BTK degradation agent and application thereof

Abstract

The invention provides a compound with a BTK protein degradation effect as shown in a formula I and application of the compound to preparation of a medicine for treating diseases related to BTK activity. X-Y-Z Formula I

Description

Technical Field

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

[0002] Bruton's tyrosine kinase (BTK) is a member of the TEC family of non-receptor tyrosine kinases. It is expressed in B cells and myeloid cells and regulates different signaling pathways, including the PI3K, MAPK and NF-κB pathways. BTK is not only essential for the development and differentiation of B cells, but also participates in the regulation of innate responses triggered by Toll-like receptors of macrophages. In the past two decades, it has been found that many types of cancers are characterized by high activation and high regulation of different tyrosine kinases, making them new and interesting therapeutic targets in cancer treatment. The B cell receptor (BCR) located on the cell membrane of B cells is a transmembrane receptor protein composed of membrane immunoglobulin (mIg) and co-stimulatory molecules CD79a / CD79b. [3] . BCR always couples with CD79a / b heterodimers to form BCR complexes. When specific antigens bind to the BCR complex, it can cause the recruitment and activation of downstream Src family molecules such as Lyn and Fyn, and activate SYK. Activated SYK can promote the recruitment and phosphorylation of downstream effectors BTK and PLCγ2 by B cell junction proteins, and can also phosphorylate the tyrosine residues in the cytoplasmic tail of CD19, thereby activating PI3K. PI3K produces PIP3, an essential messenger for activating downstream pathways, which usually binds to the PH domain of BTK and allows SYK and LYN to activate BTK through complete transphosphorylation of the Y551 site. Activated BTK can activate PLC-γ2 and further activate multiple downstream signaling pathways, including MAPK, ERK, NF-κB, NF-AT and other signaling pathways, thereby regulating the expression of genes and cytokines, affecting various biological processes such as B cell survival, proliferation, apoptosis and differentiation.

[0003] Since BTK plays an important role in the growth and migration of B-cell malignancies, inhibitors targeting BTK are an important research topic in the treatment of B-cell malignancies. [4] In the past decade, a large number of BTK inhibitors have been developed. These small molecule BTK inhibitors can be divided into covalent inhibitors and non-covalent inhibitors according to their mechanism of action and chemical structure.

[0004] Ibrutinib is a first-generation BTK inhibitor that was launched in the United States in 2013 for the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), It is currently used to treat WM, MZL and MCL, and was approved for the treatment of chronic graft-versus-host disease (cGVHD) in 2017. Its approval is of epoch-making significance, making it one of the world's top five best-selling drugs. [2] Ibrutinib can covalently bind to the cysteine ​​residue Cys481 of the BTK protein, thereby exerting an irreversible inhibitory effect on BTK. Although ibrutinib has significant efficacy and efficacy against various lymphomas and leukemias in clinical practice, it also has some clinical limitations, such as off-target toxicity and primary and endogenous drug resistance.

[0005] The second-generation BTK inhibitors (BTKI) have better target selectivity than ibrutinib, and therefore produce fewer off-target side effects. For example, Acerta Pharmaceuticals developed acalabrutinib, BeiGene developed Zanubrutinib, Ono Pharmaceutical developed Tirabrutinib, and Innovent developed Orelabrutinib. From a chemical point of view, they have a similar mechanism of action to ibrutinib, and are covalent inhibitors of BTK protein, but compared with the first-generation BTKI, their off-target effects are lower.

[0006] The most common mutation that causes resistance to first- and second-generation BTK inhibitors is a mutation in the Cys481 residue in the BTK active site, which disrupts the covalent binding between BTK and BTK inhibitors acting at this site, reducing their inhibitory activity. The third-generation BTK inhibitors came into being, such as Pirtobrutinib, Vecabrutinib, and Fenebrutinib. Compared with covalent inhibitors, the third-generation non-covalent BTK inhibitors do not rely on the binding of the BTK active site to Cys481. For example, Fenebrutinib binds to K430, M477, and D539 residues through hydrogen bonds. Therefore, the third-generation non-covalent BTK inhibitors have higher activity and less off-target toxicity against BTK with Cys481 mutations.

[0007] In addition, in recent years, the use of PROTAC technology to target and degrade BTK protein has also attracted the attention of researchers, providing a basis for the development of new effective reversible non-covalent PROTAC therapeutic molecules, especially for the treatment of B-cell lymphoma.

[0008] 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.

[0009] 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 target protein level in the cell. The current E3 ubiquitin ligases mainly include CRBN, VHL, MDM2 and cIAP1. Summary of the invention

[0010] The present invention provides a compound having a BTK protein degradation effect and use thereof in preparing a medicine for a disease related to BTK activity.

[0011] The technical solution of the present invention is as follows:

[0012] 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:

[0013]

[0014] in,

[0015] X is a group that binds to the BTK protein;

[0016] Y is a linking group;

[0017] Z is a group that binds to E3 ubiquitin ligase.

[0018] According to some embodiments of the present invention, X is selected from

[0019] Wherein, X1 and X2 are independently selected from N or CR X1 ;

[0020] R X1 Selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;

[0021] Ring A 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;

[0022] Each R A1 are independently selected from hydrogen, halogen, cyano, nitro, =O, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR A2 , -C 0～4 Alkylene-NR A2 R A3 , -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); the cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further substituted by one, two, three or four independent R A4 replace;

[0023] The R A2 , R A3 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl or halogen-substituted -C2～6 Alkynyl;

[0024] The R A4 are independently 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);

[0025] The R 1 Selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR 11 , -C 0～4 Alkylene-NR 11 R 12 , -C 0～2 Alkylene-C(O)R 11 , -C 0～2 Alkylene-C(O)NR 11 R 12 , -C 0～2 Alkylene-NR 11 C(O)R 12 , -C 0～2 Alkylene-C(O)OR 11 , -C 0～2 Alkylene-S(O)R 11 , -C 0～2 Alkylene-S(O)OR 11 , -C 0～2 Alkylene-S(O)2R 11 , -C 0～2 Alkylene-S(O)2NR 11 R 12 , -C 0～2 Alkylene-S(O)2OR11 ;

[0026] R 11 , R 12 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl or halogen-substituted -C 2～6 Alkynyl.

[0027] Preferably, the A ring is selected from 3-6 membered heterocycloalkanes; wherein the heterocycloalkanes may be further replaced by one, two or three R A1 replace;

[0028] Each R A1 are independently selected from hydrogen, -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl); the heterocycloalkyl may be further substituted by one, two, three or four independent R A4 Substitution; said R A4 are independently selected from hydrogen, =O, -C 1～3 Alkyl, halogen-substituted -C 1～3 alkyl.

[0029] Further: the A ring is selected from

[0030] As a preference: X 1 and X 2 are independently selected from N.

[0031] As a preference: the R 1 Selected from -C(O)NR 11 R 12 , R 11 , R 12 are independently selected from hydrogen or C 1～6 alkyl.

[0032] Further: R 1 Selected from

[0033] According to some embodiments of the invention, Ring A is selected from X 1 and X 2 Selected from N;

[0034] R 1 Selected from

[0035] More specifically: the X is selected from

[0036] According to some embodiments of the present invention,

[0037] The Y is selected from -(L Y ) q -;

[0038] q is an integer from 1 to 30;

[0039] 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;

[0040] 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;

[0041] 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).

[0042] According to some embodiments of the present invention, Y is selected from

[0043] 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.

[0044] According to some embodiments of the present invention, Y is selected from

[0045] 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.

[0046] According to some embodiments of the present invention, Z is selected from

[0047] In some specific embodiments of the present invention, the compound described in formula I is specifically:

[0048]

[0049]

[0050] 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.

[0051] The above-mentioned pharmaceutical composition further includes pharmaceutically acceptable carriers, excipients, and vehicles.

[0052] The present invention also provides the use of any of the above-mentioned 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 diseases associated with BTK activity.

[0053] 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.

[0054] 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 BTK activity.

[0055] 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.

[0056] A method for preventing and / or treating a disease associated with BTK 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] "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

[0061] “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.

[0062] 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.

[0063] "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).

[0064] "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 from 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:

[0065] 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.

[0066] "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.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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

[0079] 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.

[0080] 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.

[0081] The "halogen" mentioned in the present invention refers to fluorine, chlorine, bromine or iodine.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] The "-OR", "-N(R)2" and the like described in the present invention refer to that the R group is connected to the oxygen atom or the nitrogen atom by a single bond.

[0086] The "=O" mentioned in the present invention means that an oxygen atom replaces two hydrogen atoms in a molecule through a double bond.

[0087] 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.

[0088] The group description of the present invention It is used to describe the position of group substitution.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] The terms "treat," ...

[0094] 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.

[0095] 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.

[0096] 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

[0097] 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.

[0098] 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.

[0099] The reagents described in the examples are abbreviated as follows: TEA: triethylamine; TFA: trifluoroacetic acid; DMSO: dimethyl sulfoxide; DMF: N,N-dimethylformamide; BINAP: 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); DIPEA: N,N-diisopropylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; THF: tetrahydrofuran; MeOH: methanol; DCM: dichloromethane; Py: pyridine; EDCI: 1-ethyl-3-(3-dimethylammoniumpropyl)carbonammonium; Pd(AcO)2: palladium acetate; NaBH(OAc)3: sodium triacetoxyborohydride.

[0100] 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.

[0101] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shift (δ) is given in units of 10-6 (ppm). NMR was measured using a (Bruker AvanceIII 400 and Bruker Avance 600) nuclear magnetic spectrometer, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (Methol-d4), and the internal standard was tetramethylsilane (TMS). LC-MS was measured using a Shimadzu LC-MS2020 (ESI)). HPLC was measured using a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium pressure preparative chromatography) used a Gilson GX-281 reverse phase preparative chromatograph. Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, 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.

[0102] Example 1. Preparation of Compound A1

[0103]

[0104]

[0105] Step 1. Synthesis of compound 3

[0106]

[0107] Compound 1 (1.83 g, 10.00 mmol), compound 2 (1.74 g, 10.00 mmol), TEA (3.04 g, 30.00 mmol, 4.18 mL) and THF (50.00 mL) were added to a 250 mL reaction bottle and stirred at room temperature for 16 hours. After the reaction was complete (LC-MS monitoring), the product was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound 3 (2.40 g, 7.48 mmol, 74.82% yield).

[0108] Step 2: Preparation of Compound 5

[0109]

[0110] Under nitrogen protection, compound 3 (2.40 g, 7.48 mmol), compound 4 (2.07 g, 7.48 mmol), dioxane (50.00 mL), Cs2CO3 (37.41 mmol), BINAP (232.94 mg, 374.09 μmol) and Pd(OAc)2 (84.74 mg, 374.09 μmol) were added to a 250 mL reaction bottle in sequence. The temperature was raised to 100 °C and stirred for 16 hours. After the reaction was complete (LC-MS monitoring), it was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound 5 (3.00 g, 5.35 mmol, 71.51% yield).

[0111] Step 3. Preparation of Compound 6

[0112]

[0113] Compound 5 (3.00 g, 5.35 mmol), methanol (20.00 mL), Cs2CO3 (6.97 g, 21.40 mmol), DMSO (836.12 mg, 10.70 mmol, 759.83 μL) and H2O2 (727.99 mg, 21.40 mmol) were added sequentially to a 250 mL reaction bottle. The mixture was stirred at room temperature for 2 hours (monitored by LC-MS). The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound 6 (2.00 g, 3.46 mmol, 64.59% yield).

[0114] Step 4: Preparation of Compound 7

[0115]

[0116] Compound 6 (1.00 g, 1.73 mmol), DCM (10.00 mL) and TFA (1.97 g, 17.28 mmol) were added to a 50 mL reaction bottle. After stirring at room temperature for half an hour (monitored by LC-MS), the mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound 7 (800.00 mg, 1.67 mmol, 96.74% yield).

[0117] Step 5. Preparation of Compound 9

[0118]

[0119] Compound 7 (0.10 g, 208.95 μmol), compound 8 (52.69 mg, 208.95 μmol), DMF (5.00 mL), KI (34.69 mg, 208.95 μmol) and K2CO3 (626.84 μmol) were added to a 50 mL reaction bottle, the temperature was raised to 60 °C with stirring, and after the reaction was complete (monitored by LC-MS), it was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound 9 (100 mg, 153.89 μmol, 73.65% yield).

[0120] Step 6. Preparation of Compound 10

[0121]

[0122] Compound 9 (0.10 g, 153.89 μmol), DCM (5.00 mL) and TFA (175.47 mg, 1.54 mmol) were added to a 50 mL reaction bottle and stirred at room temperature for half an hour (monitored by LC-MS). The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound 10 (80.00 mg, 145.53 μmol, 94.57% yield).

[0123] Step 7. Preparation of Compound 12

[0124]

[0125] To a 25 mL reaction bottle at 0°C were added compound 11 (34.26 mg, 0.14 mmol), DMF (5.00 mL), DIPEA (56.22 mg, 435.00 μmol, 75.77 μL) and HATU (55.14 mg, 145.00 μmol). After stirring for 2 minutes, compound 10 (80.00 mg, 145.53 μmol) was added to the system. The mixture was heated to room temperature and stirred for 10 minutes (monitored by LC-MS). The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound 12 (80.00 mg, crude product).

[0126] Step 8. Preparation of Compound 13

[0127]

[0128] Compound 12 (80.00 mg, 104.18 μmol), THF (5.00 mL), water (1.00 mL), and LiOH (12.47 mg, 520.88 μmol) were added sequentially to a 25 mL reaction bottle. After stirring at room temperature for 16 hours (monitored by LC-MS), 6 M hydrochloric acid was added to the reaction mixture to adjust the pH value to 5. The solvent was removed by concentration under reduced pressure to obtain compound 13 (crude product).

[0129] Step 9. Preparation of Compound A1

[0130]

[0131] Compound 13 (crude), compound 14 (14.87 mg, 106.11 μmol), Py (3.00 mL) and EDCI (40.68 mg, 212.23 μmol) were added to a 25 mL reaction bottle in sequence. The mixture was stirred at room temperature for 2 hours (LC-MS monitoring), purified by MPLC, and concentrated under reduced pressure to remove the solvent to obtain compound A1 (2.00 mg, 2.08 μmol, 1.96% yield, purity 91.2%). LC-MS: C 45 H 53 N 11 O6S, [M+H] + 876.4; found 876.5. 1 H NMR (600MHz, DMSO-d6) δ11.29-10.88(m,2H),8.66-8.52(m,1H),8.13-8.03(m,1H),7.89-7.81(m,1H),7.75(d,J=2 .8Hz,1H),7.65(s,1H),7.57-7.45(m,4H),7.32(d,J=2.8Hz,1H),7.19-7.08(m,2H),4.43-4.24(m,3H),4.16(d,J= 10.0Hz,1H),3.97-3.80(m,2H),3.64-3.56(m,1H),3.28-3.19(m,6H),3.07-2.91(m,5H),2.87(d,J=18.0Hz,1H),2 .70(s,3H),2.45-2.37(m,1H),2.34(d,J=7.2Hz,2H),1.96(t,J=11.6Hz,2H),1.85-1.68(m,6H),1.65-1.48(m,6H).

[0132] Synthesis of intermediates

[0133]

[0134] Synthesis of compound 20

[0135]

[0136] Compound 7 (100.00 mg, 208.95 μmol), compound 15 (36.19 mg, 208.95 μmol) and methanol (5.00 mL) were added in sequence to a 25 mL reaction bottle and stirred at room temperature for 2 hours. NaBH(OAc)3 (88.57 mg, 417.90 μmol) was added to the reaction mixture and stirred at room temperature for 1 hour (monitored by LC-MS). The mixture was purified by MPLC and concentrated under reduced pressure to remove the solvent to obtain compound 20 (100.00 mg, 157.28 μmol, 75.27% yield).

[0137] Synthesis of Intermediates 21-24

[0138] By referring to the synthesis method of compound 20, the raw materials 16-19 in the following table 1 are used to replace compound 15, and the other raw materials and operation methods remain unchanged, and intermediates 21-24 can be obtained.

[0139] Table 1. Intermediates 21-24

[0140]

[0141]

[0142] By referring to the synthesis method of compound A1, compounds A2-A6 can be obtained by replacing compound 9 with raw materials 20-24 in the following table 2 and keeping other raw materials and operation methods unchanged.

[0143] Table 2. Compounds A2-A6

[0144]

[0145]

[0146]

[0147] Example 2. Preparation of Compounds B1-B4

[0148] Synthesis of intermediates

[0149] By referring to the synthesis method of compound 20, compound 25 is used to replace compound 1, and raw materials 16-19 in the following table 3 are used to replace compound 15, and other raw materials and operation methods remain unchanged, intermediates 26-29 can be obtained.

[0150] Table 3. Intermediates 26-29

[0151]

[0152]

[0153] Synthesis of Compounds B1-B4

[0154] By referring to the synthesis method of compound A1, compounds B1-B4 can be obtained by replacing compound 9 with raw materials 26-29 in the following table 4 and keeping other raw materials and operation methods unchanged.

[0155] Table 4. Compounds B1-B4

[0156]

[0157]

[0158]

[0159] Experimental Example 1: Evaluation of the effect of compounds on BTK protein degradation in TMD8 and OCI-LY10 cells by Western blot

[0160] 1. Experimental instruments and reagents:

[0161] SDS-PAGE gel (4-12%) (Genscript), PMSF 100mM (Biyotime), Cocktail 100× (Biyotime), P / S (Hyclone), FBS (Corning), 4× loading buffer (Thermo), Anti-BTKantibody (Abcam), Tween-20, Anti-rabbit IgG-HRP (CST), Anti-β-actin-HRP (Abcam), RIPA (Biyotime), TMD8 (Qingqi (Shanghai) Biotechnology Development Co., Ltd.), OCI-LY10 (Guangzhou Jinio Biotechnology Co., Ltd.), skim milk powder (Shenggong Biotechnology), BCA Protein Assay Kit (TIANGEN), 6well plate (costar), PVDF membrane equilibration liquid (Genscript), MOPS Running Buffer liquid (20x) (Genscript), gel imager (Thermofisher), PVDF membrane (Millipore), 1.5 mL centrifuge tube (AXYGEN), semi-dry transfer instrument (Genscript), Roswell Park Memorial Institute (RPMI) 1640 (Gibco), DMEM (High Glucose) (Hyclone), Normocin (invivogen), Immobilon Western Chemilunescent HRP Substrate (Millipore).

[0162] 2. Experimental methods:

[0163] 1) Compound incubation with cells: 1 mL of 2×10 6 TMD8 cells (culture medium 89% DMEM, 10% FBS, 1% P / S, Normocin) and 1 mL of 2×106 OCI-LY10 cells (culture medium 89% 1640, 10% FBS, 1% P / S) were seeded in 6-well cell culture plates, respectively. The compounds were diluted with DMSO to six concentration points, and then the compounds diluted in DMSO were diluted again into TMD8 and OCI-LY10 culture medium, respectively. 1 mL of the diluted compound was directly added to the six-well plate of the cell culture dish and incubated for 24 h.

[0164] 2) Protein extraction: After the compound and cells were incubated for 24 hours, the cells were collected in a 1.5 mL centrifuge tube, washed twice with ice PBS, and 70 μL RIPA lysis buffer was added to the supernatant and lysed on ice for 60 minutes; the cell lysate was then centrifuged in a low-temperature centrifuge for 10 minutes at 15,000 rpm, and the supernatant was collected; the protein in the obtained cell lysate supernatant was quantified using the BCA Protein Assay Kit. 4× loading buffer was added to the cell lysate supernatant and incubated at 95°C for 10 minutes to obtain a sample. The obtained sample was stored in a -80°C refrigerator for use the next day.

[0165] 3) Western blot: Take 20 μg of sample for SDS-PAGE and transfer, use 5% skim milk to block the membrane at room temperature for 1 hour, then incubate with Anti-BTK antibody, Anti-β-actin-HRP antibody at 4°C overnight, wash three times with TBST, incubate with Anti-rabbit IgG-HRP secondary antibody at room temperature for 1 hour, wash three times with TBST after incubation, use Immobilon Western Chemiluminescent HRP Substrate for color development, and use a gel imaging instrument for analysis.

[0166] The above experimental results of the compounds of the present invention are shown in the following table:

[0167] Table 5: Degradation of BTK protein by compounds in TMD8 cell line

[0168]

[0169]

[0170] Among them, ++ represents 1μM>DC 50 >0.1μM, +++ represents 0.1μM>DC 50 >0.01μM, ++++ represents 0.01μM>DC 50 >0.001μM, +++++ represents DC 50 <0.0001 μM.

[0171] Table 6: Degradation of BTK protein by compounds in OCI-LY10 cell line

[0172] serial number <![CDATA[DC 50 ]]> serial number <![CDATA[DC 50 ]]> A1 ++ A6 ++++ A2 +++ B1 +++ A3 ++++ B2 +++ A4 +++++ B3 +++ A5 ++++ B4 ++++

[0173] Among them, ++ represents 1μM>DC 50 >0.1μM, +++ represents 0.1μM>DC 50 >0.01μM, ++++ represents 0.01μM>DC 50 >0.001μM, +++++ represents DC 50 <0.0001 μM.

[0174] The above experimental results show that the compounds of the present invention can effectively degrade BTK protein, providing a new medicinal possibility for the development of new BTK degraders.

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 BTK 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, X1 and X2 are independently selected from N or CR X1 ; R X1 Selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl; Ring A 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 are independently selected from hydrogen, halogen, cyano, nitro, =O, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR A2 , -C 0～4 Alkylene-NR A2 R A3 , -C 0～2 Alkylene-(3- to 10-membered cycloalkyl), -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl), -C 0～2 Alkylene-(6-10 membered aromatic ring), -C 0～2 Alkylene-(5-10 membered aromatic heterocycle); the cycloalkyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further replaced by one, two, three or four independent R A4 replace; The R A2 , R A3 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl or halogen-substituted -C 2～6 Alkynyl; The R A4 are independently 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 R 1 Selected from hydrogen, halogen, cyano, nitro, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR 11 , -C 0～4 Alkylene-NR 11 R 12 , -C 0～2 Alkylene-C(O)R 11 , -C 0～2 Alkylene-C(O)NR 11 R 12 , -C 0～2 Alkylene-NR 11 C(O)R 12 , -C 0～2 Alkylene-C(O)OR 11 , -C 0～2 Alkylene-S(O)R 11 , -C 0～2 Alkylene-S(O)OR 11 , -C 0～2 Alkylene-S(O)2R 11 , -C 0～2 Alkylene-S(O)2NR 11 R 12 , -C 0～2 Alkylene-S(O)2OR 11 ; R 11 , R 12 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl or halogen-substituted -C 2～6 Alkynyl.

3. The compound according to claim 2, characterized in that: The A ring is selected from 3-6 membered heterocycloalkanes; wherein the heterocycloalkanes may be further replaced by one, two or three R A1 replace; Each R A1 are independently selected from hydrogen, -C 0～2 Alkylene-(3- to 10-membered heterocycloalkyl); the heterocycloalkyl may be further substituted by one, two, three or four independent R A4 Substitution; said R A4 are independently selected from hydrogen, =O, -C 1～3 Alkyl, halogen-substituted -C 1～3 alkyl.

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: X 1 and X 2 are independently selected from N.

6. The compound according to claim 2, characterized in that: The R 1 Selected from -C(O)NR 11 R 12 , R 11 , R 12 are independently selected from hydrogen or C 1～6 alkyl.

7. The compound according to claim 6, characterized in that: R1 is selected from 8. The compound according to claim 2, characterized in that: Ring A is selected from X 1 and X 2 Selected from N; R 1 Selected from 9. The compound according to any one of claims 1 to 2, characterized in that: The X is selected from 10. 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).

11. The compound according to claim 10, 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.

12. The compound according to claim 11, characterized in that: The Y is selected from 13. 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.

14. The compound according to claim 13, characterized in that: The Z is selected from 15. The compound according to claims 1 to 14, characterized in that: The compound is specifically:

16. A pharmaceutical composition comprising a preparation prepared from the compound according to any one of claims 1 to 15, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition according to claim 16, characterized in that: It further includes pharmaceutically acceptable carriers, excipients, and vehicles.

18. Use of the compound according to any one of claims 1 to 15, 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 16 to 17 in the preparation of a medicament for preventing and / or treating a disease associated with BTK activity.

19. Use of the compound according to any one of claims 1 to 15, 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 16 to 17 in the preparation of a medicament for preventing and / or treating cancer.

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