an integer from 1 to 30;

[0034] Each L Y are independently selected from C(R)2, C(O), O, S, S(O), S(O)2, NR, -CR=CR-, -C≡C-, 3-10-membered cycloalkane, 3-10-membered heterocycloalkane, 6-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spiro ring, 5-12-membered spiro heterocycle, 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein the cycloalkane, heterocycloalkane, aromatic ring, aromatic heterocycle, spiro ring, spiro heterocycle, bridged ring, bridged heterocycle may be further substituted by one, two or three R YL replace;

[0035] Each R YL are independently selected from hydrogen, halogen, cyano, nitro, C 1～6 Alkyl, halogen substituted C 1～6 Alkyl, -OR, -N(R)2;

[0036] Each R is independently selected from hydrogen, halogen, -C 1～6 Alkyl, halogen substituted C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered carbocyclic group), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl).

[0037] According to some embodiments of the present invention, Y is selected from Wherein, n is selected from an integer of 0 to 10; preferably, n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8.

[0038] According to some embodiments of the present invention, Y is selected from

[0039] In some embodiments of the invention, the E3 ubiquitin ligase is selected from the group consisting of CRBN, von Hippel-Lindau (VHL), XIAP, MDM2, cIAP-1.

[0040] According to some embodiments of the present invention, Z is selected from

[0041] In some specific embodiments of the present invention, the compound described in formula I is specifically:

[0042]

[0043]

[0044] The present invention also provides a pharmaceutical composition comprising a preparation prepared from any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0045] The above-mentioned pharmaceutical composition further includes pharmaceutically acceptable carriers, excipients, and vehicles.

[0046] The present invention also provides the use of any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of drugs for preventing and / or treating diseases associated with SMARCA2 activity.

[0047] The present invention also provides the use of any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions in the preparation of drugs for preventing and / or treating cancer.

[0048] The present invention also provides any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in preventing and / or treating diseases associated with SMARCA2 activity.

[0049] The present invention also provides any of the above compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions for use in preventing and / or treating cancer.

[0050] A method for preventing and / or treating a disease associated with SMARCA2 activity, comprising administering an effective amount of any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions to a subject in need thereof.

[0051] A method for preventing and / or treating cancer, comprising administering an effective amount of any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions to a subject in need thereof.

[0052] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0053] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined in this document, the meaning that a person skilled in the art can give them should be given based on the disclosure and context.

[0054] "Substitution" means that the hydrogen atom in a molecule is replaced by another different atom or group; or the lone pair of electrons in an atom in a molecule is replaced by another atom or group. For example, the lone pair of electrons on the S atom can be replaced by an O atom to form

[0055] “Can be further substituted” means that “substitution” can but does not have to occur, and the description includes situations where it occurs or does not occur.

[0056] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1～6 The alkyl group refers to an alkyl group containing 1 to 6 carbon atoms.

[0057] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. Alkyl groups may also be part of other groups, such as -O(C 1～6 alkyl).

[0058] "Alkylene" refers to a divalent saturated aliphatic hydrocarbon radical having the specified number of member atoms. a ~ b Alkylene refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups. For example, the term "propylene" can be exemplified by the following structure: Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures:

[0059] The C0-4 alkylene group of the present invention can be a C0 alkylene group, a C1 alkylene group (e.g., -CH2-), a C2 alkylene group (e.g., -CH2CH2-, etc.), a C3 alkylene group or a C4 alkylene group; the C0 alkylene group means that the group here does not exist and is connected in the form of a chemical bond, such as A-C0 alkylene-B means AB, that is, the A group and the B group are directly connected by a chemical bond.

[0060] "Carbocyclyl" described in the present invention refers to a partially saturated cyclic group with multiple carbon atoms and no ring heteroatoms having a single ring or multiple rings (fused, bridged, spiro) saturated or non-aromatic. The term "carbocyclyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of monocarbocyclyl groups include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of carbocyclyl groups of condensed carbocyclyl systems include dicyclohexyl, dicyclopentyl, dicyclooctyl, etc., and two such dicycloalkyl polycyclic structures are exemplified and named below: Biscyclohexyl and Examples of carbocyclyl groups of the bridged carbocyclyl system include adamantyl, etc. Examples of the carbocyclyl group of the spirocarbocyclyl system include The term "carbocyclic group" also includes the case where an aromatic ring is fused with a non-aromatic ring to form a partially saturated cyclic group, and the attachment point can be located at a non-aromatic carbon atom or an aromatic carbon atom, examples of which include 1,2,3,4-tetrahydronaphthalene-5-yl and 5,6,7,8-tetrahydronaphthalene-5-yl.

[0061] The "cycloalkane" described in the present invention refers to a partially saturated divalent cyclic alkane having multiple carbon atoms and no ring heteroatoms, having a single ring or multiple rings (fused), saturated or non-aromatic. The term "cycloalkane" includes cycloolefins, such as cyclohexene. Examples of monocarbocyclic groups include, for example, cyclopropane, cyclobutane, cyclohexane, cyclopentane, cyclooctane, cyclopentene and cyclohexene. Examples of fused cycloalkane systems include dicyclohexane, dicyclopentane, dicyclooctane, etc. The "cycloalkane" described in the present invention includes but is not limited to wait.

[0062] The "heterocycloalkane" described in the present invention refers to a saturated ring or a non-aromatic partially saturated divalent ring having a single ring or multiple rings (fused) containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. Examples of heterocycloalkane of a monoheterocycloalkane system are oxetane, azetidine, pyrrolidine, 2-oxo-pyrrolidine, tetrahydrofuran, tetrahydro-thiophene, pyrazolidine, imidazolidine, thiazolidine, piperidine, tetrahydropyran, tetrahydrothiopyran, piperazine, morpholine, thiomorpholine, 1,1-dioxo-thiomorpholine, azepane, diazepane, etc. Examples of fused heterocycloalkane systems include 8-aza-bicyclo[3.2.1]octane, quinuclidine, 8-oxa-3-aza-bicyclo[3.2.1]octane, 9-aza-bicyclo[3.3.1]nonane, etc. The term "heterocycloalkane" also includes the case where an aromatic ring containing at least one heteroatom is fused with a non-aromatic ring to form a partially saturated ring, and the connection point can be located at a non-aromatic carbon atom, an aromatic carbon atom or a heteroatom. The "heterocycloalkane" described in the present invention includes but is not limited to wait.

[0063] The term "spiro ring" as used herein refers to a saturated or non-aromatic partially saturated divalent ring formed by two or more rings having multiple carbon atoms and no ring heteroatoms. Examples of spiro ring systems include wait.

[0064] The "spiro heterocycle" described in the present invention refers to a saturated ring or a non-aromatic partially saturated divalent ring formed by two or more rings containing at least one heteroatom. Examples of spiro heterocyclic systems include wait.

[0065] The "bridged ring" described in the present invention is a saturated or non-aromatic partially saturated divalent ring formed by bridging multiple rings having multiple carbon atoms and no ring heteroatoms. Examples of bridged ring systems include wait.

[0066] The "bridged heterocycle" in the present invention refers to a saturated ring or a non-aromatic partially saturated divalent ring formed by bridging multiple rings containing at least one heteroatom; examples of bridged heterocyclic ring systems include wait.

[0067] The unsaturated mentioned in the present invention refers to the presence of carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc. in the groups or molecules.

[0068] The term "alkenyl" as used herein refers to a straight or branched hydrocarbon group having at least one vinyl unsaturated site (>C=C<). a-b Alkenyl refers to an alkenyl group having from a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0069] The "alkenylene" mentioned in the present invention refers to a straight or branched divalent carbon chain having at least one carbon-carbon double bond. a-b Alkenylene refers to an alkenylene group having a to b carbon atoms.

[0070] The term "alkynyl" as used herein refers to a linear monovalent hydrocarbon group or a branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon groups having one triple bond and one double bond. For example, C 2-6 Alkynyl is meant to include ethynyl, propynyl, and the like.

[0071] The "alkynylene group" described in the present invention refers to a straight-chain divalent hydrocarbon group or a branched divalent hydrocarbon group containing at least one triple bond. a-b Alkyne refers to an alkynylene group having a to b carbon atoms.

[0072] The "heterocycloalkyl" described in the present invention refers to a saturated ring or a non-aromatic partially saturated ring having a single ring or multiple rings (fused, bridged, spiro) containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It usually refers to a monovalent saturated or partially unsaturated monocyclic or polycyclic ring system with multiple ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Examples of heterocycloalkyl groups of monoheterocycloalkyl systems are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, etc. Examples of heterocycloalkyl groups of fused heterocycloalkyl systems include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, etc. Examples of heterocycloalkyl groups of bridged heterocycloalkyl systems include etc. Examples of heterocycloalkyl groups of the spiroheterocycloalkyl system include Examples of partially saturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl, etc. The term "heterocycloalkyl" also includes a partially saturated cyclic group formed by condensing an aromatic ring containing at least one heteroatom with a non-aromatic ring, and the attachment point can be located at a non-aromatic carbon atom, an aromatic carbon atom or a heteroatom, examples include

[0073] The "aromatic ring" described in the present invention refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl is generally a monocyclic, bicyclic or tricyclic aromatic group having multiple carbon atoms. In addition, the term "aryl" used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.

[0074] The "aromatic heterocycle" described in the present invention refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It is usually an aromatic monocyclic or bicyclic hydrocarbon containing multiple ring atoms, wherein one or more ring atoms are selected from O, N, and S heteroatoms. Preferably there are one to three heteroatoms. Heterocyclic aromatic groups, for example, represent: pyridyl, indolyl, quinoxalyl, quinolyl, isoquinolyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiapyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl.

[0075] The "halogen" mentioned in the present invention refers to fluorine, chlorine, bromine or iodine.

[0076] The term "halogen-substituted alkyl" as used herein refers to an alkyl group in which one or more hydrogen atoms are substituted by halogen. 1～4 The alkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which the hydrogen atoms are substituted by one or more halogen atoms; examples thereof include monofluoromethyl, difluoromethyl and trifluoromethyl.

[0077] The term "halogen-substituted alkenyl" as used herein means that one or more hydrogen atoms in the alkenyl group are substituted by halogen. 2-6 The alkenyl group refers to an alkenyl group containing 2 to 6 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms; examples thereof include monofluorovinyl, bisfluorovinyl and trifluoropropenyl.

[0078] The term "halogen-substituted alkynyl" as used herein means that one or more hydrogen atoms in the alkynyl group are substituted by halogen. 2-6 The alkynyl group refers to an alkynyl group containing 2 to 6 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms; examples thereof include monofluoroethynyl, bisfluoroethynyl and trifluoropropynyl.

[0079] The "-OR", "-N(R)2" and the like described in the present invention mean that the R group is connected to the oxygen atom or the nitrogen atom by a single bond.

[0080] The "=O" mentioned in the present invention means that an oxygen atom replaces two hydrogen atoms in a molecule through a double bond.

[0081] In the "-C(O)R", "-S(O)2R" and the like described in the present invention, the oxygen atom is connected to the carbon atom or the sulfur atom by a double bond, and the R group is connected to the oxygen atom or the sulfur atom by a single bond. For another example, "-S(O)(NH)R" means that the oxygen atom and the nitrogen atom are connected to the sulfur atom by a double bond, and the R group is connected to the sulfur atom by a single bond.

[0082] The “---” in the description of the group of the present invention, It is used to describe the position of group substitution.

[0083] The "deuterated compound" of the present invention refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0084] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form and physiologically compatible with the receptor.

[0085] The terms "salts" and "pharmaceutically acceptable salts" refer to acidic and / or basic salts of the above compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final separation and purification of the compounds. They can also be obtained by mixing the above compounds, or their stereoisomers, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may be precipitated in the solution and collected by filtration, or recovered after evaporation of the solvent, or obtained by freeze-drying after reaction in an aqueous medium.

[0086] The term "prevention" includes suppressing and delaying the onset of a disease, and includes not only prevention before the development of a disease but also prevention of recurrence of a disease after treatment.

[0087] The terms "treat," ...

[0088] In certain embodiments, one or more compounds of the present invention may be used in combination with each other. It is also possible to select the compounds of the present invention and any other active agent for use in combination to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately or sequentially.

[0089] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0090] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0091] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0092] Unless otherwise specified in the examples, the reaction is carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, which is 20°C to 30°C. Unless otherwise specified in the examples, M is moles per liter.

[0093] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). -6 The unit of (ppm) is given. NMR is measured by nuclear magnetic spectrometer (Bruker AvanceIII 400 and Bruker Avance 600), and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (Methanol-d4), and the internal standard is tetramethylsilane (TMS). LC-MS is measured by Shimadzu LC-MS2020 (ESI)). HPLC is measured by Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium pressure preparative chromatography) uses Gilson GX-281 reverse phase preparative chromatograph. Thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications used for thin layer chromatography separation and purification products are 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

[0094] Pd(dppf)Cl2:[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; TMSCl: trimethylchlorosilane; Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; HOBt: hydroxybenzotriazole; dioxane: dioxane;

[0095] Found: The MS value displayed when the product is determined by LC-MS.

[0096] Example 1. Preparation of Compound A

[0097]

[0098] Step 1. Preparation of compound 3

[0099]

[0100] Compound 1 (2.95 g, 14.13 mmol), DIPEA (4.87 g, 37.68 mmol, 6.56 mL), 2 (2.00 g, 9.42 mmol) and DMSO (40 mL) were added to a 50 mL reaction bottle. After stirring at 120 °C for 2 hours, water was added to quench the reaction. The reactants were extracted with EA (80 mL × 3), the organic phase was washed with water, dried with Na2SO4, filtered, and the solvent was evaporated. The mixture was purified by MPLC to obtain compound 3 (1.70 g, 5.00 mmol, 53.11% yield).

[0101] Step 2: Preparation of Compound 5

[0102]

[0103] Compound 3 (1.66 g, 4.88 mmol), 4 (1.23 g, 5.37 mmol), PoPd (122.55 mg, 244.25 μmol), sSPhos (251.33 mg, 488.49 μmol), Cs2CO3 (3.18 g, 9.77 mmol) and dioxane / H2O (50 mL, 4:1) were added to a 50 mL reaction bottle in sequence under nitrogen protection. After heating at 110 °C for 2 hours, water was added to quench the reaction, and the mixture was extracted with EA (3 × 80 mL). The organic phase was washed with saturated brine, dried over Na2SO4, filtered, and the solvent was evaporated. The mixture was purified by MPLC to obtain compound 5 (2.27 g, 4.66 mmol, 95.30% yield).

[0104] Step 3. Preparation of Compound 6

[0105]

[0106] Compound 5 (2.27 g, 4.72 mmol) and HCl (4 M dioxane solution, 20 mL) were added to a 50 mL reaction bottle in sequence. After stirring at room temperature for 1 hour, the solvent was evaporated to obtain compound 6 (1.86 g, crude product).

[0107] Step 4: Preparation of Compound 8

[0108]

[0109] Compound 6 (1.86 g, 4.8 mmol), DIPEA (1.86 g, 14.40 mmol, 2.51 mL), 7 (1.39 g, 7.20 mmol) and DMF (50 mL) were added to a 50 mL reaction bottle in sequence. After stirring at 120 °C for 2 hours, water was added to quench the reaction. The reactants were extracted with EA (80 mL × 3), the organic phase was washed with saturated brine, dried with Na2SO4, filtered, and the solvent was evaporated. The mixture was purified by MPLC to obtain compound 8 (1.24 g, 2.28 mmol, 47.45% yield).

[0110] Step 5. Preparation of Compound 10

[0111]

[0112] Compound 8 (543.00 mg, 997.35 μmol), 9 (339.23 mg, 1.10 mmol), PoPd (25.02 mg, 49.87 μmol), sSPhos (51.31 mg, 99.73 μmol), Cs2CO3 (650.27 mg, 1.99 mmol) and dioxane / H2O (25 mL, 4:1) were added into a 50 mL reaction bottle in sequence under nitrogen protection. After heating at 100 °C for 2 hours, water was added to quench the reaction, and the mixture was extracted with EA (3×80 mL). The organic phase was washed with saturated brine, dried over Na2SO4, filtered, and the solvent was evaporated. The mixture was purified by MPLC to obtain compound 10 (646.78 mg, crude product).

[0113] Step 6. Preparation of Compound 11

[0114]

[0115] Compound 10 (2.27 g, 4.72 mmol), HCOOH (92.05 mg, 2.00 mmol, 75.45 μL), Pd / C (300.00 mg) and THF (5 mL) were added to a 50 mL reaction bottle in sequence. After stirring for 2 hours under H2, the solvent was evaporated to obtain compound 11 (558.67 mg, crude product).

[0116] Step 7. Preparation of Compound 12

[0117]

[0118] Compound 11 (558.67 mg, 1 mmol) and HCl (4 M dioxane solution, 10 mL) were added sequentially into a 50 mL reaction bottle. After stirring at room temperature for 1 hour, the solvent was evaporated to obtain compound 12 (400.00 mg, crude product).

[0119] Step 8. Preparation of Compound A

[0120]

[0121] Compound 13 (31.35 mg, 95.78 μmol), EDCI (19.82 mg, 103.76 μmol), HOBT (14.02 mg, 103.76 μmol), DIPEA (51.58 mg, 399.08 μmol, 69.51 μL) and DMF (2 mL) were added to a 50 mL reaction bottle. After stirring at room temperature for 10 minutes, compound 12 (36.60 mg, 79.82 μmol) was added. After stirring at room temperature for 2 hours, compound A (22.30 mg, 29.01 μmol, 36.35% yield, 99.9% purity) was obtained by MPLC purification. LC-MS m / z: [M+H] + calcd.for C 41 H 42 N 11 O5 + :768.3; found:768.2. 1 H NMR (400MHz, Methanol-d4) δ8.42(s,2H),7.76(dt,J=8.0,1.2Hz,1H),7.51-7.38(m,3H),7.28(dd,J=8.0 7.2Hz,1H),7.22(dd,J=8.0 7.2Hz,1H),7.08-6.97(m,2H),4.93(s,2H),4.41(d,J=9.6Hz,2H),4.26-4.10(m,2H),3.94(s,1H),3.82(d ,J=12.4Hz,2H),3.36(s,2H),3.20-2.95(m,4H),2.88-2.79(m,1H),2.17-2.05(m,4H),2.01-1.65(m,4H).

[0122] Example 2. Preparation of Compound B1

[0123]

[0124] Step 1. Preparation of compound 15

[0125]

[0126] Compound 14 (77.00 mg, 167.92 μmol), EDCI (38.49 mg, 201.50 μmol), HOBT (27.23 mg, 201.50 μmol), DIPEA (108.51 mg, 839.59 μmol, 146.24 μL) and DMF (2 mL) were added to a 50 mL reaction bottle. After stirring at room temperature for 10 minutes, compound 12 (36.60 mg, 79.82 μmol) was added. After stirring at room temperature for 2 hours, compound 15 (45.00 mg, 73.08 μmol, 43.52% yield) was obtained by MPLC purification.

[0127] Step 2: Preparation of Compound 16

[0128]

[0129] Compound 15 (45.00 mg, 73.08 μmol) and HCl (4 M dioxane solution, 5 mL) were added sequentially into a 50 mL reaction bottle. After stirring at room temperature for 1 hour, the solvent was evaporated to obtain compound 16 (36.00 mg, crude product).

[0130] Step 3. Preparation of Compound B1

[0131]

[0132] Compound 13 (21.33 mg, 65.17 μmol), EDCI (12.45 mg, 65.17 μmol), HOBT (8.81 mg, 65.17 μmol), DIPEA (35.09 mg, 271.52 μmol, 47.29 μL) and DMF (2 mL) were added to a 50 mL reaction bottle. After stirring at room temperature for 10 minutes, compound 16 (28.00 mg, 54.30 μmol) was added. After stirring at room temperature for 2 hours, compound B1 (22.40 mg, 26.94 μmol, 49.61% yield, 99.2% purity) was obtained by MPLC purification. LC-MS m / z: [M+H] + calcd.for C 43 H 45 N 12 O6 + :825.4; found:825.3. 1H NMR (400MHz, Methanol-d4) δ8.36 (s, 2H), 7.80-7.72 (m, 1H), 7.54 (dd, J = 8.0, 6.8Hz, 2H), 7.49 (s, 1H), 7.46-7. 38(m,1H),7.31(dd,J=8.0,7.2Hz,1H),7.26(dd,J=8.0,7.2Hz,1H),7.02(d,J=8.0Hz,2H),4.93(s,2H),4.69(d ,J=13.2Hz,1H),4.55-4.15(m,6H),4.06(d,J=13.2Hz,2H),3.82(d,J=12.0Hz,2H),3.35(s,1H),3.26(d,J=12. 4Hz,1H),3.02(s,2H),2.81(m,2H),2.21-2.02(m,4H),1.95-1.87(m,2H),1.87-1.74(m,1H),1.71-1.57(m,1H).

[0133] By referring to the synthesis method of compound B1, replacing compound 14 with the raw materials in the following table 1, and keeping other raw materials and operation methods unchanged, compounds B2, B3 and B4 can be obtained.

[0134] Table 1. Compounds B2, B3 and B4

[0135]

[0136]

[0137] Example 3. Preparation of Compound C1

[0138]

[0139] Step 1. Preparation of Compound 21

[0140]

[0141] Compound 12 (45.00 mg, 98.13 μmol), 20 (43.98 mg, 196.27 μmol), KI (16.29 mg, 98.13 μmol), NaHCO3 (24.73 mg, 294.40 μmol) and DMF (2 mL) were added to a 50 mL reaction bottle in sequence. After heating at 60 ° C for 16 hours, the reaction was cooled to room temperature and purified by MPLC to obtain compound 21 (30.00 mg, 49.86 μmol, 50.80% yield).

[0142] Step 2: Preparation of Compound 22

[0143]

[0144] Compound 21 (30 mg, 49.86 μmol), TFA (0.5 mL) and DCM (2 mL) were added to a 50 mL reaction bottle in sequence. After stirring at room temperature for 1 hour, the solvent was evaporated to obtain compound 22 (25.0 mg, crude product).

[0145] Step 3. Preparation of Compound C1

[0146]

[0147] Compound 13 (20.81 mg, 63.59 μmol), EDCI (13.25 mg, 69.37 μmol), HOBT (9.37 mg, 69.37 μmol), DIPEA (37.36 mg, 289.06 μmol, 50.35 μL) and DMF (2 mL) were added to a 50 mL reaction bottle. After stirring at room temperature for 10 minutes, compound 22 (29.00 mg, 57.81 μmol) was added. After stirring at room temperature for 2 hours, compound C1 (3.60 mg, 4.30 μmol, 7.44% yield, 96.9% purity) was obtained by MPLC purification. LC-MS m / z: [M+H] + calcd.forC 43 H 47 N 12 O5 + :811.4; found:811.4. 1 H NMR (400MHz, DMSO-d6) δ14.14(s,1H),12.30(s,1H),11.21(s,1H),9.65(t,J=5.6Hz,1H),8.15(d, J=6.0Hz,1H),7.91(dd,J=8.0,1.6Hz,1H),7.64(dd,J=8.0,1.2Hz,1H),7.56-7.49(m,2H),7.33-7. 15(m,3H),6.92-6.79(m,2H),6.65(d,J=6.0Hz,1H),6.00(s,2H),4.79(s,2H),4.31-4.00(m,4H),3 .49(d,J=6.4Hz,2H),3.39-3.34(m,2H),3.05-2.90(m,6H),2.55(s,2H),2.12(s,4H),1.86(s,6H).

[0148] By referring to the synthesis method of compound C1, replacing compound 20 with the raw materials in the following table 2, and keeping other raw materials and operation methods unchanged, compounds C2-C7 and D1-D7 can be obtained.

[0149] Table 2. Compounds C2-C7 and D1-D7

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157] Example 1: SMARCA2 and SMARCA4 degradation assay

[0158] The present invention uses Western Blot to evaluate the degradation activity of the compound on SMARCA2 and SMARCA4 of human non-small cell lung cancer cell line A549 and human cervical cancer cell line HeLa cells. A549 cells are cultured in RPMI-1640 medium containing 10% fetal bovine serum, and HeLa cells are cultured in DMEM medium containing 10% fetal bovine serum. The cells are digested with trypsin and 10 6Cells were seeded in 6-well plates and cultured overnight at 37°C and 5% CO2 to allow the cells to adhere to the wall. The next day, different concentrations of the test compound were added to the 6-well plate to treat the cells for 24 hours. After 24 hours, the culture medium in the cells was removed, washed twice with ice PBS, and lysed on ice for 1 hour with RIPA lysis buffer containing 1mM PMSF and 1X cocktai; the cell lysate was collected in a 1.5ml centrifuge tube, centrifuged at 14000rpm for 10 minutes in a low-temperature centrifuge, and the supernatant was collected; the protein of the obtained cell lysate supernatant was quantified using the BCAProtein Assay Kit. 4X loading buffer was added to the cell lysate supernatant and denatured at 95°C for 10 minutes to obtain the sample. The sample proteins were separated by SDS-PAGE and transferred to PVDF membrane. After blocking with 5% skim milk for 1 hour, the membrane was incubated with SMARCA2 (Cell Signaling Technology, Cat#11966S) and SMARCA4 (Abcam, Cat#ab110641) antibodies at 4°C, and then incubated with secondary antibody (Anti-rabbit IgG-HRP, Cell Signaling Technology, Cat#7074S) at room temperature for 1 hour. Immobilon Western Chemiluminescent HRP Substrate was used to detect the bands on the membrane.

[0159] The above experimental results of the compounds of the present invention are shown in the following table:

[0160] Table 3: Degradation of SMARCA2 protein by compounds in A549 cell line

[0161] serial number <![CDATA[DC 50 SMARCA2 ]]> serial number <![CDATA[DC 50 SMARCA2 ]]> A ++ C2 + B1 + C3 ++ B2 + C4 +++ B3 + C5 +++ B4 + C6 ++++ C1 ++

[0162] Among them, + represents 1000μM>DC 50 >1μM, ++ represents 1μM>DC 50 >0.1μM, +++ represents 0.1μM>DC 50 >0.01μM, ++++ represents DC 50 <0.01 μM.

[0163] Table 4: Degradation of SMARCA2 protein by compounds in HeLa cell line

[0164]

[0165] Among them, + represents 1000μM>DC 50 >1μM, ++ represents 1μM>DC 50>0.1μM, +++ represents 0.1μM>DC 50 >0.01μM, ++++ represents DC 50 <0.01μM;√ represents 5>Selectivity SM4 / SM2 >1,√√ represents 10>Selectivity SM4 / SM2 >5, √√√ represents 5 Selectivity SM4 / SM2 >10.

[0166] The above experimental results show that the compounds of the present invention can effectively degrade SMARCA2 protein, providing a new medicinal possibility for the development of new SMARCA2 protein degradation drugs.

Claims

1. A compound of formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a tautomer thereof, or a polymorph thereof, or a solvate thereof, or an N-oxide thereof, or an isotope-labeled compound thereof, or a metabolite thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof: in, X is a group that binds to the SMARCA2 protein; Y is a linking group; Z is a group that binds to E3 ubiquitin ligase.

2. The compound according to claim 1, characterized in that: The X is selected from Wherein, the A ring is selected from 3-10 membered cycloalkanes, 3-10 membered heterocycloalkanes, 6-10 aromatic rings or 5-10 membered aromatic heterocycles; wherein the cycloalkanes, heterocycloalkanes, aromatic rings or aromatic heterocycles may be further replaced by one, two or three R A1 replace; Each R A1 is selected from hydrogen, halogen, cyano, nitro, =O, -OH, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3- to 12-membered cycloalkyl), -C 0～2 Alkylene-(3- to 12-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); wherein the cycloalkane, heterocycloalkane, aromatic ring, aromatic heterocycle may be further replaced by one, two or three R A2 replace; Each R A2 is selected from hydrogen, halogen, cyano, nitro, =O, -OH, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3- to 12-membered cycloalkyl), -C 0～2 Alkylene-(3- to 12-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); Ring B is selected from 3-10 membered cycloalkanes, 3-10 membered heterocycloalkanes, 6-10 aromatic rings, 5-10 membered aromatic heterocycles, 5-12 membered spiro rings, 5-12 membered spiro heterocycles, 5-12 membered bridged rings, and 5-12 membered bridged heterocycles; wherein the cycloalkanes, heterocycloalkanes, aromatic rings, aromatic heterocycles, spiro rings, spiro heterocycles, bridged rings, and bridged heterocycles may be further substituted by one, two, or three R B1 replace; Each R B1 is selected from hydrogen, halogen, cyano, nitro, =O, -OH, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3- to 12-membered cycloalkyl), -C 0～2 Alkylene-(3- to 12-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); The C ring is selected from 3-10 membered cycloalkanes, 3-10 membered heterocycloalkanes, 6-10 aromatic rings or 5-10 membered aromatic heterocycles; wherein the cycloalkanes, heterocycloalkanes, aromatic rings or aromatic heterocycles may be further replaced by one, two or three R C1 replace; Each R C1 is selected from hydrogen, halogen, cyano, nitro, =O, -OH, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -O(C 1～6 Alkyl), -O(halogen substituted C 1～6 Alkyl), -NH2, -NH(C 1～6 Alkyl), -N(C 1～6 Alkyl)(C 1～6 Alkyl), -C 0～2 Alkylene-(3- to 12-membered cycloalkyl), -C 0～2 Alkylene-(3- to 12-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5- to 10-membered aromatic heterocycle).

3. The compound according to claim 2, characterized in that: The A ring is selected from a 6-membered aromatic heterocycle; the aromatic heterocycle may be further replaced by one, two or three R A1 replace; Each R A1 is selected from hydrogen, halogen, -NH2, -(6-membered aromatic ring); wherein the aromatic ring may be further replaced by one, two or three R A2 replace; Each R A2 Selected from hydrogen, -OH.

4. The compound according to claim 3, characterized in that: The A ring is selected from 5. The compound according to claim 2, characterized in that: The B ring is selected from an 8-membered bridged heterocyclic ring.

6. The compound according to claim 5, characterized in that: The B ring is selected from 7. The compound according to claim 2, characterized in that: The C ring is selected from 6-membered aromatic heterocycles.

8. The compound according to claim 7, characterized in that: The C ring is selected from 9. The compound according to claim 2, characterized in that: Ring A is selected from Ring B is selected from The C ring is selected from 10. The compound according to any one of claims 1 to 2, characterized in that: The X is selected from 11. The compound according to claim 1, characterized in that: The Y is selected from -(L Y ) q -; q is an integer from 1 to 30; Each L Y are independently selected from C(R)2, C(O), O, S, S(O), S(O)2, NR, -CR=CR-, -C≡C-, 3-10-membered cycloalkane, 3-10-membered heterocycloalkane, 6-10-membered aromatic ring, 5-10-membered aromatic heterocycle, 5-12-membered spiro ring, 5-12-membered spiro heterocycle, 5-12-membered bridged ring, 5-12-membered bridged heterocycle; wherein the cycloalkane, heterocycloalkane, aromatic ring, aromatic heterocycle, spiro ring, spiro heterocycle, bridged ring, bridged heterocycle may be further substituted by one, two or three R YL replace; Each R YL are independently selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -OR, -N(R)2; Each R is independently selected from hydrogen, halogen, -C 1～6 Alkyl, halogen-substituted -C 1～6 Alkyl, -C 0～2 Alkylene-(3-10 membered carbocyclic group), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl).

12. The compound according to claim 11, characterized in that: The Y is selected from Wherein, n is selected from an integer of 0 to 10; preferably, n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8.

13. The compound according to claim 12, characterized in that: The Y is selected from 14. The compound according to claim 1, characterized in that: The E3 ubiquitin ligase is selected from CRBN, vonHippel-Lindau (VHL), XIAP, MDM2, and cIAP-1.

15. The compound according to claim 14, characterized in that: The Z is selected from 16. The compound according to any one of claims 1 to 15, characterized in that: The compound is specifically:

17. A pharmaceutical composition comprising a preparation prepared from the compound according to any one of claims 1 to 16, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition according to claim 17, characterized in that: It further includes pharmaceutically acceptable carriers, excipients, and vehicles.

19. Use of the compound according to any one of claims 1 to 16, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 17 to 18 in the preparation of a medicament for preventing and / or treating a disease associated with SMARCA2 activity.

20. Use of the compound according to any one of claims 1 to 16, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 17 to 18 in the preparation of a medicament for preventing and / or treating cancer.

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