Compound containing lactam structure

Abstract

The present application belongs to the field of pharmaceutical chemistry. The present application relates to a compound containing a lactam structure, in particular to a compound of Formula I, a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof in the treatment of related diseases (such as cancer). PTM-L-CLM Formula I

Description

Compounds containing lactam structures Technical Field

[0001] The present application relates to a compound containing a lactam structure, a preparation method thereof, a pharmaceutical composition containing the compound, and its use in treating related diseases (such as cancer). Background Art

[0002] Non-Hodgkin's lymphoma (NHL) is one of the most common malignancies worldwide and poses a serious threat to human health. Currently, a variety of therapies have been approved for the treatment of NHL, including chemotherapy drugs, antibody drugs, and small molecule targeted drugs. Clinical data show that existing therapies still have problems with poor efficacy and drug resistance. For example, Bruton's tyrosine kinase (BTK) inhibitors have shown good efficacy in the early stages of NHL treatment. BTK is primarily expressed in B cells and myeloid cells and is a target with good targeting and safety. However, disease progression or relapse caused by primary or acquired drug resistance is still inevitable.

[0003] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds can induce the recognition of target proteins by the cell's proteasome, causing their degradation and effectively reducing their levels in cells. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology has become possible for the treatment of various diseases and has received widespread attention in recent years.

[0004] BCL6 is a transcriptional repressor that regulates the development and function of germinal center B cells. High BCL6 protein expression, caused by various factors such as exon mutations, regulatory pathway mutations, somatic Bcl6 translocations, and promoter mutations, can lead to rapid proliferation of germinal center B cells, thereby promoting the formation of B cell lymphomas. At the same time, BCL6 can inhibit cell cycle checkpoints, differentiation-related genes, and DNA damage responses. Preclinical studies have shown that the loss of BCL6 in lymphoma cells can cause tumor progression to arrest. Therefore, BCL6 is a potential target for the treatment of various lymphomas. Novel PROTAC drugs that target BCL6 proteins and E3 ubiquitin ligases can be used to treat BCL6-related tumor diseases.

[0005] It is necessary to develop new PROTAC drugs for the treatment of lymphomas such as NHL to address problems such as poor effectiveness of existing therapies and drug resistance.

[0006] Detailed Description of the Invention

[0007] In one aspect, the present application relates to a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, PTM-L-CLM I

[0008] in,

[0009] CLM was selected from the E3 ubiquitin ligase binding moiety;

[0010] L is selected from a linking group;

[0011] The PTM is selected from a portion that binds to the target protein.

[0012] In some embodiments, the target proteins for the PTM moiety are diverse and are selected from proteins that are expressed in a cell such that at least a portion of the sequence is found in the cell and can bind to the PTM moiety. The term "protein" encompasses oligopeptides and polypeptide sequences that are sufficiently long to bind to the PTM moiety of the present disclosure. As further described herein, any protein in a eukaryotic or microbial system, including viruses, bacteria, or fungi, is a target protein for ubiquitination mediated by the compounds of the present disclosure. Preferably, the target protein is a eukaryotic protein.

[0013] The term "target protein" is used to describe a protein or polypeptide that is targeted for binding to a PTM according to the present disclosure and degradation by a ubiquitin ligase according to the present disclosure. The target protein includes proteins and peptides having any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, storage, transport, and signal transduction. In certain embodiments, the target protein comprises a structural protein, a receptor, an enzyme, a cell surface protein, a protein involved in the integral function of the cell (including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (metabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell movement, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimuli), behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity). Proteins of interest can include proteins from eukaryotic and prokaryotic organisms (including microbes, viruses, fungi, and parasites, including humans, microbes, viruses, fungi, and parasites that are targets for drug therapy, etc.), other animals (including domesticated animals), microbes used to identify targets for antibiotics and other antimicrobial agents and plants, and even viruses, etc.

[0014] More specifically, target proteins include, for example, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, BclIBax and other chaperones in the apoptotic pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type 4, PDEI, PDEII, PDEIII, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein (i.e., Gq), histamine receptor, 5-lipoxygenase, tryptase-like serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosome, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW STAT, RXR and the like, HIV 1 protease, HIV 1 integrase, influenza, ceramidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein (and MRP), tyrosine kinase, CD23, CD124, tyrosine kinase p56lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Cat+ channel, VCAM, VLA-4 integrin, selectin, CD40 / CD40L, neurokinin and receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus 1 (HSV-1), protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transfer protein inhibitor, bile acid transport inhibitor, 5-alpha reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neuropeptide Y and receptor, estrogen receptor, androgen receptor (AR), adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA of NGF α receptor, beta-amyloid protein, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her-21 neutrophil, telomerase inhibition, cytoplasmic phospholipase A2 and EGF receptor tyrosine kinase. Other target proteins include, for example, ecdysone 20-monooxygenase, GABA-gated chloride channel ion channels, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel and chloride channel. Additional target proteins include acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase and enolpyruvylshikimate-phosphate synthase.

[0015] In some embodiments, the PTM is selected from molecules (including small molecule compounds, polypeptides, proteins, nucleic acids, antibodies, etc.) having anti-cancer, anti-neurodegenerative, anti-microbial, anti-viral, anti-HIV or anti-fungal effects.

[0016] In some embodiments, the PTM is selected from molecules (including small molecule compounds, polypeptides, proteins, nucleic acids, antibodies, etc.) that act on AR, ER, kinases (e.g., tyrosine kinases, threonine / serine kinases), phosphatases, MDM2, proteins with human BET bromodomains, Hsp90, HDAC, human lysine methyltransferases, RAF receptors, FKBP, angiogenesis inhibitors (vascular growth factors), receptors or proteins related to immunosuppression, aryl hydrocarbon receptors (AHR), thyroid hormone receptors, HIV protease, HIV integrase, HCV protease, HBV protease or acyl protein thioesterase 1 and / or acyl protein thioesterase 2.

[0017] In some embodiments, the PTM is selected from a molecule (including small molecule compounds, polypeptides, proteins, nucleic acids, antibodies, etc.) that acts on FLT-3, VEGFR, EGFR TK, Aurora kinase, PIK-1, Bcl-2, HDAC, c-MET, PARP, Cdk, IGFR-TK, anti-HGF antibody, PI3K kinase, BRAF, BCL6, SMARCA2 (BRM), SMARCA4, AR-V7, Map kinase kinase (mek) or VEGF trap.

[0018] In some embodiments, the PTM is selected from molecules (including small molecule compounds, polypeptides, proteins, nucleic acids, antibodies, etc.) that act on ALK, BET, CDK, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEE1, MEK, BCR-ABL, MET, RAS, BTK, VEGFR, JAK, HER2, HDM2, HDAC, Akt, PI3K, mTOR, AR, ER, PDEδ, SRC, MDM2, RAF, IRAK4, STAT3 and c-Myc.

[0019] In some embodiments, the PTM is selected from molecules (including small molecule compounds, polypeptides, proteins, nucleic acids, antibodies, etc.) that act on ALK, BRD4, CDK4 / 6, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEEl, MEK, BCR-ABL, MET, KRAS, EGFR, BTK, AR, ER, PDEδ, JAK, MDM2 or RAF. In some embodiments, the PTM is selected from molecules (including small molecule compounds, polypeptides, proteins, nucleic acids, antibodies, etc.) that act on BTK.

[0020] In some embodiments, the PTM is selected from a portion that binds to the target protein BCL6.

[0021] In some embodiments, the PTM is selected from a small molecule compound. In some embodiments, the PTM is linked to L via a covalent bond.

[0022] In some embodiments, the PTM further comprises a pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition thereof of the molecule.

[0023] In some embodiments, the E3 ubiquitin ligase binding moiety is selected from a cereblon E3 ubiquitin ligase binding moiety, a VHL E3 ubiquitin ligase binding moiety, an IAP E3 ubiquitin ligase binding moiety, or an MDM2 E3 ubiquitin ligase binding moiety. In some embodiments, the E3 ubiquitin ligase binding moiety is selected from a cereblon E3 ubiquitin ligase binding moiety. In some embodiments, the CLM is selected from a small molecule compound. In some embodiments, the CLM is covalently linked to L.

[0024] In one aspect, the present application relates to a compound of formula II, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0025] in,

[0026] Indicates a single bond or a double bond;

[0027] Ring W is selected from

[0028] Ring A is absent or selected from C 3-15 Cycloalkenyl, 3-15 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0029] Ring B is selected from phenyl or 5-6 membered heteroaryl;

[0030] Ring C is selected from furyl, oxazolyl, isoxazolyl or pyrazolyl;

[0031] When ring A is absent or selected from phenyl, ring B is selected from phenyl, and ring C is selected from oxazolyl, isoxazolyl or pyrazolyl;

[0032] X a 、X b 、X c 、X d 、X e 、X f and X g are independently selected from C, CH, CH2, N, NH, O or S;

[0033] X19 、X 20 、X 21 , and X 22 are independently selected from CH or N;

[0034] X h Selected from CH2 or NH;

[0035] Each R 1 are independently selected from deuterium, halogen, -OH, -NH2, -CN, the following groups optionally substituted with one or more substituents: C 1-10 Alkyl, C 1-10 Alkoxy, (C 1-10 Alkyl)NH-, (C 1-10 Alkyl) 2N-, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl;

[0036] n is selected from 0, 1, 2, 3, 4, 5 or 6;

[0037] X 5 Selected from C(R f ) or N;

[0038] R f is selected from H, halogen, deuterium or C optionally substituted by one or more substituents 1-6 alkyl;

[0039] L 1 is selected from a bond, -NH-, -O-, -S-, -CONH- or -CON(C 1-6 alkyl)-, said L 1 Connected to ring C or ring E in ring W, when L 1 When selected from the bond, then X 5 Connected to ring C or ring E in ring W;

[0040] L is selected from a linking group;

[0041] The PTMs were selected from small molecule compounds targeting BCL6.

[0042] In some embodiments, ring W is selected from Ring C is selected from furyl, oxazolyl or isoxazolyl, wherein Ring A, Ring B, X a 、X b 、X c 、X d 、X e 、X f and X gThe definition of is as described in the present application, when ring A is absent or selected from phenyl, ring B is selected from phenyl, and ring C is selected from oxazolyl or isoxazolyl.

[0043] In one aspect, the present application also relates to a compound of formula III, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0044] in,

[0045] Ring W, L 1 、R 1 , n and X 5 is as defined in this application;

[0046] L is selected from a linking group;

[0047] X 8 Selected from C(R d )、C(R d R e )、N、N(R d ), O or S;

[0048] X 9 Selected from bonds, C(R g )、C(R g R h )、N、N(R g ), O or S;

[0049] R d 、R e 、R g and R h are independently selected from hydrogen, deuterium, halogen, -CN, or the following groups optionally substituted with one or more R': R v -、R v O-、R v S-、R s R v N-、R v C(O)-、R v S(O)2-、R v S(O)-、R v =N-、R v OC(O)-、R v C(O)O-、R v S(O)O-、R v OS(O)-、R v S(O)2O-、R v OS(O)2-、R s R v NC(O)-、R v C(O)NH-、R vOC(O)NH-、R s R v NC(O)O-、R v S(O)NH-、R s R v NS(O)-、R v S(O)2NH-、R s R v NS(O)2-or R s R v S(O)=N-;

[0050] or R d and R g Together with the carbon or nitrogen atom to which it is connected, it forms a C 5-12 Carbocyclic or 5-12 membered heterocyclic, the C 5-12 Carbocyclyl or 5-12 membered heterocyclyl is optionally substituted with one or more R";

[0051] R s and R v are independently selected from H, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-3 Alkylene-, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl C 1-3 Alkylene-, C 3-12 Cycloalkenyl, C 3-12 Cycloalkenyl C 1-3 Alkylene-, 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl C 1-3 Alkylene-, C 6-12 Aryl, C 6-12 Aryl C 1-3 Alkylene-, 5-12 membered heteroaryl, or 5-12 membered heteroarylC 1- 3-alkylene-;

[0052] Each R' or R" is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, R k O-、R k S-、R j R k N-、R k C(O)-、R k S(O)2-、R k S(O)-、R k OC(O)-、R kC(O)O-、R k S(O)O-、R k OS(O)-、R k S(O)2O-、R k OS(O)2-、R j R k NC(O)-、R k C(O)NH-、R k OC(O)NH-、R j R k NC(O)O-、R k S(O)NH-、R j R k NS(O)-、R k S(O)2NH-、R j R k NS(O)2-、C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl;

[0053] R j and R k are independently selected from H, C optionally substituted with one or more groups selected from deuterium, halogen, -OH, -NH2 or -CN 1- 6-alkyl;

[0054] Each R 2 and R 3 are independently selected from deuterium, halogen, -CN, -OH, -NH2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O-, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl is optionally substituted with one or more of the following groups: deuterium, halogen, -CN, -OH, -NH2 or C 1-6 Alkyl, each R 2 Replace in X10 、X 11 or X 12 superior;

[0055] m is selected from 0, 1, 2, or 3;

[0056] p is selected from 0, 1, 2, 3, 4 or 5;

[0057] R 4 Selected from hydrogen, -CN, -OH, -NH2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O-, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl C 1-3 Alkylene-, 3-12 membered heterocycloalkyl C 1-3 Alkylene-, C 6-12 Aryl C 1-3 Alkylene-, or 5-12 membered heteroaryl C 1-3 Alkylene-, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6- 12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl C 1-3 Alkylene-, 3-12 membered heterocycloalkyl C 1-3 Alkylene-, C 6-12 Aryl C 1-3 Alkylene-, or 5-12 membered heteroaryl C 1-3 Alkylene - optionally substituted with one or more of the following groups: deuterium, halogen, -CN, -OH, -NH2, C 1-6 Alkyl O-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl;

[0058] X 10 、X 11、X 12 、X 13 、X 14 、X 15 、X 16 and X 17 are independently selected from CH or N;

[0059] R t Selected from H or C 1-6 alkyl.

[0060] In some embodiments, the ring W, L 1 、R 1 、X 5 , L, X 8 、X 9 、R d 、R e 、R g 、R h 、R s 、R v , R', R", R j 、R k 、R 2 、R 3 、R 4 、X 10 、X 11 、X 12 、X 13 、X 14 、X 15 、X 16 、X 17 , or R t One or more deuteriums are optionally present in each group independently (ie, there are no deuteriums or one, two, three, four, five, or six, or more deuteriums are present).

[0061] In some embodiments, R d 、R e 、R g and R h are independently selected from hydrogen, halogen, -CN, or the following groups optionally substituted with one or more R': R v -、R v O-、R v S-、R s R v N-、R v C(O)-、R v S(O)2-、R v S(O)-、R v =N-、R v OC(O)-、R v C(O)O-、R v S(O)O-、Rv OS(O)-、R v S(O)2O-、R v OS(O)2-、R s R v NC(O)-、R v C(O)NH-、R v OC(O)NH-、R s R v NC(O)O-、R v S(O)NH-、R s R v NS(O)-、R v S(O)2NH-、R s R v NS(O)2-or R s R v S(O)=N-;

[0062] or R d and R g Together with the carbon or nitrogen atom to which it is connected, it forms a C 5-12 Carbocyclic or 5-12 membered heterocyclic, the C 5-12 Carbocyclyl or 5-12 membered heterocyclyl is optionally substituted with one or more R";

[0063] Each R' or R" is independently selected from halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, R k O-、R k S-、R j R k N-、R k C(O)-、R k S(O)2-、R k S(O)-、R k OC(O)-、R k C(O)O-、R k S(O)O-、R k OS(O)-、R k S(O)2O-、R k OS(O)2-、R j R k NC(O)-、R k C(O)NH-、R k OC(O)NH-、R j R k NC(O)O-、R k S(O)NH-、R j R kNS(O)-、R k S(O)2NH-、R j R k NS(O)2-、C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl;

[0064] R j and R k are independently selected from H, C optionally substituted with one or more groups selected from halogen, -OH, -NH2 or -CN 1-6 alkyl;

[0065] Each R 2 and R 3 are independently selected from halogen, -CN, -OH, -NH2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O-, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl is optionally substituted with one or more of the following groups: halogen, -CN, -OH, -NH2 or C 1-6 Alkyl, each R 2 Replace in X 10 、X 11 or X 12 superior;

[0066] R 4 Selected from hydrogen, -CN, -OH, -NH2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O-, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl C 1-3 Alkylene-, 3-12 membered heterocycloalkyl C 1-3 Alkylene-, C 6-12 Aryl C 1-3 Alkylene-, or 5-12 membered heteroaryl C 1-3 Alkylene-, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6- 12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl C 1-3 Alkylene-, 3-12 membered heterocycloalkyl C 1-3 Alkylene-, C 6-12 Aryl C 1-3 Alkylene-, or 5-12 membered heteroaryl C 1-3 Alkylene - optionally substituted with one or more of the following groups: halogen, -CN, -OH, -NH2, C 1-6 Alkyl O-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl.

[0067] In some embodiments, the CLM is selected from in Ring W, R 1 、n、L 1 and X 5 The definition of is as described in this application.

[0068] In some embodiments, the CLM is selected from in Ring A, Ring B, Ring C, R 1 、n、L 1 and X 5 The definition of is as described in this application.

[0069] In some embodiments, CLM or Selected from where X a 、X b 、X c 、X d 、Xe 、X f 、X g 、R 1 、n、L 1 and X 5 The definition of is as described in this application.

[0070] In some embodiments, CLM or Selected from where X h 、X 19 、X 20 、X 21 、X 22 、R 1 、n、L 1 and X 5 The definition of is as described in this application.

[0071] In some embodiments, the PTM is selected from in X 8 、X 9 、R 2 、R 3 ,m,p,R 4 、X 10 、X 11 、X 12 、X 13 、X 14 、X 15 、X 16 、X 17 and R t is defined as described herein. In some embodiments, the PTM is selected from

[0072] In some embodiments, ring W is selected from Among them, ring A, ring B, ring C, X a 、X b 、X c 、X d 、X e 、X f and X g The definition of is as described in this application.

[0073] In some embodiments, Ring A is absent or is selected from C 3-15 cycloalkenyl, 3-15 membered heterocycloalkenyl containing 1-3 heteroatoms selected from N or O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N or O or S. In some embodiments, ring A is absent or selected from C 3-12In some embodiments, ring A is absent or selected from C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl containing 1-3 heteroatoms selected from N or O or S, phenyl, or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N or O or S. In some embodiments, C 3-12 Cycloalkenyl is selected from C 3-8 In some embodiments, the 3-12 membered heterocycloalkenyl group is selected from the group consisting of 4-9 membered heterocycloalkenyl groups.

[0074] In some embodiments, Ring A is absent or is selected from C 5-15 In some embodiments, ring A is absent or is selected from C 5-15 cycloalkenyl, 5-15 membered heterocycloalkenyl containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S.

[0075] In some embodiments, Ring A is absent or is selected from C 5-10 In some embodiments, ring A is absent or is selected from C 5-10 cycloalkenyl, 5-10 membered heterocycloalkenyl containing 1-3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S.

[0076] In some embodiments, Ring A is absent or is selected from C 5-7 In some embodiments, ring A is absent or is selected from C 5-7 cycloalkenyl, 5-9 membered heterocycloalkenyl containing 1-3 heteroatoms selected from N or O or S, phenyl or 5-6 membered heteroaryl containing 1-3 heteroatoms selected from N or O or S. In some embodiments, ring A is absent or selected from C 5-7 In some embodiments, ring A is absent or is selected from C 5- 7-membered cycloalkenyl, 5-7-membered heterocycloalkenyl containing 1-2 N atoms or phenyl.

[0077] In some embodiments, Ring A is absent or is selected from C5 cycloalkenyl, C6 cycloalkenyl, C7 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered, or 9-membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, or oxazolyl.

[0078] In some embodiments, Ring A is absent or is selected from cyclopentenyl, monocyclohexenyl, bicyclohexenyl, monocycloheptenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy, ...

[0079] In some embodiments, Ring A is selected from C 5-10 cycloalkenyl or 5-10 membered heterocycloalkenyl.

[0080] In some embodiments, Ring A is selected from C 5-7 cycloalkenyl or 5-10 membered heterocycloalkenyl.

[0081] In some embodiments, Ring A is selected from C 5-6 Cycloalkenyl or 5-6 membered heterocycloalkenyl.

[0082] In some embodiments, R 1 The substitution position of is selected from Ring A or Ring B. In some embodiments, R 1 The substitution position of is selected from Ring A. In some embodiments, R 1 The substitution position of is selected from Ring B. In some embodiments, R 1 The substitution position is selected from ring C.

[0083] In some embodiments, Ring A is linked to L. In some embodiments, Ring B is linked to L. In some embodiments, Ring C is linked to L.

[0084] In some embodiments, Ring B is selected from phenyl or 6-membered heteroaryl. In some embodiments, Ring B is selected from phenyl.

[0085] In some embodiments, Ring C is selected from furanyl, oxazolyl, or isoxazolyl.

[0086] In some embodiments, Ring C is selected from furanyl or isoxazolyl. In some embodiments, Ring C is selected from oxazolyl or isoxazolyl. In some embodiments, when Ring A is absent or selected from phenyl and Ring B is selected from phenyl, Ring C is selected from oxazolyl or isoxazolyl.

[0087] In some embodiments, the moiety Selected from

[0088] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0089] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0090] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0091] In some embodiments, the moiety Selected from

[0092] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0093] In some embodiments, the moiety By n R 1 Replace each independently.

[0094] In some embodiments, X e Selected from C.

[0095] In some embodiments, X f and X g are independently selected from CH or CH2.

[0096] In some embodiments, X a 、X b 、Xc and X d are independently selected from C, CH, CH2, N or NH.

[0097] In some embodiments, the moiety Selected from

[0098] In some embodiments, the moiety Selected from

[0099] In some embodiments, the moiety Selected from

[0100] In some embodiments, the moiety Selected from

[0101] In some embodiments, X 19 、X 20 、X 21 , and X 22 are each independently selected from CH.

[0102] In some embodiments, the moiety Selected from

[0103] In some embodiments, the moiety Selected from

[0104] In some embodiments, each R 1 independently selected from deuterium, halogen, -OH, -NH2, -CN, the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-10 Alkyl)NH-, (C 1-10 Alkyl) 2N-, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0105] In some embodiments, each R 1 independently selected from deuterium, halogen, -OH, -NH2, -CN, the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 1-6Alkoxy or halogenated C 1-6 In some embodiments, the R 1 The substituents in are selected from halogen, -OH, -NH2, -CN, -CHO or -COOH.

[0106] In some embodiments, each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl.

[0107] In some embodiments, each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 alkyl.

[0108] In some embodiments, each R 1 independently selected from halogen, -OH, -NH2, -CN or C 1-3 In some embodiments, each R 1 independently selected from halogen or C 1-3 In some embodiments, each R 1 In some embodiments, each R 1 In some embodiments, each R 1 Independently selected from fluoro or methyl.

[0109] In some embodiments, n is selected from 0, 1, or 2. In some embodiments, n is selected from 0 or 1.

[0110] In some specific embodiments, n is selected from 0.

[0111] In some embodiments, the moiety Selected from

[0112] In some embodiments, X 5 Selected from C(R f ).

[0113] In some embodiments, R f is selected from H, fluorine, chlorine, bromine, deuterium or C optionally substituted by one or more substituents 1-3 alkyl.

[0114] In some embodiments, R fSelected from H, fluorine, chlorine, bromine, deuterium or C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more of the following groups: halogen, -OH, -NH2, or -CN.

[0115] In some embodiments, R f is selected from H, fluorine, deuterium or methyl. In some embodiments, R f Selected from H.

[0116] In some embodiments, X 5 is selected from CH or N.

[0117] In some embodiments, X 5 Selected from CH.

[0118] In some embodiments, Selected from

[0119] In some embodiments, the L 1 In some embodiments, the L 1 Select from keys.

[0120] In some embodiments, CLM or Selected from In some embodiments, CLM or Selected from

[0121] In some embodiments, CLM or Selected from In some embodiments, CLM or Selected from In some embodiments, CLM or Selected from In some embodiments, CLM or Selected from In some embodiments, CLM or Selected from

[0122] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-50 Alkylene, C 2-50 Alkenylene or C 2-50 Alkynylidene, optionally, the C 1-50 Alkylene, C 2-50Alkenylene or C 2-50 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-15 Cycloalkyl, 3-15 membered heterocycloalkyl, 4-15 membered heterocycloalkenyl, C 6-15 Aryl, 5-15 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted.

[0123] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 Alkynylidene, optionally, the C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted.

[0124] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-20 Alkylene, C 2-20 Alkenylene or C 2-20 Alkynylidene, optionally, the C 1-20 Alkylene, C 2-20 Alkenylene or C 2-20 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-10 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-10 Aryl, any 5-10 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted.

[0125] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-15 Alkylene, C 2-15 Alkenylene or C 2-15 Alkynylidene, optionally, the C 1-15 Alkylene, C 2-15 Alkenylene or C 2-15 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, C 6-8 Aryl, 5-8 membered heteroaryl, -NH-, -N(C1-4 alkyl)- or -S-substituted.

[0126] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-10 Alkylene, C 2-10 Alkenylene or C 2-10 Alkynylidene, optionally, the C 1-10 Alkylene, C 2-10 Alkenylene or C 2-10 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-substituted.

[0127] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene, optionally, the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-substituted.

[0128] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 Alkynylidene, optionally, the C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 One or more (e.g., one or two, one or three, etc.) -CH2- in the alkynylene group are independently optionally replaced by -O-, C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-substituted.

[0129] In some embodiments, the L is selected from C optionally substituted with one or more substituents. 1-10 Alkylene or C 2-10 Alkynylidene, optionally, the C 1-10 Alkylene or C 2-10One or more -CH2- in the alkynylene group are independently optionally selected from -O-, C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, -NH-, -N(C 1-6 alkyl)- or -S-substituted.

[0130] In some embodiments, the L is selected from C optionally substituted with one or more substituents. 1-6 Alkylene or C 2-6 Alkynylidene, optionally, the C 1-6 Alkylene or C 2-6 One or more -CH2- in the alkynylene group are independently optionally selected from -O-, C 3-10 Cycloalkyl, 4-11 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, -NH-, -N(C 1-3 alkyl)- or -S-substituted.

[0131] In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 The cycloalkyl or 4-12 membered heterocycloalkyl is optionally substituted with one or more halogen, -OH, -NH2 or CN.

[0132] In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, (C 1-6 alkyl)NH- or (C 1-6 Alkyl)2N-.

[0133] In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, (C 1-4 Alkyl)NH-, (C1-4 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl.

[0134] In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl or C 1-6 Alkoxy.

[0135] In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN or C optionally substituted with halogen or hydroxyl. 1-3 In some embodiments, in the definition of L, the substituent is -F, =O, methyl or HOCH2-.

[0136] In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl.

[0137] In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, (C 1-4 Alkyl)NH-, (C 1-4 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl.

[0138] In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl or C 1-6 In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN or C 1- In some embodiments, in the definition of L, the substituent is methyl or ═O.

[0139] In some embodiments, the L is selected from -LNK 1 -Cy 1 -LNK-Cy2 -LNK 2 -Cy 3 -LNK 3 -Cy 4 -LNK 4 -,in,

[0140] Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl or 4-12 membered heterocycloalkenyl;

[0141] LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-12 Alkylene, C 2-12 Alkenylene, C 2-12 Alkynylidene or C 1-12 heteroalkylene;

[0142] Each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1- 6 alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl.

[0143] In some embodiments, Cy 1 、Cy 2 and Cy 3 In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 In some embodiments, Cy 2 and Cy 3 In some embodiments, LNK 1 and LNK 2 In some embodiments, LNK 3 and LNK 4Selected bond.

[0144] In some embodiments, L is selected from -Cy 1 -, -Cy 2 -, -LNK 1 -, -Cy 1 -LNK-, -Cy 1 -Cy 2 -, -LNK 1 -Cy 1 -LNK-, -LNK-Cy 2 -LNK 2 -, -Cy 1 -Cy 2 -LNK 2 -, -LNK 1 -Cy 1 -Cy 2 -, -Cy 1 -LNK-Cy 2 -, -LNK 1 -Cy 1 -Cy 2 -LNK 2 -, -LNK 1 -Cy 1 -LNK-Cy 2 -, -Cy 1 -LNK-Cy 2 -LNK 2 -, -Cy 1 -Cy 2 ]>-Cy 3 -, -Cy<000067]>-LNK-Cy 2 -Cy 3 -, -Cy 1 -Cy 2 -LNK 2 -Cy 3 -, -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -, -Cy 1 -LNK-Cy 2 -Cy 3 -LNK 3 -, -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -, -Cy 1 -LNK-Cy 2 -Cy3 -Cy 4 -LNK 4 In some embodiments, L is selected from -Cy 1 -Cy 2 -LNK 2 -. In some embodiments, the L is selected from -LNK 1 -Cy 1 -Cy 2 -. In some embodiments, the L is selected from -Cy 1 -LNK-Cy 2 -. In some embodiments, the L is selected from -LNK 1 -Cy 1 -Cy 2 -LNK 2 -. In some embodiments, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -. In some embodiments, the L is selected from -Cy 1 -LNK-Cy 2 -LNK 2 -.

[0145] In some embodiments, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene or C 1-10 Heteroalkylene.

[0146] In some embodiments, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene or C 1-6 Heteroalkylene.

[0147] In some embodiments, LNK, LNK 1 、LNK 2 、LNK 3and LNK 4 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene or C 1-4 Heteroalkylene.

[0148] In some embodiments, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-6 Alkylene, C 2-6 Alkynylidene or C 1-6 Heteroalkylene.

[0149] In some embodiments, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-4 Alkylene, C 2-4 Alkynylidene or C 1-4 Heteroalkylene.

[0150] In some embodiments, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, or optionally substituted by one or more R c Substituted with the following groups: C 1-3 Alkylene, C 2-3 Alkynylidene or C 1-3 Heteroalkylene.

[0151] In some embodiments, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, or optionally substituted by one or more R c Substituted with the following groups: C 1-3 Alkylene, C2 alkynylene or C 1-2 Heteroalkylene.

[0152] In some embodiments, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 In some embodiments, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 In some embodiments, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 In some embodiments, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from optionally one or more R c Substituted C 1-3 In some embodiments, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from optionally one or more R c Substituted -CH2-.

[0153] In some embodiments, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 Each is independently selected from a bond, -NH-, -O-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, -C(CH3)2-, ethynylene, -C(O)- or -C(O)CH2-.

[0154] In some embodiments, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are each independently selected from -CH2-.

[0155] In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 3-11cycloalkyl, 4-12 membered heterocycloalkyl or 4-11 membered heterocycloalkenyl.

[0156] In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 4-10 cycloalkyl, 4-11 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl.

[0157] In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 4-6 Cycloalkyl, C9 cycloalkyl, 4-11 membered heterocycloalkyl or 6 membered heterocycloalkenyl.

[0158] In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl. In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from optionally one or more R b Substituted C 4-6 In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from optionally one or more R b Substituted 4-6 membered heterocycloalkyl.

[0159] In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, or optionally substituted by one or more R bsubstituted with the following groups: cyclobutyl, cyclopentyl, cyclohexyl, spironanyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl, piperazinyl, monoazaspiroheptanyl, monoazaspirooctanyl, monoazaspironanyl, diazaspironanyl, monoazaspirodecanyl, diazaspirodecanyl, monoazaspiroundecyl, diazaspiroundecyl, monoazabicyclohexane, octahydrocyclopentapyrrolyl, diazabicyclooctanyl or monoazabicyclononanyl. In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from optionally one or more R b In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from optionally one or more R b Substituted: azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.

[0160] In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond,

[0161] In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from In some embodiments, Cy1 、Cy 2 、Cy 3 or Cy 4 are independently selected from In some embodiments, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from

[0162] In some embodiments, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-10 The cycloalkyl or 4-10 membered heterocycloalkyl is optionally substituted with one or more halogen, -OH, -NH2 or -CN.

[0163] In some embodiments, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, (C 1-6 alkyl)NH- or (C 1-6 Alkyl)2N-.

[0164] In some embodiments, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, (C 1-4 Alkyl)NH-, or (C 1-4 Alkyl)2N-.

[0165] In some embodiments, each R b and R care each independently selected from halogen, =O, -OH, -NH2, -CN or C optionally substituted by halogen or hydroxyl 1-3 alkyl.

[0166] In some embodiments, each R b and R c Each is independently selected from -F, =O, methyl or HOCH2-.

[0167] In other embodiments, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl.

[0168] In other embodiments, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 alkyl)NH- or (C 1-6 Alkyl)2N-.

[0169] In other embodiments, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, (C 1-4 Alkyl)NH-, or (C 1-4 Alkyl)2N-.

[0170] In other embodiments, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN or C 1-3 alkyl.

[0171] In other embodiments, each R b and R c Each is independently selected from =0 or methyl.

[0172] In some embodiments, L or -LNK 1- is selected from a bond, -O-, -NH-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, -C(CH3)2-, ethynylene, -C(O)- or -C(O)CH2-.

[0173] In some embodiments, L is selected from a bond, -NHCH2-, -CH2NHCH2-, -CH2-, -C(O)CH2-,

[0174] In some embodiments, L is selected from

[0175] In some embodiments, Ring A or Ring G is linked to L.

[0176] In some embodiments, X 8 Selected from C(R d ) or C(R d R e ). In some embodiments, X 8 Selected from C(R d ) or CH2.

[0177] In some embodiments, X 9 Selected from a bond or C(R g ).

[0178] In some embodiments, X 9 Selected from a bond or CH.

[0179] In some embodiments, X 8 Selected from C(R d ). In some embodiments, X 9 Selected from C(R g ).

[0180] In some embodiments, R d 、R e 、R g and R h are independently selected from hydrogen, halogen, -CN, or the following groups optionally substituted with one or more R': R v -、R v O-、R v S- or R s R v N-.

[0181] In some embodiments, R s and Rv are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkylene-, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl C 1-3 Alkylene-, C 3-6 Cycloalkenyl, C 3-6 Cycloalkenyl C 1-3 Alkylene-, 3-6 membered heterocycloalkenyl, 3-6 membered heterocycloalkenyl C 1-3 Alkylene-, C 6-12 Aryl, C 6-12 Aryl C 1-3 Alkylene-, 5-6 membered heteroaryl or 5-6 membered heteroarylC 1-3 Alkylene-.

[0182] In some embodiments, R s and R v are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl.

[0183] In some embodiments, R d 、R e 、R g and R h are independently selected from hydrogen, halogen, -CN, or the following groups optionally substituted with one or more R': C 1-6 Alkyl-, C 1-6 Alkyl O-, C 1-6 Alkyl S- or C 1-6 Alkyl NH-.

[0184] In some embodiments, R d 、R e 、R g and R h are independently selected from hydrogen, or C optionally substituted by one or more R' 1-4 In some embodiments, R d 、R e 、R g and R h are independently selected from hydrogen, or CH3O- optionally substituted by one or more R'.

[0185] In some embodiments, R g In some embodiments, R d is selected from C optionally substituted with one or more R'1-4 Alkyl O-.

[0186] In some embodiments, R d and R g Together with the carbon or nitrogen atom to which it is connected, it forms a C 5-10 Carbocyclic or 5-10 membered heterocyclic, the C 5-10 The carbocyclyl or 5- to 10-membered heterocyclyl is optionally substituted with one or more R".

[0187] In some embodiments, the R d and R g Together with the carbon or nitrogen atom to which it is connected, it forms a C 6-10 Carbocyclic or 6-10 membered heterocyclic, the C 6-7 The carbocyclyl or 6-7 membered heterocyclyl is optionally substituted with one or more R".

[0188] In some embodiments, the R d and R g Together with the carbon atom or nitrogen atom to which it is attached, it forms a 7-membered heterocyclic group containing nitrogen and oxygen heteroatoms, and the 7-membered heterocyclic group containing nitrogen and oxygen heteroatoms is optionally substituted by one or more R".

[0189] In some embodiments, each R' or R" is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, R k O-、R k S-、R j R k N-、R k C(O)-、R k S(O)2-、R k S(O)-、R k OC(O)-、R k OS(O)-、R k OS(O)2-、R j R k NC(O)-、R j R k NS(O)-、R j R k NS(O)2-、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl or 5-6 membered heteroaryl.

[0190] In some embodiments, each R' is independently selected from R j R k NC(O)-. In some embodiments, each R' is independently selected from CH3NHC(O)-.

[0191] In some embodiments, R j and R k are independently selected from H, C optionally substituted with one or more groups selected from halogen, -OH, -NH2 or -CN 1-3 In some embodiments, R j and R k are independently selected from H or C 1-3 In some embodiments, R j and R k are independently selected from H or methyl.

[0192] In some embodiments, R e In some embodiments, R g and R h Selected from hydrogen.

[0193] In some embodiments, R d Selected from hydrogen or

[0194] In some embodiments, R d and R g Together with the carbon atom or nitrogen atom to which it is attached, it forms a 7-membered heterocyclic group, which is optionally substituted with one or more R". In some embodiments, R d and R g Together with the carbon or nitrogen atom to which it is attached, described is optionally substituted with one or more R". In some embodiments, R d and R g Together with the carbon or nitrogen atom to which it is attached,

[0195] In some embodiments, each R" is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, R k O-、R k S-、R j R k N-、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 In some embodiments, each R" is independently selected from halogen or C 3-6 In some embodiments, each R" is independently selected from halogen (eg, F, Cl, Br, I) or cyclopropyl. In some embodiments, each R" is independently selected from -F, -Cl or C 3-4 Cycloalkyl.

[0196] In some embodiments, each R2 and R 3 are independently selected from halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl O-, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Alkyl, 3-6 heterocycloalkyl, C 6-12 Aryl or 5-6 heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl O-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Alkyl, 3-6 heterocycloalkyl, C 6-12 Aryl or 5-6 heteroaryl are optionally substituted by one or more of the following groups: halogen, -CN, -OH, -NH2 or C 1-6 Alkyl, each R 2 Replace in X 10 、X 11 or X 12 superior.

[0197] In some embodiments, each R 2 and R 3 are independently selected from halogen, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl O-, C 1-4 Alkyl S-, C 1-4 Alkyl NH- or (C 1-4 Alkyl) 2N-, the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl O-, C 1-4 Alkyl NH- or (C 1-4 alkyl)2N- is optionally substituted with one or more of the following groups: halogen, -CN, -OH, -NH2 or C 1-6 Alkyl, each R 2 Replace in X 10 、X 11 or X 12 superior.

[0198] In some embodiments, each R 2Replace in X 10 、X 11 or X 12 superior.

[0199] In some embodiments, each R 2 and R 3 are independently selected from halogen, -CN, -OH, -NH2, C 1-4 Alkyl or C 1-4 In some embodiments, each R 2 and R 3 are independently selected from halogen, -CN, C 1-3 Alkyl or C 1-3 Alkyl O-.

[0200] In some embodiments, each R 2 and R 3 are independently selected from -F, -Cl, -Br, -CN or CH3O-. In some embodiments, each R 2 Selected from C 1-3 In some embodiments, each R 2 In some embodiments, each R 3 Independently selected from -F, or -Cl.

[0201] In some embodiments, m and p are each independently selected from 0, 1, or 2.

[0202] In some embodiments, R 4 Selected from hydrogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl O-, C 1- 6-alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl C 1-3 Alkylene-, 3-6 membered heterocycloalkyl C 1-3 Alkylene-, C 6-10 Aryl C 1-3 Alkylene- or 5-6 membered heteroaryl C 1-3 Alkylene-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl O-, C 1-6 Alkyl NH-, (C1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl C 1-3 Alkylene-, 3-6 membered heterocycloalkyl C 1-3 Alkylene-, C 6-10 Aryl C 1-3 Alkylene- or 5-6 membered heteroaryl C 1-3 Alkylene - optionally substituted with one or more of the following groups: halogen, -CN, -OH, -NH2, C 1-6 Alkyl O-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl or 5-6 membered heteroaryl.

[0203] In some embodiments, R 4 Selected from hydrogen, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl O-, C 1- 4-alkyl S-, C 1-4 Alkyl NH- or (C 1-4 Alkyl)2N-.

[0204] In some embodiments, R 4 Selected from C 1-6 In some embodiments, R 4 Selected from C 1-3 alkyl.

[0205] In some embodiments, R 4 is selected from methyl or isopropyl.

[0206] In some embodiments, X 10 and X 11 Selected from CH, X 12 is selected from CH or N.

[0207] In some embodiments, X 13 and X 15 Selected from CH or N, X 14 、X 16 and X 17 Selected from CH.

[0208] In some embodiments, R t Selected from H or C 1-3 In some embodiments, Rt In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from z is selected from 0, 1, 2, 3 or 4; or z is selected from 1, 2 or 3.

[0209] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0210] In some embodiments, when ring W is selected from Structural part Selected from X 8 Selected from -C(R d )-,X 9 Selected from -C(R g )-, where R d and R g Together with the carbon or nitrogen atom to which it is connected, it forms a C 5-12 Carbocyclic or 5-12 membered heterocyclic, the C 5-12 Carbocyclyl or 5-12 membered heterocyclyl is optionally substituted by one or more R"; X 10 、X 11 、X 12 、R 2 、R 4 , and m are defined as described in this application.

[0211] In some embodiments, when ring W is selected from Structural part Selected from X 8 Selected from -C(R d R e )-or-N(R d )-,R d 、X 10 、X 11 、X 12 、R 2 、R4 , and m are defined as described in this application.

[0212] In some embodiments, when Ring A is selected from a bond, Ring B is selected from phenyl or pyridinyl, and Ring C is selected from pyrazolyl, X 13 Selected from N, X 15 Selected from CH.

[0213] In some embodiments, when Ring A is selected from a bond, Ring B is selected from phenyl or pyridyl, the moiety Selected from

[0214] In some embodiments, when Selected from X 13 Selected from N, X 15 Selected from CH.

[0215] In some embodiments, when Selected from Structural part Selected from

[0216] In some embodiments, when Selected from Structural part Selected from

[0217] In some embodiments, the moiety Selected from In some embodiments, the moiety Selected from

[0218] In some embodiments, the PTM, the structural moiety Selected from In some embodiments, the PTM, the structural moiety Selected from In some embodiments, the PTM, the structural moiety Selected from

[0219] In some embodiments, in compounds of Formula I and Formula II, PTM is selected from in,

[0220] Indicates a single bond or a double bond;

[0221] X 8 C(R d ), R d Selected from the following groups optionally substituted with one or more R': C 1-12 Alkyl O-, C 1-12 Alkyl S-, C 1-12 Alkyl C(O)-, C 1-12 Alkyl NHC(O)- or C 1-12 AlkylNHC(O)O-;

[0222] Each R' is independently selected from deuterium, halogen, -CN, -NH2, R k C(O)-、R j R k NC(O)-、R j R k NC(O)O-or R j R k NS(O)-;R j and R k are independently selected from H, optionally substituted by -NH2, 1-6 alkyl;

[0223] X 9 Selected from C(R g ), R g Selected from hydrogen, halogen or C 1-12 alkyl;

[0224] or R d and R g Together with the carbon atom or nitrogen atom to which it is attached, it forms a 5-12 membered heterocyclic group containing 1-3 heteroatoms or heteroatom groups selected from N, O, S or NH, wherein the 5-12 membered heterocyclic group is optionally substituted by one or more R";

[0225] Each R" is independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, or a 3-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S;

[0226] R 4 Selected from hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl or C 3-12 Cycloalkyl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl or C3-12 Cycloalkyl is optionally substituted with one or more halogens;

[0227] Each R 2 independently selected from halogen, -CN, -OH, -NH2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O- or C 1-12 Alkyl S-, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O- or C 1-12 Alkyl S- is optionally substituted with one or more of the following halogens;

[0228] m is selected from 0, 1 or 2;

[0229] Each R 3 independently selected from halogen, -CN, -OH, -NH2 or C 1-12 Alkyl, the C 1-12 The alkyl group is optionally substituted with one or more halogens;

[0230] p is selected from 0, 1 or 2;

[0231] X 12 、X 13 and X 15 are independently selected from CH or N.

[0232] In some embodiments, in a PTM, Indicates a single bond or a double bond;

[0233] X 8 C(R d ), R d is C optionally substituted by R' 1-12 Alkyl O-, R' is deuterium, halogen, -CN, -NH2, R j R k NC(O)-,R j and R k are independently selected from H or C 1-6 Alkyl (preferably R j and R k are independently selected from H or C 1-3 alkyl); preferably, X 8 is CH3NHC(O)CH2O-;

[0234] X 9 Selected from C(R g ), R g is hydrogen;

[0235] or R d and R g The carbon atom or nitrogen atom to which it is attached forms a 5-10 membered heterocyclic group (e.g., a 6-8 membered heterocyclic group, a 6-8 membered heterocycloalkenyl group) containing 1-3 heteroatoms or heteroatoms selected from N, O, S or NH, wherein the 5-12 membered heterocyclic group is optionally substituted by one or more R "; each R " is independently selected from halogen or C 3-10 Cycloalkyl (e.g. C 3-6 Cycloalkyl, C 3-5 Cycloalkyl or C 3-4 cycloalkyl); preferably, R d and R g Together with the carbon atom or nitrogen atom to which it is attached, it forms the following group which is optionally substituted by one or more R": (For example );

[0236] R 4 is C optionally substituted by one or more halogens 1-12 Alkyl (e.g. C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 alkyl);

[0237] R 2 Replace in X 12 Up, R 2 Selected from C 1-12 Alkyl O- or C 1-12 Alkyl S-(preferably, R 2 C 1-12 Alkyl O-, C 1-6 Alkyl O-, C 1-5 Alkyl O-, C 1-4 Alkyl O- or C 1-3 Alkyl O-);

[0238] m is selected from 0 or 1;

[0239] R 3 is halogen (e.g. fluorine, chlorine, bromine or iodine);

[0240] p is selected from 0 or 1;

[0241] X 12 and X 13 are independently selected from CH or N, X 15 is N.

[0242] In some embodiments, in compounds of Formula I and Formula II, PTM is selected from in,

[0243] X 8 C(R d ), R d Selected from the following groups optionally substituted with one or more R': C 1-12 Alkyl O-, C 1-12 Alkyl S-, C 1-12 Alkyl C(O)-, C 1-12 Alkyl NHC(O)- or C 1-12 AlkylNHC(O)O-;

[0244] Each R' is independently selected from deuterium, halogen, -CN, -NH2, R k C(O)-、R j R k NC(O)-、R j R k NC(O)O-or R j R k NS(O)-;R j and R k are independently selected from H, optionally substituted by -NH2, 1-6 alkyl;

[0245] X 9 Selected from C(R g ), R g Selected from hydrogen, halogen or C 1-12 alkyl;

[0246] or R d and R g Together with the carbon atom or nitrogen atom to which it is attached, it forms a 5-12 membered heterocyclic group containing 1-3 heteroatoms or heteroatom groups selected from N, O, S or NH, wherein the 5-12 membered heterocyclic group is optionally substituted by one or more R";

[0247] Each R" is independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, or a 3-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O or S;

[0248] R 4 Selected from hydrogen, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl or C 3-12 Cycloalkyl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl or C 3-12 Cycloalkyl is optionally substituted with one or more halogens;

[0249] R 2 Selected from halogen, -CN, -OH, -NH2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O- or C 1-12 Alkyl S-, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O- or C 1-12 Alkyl S- is optionally substituted with one or more of the following halogens;

[0250] m is selected from 0 or 1;

[0251] R 3 Selected from halogen, -CN, -OH, -NH2 or C 1-12 Alkyl, the C 1-12 The alkyl group is optionally substituted with one or more halogens;

[0252] X 12 and X 13 are independently selected from CH or N;

[0253] In some preferred embodiments, X 8 C(R d ), R d is C optionally substituted by R' 1-12 Alkyl O-, R' is deuterium, halogen, -CN, R j R k NC(O)-,R j and R k are independently selected from H or C 1-6 Alkyl (preferably R j and R k are independently selected from H or C 1-3 alkyl); preferably, X 8 is CH3NHC(O)CH2O-;

[0254] X 9 Selected from C(R g ), R g is hydrogen;

[0255] or R d and R gThe carbon atom or nitrogen atom to which it is attached forms a 5-10 membered heterocyclic group (e.g., a 6-8 membered heterocyclic group, a 6-8 membered heterocycloalkenyl group) containing 1-3 heteroatoms or heteroatoms selected from N, O, S or NH, wherein the 5-12 membered heterocyclic group is optionally substituted by one or more R "; each R " is independently selected from halogen or C 3-10 Cycloalkyl (e.g. C 3-6 Cycloalkyl, C 3-5 Cycloalkyl or C 3-4 cycloalkyl); preferably, R d and R g Together with the carbon atom or nitrogen atom to which it is attached, it forms the following group which is optionally substituted by one or more R": (For example );

[0256] R 4 is C optionally substituted by one or more halogens 1-12 Alkyl (e.g. C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl or C 1-3 alkyl);

[0257] R 2 Selected from C 1-12 Alkyl O- or C 1-12 Alkyl S-(preferably, R 2 C 1-12 Alkyl O-, C 1-6 Alkyl O-, C 1-5 Alkyl O-, C 1-4 Alkyl O- or C 1-3 Alkyl O-);

[0258] m is selected from 0 or 1;

[0259] R 3 is halogen (e.g. fluorine, chlorine, bromine or iodine);

[0260] X 12 and X 13 are independently selected from CH or N.

[0261] In some embodiments, in the compound of Formula I, CLM is in, represents a single bond or a double bond. In some embodiments, CLM is In some embodiments, the CLM is In some embodiments, the CLM is

[0262] In some embodiments, X 5 Selected from C(Rf ), R f Selected from H, halogen, deuterium or C 1-6 In some embodiments, X 5 Selected from C(R f ), R f Selected from H or deuterium (such as R f for H).

[0263] In some embodiments, L 1 In some embodiments, L 1 is the key.

[0264] In some embodiments, in compounds of Formula I and Formula II, Ring W is selected from In some embodiments, the ring C or ring E and the L 1 Connect, when L 1 When the ring C or ring E and the X are 5 connect.

[0265] In some embodiments, the moiety Selected from Ring A is absent or selected from C 5-10 cycloalkenyl, 5-10 membered heterocycloalkenyl containing 1-2 heteroatoms selected from N, O or S, or phenyl.

[0266] In some embodiments, the moiety Selected from Ring A is absent or selected from C 5-10 cycloalkenyl, 5-10 membered heterocycloalkenyl containing 1-2 heteroatoms selected from N, O or S, or phenyl.

[0267] In some embodiments, Ring A is absent or is selected from C 5-7 In some embodiments, ring A is absent or is selected from C 5-7 Cycloalkenyl, 5-7 membered heterocycloalkenyl containing 1-2 N atoms or phenyl.

[0268] In another aspect, the present application relates to a compound of Formula IV, Formula V, Formula VIA, Formula VIB, Formula VIC, Formula VIIA, Formula VIIB, Formula VIIC, Formula VIID, Formula VIIE or Formula VIIF, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0269] Among them, X 18 selected from CH or N;

[0270] u is selected from 0, 1, 2, 3, 4, 5 or 6;

[0271] L, Ring A, Ring B, Ring C, R 1 、n、L 1 、X 5 、X 8 、X 9 、R d , R”, R 2 、R 3 ,m,p,R 4 、X 12 、X 13 、X 15 、R t 、X a 、X b 、X c 、X d 、X e 、X f and X g The definition of is as described in this application.

[0272] In some embodiments, X 18 Selected from CH.

[0273] In some embodiments, u is selected from 2, 3, or 4.

[0274] In some embodiments, the moiety As described in this application.

[0275] In some embodiments, the moiety The definition of Definition of .

[0276] In some embodiments, the PTM, the structural moiety Selected from

[0277] In some embodiments, the PTM, the structural moiety Selected from z is selected from 0, 1, 2, 3 or 4.

[0278] The present application relates to a compound of formula X, a structural moiety, a derivative thereof (e.g., protac), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0279] in,

[0280] and X 5is as defined in this application;

[0281] X a 、X b 、X c and X d are independently selected from C, CH, CH2, N, NH, O or S, provided that X d Selected from N, or, the X a 、X b 、X c and X d At least two of them are selected from N or NH;

[0282] Each R 1a are independently selected from deuterium, halogen, -OH, -NH2, -CN, -CHO, the following groups optionally substituted with one or more substituents: C 1-10 Alkyl, C 1-10 Alkoxy, (C 1-10 Alkyl)NH-, (C 1-10 Alkyl) 2N-, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl or C 1-10 Alkyl OC(O)-;

[0283] k is selected from 0, 1, 2 or 3.

[0284] In some embodiments, X a 、X b 、X c and X d are independently selected from C, CH, CH2, N or NH.

[0285] In some embodiments, each R 1a independently selected from deuterium, halogen, -OH, -NH2, -CN, -CHO, the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl) 2N-, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl or C 1-6 AlkylOC(O)-.

[0286] In some embodiments, each R 1aindependently selected from deuterium, halogen, -OH, -NH2, -CN, -CHO, C 1-6 Alkyl, C 4-12 (such as C 4- 10 、C 4-8 or C 4-6 )cycloalkyl, 4-12 membered (e.g., 4-10 membered or 5-6 membered) heterocycloalkyl or C 1-6 Alkyl OC(O)-, the C 1-6 Alkyl, C 4-12 Cycloalkyl, 4-12 membered heterocycloalkyl or C 1-6 Alkyl OC(O)- is optionally substituted with one or more of the following groups: halogen, -OH, -NH2, -CN, -CHO or COOH.

[0287] In some embodiments, each R 1a Independently selected from C 4-12 (such as C 4-10 、C 4-8 or C 4-6 )cycloalkyl or 4-12 membered (e.g., 4-10 membered or 5-6 membered) heterocycloalkyl. In some embodiments, each R 1a Independently selected from fluorine, chlorine, bromine, -CHO, -C 1-3 In some embodiments, each R 1a In some embodiments, each R 1a are independently selected from piperidinyl.

[0288] In some embodiments, k is selected from 0 or 1.

[0289] In some embodiments, Ring G is an aromatic ring. In some embodiments, Ring G is selected from

[0290] In some embodiments, the moiety Selected from

[0291] The present application provides the following compounds, structural moieties, derivatives thereof (e.g., protac), or pharmaceutically acceptable salts thereof:

[0292] The present application relates to compounds of formula XI, moieties, derivatives thereof (e.g., protac), stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0293] in,

[0294] X 5 and L 1 is as defined in this application;

[0295] Ring B is selected from phenyl or 5-6 membered heteroaryl;

[0296] X 18 selected from CH or N;

[0297] X 23 、X 24 、X 25 and X 26 are independently selected from CH2 or NH;

[0298] Each R 1b are independently selected from deuterium, halogen, -OH, -NH2, -CN, the following groups optionally substituted with one or more substituents: C 1-10 Alkyl, C 1-10 Alkoxy, (C 1-10 Alkyl)NH-, (C 1-10 Alkyl) 2N-, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl;

[0299] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0300] In some embodiments, Ring B is selected from phenyl or 6-membered heteroaryl. In some embodiments, Ring B is selected from phenyl.

[0301] In some embodiments, X 18 Selected from N.

[0302] In some embodiments, the moiety Selected from

[0303] In some embodiments, X 23 、X 24 、X 25 and X 26 are independently selected from CH2. In some embodiments, X 23 、X 24 、X 25 and X 26 One of them is selected from NH, and the other is selected from CH2.

[0304] In some embodiments, each R 1bindependently selected from deuterium, halogen, -OH, -NH2, -CN, -CHO, the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl) 2N-, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl or C 1-6 AlkylOC(O)-.

[0305] In some embodiments, each R 1b independently selected from deuterium, halogen, -OH, -NH2, -CN, -CHO, C 1-6 Alkyl, C 4-12 (such as C 4- 10 、C 4-8 or C 4-6 )cycloalkyl, 4-12 membered (e.g., 4-10 membered or 5-6 membered) heterocycloalkyl or C 1-6 Alkyl OC(O)-, the C 1-6 Alkyl, C 4-12 Cycloalkyl, 4-12 membered heterocycloalkyl or C 1-6 Alkyl OC(O)- is optionally substituted with one or more of the following groups: halogen, -OH, -NH2, -CN, -CHO, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkylamino, di-C 1-4 Alkylamino, or -COOH.

[0306] In some embodiments, each R 1b independently selected from C optionally substituted with one or more halogen, -OH, -NH2 or -CN 1-4 In some embodiments, each R 1b Selected from HOCH2-.

[0307] In some embodiments, n is selected from 0 or 1.

[0308] The present application relates to the following compounds, structural moieties, stereoisomers thereof, derivatives thereof (such as PROTACs), or pharmaceutically acceptable salts thereof:

[0309] On the other hand, the present application relates to the use of the compounds (e.g., Formula I, II, X, XI or specific compounds), structural parts, isomers thereof (e.g., stereoisomers), and derivatives thereof in PROTAC molecules. On the other hand, the present application relates to the use of the compounds (e.g., Formula I, II, X, XI or specific compounds), structural parts, isomers thereof (e.g., stereoisomers), and derivatives thereof for constituting a portion of a PROTAC molecule. On the other hand, the present application relates to the compounds (e.g., Formula I, II, X, XI or specific compounds), structural parts, isomers thereof (e.g., stereoisomers), and derivatives thereof in the form of PROTAC molecules. On the other hand, the present application relates to the use of the compounds (e.g., Formula I, II, X, XI or specific compounds), structural parts, isomers thereof (e.g., stereoisomers), and derivatives thereof for degrading proteins, for example, the compounds (e.g., Formula I, II, X, XI or specific compounds), structural parts, isomers thereof (e.g., stereoisomers), and derivatives thereof for degrading proteins in the form of PROTAC molecules. On the other hand, the present application relates to the use of the compound (e.g., Formula I, II, X, XI or a specific compound), a structural portion, an isomer thereof (e.g., a stereoisomer), and a derivative thereof in the form of a PROTAC molecule for degrading proteins. The present application relates to the use of the compound (e.g., Formula I, II, X, XI or a specific compound), a structural portion, an isomer thereof (e.g., a stereoisomer), and a derivative thereof (e.g., as a preparation intermediate) in the preparation of a PROTAC molecule. The present application relates to the use of the compound (e.g., Formula I, II, X, XI or a specific compound), a structural portion, an isomer thereof (e.g., a stereoisomer), and a derivative thereof (e.g., as a preparation intermediate) in the preparation of a protein degrader.

[0310] A "derivative" is a compound or a group of compounds produced by replacing or replacing one or more hydrogen atoms in the basic structure of a parent compound with other groups or structural moieties. The derivatives of this application refer to derivative compounds that retain the parent structure. For example, a parent compound is derived into a PROTAC molecule, specifically a PTM-L-CLM molecule (i.e., a compound of Formula I described herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof), wherein PTM is a protein target portion that binds to a target protein or target polypeptide (such as a target protein binding portion described herein); L is a linker group, and CLM refers to an E3 ubiquitin ligase binding portion.

[0311] Among them, "PROTAC (proteolysis targeting chimera) molecule" is a class of bifunctional compounds that can simultaneously bind to a target protein and an E3 ubiquitin ligase, and such compounds can induce the target protein to be recognized by the proteasome of the cell, causing degradation of the target protein, and can effectively reduce the content of the target protein in the cell. Specific examples include compounds of formula I, II or III described herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof. Specific examples include compounds of formula I described herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0312] In some embodiments, the CLM described herein can be selected from a group formed by a compound of formula X, a structural moiety, a derivative thereof (eg, protac), or a pharmaceutically acceptable salt thereof.

[0313] In some embodiments, the CLM described herein can be selected from a group formed by a compound of formula XI, a structural moiety, a derivative thereof (eg, protac), or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, the CLM described herein can be selected from the group consisting of the following compounds, moieties, derivatives thereof (e.g., protac), or pharmaceutically acceptable salts thereof:

[0315] In some embodiments, the CLM described herein can be selected from the group consisting of the following compounds, moieties, derivatives thereof (e.g., protac), or pharmaceutically acceptable salts thereof:

[0316] In some embodiments, the above-mentioned heterocycloalkenyl, heteroaryl, heterocycloalkyl or heteroalkylene group contains one or more heteroatoms or heteroatoms independently selected from -O-, -NH-, -N-, -S-, -C(=O)-, -C(=O)NH-, -C(=O)O-, -S(=O)- or -S(=O)2-; in some embodiments, the above-mentioned heterocycloalkenyl, heteroaryl, heterocycloalkyl or heteroalkylene group contains one or more heteroatoms or heteroatoms independently selected from -O-, -NH-, -N- or -S-; in some embodiments, the above-mentioned heterocycloalkenyl, heteroaryl, heterocycloalkyl or heteroalkylene group contains one or more heteroatoms or heteroatoms independently selected from -O-, -NH- or -N-. In some embodiments, the number of the heteroatoms or heteroatoms is independently selected from 1, 2, 3, 4, 5 or 6; or selected from 1, 2, 3 or 4; or selected from 1, 2 or 3; or selected from 1 or 2.

[0317] In some embodiments, the heteroatoms in the heterocycloalkenyl group are selected from N, NH, O, or S. In some embodiments, the heteroatoms in the heterocycloalkenyl group are selected from N, O, or S. In some specific embodiments, the heteroatoms in the heterocycloalkenyl group are selected from N or O. In some embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1, 2, 3, or 4. In some embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1, 2, or 3. In some specific embodiments, the number of heteroatoms in the heterocycloalkenyl group is selected from 1 or 2.

[0318] In some embodiments, the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.

[0319] In some embodiments, the C 1-10 Selected from C 1-9 、C 1-8 、C 1-7 、C 1-6 、C 1-4 、C 1-3 , or C 1-2 In some embodiments, C 1- 6 from C 1-4 、C 1-3 , or C 1-2 In some embodiments, the C 1-4 is selected from C4, C3, C2, or C1. In some embodiments, the C 1-3 Selected from C3, C2, or C1.

[0320] In some embodiments, the C 2-10 Selected from C 2-8 、C 2-6 、C 2-5 、C 2-4 、C 2-3 In some embodiments, the C 2-6 Selected from C 2- 4. or C 2-3 In some embodiments, the C 2-4 Selected from C4, C3, or C2.

[0321] In some embodiments, the C 3-6 Selected from C 3-5 、C 3-4 、C 4-6 、C 4-5 , or C 5-6 In some embodiments, the C 6-10 Selected from C6-9 、C 6-8 、C 6-7 、C 7-10 、C 7-9 、C 7-8 、C 8-10 、C 8-9 , or C 9-10 In some embodiments, the C 3-10 Selected from C 3-9 、C 3-8 、C 3-7 、C 3-6 、C 3-5 、C 3-4 、C 4-10 、C 4-9 、C 4-8 、C 4-7 、C 4-6 、C 4-5 、C 5-10 、C 5-9 、C 5-8 、C 5-7 、C 5-6 、C 6-10 、C 6-9 、C 6-8 、C 6-7 、C 7-12 、C 7-10 、C 7-9 、C 7-8 、C 8-12 、C 8-10 、C 8-9 、C 9-12 , or C 9-10 In some embodiments, the C 3-15 Selected from C 3-12 or C 3-10 In some embodiments, the C 3-12 Selected from C 3-10 In some embodiments, the C 6-12 Selected from C 6-10 .

[0322] In some embodiments, the 3-6 yuan is selected from 3-5 yuan, 3-4 yuan, 4-6 yuan, 4-5 yuan, or 5-6 yuan. In some embodiments, the 5-10 yuan is selected from 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, and 9-10 yuan. In some embodiments, the 3-10 yuan is selected from 3-9 yuan, 3-8 yuan, 3-7 yuan, 3-6 yuan, 3-5 yuan, 3-4 yuan, 4-10 yuan, 4-9 yuan, 4-8 yuan, 4-7 yuan, 4-6 yuan, 4-5 yuan, 5-10 yuan, 5-9 yuan, 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, 9-10 yuan. In some embodiments, the 3-15 yuan is selected from 3-12 yuan or 3-10 yuan. In some embodiments, the 3-12 yuan is selected from 3-10 yuan. In some embodiments, the 5-12 yuan is selected from 5-10 yuan.

[0323] It should be understood that any embodiment of the compounds of the present application as described above and the specific rings A, B, C, R, and R in the compounds of the present application as described above are not limited to the embodiments of the compounds of the present application as described above. 1 ,n,X 5 , L, X 6 、R 2 、R 3 、R 4 Any specific substituent described for the substituents of ring A, ring B, ring C, ring E, etc. can be independently combined with substituents of other embodiments and / or compounds of the present application to form embodiments of the present invention not specifically described above. In addition, any specific substituents described in the specific embodiments and / or claims for any specific ring A, ring B, ring C, R 1 ,n,X 5 , L, X 6 、R 2 、R 3 、R 4 When a substituent range is disclosed for ring G, ring E, etc., it should be understood that one or more substituents can be deleted from the range, and the remaining substituent range should also be considered as an embodiment of the present application.

[0324] In some embodiments, the PTM or molecule acting on BTK is selected from

[0325] In some embodiments, the VHL E3 ubiquitin ligase binding moiety is selected from the group consisting of:

[0326] In some embodiments, the IAP E3 ubiquitin ligase binding moiety is selected from the group consisting of:

[0327] In some embodiments, the MDM2 E3 ubiquitin ligase binding moiety is selected from the group consisting of:

[0328] In some embodiments, the CLM is selected from the following moieties:

[0329] Among them, R a are independently selected from hydroxy, halogen, amino, cyano or C 1-8 alkyl;

[0330] q is selected from 0, 1, 2 or 3;

[0331] X 4 is selected from N or optionally substituted CH.

[0332] In some embodiments, wherein R a are independently selected from hydroxy, halogen, amino, cyano or C 1-6 alkyl.

[0333] In some embodiments, wherein R a are independently selected from hydroxy, halogen, amino, cyano or C 1-4 alkyl.

[0334] In some embodiments, wherein R a are independently selected from hydroxy, halogen, amino, cyano or C 1-3 alkyl.

[0335] In some embodiments, wherein R a are independently selected from hydroxy, halogen, amino or cyano.

[0336] In some embodiments, wherein R a are independently selected from halogen or amino.

[0337] In some embodiments, q is selected from 0, 1, or 2. In some embodiments, q is selected from 0 or 1.

[0338] In some embodiments, X 4 is selected from N or CH, wherein CH is optionally substituted by hydroxy, halogen, amino, cyano or C 1-4 alkyl.

[0339] In some embodiments, X 4 In some embodiments, X4 Selected from CH.

[0340] In some embodiments, the CLM is selected from the following moieties:

[0341] The present application also relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof:

[0342] This application also covers solutions obtained by any combination, deletion or replacement of the above embodiments.

[0343] On the other hand, the present application relates to a pharmaceutical composition, which contains the above-mentioned compound, structural portion (compound or derivative containing the structural portion), derivative thereof, stereoisomer thereof or pharmaceutically acceptable salt thereof. Optionally, the pharmaceutical composition of the present application also includes pharmaceutically acceptable excipients.

[0344] On the other hand, the present application relates to the use of the above-mentioned compounds, structural parts (compounds or derivatives containing the structural parts), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of drugs for preventing or treating diseases.

[0345] On the other hand, the present application relates to the use of the above-mentioned compounds, structural portions (compounds or derivatives comprising the structural portions), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of drugs for preventing or treating diseases that are treated by degrading target proteins (such as BCL6) bound to targeting ligands.

[0346] On the other hand, the present application relates to the use of the above-mentioned compounds, structural parts (compounds or derivatives containing the structural parts), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of drugs for preventing or treating diseases that are treated by binding to cerebellar proteins in vivo.

[0347] On the other hand, the present application relates to the use of the above-mentioned compounds, structural parts (compounds or derivatives containing the structural parts), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of drugs for preventing or treating BCL6-related diseases.

[0348] The present application relates to a method for treating or preventing a disease, comprising administering a therapeutically effective amount of the above-mentioned compound, structural portion (compound or derivative comprising the structural portion), derivative thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, to a mammal (preferably a human) in need of such treatment.

[0349] The present application relates to a method for treating or preventing a disease in a mammal by degrading a target protein (such as BCL6) bound to a targeting ligand, comprising administering a therapeutically effective amount of the above-mentioned compound, structural portion (compound or derivative comprising the structural portion), derivative thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, to a mammal (preferably a human) in need of such treatment.

[0350] The present application relates to a method for treating or preventing a disease that is treated by binding to a cerebellar protein in vivo, comprising administering a therapeutically effective amount of the above-mentioned compound, structural portion (compound or derivative containing the structural portion), derivative thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, of the present application to a mammal (preferably a human) in need of such treatment.

[0351] On the other hand, the present application relates to a method for treating a BCL6-related disease in a mammal, comprising administering a therapeutically effective amount of the above-mentioned compound, structural portion (compound or derivative comprising the structural portion), derivative thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, to a mammal (preferably a human) in need of such treatment.

[0352] On the other hand, the present application relates to the above-mentioned compound, structural portion (compound or derivative containing the structural portion), derivative, stereoisomer, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for preventing or treating diseases.

[0353] On the other hand, the present application relates to the above-mentioned compounds, structural portions (compounds or derivatives comprising the structural portions), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preventing or treating diseases treated by degrading target proteins (such as BCL6) bound to targeting ligands.

[0354] On the other hand, the present application relates to the above-mentioned compounds, structural parts (compounds or derivatives containing the structural parts), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preventing or treating diseases that are treated by binding to cerebellar proteins in vivo.

[0355] On the other hand, the present application relates to the above-mentioned compounds, structural parts (compounds or derivatives containing the structural parts), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preventing or treating BCL6-related diseases.

[0356] On the other hand, the present application relates to the use of the above-mentioned compound, structural portion (compound or derivative containing the structural portion), derivative, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof in preventing or treating diseases

[0357] On the other hand, the present application relates to the use of the above-mentioned compounds, structural portions (compounds or derivatives comprising the structural portions), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in preventing or treating diseases that are treated by degrading target proteins (such as BCL6) bound to targeting ligands.

[0358] On the other hand, the present application relates to the use of the above-mentioned compounds, structural parts (compounds or derivatives containing the structural parts), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in preventing or treating diseases that are treated by binding to cerebellar proteins in vivo.

[0359] On the other hand, the present application relates to the use of the above-mentioned compounds, structural parts (compounds or derivatives containing the structural parts), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in preventing or treating BCL6-related diseases.

[0360] In some embodiments, the above-mentioned diseases or BCL6-related diseases are selected from disorders treated by degradation and / or inhibition of proteins (BCL6) that bind to BCL6 target protein ligands; in some embodiments, the above-mentioned BCL6-related diseases are selected from disorders treated by binding to cerebellum proteins in vivo; in some embodiments, the above-mentioned diseases or disorders are selected from cancers, such as prostate cancer.

[0361] In some embodiments, the above-mentioned diseases or conditions treated by binding to cerebellar proteins in vivo and / or the conditions treated by degrading target proteins bound to targeting ligands are selected from BCL6-related diseases; in some embodiments, the above-mentioned diseases or BCL6-related diseases are selected from cancer.

[0362] In some aspects, the present application comprises the above-defined variables and embodiments thereof, and any combination thereof.

[0363] Technical Effects

[0364] The compounds of this application have binding and degradation activities against BCL6 proteins (e.g., BCL6 in OCI-LY1 cells) and anti-proliferative activity against cells expressing BCL6. Furthermore, the compounds of this application have good in vitro liver microsomal stability and pharmacokinetic properties (specifically, parameters such as AUC) in mammals (e.g., mice, rats, and humans), and can inhibit tumor growth in vivo, showing promising drug development prospects.

[0365] definition

[0366] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term should not be construed as undefined or unclear unless specifically defined, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0367] As used herein, "one or more" refers to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine, or ten; in some embodiments, the "one or more" is selected from one, two, three, four, five, or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two.

[0368] Unless otherwise specified, Used to indicate The hydrogen atom at any position of the group can be replaced by a group connected by "—", for example, by L.

[0369] The term "substituted" means that any one or more hydrogen atoms or lone pairs of electrons on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are replaced. Oxo groups do not occur on aromatic groups. For example, for It can be represented by one or more R 1 Substituent substituted, wherein the R 1 It can be substituted on ring G or ring E, for example, X on the ring a 、X b 、X c 、X d 、X e 、X f and X gand its substituents, and -NH-.

[0370] The term "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence of the event or situation and the non-occurrence of the event or situation. "Optionally substituted" includes unsubstituted and substituted. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible and / or cannot be synthesized will be introduced.

[0371] In this article, C m-n , means that the moiety has an integer number of carbon atoms in a given range. For example, "C 1-6 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.

[0372] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. For example, if a group contains two R's, each R has an independent option.

[0373] When a bond cross-links two atoms in a ring (including a monocyclic, fused, or spirocyclic ring), the bond can be bonded to any atom in the ring (including a monocyclic, fused, or spirocyclic ring). Indicates that the bonds on both sides can be connected to any two different atoms on ring A, ring B or ring C; for example Indicates that the bonds on both sides can be connected to any two different atoms on ring A, the middle benzene ring or ring C; further, for example It means that the bonds on both sides can be connected to any two different atoms in the four rings in the system.

[0374] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0375] The term "hydroxy" refers to an -OH group.

[0376] The term "amino" refers to a -NH2 group.

[0377] The term "cyano" refers to a -CN group.

[0378] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.

[0379] The term "alkylene" refers to a divalent group formed by removing a hydrogen from any position of an alkyl group, for example, the term "C 1-6 "Alkyl" refers to an alkylene group containing 1 to 6 carbon atoms; the term "C 1-4 "Alkyl" refers to an alkylene group containing 1 to 4 carbon atoms, including but not limited to -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-.

[0380] The term "alkenylene" refers to a divalent group formed by removing a hydrogen atom from any position of an alkenyl group, for example, the term "C 2-6 "Alkenyl" refers to an alkenylene group containing 2 to 6 carbon atoms; the term "C 2-4 "Alkenyl" refers to an alkenylene group containing 2 to 4 carbon atoms, including but not limited to -CH2CH=CH-, -CH2CH2CH=CH- or -CH2CH=CHCH2-.

[0381] The term "alkynylene" refers to a divalent group formed by removing a hydrogen atom from any position of an alkynyl group, for example, the term "C 2-6 "Alkynyl" refers to an alkynylene group containing 2 to 6 carbon atoms; the term "C 2-4 The term "alkynyl" refers to an alkynylene group containing 2 to 4 carbon atoms, including but not limited to -C≡C-, -H2C-C≡C-, -H2C-H2C-C≡C- or -H2C-C≡C-CH2-.

[0382] The term "heteroalkyl" refers to a straight or branched chain heteroalkyl group consisting of a certain number of carbon atoms and at least one heteroatom. It preferably has 1 to 14 carbon atoms, more preferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms in the chain, wherein the heteroatom is preferably selected from S, O and N heteroatoms, and the number is preferably 1, 2 or 3. For example, C mHeteroalkyl refers to an alkyl group with heteroatoms inserted in the chain and consisting of m carbon atoms and at least one heteroatom (e.g., 1-3 heteroatoms selected from S, O, and N) located between any two carbon atoms. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroatom or heteroatom group can be located at any internal position of the heteroalkyl group, including the position where the hydrocarbon group is attached to the rest of the molecule. Exemplary heteroalkyl groups include alkyl ethers, secondary alkylamines, tertiary alkylamines, amides, sulfides, and the like, including alkoxy, alkylthio, and alkylamino groups; unless otherwise specified, C 1-6 Heteroalkyl groups include C1, C2, C3, C4, C5 and C6 heteroalkyl groups, such as C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino.

[0383] The term "heteroalkylene" refers to a divalent radical formed by removing one hydrogen from any position of a heteroalkyl group and comprising 1 or more (e.g., 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2) carbon atoms and 1 or more heteroatoms (e.g., 1-3 heteroatoms selected from S, O, and N) in the chain.

[0384] The term "alkoxy" refers to an -O-alkyl group.

[0385] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Non-limiting examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

[0386] The term "carbocyclyl" refers to a cyclic group whose ring atoms are C (e.g., a cyclic group containing 3-12 carbon atoms, 3-10 carbon atoms, 3-8 carbon atoms, 3-6 carbon atoms), which may be fully saturated or not fully saturated and may exist as a monocyclic, bridged or spirocyclic ring.

[0387] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged ring, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 4 to 16-membered ring, a 4 to 12-membered ring, a 4 to 10-membered ring, or a 4 to 8-membered ring. Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.

[0388] The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 16 membered rings (e.g., 3 to 10 membered rings, or 5 to 8 membered rings). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0389] The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 16-membered ring, a 3-11-membered ring, a 3 to 10-membered ring, a 3 to 7-membered ring, a 3 to 6-membered ring or a 3 to 5-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and / or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and aziridine groups; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl groups; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl groups; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl groups; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl groups. Preferably, the heterocycloalkyl group is a monocyclic group having 5 or 6 ring atoms.

[0390] The term "spirocycle" refers to a fully saturated or partially unsaturated polycyclic system in which the monocyclic rings share a carbon atom (called a spiro atom), including carbocycles and heterocycles. Unless otherwise indicated, the spirocycle is 5 to 20 members, preferably 6 to 14 members, and more preferably 8 to 12 members. When the spirocycle is a heterocycle, one or more (e.g., 1 to 5, or 1 to 3) ring atoms in the polycyclic ring are selected from N, O, S(O) n 、P(O) n (wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0391] The term "spiroalkyl" refers to a fully saturated, all-carbon polycyclic ring that shares a carbon atom (called a spiro atom) between monocyclic rings. Unless otherwise indicated, the spiroalkyl is 5 to 20 yuan, preferably 6 to 14 yuan, and more preferably 8 to 12 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl is divided into a single spiroalkyl, a double spiroalkyl or a multi-spiroalkyl, preferably a single spiroalkyl and a double spiroalkyl, more preferably a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or a 5 yuan / 6 yuan single spiroalkyl. Non-limiting examples of spiroalkyl include

[0392] The term "spiroheterocycloalkyl" refers to a fully saturated polycyclic ring in which the monocyclic rings share a carbon atom (called a spiro atom), and one or more (e.g., 1-5, or 1-3) ring atoms in the polycyclic ring are selected from N, O, S(O), n 、P(O) n (wherein n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms. Unless otherwise indicated, the spiro heterocycloalkyl is 5 to 20 yuan, preferably 6 to 14 yuan, more preferably 6 to 10 yuan. According to the number of shared spiro atoms between the rings, the spiro heterocycle is divided into a monospiro heterocycle, a dispiro heterocycle or a polyspiro heterocycle, preferably a monospiro heterocycle or a dispiro heterocycle, more preferably a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or a 5 yuan / 6 yuan monospiro heterocycle. Non-limiting examples of spiro heterocycloalkyl include wait.

[0393] The term "heterocycloalkenyl" includes cycloalkenyl groups in which one or more carbon atoms (e.g., 1-5, 1-4, 1-3, 1-2) are replaced by heteroatoms, such as cycloalkenyl groups in which up to 3 carbon atoms, in one embodiment up to 2 carbon atoms, in another embodiment 1 carbon atom are independently replaced by O, S, S(O) or N, provided that at least one cycloalkenyl carbon-carbon double bond is retained. Cyclic groups that may exist as monocyclic, bridged, or spirocyclic rings may be 3 to 16-membered rings (e.g., 3 to 12-membered, 5 to 8-membered rings, such as 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, or 11-membered rings). Examples of heterocycloalkenyl groups include, but are not limited to, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazepine, pyrrolidine ... Base, azaspirocyclooctene, wait.

[0394] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene.

[0395] The term "heterocyclyl" refers to a monocyclic or fused polycyclic ring system containing at least one (e.g., 1-5, 1-4, 1-3, 1-2) ring atom selected from N, O, and S, with the remaining ring atoms being C, an unsaturated non-aromatic ring system, which may contain no double bonds or have at least one or more double bonds. Preferred heterocyclyl groups have a single 4- to 8-membered ring, especially a 5- to 8-membered ring (e.g., 5-, 6-, 7-, or 8-membered), or multiple fused rings containing 6 to 14, especially 6 to 10 (e.g., 6, 7, 8, 9, or 10) ring atoms.

[0396] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one (e.g., 1-5, 1-4, 1-3, 1-2) ring atom selected from N, O, S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryl groups have single 4 to 8-membered rings, especially 5 to 8-membered rings (e.g., 5-, 6-, 7-, or 8-membered), or multiple fused rings containing 6 to 14, especially 6 to 10 (e.g., 6, 7, 8, 9, or 10) ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

[0397] The term "substituent", "optionally substituted with one or more substituents" or "optionally substituted", the substitution or substituent substitution thereof, includes all substituents mentioned herein, such as the terms "halogen", "deuterium", "-NH2", "-NH(C 1- 4 alkyl)", "-N(C 1-4 Alkyl)2", "-OH", "-OC 1-4 Alkyl", "-CN", "C 1-4alkyl", "3-6 membered heterocycloalkyl", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include thiol, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo-cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl , heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, arylalkylene, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkylene, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group, ester group and oxo, etc., wherein the substituent is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC( -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0398] In some embodiments herein, the substituent is selected from deuterium, tritium, hydroxyl, sulfhydryl, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1- 12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester group and oxo, said substituent being optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1- 12 Alkyl)2, -NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC1-12 Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 Alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 an alkylene group or a 6- to 10-membered aryloxy group.

[0399] Unless otherwise specified, the term "hetero" refers to a heteroatom or a heteroatom group (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing these heteroatoms, for example, heteroatoms include but are not limited to oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), and boron (B). Specific heteroatoms or heteroatom groups include: -O-, -S-, -NH-, - N=, =O, =S, -P(=O)-, -P(=O)2-, -P(=O)O-, -P(=O)2O-, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, and optionally substituted -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- or -S(=O)N(H)-. Preferably, the term "hetero" refers to a heteroatom or a heteroatom group (i.e., a group containing a heteroatom) wherein the heteroatom is selected from oxygen, nitrogen or sulfur.

[0400] The term "derivative" refers to a new compound or a group of new compounds produced by one or more chemical reactions or structural evolution, retaining the basic structure of the parent compound and only undergoing changes or modifications in the side chains, functional groups or substituents.

[0401] In this application, wavy lines are used represents one of the absolute configurations of a stereocenter (e.g. one, specific express ) or one of the relative configurations (e.g. express When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, they are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are encompassed within the scope of this application.

[0402] In the present application, under non-configurational chemical reaction conditions (for example, without the use of a chiral catalyst), the compounds of the present application, such as the example compounds, prepared through chiral intermediates can maintain the original configuration of the corresponding atoms; for example, the configuration of the carbon atoms in the chiral intermediate is the same as the configuration of the corresponding carbon atoms in the corresponding example compounds prepared therefrom.

[0403] In this application, the groups or structural parts such as -LNK1 -Cy 1 -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -LNK 2 -、LNK、Cy 1 、Cy 2 、-Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK- or -LNK-Cy 2 - and its specific options, optionally can be read from left to right, corresponding to the group or fragment in the general formula on the left and right groups connected, for example, when L is selected from -Cy 1 -LNK-, when Cy 1 Selected from Reading from left to right, Cy 1 The left side is connected to the fragment PTM corresponding to the left side of the general formula, and the right side is connected to the fragment on the right side The resulting fragments are Optionally, the groups or structural parts in this application such as -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -、-Cy 1 -Cy 2 -LNK 2 -、LNK、Cy 1 、Cy 2 、-Cy 1 -LNK-Cy 2 -、-Cy 1 -LNK- or -LNK-Cy 2 - and its specific options, can be read in order from right to left, and are respectively connected to the left and right groups of the group or fragment in the general formula, for example, when L is selected from -Cy 1 -LNK-, when Cy 1 Selected from According to the reading order from right to left, Cy 1 The right side is connected to the fragment PTM corresponding to the left side of the general formula, and the left side is connected to the fragment corresponding to the right side of the general formula The fragments formed by the connection are Other groups are the same as described above.

[0404] In the absence of any indication to the contrary, the substituents herein (e.g., L 1 、X 9 ) in the definition refers to a single bond.

[0405] The term "treating" means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) inhibiting the disease or disease state, i.e., curbing its development; (ii) alleviating the disease or disease state, i.e., causing the disease or disease state to regress.

[0406] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, including preventing the occurrence of a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0407] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0408] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0409] As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

[0410] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0411] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0412] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0413] Unless the context clearly indicates otherwise, singular terms herein include plural referents and vice versa. Similarly, the word "or" herein is intended to include "and" unless the context clearly indicates otherwise.

[0414] Unless otherwise indicated, all numbers used herein expressing amounts of ingredients, measurements, or reaction conditions are to be understood as modified in all instances by the term "about." When used in conjunction with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, and more preferably ±0.1%.

[0415] The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which the proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons. For example, any compound of the present disclosure, such as pyrazole alone or as part of a heterocyclic group, may exist as a mixture of two tautomers or any number of two tautomers, i.e. or The present disclosure includes all possible tautomers of the disclosed compounds, either as single tautomers or as any mixture of such tautomers in any ratio.

[0416] The present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P.35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0417] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0418] The compounds of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure forms or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0419] The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients.

[0420] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0421] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0422] In some embodiments, the pharmaceutical composition is in oral form.

[0423] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets or dragee cores.

[0424] The pharmaceutical composition may also be suitable for parenteral administration.

[0425] In all methods of administration described herein, the compounds of formula I are administered at a dosage of 0.001 to 2000 mg / kg body weight per day in single or divided doses.

[0426] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0427] The chemical reactions described in the specific embodiments of the present application are carried out in a suitable solvent that is compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds described herein, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0428] An important consideration in synthetic route planning in this field is the selection of an appropriate protecting group for a reactive functional group (such as an amino group in this application). For example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0429] In some embodiments, the compounds of the present application can be prepared by those skilled in the art of organic synthesis using the following intermediates or their salts through the following routes:

[0430] The compound of general formula I-1 and the compound of general formula I-2 are subjected to substitution reaction to obtain the compound of general formula II;

[0431] The compound of formula I-3 and the compound of formula I-4 are subjected to reductive amination reaction to obtain the compound of formula II;

[0432] Among them, L a Indicates halogen. PTM, L, ring W, R 1 、n、L 1 and X5 The definition of is as described in this application.

[0433] This application uses the following abbreviations:

[0434] DMSO stands for dimethyl sulfoxide; DMF stands for N,N-dimethylformamide; DIPEA stands for N,N'-diisopropylethylamine; Boc stands for tert-butyloxycarbonyl; DCM stands for dichloromethane; THF stands for tetrahydrofuran; DPPF stands for 1,1'-bis(diphenylphosphino)ferrocene; Pd2(dba)3 stands for tris(dibenzylideneacetone)dipalladium(0); MeOH stands for methanol; TFA stands for trifluoroacetic acid; DMA stands for dimethylacetamide; DCE stands for dichloroethane; MeCN stands for acetonitrile; EA stands for ethyl acetate; DC 50 It indicates the drug concentration when the degradation rate reaches 50%; Dmax indicates the maximum degradation rate.

[0435] For the sake of clarity, the present invention is further illustrated by examples, but the examples are not intended to limit the scope of this application. All reagents used in this application are commercially available and can be used without further purification. DETAILED DESCRIPTION

[0436] Preparation Example 1: Synthesis of Intermediates z39 and z40

[0437] Steps 1 and 2: Preparation of intermediate z39b

[0438] A solution of intermediate z8b (69 g) and diethyl 1,3-acetonedicarboxylate (57.0 g) in DCM (350 mL) was slowly added dropwise to a mixture of tetrabutylammonium iodide (52.0 g) in a 1 M sodium bicarbonate aqueous solution (1178 mL) and DCM (500 mL) at 0°C. The mixture was allowed to react at room temperature. After the reaction, the mixture was extracted with DCM. The extract was concentrated, slurried with methyl tert-butyl ether, and filtered. The filtrate was concentrated, added with ethanol (1000 mL) and a 1 M potassium hydroxide aqueous solution (1173 mL), and reacted at 85°C. After the reaction, the pH was adjusted to neutral by adding dilute hydrochloric acid, extracted with DCM, and purified by silica gel column chromatography to yield intermediate z39b (24 g). 1 H NMR (500MHz, CDCl3) δ7.16(t,J=7.9Hz,1H),6.86–6.79(m,2H),3.83(s,3H),3.04–2.99(m,2H),2.94–2.89(m,2H),2.63–2.55(m,4H).

[0439] Step 3: Preparation of intermediate z39c

[0440] Under N₂ protection at 0°C, a 1M solution of potassium tert-butoxide in THF (157 mL) was slowly added dropwise to a stirred solution of (methoxymethyl)triphenylphosphonium chloride (49.7 g) in THF (450 mL). After the addition was complete, the resulting mixture was stirred at 0°C for 0.5 h. Intermediate z39b (23 g) was then added and the mixture was allowed to warm to room temperature. Upon completion of the reaction, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was purified by silica gel column chromatography to afford intermediate z39c (28.6 g). 1 H NMR (500MHz, DMSO) δ7.07–7.01(m,1H),6.83–6.79(m,1H),6.76–6.72(m,1H),5.91(s,1H),3.76–3.73(m,3H),3.49(s, 3H),2.80–2.72(m,2H),2.72–2.65(m,2H),2.25–2.22(m,1H),2.20–2.15(m,1H),2.06–2.00(m,1H),2.00–1.94(m,1H).

[0441] Step 4: Preparation of intermediate z39d

[0442] To the reaction flask, intermediate z39c (28.8 g), THF (200 mL), and 2M hydrochloric acid (130 mL) were added sequentially and reacted at room temperature. After completion of the reaction, saturated sodium bicarbonate solution was added to adjust the pH to neutral, and the product was extracted with ethyl acetate. The extract was concentrated to afford intermediate z39d (25.9 g).

[0443] 1 H NMR(500MHz, CDCl3)δ9.66(s,1H),7.09–7.04(m,1H),6.77–6.72(m,2H),3.81–3.79(m,3H),3 .41–3.29(m,1H),2.93–2.77(m,2H),2.75–2.54(m,2H),2.19–2.10(m,2H),1.64–1.44(m,2H).

[0444] Referring to the method of Preparation Example z22 or z23 of WO2023125944, the following steps 5 to 17 were performed:

[0445] Step 5: Preparation of intermediate z39e

[0446] Referring to the method described in step 6 of preparation example z22 or z23, intermediate z39e (25.6 g) was synthesized by replacing intermediate z22f with intermediate z39d.

[0447] 1H NMR (500MHz, CDCl3) δ7.09–7.02(m,1H),6.79–6.69(m,2H),3.79(s,3H),3.50–3.42(m,3H),2.88–2.76(m,2H),2 .43–2.35(m,1H),2.04–1.95(m,2H),1.92–1.80(m,1H),1.37–1.29(m,1H),1.18–1.07(m,1H),1.05–0.97(m,1H).

[0448] Step 6: Preparation of intermediate z39f

[0449] Referring to the method described in step 5 of preparation example z22 or z23, intermediate z39e was used instead of intermediate z22e to synthesize intermediate z39f (14.42 g).

[0450] MS (ESI, [MH] - )m / z:191.1.

[0451] Steps 7-16: Preparation of intermediates z39 and z40

[0452] Referring to the method described in steps 7-16 of Preparation Example z22 or z23, intermediate z39f was used instead of intermediate z22g to finally synthesize intermediate z39 (2.20 g) and intermediate z40 (2.31 g).

[0453] Separation conditions of intermediates z39n-1 and z39n-2:

[0454] Instrument: SFC supercritical fluid chromatograph, chromatographic column: CHIRALART Amylose-SA (5μm, 30*250mm), mobile phase A: carbon dioxide, mobile phase B: methanol (0.05% ammonia water + 0.1% glacial acetic acid), to obtain intermediate z39n-1 (5.21g) and intermediate z39n-2 (5.10g) in sequence.

[0455] The intermediate z39n-1 has a shorter retention time in the chiral chromatographic column than the intermediate z39n-2, and the intermediate z39n-2 has a longer retention time in the chiral chromatographic column than the intermediate z39n-1.

[0456] z39n-1:MS(ESI,[M+H] + )m / z:304.1.z39n-2:MS(ESI,[M+H] + )m / z:304.1.

[0457] Intermediate z39: 1H NMR(500MHz,DMSO)δ11.07(s,1H),7.51(d,J=8.0Hz,1H),7.19(d,J=8.1Hz, 1H),4.57–4.51(m,1H),4.49(td,J=5.3,1.7Hz,1H),3.41–3.34(m,1H),3.24 (t,J=5.8Hz,2H),3.02–2.87(m,2H),2.82–2.71(m,2H),2.65–2.55(m,1H), 2.23–2.13(m,1H),2.10–1.97(m,2H),1.85–1.75(m,1H),1.05–0.95(m,2H).

[0458] Intermediate z40: 1 H NMR (500MHz, DMSO) δ11.07(d,J=3.1Hz,1H),7.51(d,J=8.0Hz,1H),7.19(d,J=8.1Hz, 1H),4.53(ddd,J=11.9,5.0,1.9Hz,1H),4.49(td,J=5.3,1.7Hz,1H),3.40–3.35(m,1 H),3.24(t,J=5.8Hz,2H),3.01–2.87(m,2H),2.82–2.71(m,2H),2.60(dq,J=17.3,4. 1Hz,1H),2.23–2.13(m,1H),2.10–1.98(m,2H),1.84–1.77(m,1H),1.03–0.94(m,2H).

[0459] Preparation Example 2: Synthesis of Intermediate z41

[0460] Step 1: Preparation of intermediate z41b

[0461] At 25°C, z41a (9 g), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (11.97 g), DPPF palladium dichloride (1.83 g), potassium carbonate (16.05 g), water (20 mL), and dioxane (200 mL) were added to the reaction flask in sequence and the temperature was raised to 80°C for reaction. After completion of the reaction, intermediate z41b (2.08 g) was purified by silica gel column chromatography. MS (ESI) m / z [MH] - :335.1.

[0462] Step 2: Preparation of intermediate z41c

[0463] To the reaction flask, z41b (2 g), Pd2(dba)3 (0.547 g), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.507 g), potassium hydroxide (0.670 g), 1,4-dioxane (100 mL), and H2O (20 mL) were added sequentially. Under nitrogen protection, the resulting mixture was heated to 100°C and reacted overnight. After completion of the reaction, purification by silica gel column chromatography afforded intermediate z41c (1.8 g). MS (ESI) m / z [M+H] + :317.3.

[0464] Step 3: Preparation of intermediate z41d

[0465] To the reaction flask, z41c (2 g), MeOH (100 mL), and Pd / C (0.673 g) were added sequentially. The reaction was allowed to proceed overnight at room temperature under hydrogen protection. After completion of the reaction, the reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain intermediate z41d (1.8 g). MS (ESI) m / z [M+H] + :319.3.

[0466] Step 4: Preparation of intermediate z41e

[0467] z41d (1.4 g), THF (50 mL), NaH (0.879 g), and 3-bromopiperidine-2,6-dione (0.844 g) were added to the reaction flask in sequence and reacted at 65°C. After completion of the reaction, the reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography to obtain intermediate z41e (0.4 g). MS (ESI) m / z [M+H] + :430.4.

[0468] Step 5: Preparation of intermediate z41

[0469] To the reaction flask, z41e (400 mg), DCM (10 mL), and HCl (9.78 mL) were added sequentially, and the resulting mixture was reacted at room temperature. EA was added to the reaction solution to precipitate a solid, which was filtered to obtain intermediate z41 (0.345 g). MS (ESI) m / z [M+H] + :330.4. 1H NMR (500MHz, DMSO) δ11.14(s,1H),9.15(d,J=11.1Hz,1H),9.05–8.92(m,1H),7.83(d,J=6.0Hz,1H),7.65(s,1H),7.40(d,J=6.0Hz,1H),5.64(s, 1H),3.41–3.27(m,3H),3.03(q,J=11.9Hz,2H),2.89(d,J=17.4Hz,1H),2 .68–2.56(m,2H),2.14–2.02(m,3H),1.88(qdd,J=12.5,8.1,4.0Hz,2H).

[0470] Preparation Example 3: Synthesis of Intermediate z42

[0471] Step 1: Preparation of intermediate z42b

[0472] Z42a (10.00 g), 1-Boc-4-methanesulfonyloxypiperidine (23.65 g), cesium carbonate (46.40 g), and acetonitrile (700 mL) were added sequentially to a reaction flask and reacted at 80°C. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layers were combined, dried, concentrated, and purified by column chromatography (C18 column, 10 mmol / L aqueous ammonium acetate-acetonitrile 10%-100%) to obtain intermediates Z42b and Z43a, respectively. The leading peak was collected, extracted with ethyl acetate, and the extract was dried and concentrated to obtain intermediate Z43a (6.7 g). The trailing peak was collected, extracted with ethyl acetate, and the extract was dried and concentrated to obtain intermediate Z42b (10.7 g).

[0473] Intermediate z42b: MS (ESI, [M+H] + )m / z:337.14. 1 H NMR(500MHz,DMSO)δ8.33(s,1H),8.18(d,J=6.0Hz,1H),7.83(dd,J=6.1,1.0Hz,1H),4.9 4(td,J=9.5,4.6Hz,1H),4.14–4.06(m,2H),2.98(s,2H),1.96–1.90(m,4H),1.42(s,9H).

[0474] Intermediate z43a: MS (ESI, [M+H] + )m / z:337.25. 1H NMR (500MHz, DMSO) δ8.88(d,J=0.9Hz,1H),7.98(d,J=6.2Hz,1H),7.57(dd,J=6.1,1.0Hz,1H),4.81(tt,J=11.5,4.0Hz, 1H), 4.09 (d, J=12.8Hz, 2H), 2.96 (s, 2H), 2.13 (ddt, J=11.8, 4.5, 2.6Hz, 2H), 1.97 (qd, J=12.3, 4.4Hz, 2H), 1.42 (s, 9H).

[0475] Step 2: Preparation of intermediate z42c

[0476] To a reaction flask, intermediate z42b (10.6 g), Pd2(dba)3 (2.88 g), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (2.67 g), potassium hydroxide (3.53 g), water (200 ml), and 1,4-dioxane (50 mL) were added sequentially and reacted at 100°C. After 3 h, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate z42c (4.00 g). MS (ESI, [M+H] + )m / z:319.17.

[0477] Step 3: Preparation of intermediate z42d

[0478] To the reaction flask, intermediate z42c (4 g), 3-bromopiperidine-2,6-dione (2.97 g), sodium hydride (0.62 g), and THF (200 mL) were added in sequence and reacted at 65°C. After the reaction, the reaction solution was poured into ammonium chloride solution and extracted with ethyl acetate. After the reaction was complete, the extract was concentrated and purified by silica gel column chromatography to obtain intermediate z42d (0.39 g). MS (ESI, [M-Boc+H] + )m / z:330.20.

[0479] Step 4: Preparation of intermediate z42

[0480] To the reaction flask, intermediate z42d (0.38 g), 4M hydrochloric acid-dioxane solution (6.6 mL), and DCM (50 mL) were added sequentially and reacted at 25°C. The reaction was completed after 4 h, filtered, and the filter cake was washed with dichloromethane to obtain intermediate z42 (270 mg). HR-MS ([M-HCl+H] + )m / z:330.1558. 1H NMR (500MHz, DMSO) δ11.03(s,1H),9.20(d,J=10.7Hz,1H),8.96(d,J=11.4Hz,1H),8.12( s,1H),7.55(d,J=7.5Hz,1H),6.83(d,J=7.5Hz,1H),5.58(s,1H),4.86(tt,J=11.2,4.1Hz ,1H),3.51–3.44(m,2H),3.08(dtd,J=12.8,10.2,2.8Hz,2H),2.88(s,1H),2.60(dt,J=18 .3,4.3Hz,2H),2.30(dt,J=16.6,11.1Hz,2H),2.08(d,J=13.5Hz,2H),2.03–1.96(m,1H).

[0481] Preparation Example 4: Synthesis of Intermediate z43

[0482] Step 1: Preparation of intermediate z43b

[0483] Referring to the method described in Step 2 of Preparation Example 3, intermediate z43a was used instead of intermediate z42b to synthesize intermediate z43b (4.00 g).

[0484] MS (ESI, [M+H] + )m / z:319.17.

[0485] Step 2: Preparation of intermediate z43c

[0486] Referring to the method described in Step 3 of Preparation Example 3, intermediate z43b was used instead of intermediate z42c to synthesize intermediate z43c (0.5 g).

[0487] MS (ESI, [M-Boc+H] + )m / z:330.20.

[0488] Step 3: Preparation of intermediate z43

[0489] Referring to the method described in step 4 of Preparation Example 3, intermediate z43c was used instead of intermediate z42d to synthesize intermediate z43 (380 mg).

[0490] HR-MS ([M-HCl+H] + )m / z:330.1559. 1 H NMR (500MHz, DMSO) δ10.99 (s, 1H), 9.28 (d, J = 11.2Hz,

[0491] 1H),9.04(d,J=10.8Hz,1H),8.60(s,1H),7.27(d,J=7.6Hz,1H),6.55(d,J=7.6Hz,1H),5.47(s,1H),4.71(tt,J=9.9,5.2Hz,1H),3. 40(d,J=12.6Hz,2H),3.11–3.02(m,2H),2.86(t,J=14.3Hz,1H),2.63–2.54(m,2H),2.27(dh,J=14.6,4.4Hz,4H),2.03–1.93(m,1H).

[0492] Preparation Example 5: Synthesis of Intermediate z44

[0493] Step 1: Preparation of intermediate z44b

[0494] At 25°C, z44a (5 g), 1-Boc-4-methanesulfonyloxypiperidine (18.31 g), cesium carbonate (32 g), and N,N-dimethylformamide (120 mL) were added to the reaction flask in sequence and the temperature was raised to 120°C for reaction. After the reaction was completed, the reaction solution was quenched with water and extracted with ethyl acetate. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate z44b (5.88 g). MS (ESI) m / z [M+H] + :336.1.

[0495] Step 2: Preparation of intermediate z44c

[0496] At 25°C, z44b (5.78 g), tris(dibenzylideneacetone)palladium (1.58 g), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (1.46 g), potassium hydroxide (1.93 g), water (15 mL), and dioxane (150 mL) were added to the reaction flask in sequence and reacted at 100°C. After completion of the reaction, the product was purified by silica gel column chromatography to obtain intermediate z44c (4.50 g). MS (ESI) m / z [M+H] + :318.1.

[0497] Step 3: Preparation of intermediate z44d

[0498] z44c (4.5 g), THF (50 mL), NaH (2.84 g), and 3-bromopiperidine-2,6-dione (2.72 g) were added to the reaction flask in sequence and reacted at 65°C. After completion of the reaction, the reaction was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain intermediate z44d (0.7 g). MS (ESI) m / z [M+H] + :429.5.

[0499] Step 4: Preparation of intermediate z44

[0500] z44d (500 mg), DCM (10 mL), and HCl (9.78 mL) were added to the reaction flask in sequence, and the resulting mixture was reacted at room temperature. EA was added to the reaction solution to precipitate a solid, which was filtered to obtain intermediate z44 (0.4 g). MS (ESI) m / z [M+H] + :329.5. 1 H NMR (500MHz, DMSO) δ10.96(s,1H),9.05(d,J=10.9Hz,1H),8.94(d,J=11.4Hz,1H),7.34(d,J =7.5Hz,1H),7.15(d,J=3.2Hz,1H),6.79(d,J=7.5Hz,1H),6.58(d,J=3.2Hz,1H),5.50(s,1H ),4.63(tt,J=11.9,4.0Hz,1H),3.47–3.40(m,2H),3.14–3.03(m,2H),2.85(s,1H),2.66–2. 55(m,2H),2.21(qt,J=12.8,3.9Hz,2H),2.07(d,J=12.3Hz,2H),1.97(tt,J=6.3,3.0Hz,1H).

[0501] Preparation Example 6: Synthesis of Intermediate z45

[0502] Step 1: Preparation of intermediate z45b

[0503] 2,4-Dichloro-3-nitropyridine (5 g), DMF (100 mL), 1-Boc-4-aminopiperidine (5.19 g), and potassium carbonate (3.58 g) were added to the reaction flask in sequence. Under N2 protection, the resulting mixture was reacted at room temperature overnight. After the reaction was completed, EA and water were added to the reaction solution for extraction. After washing with saturated brine, the product was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain intermediate z45b (10 g). MS (ESI) m / z [M+H] + :357.8

[0504] Step 2: Preparation of intermediate z45c

[0505] To the reaction flask, z45b (9 g), MeOH (300 mL), ammonium chloride (6.75 g), and Zn (33.0 g) were added sequentially, and the resulting mixture was reacted at 50°C. After completion of the reaction, the reaction mixture was filtered, and the filter cake was washed with methanol. The filter cake was collected and purified by silica gel column chromatography to obtain intermediate z45c (6.5 g). MS (ESI) m / z [M+H]+ :327.8.

[0506] Step 3: Preparation of intermediate z45d

[0507] To a reaction flask, z45c (6 g), p-toluenesulfonic acid (0.316 g), toluene (50 mL), and triethyl orthoformate (5.44 g) were added sequentially. The resulting mixture was reacted at 120°C under N2 protection. After completion of the reaction, the solvent was evaporated under reduced pressure, PE was added for pulping, and the filter cake was collected by filtration to obtain intermediate z45d (6 g). MS (ESI) m / z [M+H] + :337.8.

[0508] Step 4: Preparation of intermediate z45e

[0509] To the reaction flask were added z45d (6 g), Pd2(dba)3 (1.631 g), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (1.513 g), KOH (1.999 g), 1,4-dioxane (100 mL), and water (25.00 mL) in sequence. Under nitrogen protection, the resulting mixture was heated to 100°C for reaction. After completion of the reaction, the reaction solution was purified by silica gel column chromatography to obtain intermediate z45e (4.7 g). MS (ESI) m / z [M+H] + :319.3.

[0510] Step 5: Preparation of intermediate z45f

[0511] To a reaction flask, z45e (3.65 g), THF (200 mL), and NaH (0.550 g) were added sequentially. The resulting mixture was heated to 65°C and stirred for 10 minutes. A solution of 3-bromopiperidine-2,6-dione (2.64 g) in THF (200 mL) was added dropwise to the reaction mixture. After the addition was complete, the mixture was reacted at 65°C. After completion, the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and purified by silica gel column chromatography to obtain intermediate z45f (0.8 g).

[0512] MS (ESI) m / z [M+H] + :430.4.

[0513] Step 6: Preparation of intermediate z45

[0514] To the reaction flask, z45f (700 mg) and DCM:TFA = 1:1 (v:v, 20 mL) were added sequentially, and the resulting mixture was reacted at room temperature. After the reaction was complete, DCM was added to the reaction solution, and the solvent was evaporated under reduced pressure to obtain intermediate z45 (0.66 g). MS (ESI) m / z [M+H] + :330.4.1 H NMR (500MHz, DMSO) δ11.02(s,1H),8.80(d,J=11.0Hz,1H),8.56(d,J=11.6Hz,1H),8.16(s,1H),7.55(d,J=7.4Hz,1H),6.83(d,J=7.5Hz,1H),4.65 (p,J=8.1Hz,2H),3.49(d,J=12.7Hz,2H),3.10(s,2H),2.87(s,1H),2.68 –2.57(m,2H),2.20(td,J=6.4,3.1Hz,4H),2.01(dt,J=10.6,5.3Hz,1H).

[0515] Preparation Example 7: Synthesis of Intermediate z46

[0516] Step 1: Preparation of intermediate z46b

[0517] To the reaction flask, intermediate z46a (8.59 g) and acetonitrile (800 mL) were added in sequence, the temperature was lowered to 0°C, NBS (11.27 g) was added, and the reaction was continued at 0°C. After the reaction was completed, the reaction solution was poured into water and filtered. The filter cake was washed with water and dried to obtain intermediate z46b (11.27 g). MS (ESI, [M+H] + )m / z:231.1.

[0518] Step 2: Preparation of intermediate z46c

[0519] Refer to the preparation method of intermediate z41b in step 1 of Preparation Example 2, and replace intermediate z41a with intermediate z46b to obtain intermediate z46c (5.80 g). MS (ESI) m / z [M+H] + :334.1.

[0520] Step 3: Preparation of intermediate z46d

[0521] Refer to the preparation method of intermediate z41c in step 2 of Preparation Example 2, and replace intermediate z41b with intermediate z46c to obtain intermediate z46d (2.58 g). MS (ESI) m / z [M+H] + :316.1.

[0522] Step 4: Preparation of intermediate z46e

[0523] To the reaction flask, z46d (2.50 g), MeOH (80 mL), Pd / C (1.00 g), Pd(OH)2 / C (1.00 g), and acetic acid (0.5 mL) were added sequentially and reacted at 60°C under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered, and the solvent was evaporated under reduced pressure. The filtrate was concentrated and purified by silica gel column chromatography to obtain intermediate z46e (2.45 g). MS (ESI) m / z [M+H] + :320.1.

[0524] Step 5: Preparation of intermediate z46f

[0525] To the reaction flask, intermediate z46e (2.40 g), 2,6-bis(benzyloxy)-3-iodopyridine (3.76 g), cuprous iodide (0.71 g), L-proline (0.43 g), cesium carbonate (7.34 g), and 1,4-dioxane (50 mL) were added in sequence and reacted at 100°C under nitrogen. After the reaction, the reaction solution was concentrated and purified by silica gel column chromatography to obtain intermediate z46f (1.77 g). MS (ESI, [M+H] + )m / z:609.3.

[0526] Step 6: Preparation of intermediate z46g

[0527] To the reaction flask, z46f (1.77 g), MeOH (40 mL), and Pd / C (1.00 g) were added sequentially and reacted at 60°C under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered, and the solvent was evaporated under reduced pressure. The filtrate was concentrated and purified by silica gel column chromatography to obtain intermediate z46g (0.77 g). MS (ESI) m / z [M+H] + :431.2

[0528] Step 7: Preparation of intermediate z46

[0529] Refer to the preparation method of compound z41 in step 5 of Preparation Example 2, and replace intermediate z41e with intermediate z46g to obtain intermediate z46 (0.71 g).

[0530] MS (ESI) m / z [M+H] + :331.1. 1H NMR(500MHz,DMSO)δ10.88(s,1H),9.17(d,J=10.7Hz,1H),9.01–8.84(m,1H),6.66(d, J=3.9Hz,1H),5.98(d,J=3.9Hz,1H),5.29–5.05(m,1H),4.16–4.06(m,2H),3.69–3.61( m,1H),3.61–3.53(m,1H),3.33(d,2H),3.03–2.92(m,3H),2.89–2.78(m,1H),2.58–2. 52(m,1H),2.46–2.34(m,1H),2.03–1.95(m,2H),1.93–1.85(m,1H),1.83–1.72(m,2H).

[0531] Preparation Example 8: Synthesis of Intermediate 5h

[0532] Step 1: Preparation of intermediate 5a

[0533] To a reaction flask, sodium hydride (60% wt, 31.6 g) and DMF (1000 mL) were added sequentially. Under N2 protection, the reaction was cooled to 10°C, 4-fluoroindole (89.0 g) was added dropwise, and stirring continued at room temperature for 30 min. 2-Iodopropane (85 mL) was slowly added dropwise to the reaction system, and the reaction was allowed to react at room temperature for 2 h. The reaction system was cooled to 10°C again, sodium hydride (60% wt, 20 g) was added portionwise, and stirring continued at room temperature for 30 min. 2-Iodopropane (85 mL) was slowly added dropwise to the system, and the reaction was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction solution was slowly poured into ice water, extracted with petroleum ether, dried, and concentrated to obtain intermediate 5a (137.0 g).

[0534] MS (ESI, [M+H] + )m / z:178.2.

[0535] Step 2: Preparation of intermediate 5b

[0536] In a reaction flask, add intermediate 5a (132g) and DMSO (500mL) in sequence, raise the temperature to 80°C, and slowly add tert-butyl hydroperoxide (287g) and a DMSO (900mL) solution of elemental iodine (194g) dropwise. After the addition is complete, maintain the reaction at 80°C. After the reaction is complete, add saturated sodium sulfite to quench the reaction, extract with ethyl acetate, and purify the extract by silica gel column chromatography to obtain intermediate 5b (63.0g). MS (ESI, [M+H] + )m / z:208.2.

[0537] Step 3: Preparation of intermediate 5c

[0538] To the reaction flask, intermediate 5b (60.5 g), acetonitrile (500 mL), water (1000 mL), and NBS (67.6 g) were added in sequence and reacted at room temperature. After the reaction was completed, the mixture was filtered and the filter cake was dried to obtain intermediate 5c (79.0 g). 1 H NMR (500MHz, DMSO) δ7.92 (dd, J = 8.5, 7.3Hz, 1H), 7.11 (d, J = 8.6Hz, 1H), 4.43 (hept, J = 6.9Hz, 1H), 1.40 (d, J = 6.9Hz, 6H).

[0539] Step 4: Preparation of Intermediate 5d

[0540] Under nitrogen at 0°C, trimethylsilylated diazomethane (2M, 67.3 mL) was slowly added dropwise to a solution of intermediate 5c (35 g) and triethylamine (33.9 mL) in ethanol (1000 mL). The mixture was allowed to react at room temperature. After completion of the reaction, the reaction solution was concentrated and purified by silica gel column chromatography to afford intermediate 5d (19.7 g).

[0541] MS (ESI, [M+H] + )m / z:300.2.

[0542] Step 5: Preparation of intermediate 5e

[0543] To the reaction flask, intermediate 5d (19 g), 2-bromo-N-methylacetamide (11.55 g), DMF (250 ml), and cesium carbonate (41.3 g) were added in sequence and reacted at room temperature. After the reaction was completed, water was added, the mixture was filtered, and the filter cake was dried to obtain intermediate 5e (7.1 g). MS (ESI, [M+H] + )m / z:371.1.

[0544] Step 6: Preparation of intermediate 5f

[0545] To the reaction flask, intermediate 5e (7 g), benzophenone imine (5.47 g), Pd2(dba)3 (1.727 g), BINAP (2.348 g), cesium carbonate (18.43 g), and 1,4-dioxane (150 mL) were added in sequence and reacted at 100°C under nitrogen. After the reaction was complete, the mixture was cooled to room temperature, diluted with dichloromethane, and filtered. The filtrate was purified by silica gel column chromatography to obtain intermediate 5f (3.0 g). MS (ESI, [M+H] + )m / z:472.2.

[0546] Step 7: Preparation of Intermediate 5g

[0547] To the reaction flask, intermediate 5f (3 g), hydroxylamine hydrochloride (0.884 g), sodium acetate (1.566 g) and methanol (50 mL) were added in sequence and reacted at room temperature. After the reaction was completed, the reaction solution was concentrated and purified by silica gel column chromatography to obtain intermediate 5g (1.0 g). MS (ESI, [M+H] + )m / z:308.2.

[0548] Step 8: Preparation of Intermediate 5h

[0549] To the reaction flask, add intermediate 5g (0.6g), DMF (10mL), DIPEA (1.023mL) and 2,4,5-trichloropyrimidine (466mg) in sequence and react at 70°C. After the reaction is complete, cool to room temperature, add water, filter, and dry the filter cake to obtain intermediate 5h (0.8g). MS (ESI, [M+H] + )m / z:454.1.

[0550] Preparation Example 9: Synthesis of Intermediate 9d

[0551] Step 1: Preparation of intermediate 9c

[0552] To the reaction flask, z7n (300 mg) and THF (30 mL) were added sequentially. The temperature was lowered to approximately -10°C, followed by the addition of acrylamide (90 mg) and potassium tert-butoxide (172 mg, 1.533 mL). Under nitrogen protection, the mixture was reacted at room temperature. After completion of the reaction, the reaction solution was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 mL). The organic phase was purified by silica gel column chromatography to yield intermediate 9c (150 mg). MS (ESI) m / z [M+H] + :287.2.

[0553] Step 2: Preparation of intermediate 9d

[0554] In a reaction flask, 2-iodobenzoic acid (293 mg) was added to a solution of 9c (150 mg) in MeCN (20 mL) at room temperature. The reaction mixture was allowed to react at 90°C for 2 h. After completion of the reaction, the filtrate was filtered and the solvent was removed under reduced pressure to obtain intermediate 9d (0.150 g). MS (ESI) m / z [M+H] + :285.2.

[0555] Preparation Example 10: Synthesis of Intermediate z47

[0556] Step 1: Preparation of intermediate z47a

[0557] Under ice bath, sodium borohydride (25 g) was added to a solution of intermediate z39b (64 g) in methanol (1200 mL) and the mixture was allowed to react at 5°C. After completion of the reaction, 2M aqueous hydrochloric acid solution was added to quench the reaction. The mixture was extracted with dichloromethane and concentrated. The resulting concentrate was purified by silica gel column chromatography to obtain intermediate z47a (54 g). MS (ESI, [M+H] + )m / z:193.12.

[0558] Step 2: Preparation of intermediate z47b

[0559] Under ice bath, acetic anhydride (12 g) was added dropwise to a dichloromethane (500 mL) solution of intermediate z47a (15 g), triethylamine (15.5 g), and DMAP (0.4 g), and the reaction was allowed to proceed at room temperature. After completion of the reaction, water was added to quench the reaction, and the product was extracted with dichloromethane and concentrated. The resulting concentrate was purified by silica gel column chromatography to obtain intermediate z47b (18.6 g). MS (ESI, [M+H] + )m / z:235.1.

[0560] Step 3: Preparation of intermediate z47c

[0561] Under ice bath, 1M boron tribromide solution in DCM (243 mL) was added dropwise to a solution of intermediate z47b (18 g) in dichloromethane (1000 mL) and the reaction was allowed to proceed at room temperature. After completion of the reaction, water was added to quench the reaction, and the product was extracted with dichloromethane and concentrated. The resulting concentrate was purified by silica gel column chromatography to obtain intermediate z47c (15.5 g). MS (ESI, [M+H] + )m / z:221.11.

[0562] Step 4: Preparation of intermediate z47d

[0563] Acetyl chloride (11.11 g) was added dropwise to a solution of intermediate z47c (15.59 g), triethylamine (21 g), and DMAP (0.86 g) in dichloromethane (1000 mL) at -5°C. The reaction was allowed to proceed at -5°C. After completion of the reaction, water was added to quench the reaction, and the product was extracted with dichloromethane and concentrated. The resulting concentrate was purified by silica gel column chromatography to yield intermediate z47d (20 g). MS (ESI, [M+H] + )m / z:263.12.

[0564] Step 5: Preparation of intermediate z47e

[0565] Intermediate z47d (13 g), zirconium tetrachloride (46 g), and dichloromethane (250 mL) were added to a reaction flask and reacted at 40°C. After completion of the reaction, water was added to quench the reaction, and the product was extracted with dichloromethane and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate z47e (7.64 g).

[0566] MS (ESI, [M+H] + )m / z:263.12.

[0567] Step 6: Preparation of intermediate z47f

[0568] Intermediate z47e (7.5 g), sodium hydroxide (5.72 g), ethanol (250 mL), and water (150 mL) were added to the reaction flask and reacted at 25°C. After the reaction was completed, 2M aqueous hydrochloric acid was added to adjust the pH to less than 7. The product was extracted with dichloromethane and concentrated. The resulting concentrate was purified by silica gel column chromatography to obtain intermediate z47f (6.23 g). MS (ESI, [M+H] + )m / z:221.11.

[0569] Step 7: Preparation of intermediate z47g

[0570] TBS-Cl (5.54 g) was added portionwise to a dichloroethane (200 mL) solution of intermediate z47f (6.23 g) and imidazole (5.78 g) at -5°C and allowed to react at 75°C. After completion of the reaction, water was added to quench the reaction, and the product was extracted with dichloromethane and concentrated. The resulting concentrate was purified by silica gel column chromatography to obtain intermediate z47g (7.8 g). MS (ESI, [M+H] + )m / z:335.20.

[0571] Step 8: Preparation of intermediate z47h

[0572] Intermediate z47g (7.8 g), diethyl carbonate (13.77 g), toluene (200 mL), and sodium hydride (4.66 g) were added to a reaction flask and reacted at 120°C. After completion of the reaction, saturated aqueous citric acid solution was added to quench the reaction, and the product was extracted with ethyl acetate and concentrated. The resulting concentrate was purified by silica gel column chromatography to obtain intermediate z47h (9.23 g). MS (ESI, [M+H] + )m / z:361.18.

[0573] Step 9: Preparation of intermediate z47i

[0574] Intermediate z47h (9.14 g), 50 wt% aqueous hydroxylamine solution (41.90 g) and ethanol (100 mL) were added to the reaction flask and reacted at 85°C. After completion of the reaction, saturated aqueous citric acid solution was added to quench the reaction, and the mixture was extracted with ethyl acetate and concentrated to obtain intermediate z47i (10.48 g). MS (ESI, [M+H] + )m / z:376.19.

[0575] Step 10: Preparation of intermediate z47j

[0576] Intermediate z47i (10.48 g), ethanol (300 mL) and concentrated sulfuric acid (13.41 g) were added to the reaction flask and reacted at 70°C. After the reaction was completed, water was added to quench the reaction, and the product was extracted with ethyl acetate and concentrated. The resulting concentrate was purified by silica gel column chromatography to obtain intermediate z47j (6.27 g). MS (ESI, [M+H] + )m / z:290.13.

[0577] Step 11: Preparation of intermediate z47

[0578] A 1M solution of potassium tert-butoxide in THF (9.33 mL) was added dropwise to a solution of intermediate z47j (3.00 g) and acrylamide (0.81 g) in THF (250 mL) at -5°C and allowed to react at 25°C. After completion of the reaction, saturated aqueous ammonium chloride was added to quench the reaction, and the product was concentrated with ethyl acetate. The resulting concentrate was purified by silica gel column chromatography to afford intermediate z47 (1.44 g).

[0579] MS (ESI, [M+H] + )m / z:315.13. 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),7.52(d,J=8.0Hz,1H),7.19(d,J=8.1Hz,1H),4.74(d, J=4.1Hz,1H),4.53(dd,J=11.9,5.0Hz,1H),3.85(s,1H),3.27(dd,J=14.6,8.9Hz,1H),3.17( d,J=5.2Hz,1H),3.06(dd,J=14.3,9.2Hz,1H),2.74(td,J=16.1,10.2Hz,3H),2.60(dd,J=17 .4,4.2Hz,1H),2.17(dd,J=11.4,6.7Hz,1H),1.93(p,J=10.6Hz,2H),1.45(d,J=13.6Hz,2H).

[0580] Preparation Example 11: Synthesis of Intermediate z48

[0581] Step 1: Preparation of intermediate z48b

[0582] To the reaction flask, z48a (50 g), EtOH (1 L), sodium acetate (69.8 g), and hydroxylamine hydrochloride (59.2 g) were added sequentially. Under N2 protection, the resulting mixture was heated to 70°C for 2 h. After completion of the reaction, 1 L of water was added to the reaction solution, and the EtOH was evaporated under reduced pressure. The mixture was filtered and the filter cake was collected to obtain intermediate z48b (60 g). MS (ESI) m / z [M+H]+ :192.0. 1 H NMR (500MHz, DMSO) δ10.47(s,1H),7.13(t,J=7.9Hz,1H),6.79(dd,J=8.0,3.5H z,2H),3.65(s,2H),2.74(t,J=6.6Hz,2H),2.39(t,J=6.6Hz,2H),1.91(s,3H).

[0583] Step 2: Preparation of intermediate z48c

[0584] At -20°C, a mixture of thionyl chloride (410 g, 250 mL) and THF (100 mL) was slowly added dropwise to a solution of z48b (65 g) in 500 mL of tetrahydrofuran. Under nitrogen protection, the resulting mixture was reacted at 0°C for 1.5 h. After completion of the reaction, the reaction solution was slowly poured into ice water and neutralized with aqueous sodium hydroxide (272 g, 1700 mL). The solution was extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to yield intermediate z48c (72 g). MS (ESI) m / z [M+H] + :192.0. 1 H NMR (500MHz, DMSO) δ7.87(t,J=5.5Hz,1H),7.11(t,J=7.9Hz,1H),6.90(dd,J=8.2,1.1Hz,1H),6.74(dd ,J=7.6,1.0Hz,1H),4.25(d,J=5.7Hz,2H),3.77(s,3H),2.88–2.82(m,2H),2.65(dd,J=7.9,5.8Hz,2H).

[0585] Step 3: Preparation of intermediate z48d

[0586] In a reaction flask, a solution of z48c (34 g) in THF (1 L) was added dropwise to a solution of lithium aluminum tetrahydride (10.12 g, 267 mL). Under nitrogen protection, the resulting mixture was heated to 80°C for 15 min. After the reaction was complete, the reaction solution was cooled to room temperature and quenched by adding THF (1 L), anhydrous sodium sulfate (50 g), and H2O (10 mL). After stirring at room temperature for 30 min, the reaction solution was filtered and the solvent was evaporated under reduced pressure to obtain z48d (37 g). MS (ESI) m / z [M+H] + :178.1.

[0587] 1H NMR (500MHz, DMSO) δ7.03(t,J=7.8Hz,1H),6.83(d,J=8.2Hz,1H),6.72(d,J=7.4Hz,1H ),3.78(s,2H),3.74(s,3H),3.06–3.00(m,2H),2.95–2.89(m,2H),1.56–1.48(m,2H).

[0588] Step 4: Preparation of intermediate z48e

[0589] To the reaction flask, z48d (30 g), DCM (500 mL), and triethylamine (41.1 g, 56.3 mL) were added sequentially. Trifluoroacetic anhydride (42.7 g, 28.2 mL) was added dropwise under an ice bath. Under nitrogen, the resulting mixture was gradually returned to room temperature and allowed to react for 2 h. After completion of the reaction, the reaction mixture was poured into water, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to yield intermediate z48e (37 g). MS (ESI) m / z [M+H] + :274.0.

[0590] Step 5: Preparation of intermediate z48f

[0591] In a reaction flask, at 0°C under N2 protection, a solution of boron tribromide in DCM (2.0 mol / L, 135 mL) was slowly added dropwise to a stirred solution of z48e (37 g) in DCM (600 mL). The addition was complete after 30 minutes. After the reaction was complete, the reaction solution was poured into ice water and extracted with DCM. The organic phases were combined, washed with water and saturated brine, dried, filtered, and the solvent removed to obtain intermediate z48f (40 g). MS (ESI) m / z [M+H] + :260.0.

[0592] Step 6: Preparation of intermediate z48g

[0593] To the reaction flask, z48f (37 g), DCM (600 mL), DMAP (1.744 g), and triethylamine (21.67 g, 28.9 mL) were added. Acetic anhydride (16.03 g) was slowly added dropwise to the reaction solution under N2 protection at 0°C. After the addition was complete, the resulting mixture was stirred at room temperature. After the reaction was complete, the reaction solution was poured into water, extracted with DCM, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain intermediate z48g (40 g). MS (ESI) m / z [M+H] + :302.0.

[0594] Step 7: Preparation of intermediate z48h

[0595] To the reaction flask, z48g (40g), aluminum chloride (53.1g), and o-dichlorobenzene (300mL) were added sequentially and reacted at 140°C. The reaction was complete. The reaction solution was cooled to room temperature and slowly poured into 1200mL of dilute hydrochloric acid (1M) for neutralization. Ethyl acetate was added for extraction, and the product was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Petroleum ether was added for slurrying, and the product was filtered with suction. The filter cake was rinsed with petroleum ether to obtain intermediate z48h (36g).

[0596] MS (ESI) m / z [M+H] + :302.0.

[0597] Step 8: Preparation of intermediate z48i

[0598] To a reaction flask at 0°C, z48h (5 g), NaH (1.991 g, 60%), MeOH (50 mL), and H2O (8 mL) were added sequentially. The mixture was allowed to react at room temperature for 3 h, and di-tert-butyl dicarbonate (4.35 g, 4.58 mL) was added. After completion of the reaction, the reaction mixture was slowly poured into water to quench the reaction. Ethyl acetate was added for extraction, and the mixture was washed with saturated sodium chloride solution. The mixture was stirred and dried over anhydrous sodium sulfate. The solvent was removed to yield intermediate z48i (2.7 g). MS (ESI) m / z [M+H] + :306.1.

[0599] Step 9: Preparation of intermediate z48j

[0600] To a reaction flask at -5°C were added z48i (2 g), THF (50 mL), and diethyl carbonate (3.87 g) in sequence. Potassium tert-butoxide solution (4.41 g, 39.3 mL) was added portionwise, and the reaction was heated to 60°C. After completion of the reaction, water was added to the reaction solution at 0°C and stirred for 30 minutes. The THF was then concentrated to remove the THF. EA was added, and the pH was adjusted to 3 with aqueous citric acid solution. The organic layer was washed with saturated brine, and the organic layer was dried over sodium sulfate and concentrated to afford intermediate z48j (2.25 g).

[0601] MS (ESI) m / z [M+H] + :332.1.

[0602] Step 10: Preparation of intermediate z48k

[0603] To the reaction flask, z48j (2 g), EtOH (20 mL), and aqueous hydroxylamine solution (1.994 g, 1.780 mL) were added sequentially and reacted at 80°C. After completion of the reaction, the reaction solution was concentrated to remove half of the solvent. The concentrate was poured into water, and the pH was adjusted to 3 with aqueous citric acid. The product was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain intermediate z48k (2.01 g). MS (ESI) m / z [M+H] +:347.1.

[0604] Step 11: Preparation of intermediate z48l

[0605] To the reaction flask, z48k (2 g) and potassium carbonate (1.197 g) were added sequentially, followed by DMA (80 mL) and iodoethane (1.081 g, 0.554 mL), and the reaction was allowed to proceed at 80°C. After the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was purified by silica gel column chromatography to obtain intermediate z48l (1.05 g). MS (ESI) m / z [M+H] + :375.1.

[0606] Step 12: Preparation of intermediate z48m

[0607] To the reaction flask, z48l (23.85 g), acrylamide (4.30 g), and THF (700 mL) were added sequentially. Under N2 protection, the mixture was stirred at -10°C, and potassium tert-butoxide solution (6.08 g) was slowly added dropwise. After the addition was complete, the mixture was reacted at 0°C for 1 h. After the reaction was complete, the reaction solution was poured into saturated aqueous ammonium chloride solution and extracted with EA. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate z48m (24.5 g).

[0608] MS (ESI) m / z [M+H] + :400.1.

[0609] Step 13: Preparation of intermediate z48

[0610] To the reaction flask, z48m (20 g), DCM (200 mL), and hydrochloric acid (54.8 g, 376 mL) were added sequentially and reacted at room temperature. After the reaction, the solvent was evaporated under reduced pressure, EA was added to slurry, and the mixture was filtered and dried to obtain z48 (18 g). MS (ESI) m / z [M+H] + :300.1. 1H NMR (500MHz, DMSO) δ11.10(s,1H),9.38(s,2H),7.71(d,J=8.0Hz,1H),7.45(d,J=8 .1Hz,1H),4.61(dd,J=12.2,4.9Hz,1H),4.51(s,2H),3.42(t,J=5.5Hz,2H),3.30(d d,J=8.2,3.1Hz,2H),2.79(ddd,J=17.4,12.2,5.3Hz,1H),2.62(dt,J=17.3,4.0Hz ,1H),2.57–2.51(m,1H),2.19(dtd,J=13.4,5.2,3.5Hz,1H),1.97(p,J=5.3Hz,2H).

[0611] Preparation Example 12: Synthesis of Intermediate 36h

[0612] Referring to the method of Preparation Example 8, 2-iodopropane was replaced by iodomethane to prepare Intermediate 36h.

[0613] Example 1: Synthesis of Compound 1

[0614] Step 1: Preparation of intermediate 1a

[0615] To the reaction flask, intermediate z5 (250 mg), N-tert-butyloxycarbonyl-4-piperidone (297 mg), DMA (8 mL), sodium acetate (61 mg), and sodium cyanoborohydride (140 mg) were added sequentially and reacted at room temperature. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 1a (159 mg). MS (ESI, [M+H] + )m / z:483.25.

[0616] Step 2: Preparation of intermediate 1b

[0617] To the reaction flask, intermediate 1a (150 mg) and 4M hydrochloric acid dioxane solution (10 mL) were added in sequence and reacted at room temperature. After the reaction was completed, the product was concentrated to obtain intermediate 1b (220 mg). MS (ESI, [M+H] + )m / z:383.20.

[0618] Step 3: Preparation of compound 1

[0619] To the reaction flask, intermediate 1b (100 mg), intermediate 6i (297 mg, preparation process refers to Example 1 of WO2022221673), DMSO (10 mL) and DIPEA (296 mg) were added in sequence and reacted at 100°C. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain compound 1 (58 mg). MS (ESI, [M+H] + )m / z:782.31. 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.80(s,1H),8.03(s,1H),7.94(d,J=2.4Hz,2H),7.69(s,2H),7. 52(d,J=8.0Hz,1H),7.17(d,J=8.1Hz,1H),7.02(s,1H),5.31(s,1H),4.53(s,5H),3.12(d,J=6.9Hz,2H ),3.01(s,2H),2.86–2.68(m,8H),2.64(d,J=4.6Hz,3H),2.59(dd,J=17.3,4.3Hz,1H),2.46(dd,J=12. 1,4.3Hz,1H),2.21–2.13(m,1H),1.75(d,J=12.0Hz,2H),1.56(d,J=6.9Hz,6H),1.41(d,J=12.0Hz,2H).

[0620] Example 2: Synthesis of Compound 2

[0621] Step 1: Preparation of intermediate 2a

[0622] To the reaction flask, intermediate z5 (150 mg), 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (143 mg), DCE (10 mL), isopropanol (2 mL), sodium acetate (55 mg), and sodium triacetoxyborohydride (189 mg) were added in sequence and reacted at room temperature. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 2a (290 mg). MS (ESI, [M+H] + )m / z:497.27.

[0623] Step 2: Preparation of intermediate 2b

[0624] To the reaction flask, intermediate 2a (290 mg) and 4M dioxane hydrochloride solution (10 mL) were added sequentially and reacted at room temperature. After the reaction was complete, the product was concentrated to give intermediate 2b (240 mg). MS (ESI, [M+H] + )m / z:433.19.

[0625] Step 3: Preparation of compound 2

[0626] Referring to step 3 of Example 1, intermediate 2b (100 mg) was used to replace 1b to obtain compound 2 (48 mg). MS (ESI, [M+H] + )m / z:796.33. 1 H NMR(500MHz,DMSO-d6)δ11.07(s,1H),8.79(s,1H),8.04(s,1H),7.95(s,2H),7.71(q,J= 9.5Hz,2H),7.53(d,J=7.8Hz,1H),7.18(d,J=8.0Hz,1H),7.03(s,1H),5.31(s,1H),4.54 (s,5H),3.16(d,J=10.0Hz,2H),3.03(s,2H),2.89(s,3H),2.73(s,2H),2.68–2.59(m,7H ),2.32(s,2H),2.18(s,1H),1.81(d,J=12.7Hz,3H),1.57(d,J=6.8Hz,6H),1.07(s,2H).

[0627] Example 3: Synthesis of Compound 3

[0628] Step 1: Preparation of intermediate 3a

[0629] To the reaction flask, intermediate z5 (150 mg), tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (152 mg), DCE (10 mL), isopropanol (2 mL), sodium acetate (55 mg), and sodium triacetoxyborohydride (189 mg) were added in sequence and reacted at room temperature. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 3a (183 mg). MS (ESI, [M+H] + )m / z:511.28.

[0630] Step 2: Preparation of intermediate 3b

[0631] To the reaction flask, intermediate 3a (183 mg) and 4M dioxane hydrochloride solution (10 mL) were added sequentially and reacted at room temperature. After the reaction was complete, the product was concentrated to give intermediate 3b (259 mg). MS (ESI, [M+H] + )m / z:411.23.

[0632] Step 3: Preparation of compound 3

[0633] Referring to step 3 of Example 1, intermediate 3b was substituted for 1b to obtain compound 3 (60 mg). MS (ESI, [M+H] + )m / z:809.34. 1 H NMR(500MHz,DMSO-d6)δ11.07(s,1H),8.80(s,1H),8.03(s,1H),7.99–7.95(m,2H),7.69(d,J=3.3Hz,2H) ,7.55(d,J=8.0Hz,1H),7.19(d,J=8.1Hz,1H),7.01(s,1H),5.31(s,1H),4.55(s,5H),3.17(d,J=5.1Hz,2 H),3.06(s,2H),2.90–2.68(m,6H),2.67(d,J=4.7Hz,4H),2.60(dt,J=17.3,4.4Hz,3H),2.49–2.43(m,1H ),2.21–2.14(m,1H),1.73(d,J=12.6Hz,2H),1.57(d,J=6.9Hz,7H),1.46(s,2H),1.10(q,J=12.3Hz,2H).

[0634] Example 4: Synthesis of Compound 4

[0635] Step 1: Preparation of intermediate 4b:

[0636] Under nitrogen, (methoxymethyl)triphenylphosphonium chloride (5.16 g), potassium tert-butoxide (2.00 g), and THF (50 ml) were added to a reaction flask. After stirring at 0°C for 1 hour, intermediate 4a (3.00 g) was added and allowed to react at room temperature for 2 hours. After completion, the reaction was quenched with ammonium chloride solution and extracted with ethyl acetate. The extract was concentrated and purified by silica gel column chromatography to provide intermediate 4b (2.70 g). 1 H NMR(500MHz,DMSO)δ5.91(p,J=2.3Hz,1H),3.46(s,3H),3.22(dd,J=6.7,4.5Hz,4 H),2.33(t,J=2.7Hz,2H),2.29(t,J=1.8Hz,2H),1.46–1.43(m,4H),1.38(s,9H).

[0637] Step 2: Preparation of intermediate 4c:

[0638] Under nitrogen, intermediate 4b (1.00 g), acetonitrile (20 mL), and water (5 mL) were added to a reaction flask. Trifluoroacetic acid (0.057 mL) was added dropwise and the mixture was allowed to react at room temperature for 8 h. After completion of the reaction, sodium bicarbonate solution was added to adjust the pH to 7-8. The mixture was extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to afford intermediate 4c (0.79 g). 1 H NMR (500MHz, DMSO) δ9.68(s,1H),3.28–3.23(m,2H),3.21–3.13(m,3H),1.99–1.90(m,4H),1.55–1.49(m,2H),1.38(s,9H),1.36–1.32(m,2H).

[0639] Step 3: Preparation of intermediate 4d:

[0640] To the reaction flask, intermediate 4c (0.30 g), intermediate z5 (0.24 g), and anhydrous sodium acetate (0.11 g) were added in sequence. After stirring at room temperature for 10 minutes, sodium triacetoxyborohydride (0.50 g) was added and the temperature was raised to 40°C for 3 hours. After completion of the reaction, water was added to quench the reaction, and the product was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 4d (0.42 g). MS (ESI, [M+H] + )m / z:537.67.

[0641] Step 4: Preparation of intermediate 4e:

[0642] Add intermediate 4d (420 mg) and dichloromethane (30 ml) to the reaction flask, add trifluoroacetic acid (892 mg) dropwise, and react at room temperature for 4 h. After the reaction is complete, concentrate to obtain intermediate 4e (760 mg). MS (ESI, [M+H] + )m / z:437.56.

[0643] Step 5: Preparation of compound 4:

[0644] Referring to step 3 of Example 1, intermediate 4e was used to replace 1b to obtain compound 4 (192 mg). HR-MS ([M+H] + )m / z:836.3661. 1H NMR (500MHz, DMSO) δ11.07(s,1H),8.79(s,1H),8.02(s,1H),7.95(dd,J=9.5,3.6Hz,2H),7.72–7.66(m,2H),7.53(d,J=8. 0Hz,1H),7.17(d,J=8.1Hz,1H),7.00(s,1H),5.31(s,1H),4.54(d,J=12.8Hz,3H),3.66–3.58(m,2H),3.54(d,J=5.6Hz,2H ),3.12(d,J=6.3Hz,2H),3.01(d,J=6.2Hz,2H),2.76(td,J=12.0,6.0Hz,1H),2.68(d,J=4.7Hz,3H),2.67–2.53(m,8H),2. 46(dd,J=12.1,4.4Hz,1H),2.17(dq,J=13.5,4.7Hz,1H),1.96(t,J=9.8Hz,2H),1.57(d,J=6.9Hz,8H),1.50–1.43(m,4H).

[0645] Example 5: Synthesis of Compound 5

[0646] Step 1: Preparation of intermediate 5l:

[0647] To the reaction flask, intermediate 5k (0.30 g), intermediate z5 (0.24 g), and anhydrous sodium acetate (0.11 g) were added in sequence. After stirring at room temperature for 10 minutes, sodium triacetoxyborohydride (0.50 g) was added and the temperature was raised to 40°C for 3 hours. After completion of the reaction, water was added to quench the reaction, and the product was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 5l (0.42 g). MS (ESI, [M+H] + )m / z:537.67.

[0648] Step 2: Preparation of intermediate 5m:

[0649] Add intermediate 5l (420 mg) and dichloromethane (30 mL) to the reaction flask, add trifluoroacetic acid (892 mg) dropwise, and react at room temperature for 4 h. After the reaction is complete, concentrate to obtain intermediate 5m (760 mg). MS (ESI, [M+H] + )m / z:437.56.

[0650] Step 3: Preparation of compound 5:

[0651] Referring to step 3 of Example 1, intermediate 5e was substituted for 1b, and intermediate 5h was substituted for 6i to obtain compound 5 (272 mg). HR-MS ([M+H]+ )m / z:854.3568. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.69(s,1H),7.99(d,J=6.4Hz,2H),7.58–7.50(m,3H),7.17–7.12(m,2H),5.32(s, 1H),4.61(s,2H),4.53(dd,J=11.9,5.0Hz,1H),3.47(s,2H),3.38(s,2H),3.13–3.08(m,2H),2.99(dd,J=6.7,3.3Hz,2 H),2.77(td,J=11.8,5.9Hz,1H),2.67(d,J=4.6Hz,3H),2.58(ddd,J=24.6,14.0,5.4Hz,8H),2.46(dd,J=12.4,4.3Hz, 1H), 2.17(dq,J=13.8,4.9Hz,1H),1.93–1.88(m,2H),1.58(d,J=6.8Hz,6H),1.48(t,J=5.5Hz,2H),1.43–1.33(m,4H).

[0652] Example 6 Synthesis of Compound 6

[0653] Step 1: Preparation of intermediate 6m

[0654] To the reaction flask, intermediate 6l (6.80 g), triethylamine (7.61 g), and dichloromethane (300 mL) were added sequentially, and the temperature was lowered to 0°C. Trifluoromethanesulfonic anhydride (5.93 mL) was added dropwise and reacted at 25°C. After completion of the reaction, the product was quenched with water and extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to afford intermediate 6m (5.16 g). 1 H NMR (500MHz, DMSO-d6) δ5.08(tt,J=7.0,3.8Hz,1H),4.31(tt,J=7.0,5.0Hz,1H),3.65(dt,J=13.4,4.8Hz,2H),3.45(tt,J=8.5,3.8Hz,1H ),2.97(s,2H),2.46(ddt,J=11.4,8.0,3.9Hz,2H),2.38–2.31(m,2H),1.78–1.71(m,2H),1.38(s,9H),1.28(dtd,J=13.2,9.4,4.3Hz,2H).

[0655] Step 2: Preparation of intermediate 6n

[0656] To the reaction flask were added 6m (200 mg), z5 (539 mg), MeCN (20 mL), and DIPEA (302 mg) in sequence. Under nitrogen, the resulting mixture was reacted at 70°C for 2 h. After completion of the reaction, the reaction solution was purified by silica gel column chromatography to obtain intermediate 6n (0.125 g).

[0657] MS (ESI) m / z [M+H] + :553.3.

[0658] Step 3: Preparation of intermediate 6o

[0659] 6n (500 mg) and hydrochloric acid (20 mL, 4 M) were added to the reaction flask in sequence, and the resulting mixture was stirred at room temperature. After the reaction was completed, 100 mL of DCM was added to the reaction solution, and the solvent was evaporated under reduced pressure to obtain intermediate 6o (0.5 g).

[0660] Step 4: Preparation of compound 6

[0661] Referring to step 3 of Example 1, intermediate 6o was substituted for 1b to obtain compound 6 (0.075 g). MS (ESI) m / z [M+H] + :853.3. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.82(s,1H),8.04(s,1H),7.95(d,J=5.0Hz,2H),7.72–7.67(m,2H),7.54(d,J=8.0Hz,1H),7.18( d,J=8.0Hz,1H),7.02(s,1H),5.32(s,1H),4.58–4.52(m,3H),4.19(s,1H),4.12(d,J=12.6Hz,2H),3.24(td,J=9.8,4.9Hz,2H),3.1 4(s,2H),3.02(s,3H),2.77(ddd,J=17.2,12.0,5.4Hz,1H),2.67(d,J=4.7Hz,3H),2.60(dt,J=17.2,4.3Hz,1H),2.56–2.52(m,1H), 2.49–2.40(m,4H),2.18(dq,J=15.0,5.2Hz,3H),2.05(s,2H),1.83(d,J=11.4Hz,2H),1.57(d,J=6.9Hz,6H),1.38(d,J=9.3Hz,2H).

[0662] Example 7: Synthesis of Compound 7

[0663] Step 1: Preparation of intermediate 7c:

[0664] To a reaction flask, raw materials 7a (1.50 g), 7b (2.25 g), and glacial acetic acid (0.16 mL) were added sequentially. After stirring at room temperature for 10 minutes, sodium cyanoborohydride (1.18 g) was added and the mixture was allowed to react at room temperature for 3 hours. After completion, the reaction was quenched with water and extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to provide intermediate 7c (1.00 g). 1 H NMR (500MHz, DMSO) δ4.01(d,J=7.0Hz,1H),3.94(d,J=13.1Hz,2H),3.23(s,6H),2.83(s,2H),2.67(s,2H),2.37(s,1H),2.0 7(s,1H),1.68(d,J=12.1Hz,2H),1.60(d,J=12.8Hz,2H),1.54–1.47(m,1H),1.38(s,10H),1.27–1.20(m,2H),1.17(s,2H).

[0665] Step 2: Preparation of intermediate 7d:

[0666] To the reaction flask, intermediate 7c (0.50 g), pyridinium p-toluenesulfonate (4.4 g), water (30 mL), and acetone (30 mL) were added in sequence. The temperature was raised to 70°C and the reaction was carried out for 24 h. After the reaction was completed, sodium bicarbonate solution was added to adjust the pH to 6-7. The product was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 7d (0.21 g). MS (ESI, [M+H] + )m / z:297.41.

[0667] Step 3: Preparation of intermediate 7e:

[0668] To a reaction flask, Intermediate 7d (0.30 g), Intermediate z5 (0.21 g), and anhydrous sodium acetate (0.10 g) were added sequentially. After stirring at room temperature for 10 minutes, sodium triacetoxyborohydride (0.43 g) was added and the temperature was raised to 40°C for 3 hours. After completion, the reaction was quenched with water and extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to afford Intermediate 7e (0.38 g). 1H NMR (500MHz, DMSO) δ11.07(s,1H),7.53(d,J=8.0Hz,1H),7.17(d,J=8.2Hz,1H),4.54(dd,J=11 .9,5.0Hz,1H),3.95(s,2H),3.17(d,J=5.2Hz,1H),3.13(dd,J=6.8,3.3Hz,2H),3.02(dd,J=6.9 ,3.2Hz,2H),2.86–2.71(m,4H),2.66–2.56(m,6H),2.28(d,J=7.0Hz,2H),2.17(ddd,J=19.4,1 0.0,5.2Hz,3H),1.70(s,5H),1.39(d,J=3.2Hz,9H),1.31–1.22(m,3H),1.08(d,J=12.4Hz,2H).

[0669] Step 4: Preparation of intermediate 7f:

[0670] Add intermediate 7e (250 mg) and 20 mL of dichloromethane to the reaction flask, add trifluoroacetic acid (492 mg) dropwise, and react at room temperature for 2 h. After the reaction is complete, concentrate to obtain intermediate 7f (232 mg). MS (ESI, [M+H] + )m / z:480.62.

[0671] Step 5: Preparation of compound 7:

[0672] Referring to step 3 of Example 1, intermediate 7f (155 mg) was substituted for 1b to obtain compound 7 (118 mg). HR-MS ([M+H] + )m / z:879.4089. 1H NMR (500MHz, DMSO) δ11.07(s,1H),8.80(s,1H),8.03(s,1H),7.95(p,J=4.2Hz,2H),7.72–7.67(m,2H),7.52(d,J=8.0Hz,1H),7.16(d,J=8.2Hz,1 H),7.03(s,1H),5.31(s,1H),4.54(d,J=9.0Hz,5H),3.15–3.10(m,2H), 3.01(dd,J=6.6,3.3Hz,2H),2.83(d,J=13.7Hz,3H),2.81–2.72(m,2H),2 .68(d,J=4.7Hz,3H),2.59(dq,J=18.3,3.7Hz,5H),2.46(dd,J=12.2,4.4Hz,1H),2.27(d,J=7.0Hz,2H),2.17(dq,J=14.7,4.7Hz,3H),1.78(d,J= 11.9Hz,2H),1.71(d,J=12.1Hz,2H),1.57(d,J=6.9Hz,6H),1.49(s,1H), 1.35(dd,J=14.4,4.9Hz,2H),1.26–1.21(m,1H),1.08(d,J=12.1Hz,2H).

[0673] Example 8: Synthesis of Compound 8

[0674] Referring to step 3 of Example 1, intermediate 7f (230 mg) was substituted for 1b, and intermediate 5h (109 mg) was substituted for 6i to obtain compound 8 (188 mg). HR-MS ([M+H] + )m / z:897.4001. 1H NMR(500MHz,DMSO)δ11.07(s,1H),8.75(s,1H),8.09(s,1H),8.03(s,1H),7.59–7.52(m,3H),7.18–7.13(m,2H), 5.31(s,1H),4.62(s,2H),4.55(dd,J=11.9,5.0Hz,1H),4.38(s,2H),3.20–3.09(m,3H),3.01(t,J=5.2Hz,3H),2 .77(ddd,J=17.1,11.9,5.3Hz,3H),2.67(d,J=4.6Hz,6H),2.63–2.56(m,5H),2.45(dd,J=12.3,4.3Hz,1H),2.27 (d,J=6.7Hz,2H),2.17(dq,J=13.8,4.8Hz,2H),1.81–1.63(m,4H),1.58(d,J=6.8Hz,6H),1.16(d,J=69.5Hz,4H).

[0675] Example 9 Synthesis of Compound 9

[0676] Step 1: Preparation of intermediate 9a

[0677] To the reaction flask were added tert-butyl piperazine-1-carboxylate acetate (448 mg), DMSO (20 mL), 6i (700 mg), and DIPEA (622 mg) in sequence. Under N2 protection, the resulting mixture was reacted at 70°C overnight. After completion of the reaction, EA (100 mL) and water (200 mL) were poured into the reaction solution for extraction. The organic phase was separated and purified by silica gel column chromatography to afford intermediate 9a (0.81 g). MS (ESI) m / z [M+H] + :587.0. 1 H NMR (500MHz, DMSO-d6) δ8.87(s,1H),8.08(s,1H),7.94(d,J=4.4Hz,1H),7.89(d,J=2.2Hz,1H),7.76–7.67(m,2H),7.09(s,1H),5.32(s,1H ),4.54(s,2H),3.62(dd,J=6.7,3.9Hz,3H),3.38(t,J=5.2Hz,4H),2.68(d,J=4.6Hz,3H),2.54(s,1H),1.57(d,J=6.9Hz,6H),1.41(s,9H).

[0678] Step 2: Preparation of intermediate 9b

[0679] 9a (600 mg) and DCM (5 mL) were added to the reaction flask in sequence, followed by trifluoroacetic acid (2 mL), and the resulting mixture was stirred at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain intermediate 9b (0.550 g). MS (ESI) m / z [M+H] + :487.0. 1 H NMR(500MHz,DMSO-d6)δ9.03(s,1H),8.82(s,2H),8.14(s,1H),7.93(dd,J=12.2,3.5Hz,2H),7.73–7.65(m,2H),7.10(s, 1H), 4.54 (s, 2H), 3.83 (t, J = 5.3Hz, 3H), 3.17 (d, J = 6.0Hz, 4H), 2.67 (d, J = 4.7Hz, 3H), 2.54 (s, 1H), 1.57 (d, J = 6.9Hz, 6H).

[0680] Step 3: Preparation of compound 9

[0681] 9b (150 mg), 9d (120 mg), DCE (10 mL), isopropanol (2 mL), and acetic acid (9.27 mg) were added to the reaction flask in sequence. Sodium cyanoborohydride (38.8 mg) was also added, and the resulting mixture was stirred at 50°C for 2 h. After the reaction was completed, the solvent was evaporated under reduced pressure and the reaction solution was purified by silica gel column chromatography to obtain compound 9 (20 mg). MS (ESI) m / z [M+H] + :754.3. 1 H NMR(500MHz,DMSO)δ11.07(s,1H),8.84(s,1H),8.06(s,1H),7.95(d,J=10.6Hz,2H),7 .71(q,J=9.5Hz,2H),7.62(d,J=7.9Hz,1H),7.26(d,J=8.0Hz,1H),7.06(s,1H),4.56( s,3H),3.69(s,4H),3.23(d,J=15.4Hz,2H),3.02(s,2H),2.75(d,J=15.1Hz,2H),2.67 (d,J=4.7Hz,3H),2.62(s,1H),2.60–2.53(m,4H),2.18(s,1H),1.57(d,J=6.9Hz,6H).

[0682] Example 10 Synthesis of Compound 10

[0683] In a reaction flask, 2-iodobenzoic acid (293 mg) was added to a MeCN solution (20 mL) of z23 (i.e., z23, 150 mg prepared in step 16 of preparation examples z22 and z23 of WO2023125944) at room temperature, and the reaction solution was reacted at 90 ° C for 2 h. After the reaction was completed, the filtrate was filtered, the filtrate was collected, and the solvent was evaporated under reduced pressure. MeOH (10 mL), 9b (90 mg), acetic acid (5.56 mg), and sodium cyanoborohydride (23.28 mg) were added to the obtained concentrate, and the obtained mixture was reacted at room temperature under N2 protection. After the reaction was completed, the solvent was evaporated under reduced pressure and compound 10 (20 mg) was purified by silica gel column chromatography. MS (ESI) m / z [M+H] + :768.3. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.84(s,1H),8.06(s,1H),7.95(d,J=11.6Hz,2H),7.69(d,J=3.2H z,2H),7.61(d,J=8.1Hz,1H),7.27(d,J=8.1Hz,1H),7.03(s,1H),5.32(s,1H),4.60–4.52(m,3H),3.6 7(s,4H),3.24–3.15(m,2H),2.92(d,J=14.5Hz,2H),2.84(d,J=16.8Hz,1H),2.78–2.71(m,1H),2.64( d,J=4.7Hz,4H),2.59(s,1H),2.46(s,4H),2.37(d,J=7.5Hz,2H),2.19(s,1H),1.56(d,J=6.9Hz,6H).

[0684] Example 11: Synthesis of Compound 11

[0685] Step 1: Preparation of intermediate 11a

[0686] To the reaction flask, intermediate 9b (180 mg), Boc-3-azetidinone (103 mg), DCE (12 mL), isopropanol (3 mL), and sodium triacetoxyborohydride (254 mg) were added in sequence and reacted at room temperature. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 11a (90.0 mg). MS (ESI, [M+H] + )m / z:641.2.

[0687] Step 2: Preparation of intermediate 11b

[0688] To the reaction flask, intermediate 11a (90 mg), dichloromethane (4 mL), and trifluoroacetic acid (1 mL) were added sequentially and reacted at room temperature. After the reaction was completed, the product was concentrated to obtain intermediate 11b (120.0 mg). MS (ESI, [M+H] + )m / z:541.2.

[0689] Step 3: Preparation of Intermediate 11

[0690] Referring to the preparation method of compound 10 in Example 10, intermediate 9b was replaced with intermediate 11b to obtain compound 11 (75.0 mg). MS (ESI) m / z [M+H] + :823.3. 1 H NMR(500MHz,DMSO)δ11.07(s,1H),8.84(s,1H),8.05(s,1H),7.99–7.91(m,2H),7.74–7.66(m,2H) ,7.60(d,J=8.1Hz,1H),7.24(d,J=8.1Hz,1H),7.04(s,1H),5.62–4.93(m,1H),4.59–4.52(m,3H),3 .67–3.61(m,4H),3.55–3.39(m,2H),3.23–3.09(m,2H),2.93–2.71(m,6H),2.67(d,J=4.7Hz,3H), 2.64–2.56(m,2H),2.49–2.44(m,1H),2.34–2.23(m,4H),2.22–2.14(m,1H),1.57(d,J=6.8Hz,6H).

[0691] Example 12: Synthesis of Compound 12

[0692] Step 1: Preparation of intermediate 12b

[0693] Refer to the preparation method of compound 10 in Example 10, replacing intermediate 9b with intermediate 12a to obtain intermediate 12b (170.0 mg).

[0694] MS (ESI) m / z [M+H] + :594.3.

[0695] Step 2: Preparation of intermediate 12c

[0696] To the reaction flask, intermediate 12b (165 mg), dichloromethane (4 mL), and dioxane hydrochloride solution (4 M, 3.5 mL) were added in sequence and reacted at room temperature. After completion of the reaction, the product was concentrated to give intermediate 12c (165 mg). MS (ESI, [M+H]+ )m / z:494.3.

[0697] Step 3: Preparation of intermediate 12

[0698] Referring to step 3 of Example 1, intermediate 12c was substituted for 1b to obtain compound 12 (45.0 mg). MS (ESI) m / z [M+H] + :893.3. 1 H NMR (500MHz, DMSO) δ11.08(s,1H),8.81(s,1H),8.04(s,1H),8.01–7.88(m,2H),7.75–7.66(m,2H),7.62(d,J=7.9Hz,1H),7. 27(d,J=8.1Hz,1H),7.05(s,1H),5.71–4.91(m,1H),4.61–4.51(m,3H),3.66–3.54(m,4H),3.25–3.11(m,2H),3.04–2.82(m, 4H),2.82–2.72(m,2H),2.67(d,J=4.7Hz,3H),2.64–2.58(m,1H),2.54(d,J=6.2Hz,3H),2.46(dd,J=12.2,4.4Hz,1H),2.36– 2.23(m,1H),2.22–2.15(m,1H),1.97–1.78(m,2H),1.76–1.63(m,2H),1.57(d,J=6.8Hz,6H),1.30–1.19(m,2H),0.89(s,6H).

[0699] Example 13: Synthesis of Compound 13

[0700] Referring to step 3 of Example 1, intermediate 13h (80 mg) was substituted for 6i (preparation process refers to Example B.7.1. Experimental procedure for the synthesis of IM-4a in WO2018108704), and intermediate 7f (388 mg) was substituted for 1b to obtain compound 13 (36 mg). MS (ESI, [M+H] + )m / z:851.37. 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.85(s,1H),8.05(s,1H),8.00–7.92(m,2H),7.75(dd,J=9.1, 2.4Hz,1H),7.53(d,J=8.0Hz,1H),7.48(d,J=9.1Hz,1H),7.17(d,J=8.1Hz,1H),7.12(s,1H),4.59(s ,5H),3.68(s,3H),3.14(d,J=5.5Hz,2H),3.02(d,J=6.2Hz,2H),2.91–2.72(m,5H),2.67(d,J=4.7Hz ,9H),2.49(s,2H),2.29(s,2H),2.21–2.13(m,2H),1.77(s,4H),1.37(d,J=15.7Hz,3H),1.12(s,2H).

[0701] Example 14 Synthesis of Compound 14

[0702] Referring to step 3 of Example 1, intermediate 14a (150 mg, synthesis reference WO 2018108704) was substituted for 6i, and intermediate 7f (197 mg) was substituted for 1b to obtain compound 14 (0.064 g). MS (ESI) m / z [M+H] + :882.4. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.78(s,1H),8.06(s,1H),7.97(d,J=5.1Hz,1H),7.58(d,J=2.3Hz,1H),7.55–7.50 (m,2H),7.17(d,J=8.2Hz,1H),7.00(s,1H),4.55(d,J=18.9Hz,5H),3.88(d,J=9.6Hz,6H),3.17(d,J=5.2Hz,1H),3.14 (s,2H),3.02(d,J=6.7Hz,2H),2.85(t,J=12.3Hz,3H),2.76(ddd,J=17.2,11.9,5.2Hz,2H),2.67(d,J=4.6Hz,3H),2. 65–2.56(m,5H),2.48–2.43(m,1H),2.29(s,2H),2.21–2.11(m,2H),1.77(s,4H),1.36(d,J=28.3Hz,4H),1.13(s,2H).

[0703] Example 15: Synthesis of Compound 15

[0704] Preparation of compound 15:

[0705] Referring to step 3 of Example 1, intermediate 7f (155 mg) was substituted for 1b, and intermediate 15h (100 mg, preparation process is described in Example 1 of WO2023244917) was substituted for 6i to obtain compound 15 (50 mg). HR-MS ([M+H] + )m / z:852.3741. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),9.09(s,1H),8.72(d,J=2.5Hz,1H),8.30(d,J=2.5Hz,1H),8.09(s,1H),7.98(d, J=4.9Hz,1H),7.53(d,J=7.9Hz,1H),7.17(d,J=7.8Hz,2H),4.62(s,2H),4.54(dd,J=11.9,5.0Hz,3H),3.74(s,3H) ,3.16–3.11(m,2H),3.02(d,J=6.6Hz,2H),2.93–2.70(m,5H),2.67(d,J=4.6Hz,3H),2.66–2.56(m,5H),2.52(s,1H ),2.49–2.44(m,2H),2.36(s,1H),2.30(s,2H),2.17(dq,J=8.7,4.5Hz,2H),1.91(s,1H),1.79(s,3H),1.40(s,3H).

[0706] Example 16: Synthesis of Compound 16

[0707] Referring to step 3 of Example 1, intermediate 16g (100 mg, preparation process refers to Example 9 of WO2023244917) was substituted for 6i, and intermediate 7f (548 mg) was substituted for 1b to obtain compound 16 (78 mg). MS (ESI, [M+H] + )m / z:880.39. 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H),9.06(s,1H),8.68(d,J=2.5Hz,1H),8.30(d,J=2.5Hz,1H),8.08(s,1H),7.96(d,J=4. 9Hz,1H),7.53(d,J=8.0Hz,1H),7.17(d,J=8.2Hz,1H),7.10(s,1H),5.96(s,1H),4.58(s,5H),3.13(t,J=5.1Hz,2H),3.02( t,J=4.9Hz,2H),2.92–2.71(m,5H),2.68(d,J=4.7Hz,3H),2.65–2.55(m,5H),2.51(s,2H),2.47(dd,J=11.3,7.1Hz,2H),2. 29(d,J=6.8Hz,2H),2.17(dq,J=13.6,4.8Hz,2H),1.76(s,4H),1.57(d,J=6.9Hz,6H),1.36(d,J=22.6Hz,2H),1.11(s,2H).

[0708] Example 17 Synthesis of Compound 17

[0709] Referring to step 3 of Example 1, intermediate 17b (150 mg, preparation process refers to Example Intermediate A10a of WO2019197842) was substituted for 6i, and intermediate 7f (307 mg) was substituted for 1b to obtain compound 17 (0.07 g). MS (ESI) m / z [M+H] + :911.3. 1H NMR (500MHz, DMSO) δ11.07(s,1H),8.81(s,1H),8.20(d,J=2.3Hz,1H),8.04(s,1H),7.71(dd,J=9.0,2.2Hz,1H),7.53(d,J=8.0Hz,1H) ,7.44(d,J=9.1Hz,1H),7.17(d,J=8.1Hz,1H),6.25–6.16(m,1H),4.60–4.32(m,5H),3.57(s,3H),3.26–3.19(m,1H),3.13(d,J=6.8Hz, 2H),3.02(d,J=6.9Hz,2H),2.76(td,J=11.6,5.4Hz,5H),2.68–2.56(m,5H),2.46(dd,J=12.2,4.3Hz,1H),2.29(s,2H),2.18(dq,J=8. 8,4.6Hz,2H),1.73(s,4H),1.40(d,J=74.5Hz,5H),1.09(s,2H),0.71(q,J=6.2Hz,1H),0.56–0.49(m,2H),0.35(dt,J=8.7,4.6Hz,1H).

[0710] Example 18 Synthesis of Compound 18

[0711] Step 1: Preparation of intermediate 18b

[0712] Under N2 protection, 18a (1 g), THF (15 mL), and DIPEA (1.181 mL) were added sequentially to the reaction flask. After cooling to -40°C, 2,4,5-trichloropyrimidine (1.133 g) was added dropwise. The reaction was allowed to proceed at room temperature under N2 protection. After the reaction was complete, the reaction solution was filtered and the filter cake was collected to obtain intermediate 18b (1.75 g). MS (ESI) m / z [M+H] + :310.1

[0713] Step 2: Preparation of compound 18

[0714] Referring to step 3 of Example 1, intermediate 18b (150 mg) was substituted for 6i, and intermediate 7f (186 mg) was substituted for 1b to obtain compound 18 (0.06 g). MS (ESI) m / z [M+H] + :753.3. 1H NMR (500MHz, DMSO) δ11.07(s,1H),8.67(s,1H),8.00(s,1H),7.56–7.46(m,3H),7.17(d,J=8.1Hz, 1H),6.94(d,J=8.5Hz,1H),4.54(dd,J=11.9,5.0Hz,3H),3.56(s,2H),3.13(s,5H),3.02(d,J=6.2 Hz,2H),2.77(ddt,J=17.1,11.8,6.1Hz,4H),2.67–2.55(m,5H),2.48–2.43(m,1H),2.30(s,2H),2 .18(dt,J=13.0,4.6Hz,2H),2.02–1.93(m,1H),1.78(s,4H),1.46(s,4H),1.14(d,J=21.4Hz,2H).

[0715] Example 19: Synthesis of Compound 19

[0716] Step 1: Preparation of intermediate 19a:

[0717] To the reaction flask, intermediate 7d (0.30 g), intermediate z1 (0.21 g), and anhydrous sodium acetate (0.10 g) were added in sequence. After stirring at room temperature for 10 minutes, sodium triacetoxyborohydride (0.43 g) was added. Under N2 protection, the temperature was raised to 40°C and the reaction was allowed to proceed for 3 hours. After completion of the reaction, water was added to quench the reaction, and the product was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 19a (0.38 g). MS (ESI, [M+H] + )m / z:552.02.

[0718] Step 2: Preparation of intermediate 19b:

[0719] Add intermediate 19a (250 mg) and 20 mL of dichloromethane to the reaction flask, add trifluoroacetic acid (492 mg) dropwise, and react at room temperature for 2 h. After the reaction is complete, concentrate to obtain intermediate 19b (232 mg). MS (ESI, [M+H] + )m / z:452.08.

[0720] Step 3: Preparation of compound 19:

[0721] Referring to step 3 of Example 1, intermediate 19b (155 mg) was substituted for 1b to obtain compound 19 (60 mg). HR-MS ([M+H] + )m / z:851.3792. 1H NMR (500MHz, DMSO) δ11.07(s,1H),8.85(s,1H),8.05(s,1H),7.97(d,J=10.6Hz,2H),7.69(s,2H),7.63(s,1H ),7.59(s,1H),7.03(s,1H),5.32(s,1H),4.54(d,J=6.8Hz,5H),4.03(q,J=7.1Hz,1H),3.90(s,2H),3.85(s, 2H),2.94–2.70(m,5H),2.67(d,J=4.7Hz,3H),2.60(dt,J=17.2,4.2Hz,2H),2.54(s,2H),2.47(s,1H),2.24– 2.13(m,2H),1.99(s,2H),1.91(s,2H),1.76(d,J=51.1Hz,3H),1.57(d,J=6.9Hz,6H),1.44(d,J=6.4Hz,2H).

[0722] Example 20: Synthesis of Compound 20

[0723] Step 1: Preparation of intermediate 20a

[0724] To the reaction flask, intermediate z3 (182 mg), dichloroethane (25 mL), intermediate 7d (180 mg), sodium triacetoxyborohydride (296 mg), sodium acetate (45 mg), and isopropanol (5 mL) were added in sequence and reacted at 25°C. After the reaction was completed, water was added to quench the reaction, and the product was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 20a (303 mg). MS (ESI, [M+H] + )m / z:566.33.

[0725] Step 2: Preparation of compound 20

[0726] To the reaction flask, intermediate 20a (300 mg) and 4M hydrochloric acid dioxane solution (5 mL) were added sequentially and reacted at 25°C. After the reaction was completed, the reaction solution was directly concentrated, and intermediate 6i (100 mg), DMSO (10 mL) and N,N-diisopropylethylamine (530 mg) were added and reacted at 120°C. After the reaction was completed, the reaction solution was quenched with water, extracted with ethyl acetate, and the extract was concentrated and purified by silica gel column chromatography to obtain compound 20 (39 mg). MS (ESI, [M+H] + )m / z:865.38. 1H NMR(500MHz,DMSO-d6)δ11.07(s,1H),8.82(s,1H),8.04(s,1H),7.95(s,2H),7.69(s,2H),7.58(d,J=8.1Hz,1 H),7.13(d,J=8.3Hz,1H),7.03(s,1H),5.53(d,J=220.3Hz,1H),4.54(s,5H),3.77(s,2H),2.91(d,J=24.0Hz, 3H),2.73(s,7H),2.67(d,J=4.7Hz,3H),2.63–2.53(m,2H),2.46(dd,J=12.2,4.3Hz,1H),2.39(d,J=6.8Hz,2H ),2.18(dq,J=13.7,4.2Hz,2H),1.83(d,J=74.8Hz,5H),1.57(d,J=6.9Hz,6H),1.47–1.34(m,2H),1.15(s,2H).

[0727] Example 21: Synthesis of Compound 21

[0728] Step 1: Preparation of intermediate 21a:

[0729] To the reaction flask, intermediate 7d (0.30 g), intermediate z4 (0.21 g), and anhydrous sodium acetate (0.10 g) were added in sequence. After stirring at room temperature for 10 minutes, sodium triacetoxyborohydride (0.43 g) was added. Under N2 protection, the temperature was raised to 40°C and the reaction was allowed to proceed for 3 hours. After completion of the reaction, water was added to quench the reaction, and the product was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 21a (0.38 g). MS (ESI, [M+H] + )m / z:566.05.

[0730] Step 2: Preparation of intermediate 21b:

[0731] Intermediate 21a (250 mg) and dichloromethane (20 mL) were added to the reaction flask, and trifluoroacetic acid (492 mg) was added dropwise. The reaction was allowed to proceed at room temperature for 2 h. After completion of the reaction, the mixture was concentrated to obtain Intermediate 21b (232 mg). MS (ESI, [M+H] + )m / z:466.09.

[0732] Step 3: Preparation of compound 21:

[0733] Referring to step 3 of Example 1, intermediate 21b (155 mg) was substituted for 1b to obtain compound 21 (55 mg). HR-MS ([M+H] + )m / z:865.3940.1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.86(s,1H),8.05(s,1H),8.01–7.94(m,2H),7.69(d,J=1.5Hz,2H),7.57(d,J=8. 1Hz,1H),7.08(d,J=8.3Hz,1H),7.03(s,1H),5.31(s,1H),4.62–4.51(m,5H),3.68(s,2H),2.98(t,J=5.7Hz,3H),2. 89–2.79(m,3H),2.78–2.70(m,3H),2.67(d,J=4.7Hz,3H),2.60(dt,J=17.2,4.2Hz,2H),2.49–2.43(m,2H),2.36(d, J=5.1Hz,2H),2.18(dq,J=8.7,4.6Hz,2H),1.91(s,2H),1.75(d,J=62.3Hz,4H),1.57(d,J=6.9Hz,6H),1.45(s,2H).

[0734] Example 22: Synthesis of Compound 22

[0735] Step 1: Preparation of intermediate 22a

[0736] To the reaction flask, intermediate 9b (700 mg) and methanol (40 mL) were added sequentially. After stirring at 50°C to dissolve, sodium cyanoborohydride (315 mg) and N-tert-butyloxycarbonyl-4-piperidone (103 mg) were added and reacted at 50°C. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 22a (270 mg). MS (ESI, [M+H] + )m / z:669.2.

[0737] Step 2: Preparation of intermediate 22b

[0738] To the reaction flask, intermediate 22a (270 mg), dichloromethane (10 mL) and dioxane hydrochloride solution (4 M, 5 mL) were added in sequence and reacted at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain intermediate 22b (240 mg). MS (ESI, [M+H] + )m / z:569.2.

[0739] Step 3: Preparation of compound 22

[0740] Intermediate z39 (100 mg), DMSO (20 mL) and 2-iodobenzoic acid (277 mg) were added to the reaction flask in sequence and reacted at room temperature. After the reaction was completed, water and saturated sodium bicarbonate solution were added to quench the reaction, and the mixture was extracted with ethyl acetate and concentrated. The resulting concentrate was added to a solution of intermediate 22b (100 mg), sodium acetate (25.6 mg) and sodium cyanoborohydride (40 mg) in MeOH (40 mL) and reacted at 50°C. After the reaction was completed, the solvent was evaporated under reduced pressure and purified by silica gel column chromatography to obtain compound 22 (55 mg). MS (ESI, [M+H] + )m / z:879.2. 1 H NMR (500MHz, DMSO) δ11.07(d,J=3.4Hz,1H),8.82(s,1H),8.05(s,1H),7.98–7.92(m,2H),7.74–7.66(m,2H),7.50(d,J=8.0Hz,1 H),7.17(d,J=8.2Hz,1H),7.05(s,1H),5.73–4.84(m,1H),4.55(s,2H),4.54–4.49(m,1H),3.67–3.58(m,4H),3.40–3.34(m,1H) ,2.99–2.83(m,4H),2.81–2.72(m,2H),2.68(d,J=4.6Hz,3H),2.64–2.57(m,1H),2.55–2.52(m,3H),2.49–2.42(m,1H),2.24–2. 13(m,2H),2.12–1.98(m,4H),1.97–1.80(m,3H),1.77–1.69(m,2H),1.57(d,J=6.9Hz,6H),1.50–1.36(m,2H),1.01–0.87(m,2H).

[0741] Example 23: Synthesis of Compound 23

[0742] In the preparation of compound 22 in step 3 of reference example 22, intermediate z40 (100 mg) was substituted for z39 to obtain compound 23 (51 mg). MS (ESI, [M+H] + )m / z:879.2. 1H NMR(500MHz,DMSO)δ11.07(s,1H),8.82(s,1H),8.04(s,1H),7.99–7.93(m,2H),7.74–7.66(m,2H),7.50(d,J=8.0Hz,1H), 7.17(d,J=8.1Hz,1H),7.05(s,1H),5.78–4.92(m,1H),4.63–4.49(m,3H),3.69–3.58(m,4H),3.40–3.36(m,1H),2.98–2.83 (m,4H),2.81–2.72(m,2H),2.68(d,J=4.7Hz,3H),2.64–2.57(m,1H),2.55–2.51(m,3H),2.23–2.13(m,2H),2.11–1.99(m, 4H),1.97–1.89(m,1H),1.89–1.80(m,2H),1.77–1.70(m,2H),1.57(d,J=6.9Hz,6H),1.49–1.38(m,2H),1.01–0.88(m,2H).

[0743] Examples 24-29: Referring to the method described in Example 6, intermediate z5 was replaced with the following intermediates to prepare compounds 24-29, as shown in Table 1A.

[0744] Table 1A

[0745] Example 30 Synthesis of Compound 30

[0746] Step 1: Preparation of intermediate 30a

[0747] To the reaction flask were added tert-butyl piperazine-1-carboxylate acetate (0.845 mg), DMSO (20 mL), 17b (1.7 g), and DIPEA (2.43 g) in sequence. Under N2 protection, the resulting mixture was reacted at 70°C overnight. After the reaction was complete, EA (100 mL) and water (200 mL) were poured into the reaction solution for extraction. The organic phase was separated and purified by silica gel column chromatography to afford intermediate 30a (1.4 g). MS (ESI) m / z [M+H] + :618.3.

[0748] Step 2: Preparation of intermediate 30b

[0749] To the reaction flask, 30a (1.4 g) and hydrochloric acid (10 mL, 4 M dioxane solution) were added sequentially, and the resulting mixture was stirred at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain intermediate 30b (1.2 g). MS (ESI) m / z [M+H] + :518.2.

[0750] Step 3: Preparation of compound 30

[0751] 30b (100 mg), 9d (77 mg), MeOH (30 mL), sodium acetate (29.6 mg), and sodium cyanoborohydride (34.0 mg) were added to the reaction flask in sequence and reacted at 60°C for 4 h. After completion of the reaction, the reaction solution was purified by silica gel column chromatography to obtain compound 30 (120 mg). MS (ESI) m / z [M+H] + :786.2. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.84(s,1H),8.22(d,J=2.3Hz,1H),8.05(s,1H),7.71(dd,J=9.1,2.2Hz,1H),7.62(d,J=8.0Hz,1H),7.4 4(d,J=9.1Hz,1H),7.24(d,J=8.1Hz,1H),6.22(d,J=4.1Hz,1H),4.56(dd,J=11.8,5.0Hz,1H),4.41(dtd,J=30.0,13.6,7.4Hz,2H),3.62(s ,4H),3.56(s,3H),3.40–3.34(m,1H),3.21(t,J=8.9Hz,2H),2.97(dt,J=16.5,8.7Hz,2H),2.76(ddd,J=17.3,11.9,5.4Hz,1H),2.60(dt,J =17.2,4.4Hz,2H),2.48(s,3H),2.22–2.14(m,2H),1.35–1.28(m,2H),0.70(q,J=6.2Hz,1H),0.51(t,J=6.1Hz,2H),0.35(q,J=5.8Hz,1H).

[0752] Example 31 Synthesis of Compound 31

[0753] 2-iodobenzoic acid (293 mg) was added to a DMSO solution (10 mL) of z23 (i.e., z23, 150 mg prepared according to step 16 of preparation examples z22 and z23 of WO2023125944) at room temperature, and the reaction solution was reacted at 30 ° C for 2 h. After the reaction was completed, EA (100 mL) and water (200 mL) were poured into the reaction solution for extraction. The organic phase was separated and filtered, and the filtrate was collected. The solvent was evaporated under reduced pressure, and MeOH (10 mL), 30b (80 mg), sodium acetate (23.6 mg), and sodium cyanoborohydride (27.2 mg) were added to the obtained concentrate. Under N2 protection, the obtained mixture was reacted at room temperature. After the reaction was completed, the solvent was evaporated under reduced pressure and compound 31 (60 mg) was obtained by purification by silica gel column chromatography. MS (ESI) m / z[M+H] + :800.2. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.84(s,1H),8.22(d,J=2.3Hz,1H),8.05(s,1H),7.70(dd,J=9.0,2.3Hz,1H),7.60(d,J=8.0Hz,1H),7.43(d,J =9.1Hz,1H),7.25(d,J=8.1Hz,1H),6.23(d,J=4.5Hz,1H),4.56(ddd,J=11.8,5.0,1.5Hz,1H),4.39(dtd,J=30.0,13.6,7.3Hz,2H),3.60(s,3H), 3.55(s,3H),3.19(ddd,J=24.9,13.0,6.1Hz,3H),2.93–2.82(m,3H),2. 83–2.70(m,2H),2.63–2.57(m,1H),2.46(dd,J=12.2,4.5Hz,1H),2.40(t ,J=5.2Hz,4H),2.34(d,J=7.2Hz,2H),2.21–2.15(m,1H),1.33(q,J=9.4 Hz,1H),0.77–0.68(m,1H),0.53(q,J=4.9Hz,2H),0.36(q,J=5.2Hz,1H).

[0754] Example 32 Synthesis of Compound 32

[0755] Referring to the preparation process of Example 31, 37b was used instead of 30b to prepare compound 32 (100 mg). MS (ESI) m / z [M+H] + :883.3. 1H NMR (500MHz, DMSO) δ11.07(s,1H),8.83(s,1H),8.22(d,J=2.3Hz,1H),8.04(s,1H),7.70(dd,J=9.1,2.2Hz,1H),7.60(d,J=8. 0Hz,1H),7.44(d,J=9.1Hz,1H),7.25(d,J=8.1Hz,1H),6.22(s,1H),4.56(ddd,J=11.9,5.0,1.4Hz,1H),4.50–4.32(m,2H),3. 56(s,7H),3.20(ddd,J=21.2,10.6,5.5Hz,3H),2.96–2.73(m,6H),2.65–2.55(m,1H),2.47(s,5H),2.29(s,2H),2.18(dd,J=8 .8,4.4Hz,2H),1.88(s,2H),1.71(s,2H),1.43(s,2H),1.34(s,1H),0.75–0.67(m,1H),0.57–0.49(m,2H),0.39–0.32(m,1H).

[0756] Example 33: Synthesis of Compound 33

[0757] Step 1: Synthesis of compound 33

[0758] Intermediate 35c (121 mg), intermediate 30b (100 mg), methanol (10 mL), sodium acetate (32 mg), and sodium cyanoborohydride (36 mg) were added to the reaction flask in sequence and reacted at 50°C. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain compound 33 (32 mg). MS (ESI, [M+H] + )m / z:814.31. 1H NMR (500MHz, DMSO-d6) δ11.07(d,J=3.4Hz,1H),8.82(s,1H),8.20(d,J=2.3Hz,1H),8.03(s,1H),7.68(d,J=9.0Hz,1H),7.52(d,J=8. 0Hz,1H),7.42(d,J=9.1Hz,1H),7.19(d,J=8.0Hz,1H),6.20(s,1H),4.56–4.51(m,1H),4.42(d,J=5.5Hz,1H),4.39(s,1H),4.32(dd,J =19.6,6.9Hz,1H),3.54(s,6H),3.37(dd,J=14.2,7.3Hz,2H),3.20(s,2H),3.00(dd,J=14.2,7.7Hz,1H),2.83–2.67(m,4H),2.60(dd, J=17.7,4.7Hz,2H),2.48(s,3H),2.17(s,1H),2.03(d,J=28.9Hz,2H),1.37(t,J=10.5Hz,2H),0.68(s,1H),0.49(s,2H),0.33(s,1H).

[0759] Example 34: Synthesis of Compound 34

[0760] Intermediate z40 (100 mg), DMSO (20 mL) and 2-iodobenzoic acid (277 mg) were added to the reaction flask in sequence and reacted at room temperature. After the reaction was completed, water and saturated sodium bicarbonate solution were added to quench the reaction, and the mixture was extracted with ethyl acetate and concentrated. The resulting concentrate was added to a solution of intermediate 30b (90 mg), sodium acetate (29 mg) and sodium cyanoborohydride (33 mg) in MeOH (20 mL) and reacted at 25°C. After the reaction was completed, the reaction solution was evaporated to remove the solvent under reduced pressure and purified by silica gel column chromatography to obtain compound 34 (62 mg). MS (ESI, [M+H] + )m / z:828.32. 1H NMR(500MHz,DMSO-d6)δ11.07(d,J=3.4Hz,1H),8.84(s,1H),8.22(d,J=2.3Hz, 1H),8.05(s,1H),7.70(dd,J=9.0,2.2Hz,1H),7.51(d,J=8.0Hz,1H),7.44(d,J =9.1Hz,1H),7.17(d,J=8.1Hz,1H),6.21(s,1H),4.53(ddd,J=11.8,5.0,2.7Hz ,1H),4.41(ddd,J=30.5,17.5,8.4Hz,2H),3.57(d,J=15.6Hz,5H),3.36(dt,J= 16.9,8.6Hz,2H),3.24(t,J=5.2Hz,2H),2.94(dt,J=26.7,13.9Hz,2H),2.76(t d,J=12.1,5.4Hz,2H),2.60(dd,J=17.1,3.9Hz,1H),2.35(d,J=6.5Hz,4H),2.1 8(tt,J=8.7,4.5Hz,1H),2.10(d,J=7.2Hz,4H),1.98(s,1H),1.33(s,1H),1.01 –0.92(m,2H),0.75–0.69(m,1H),0.53(t,J=6.2Hz,2H),0.36(t,J=5.3Hz,1H).

[0761] Example 35: Synthesis of Compound 35

[0762] Step 1: Preparation of intermediate 35a

[0763] To the reaction flask, intermediate 30b (650 mg), 1-Boc-3-azetidinone (322 mg), methanol (50 mL), sodium acetate (103 mg), and sodium cyanoborohydride (197 mg) were added sequentially and reacted at 50°C. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 35a (290 mg). MS (ESI, [M+H] + )m / z:673.28.

[0764] Step 2: Preparation of intermediate 35b

[0765] Referring to the procedure of step 2 of Example 39, 35a was used to replace 39a to obtain intermediate 35b (350 mg). MS (ESI, [M+H] + )m / z:573.22.

[0766] Step 3: Preparation of intermediate 35c

[0767] To the reaction flask, z47 (1.44 g), 2-iodoacylbenzoic acid (3.21 g), and acetonitrile (80 mL) were added sequentially and stirred at 70°C. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the extract was concentrated to afford Intermediate 35c (1.27 g).

[0768] MS (ESI, [M+H] + )m / z:313.11.

[0769] Step 4: Preparation of compound 35

[0770] Intermediate 35c (340 mg), intermediate 35b (250 mg), methanol (50 mL), sodium acetate (53 mg), and sodium cyanoborohydride (68 mg) were added to the reaction flask in sequence and reacted at 60°C. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain compound 35 (290 mg). MS (ESI, [M+H] + )m / z:869.4. 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.84(s,1H),8.21(d,J=2.4Hz,1H),8.05(s,1H),7.70(dd,J=9.0,2.2Hz,1H),7.51(d,J=8.0Hz,1H),7. 43(d,J=9.1Hz,1H),7.17(d,J=8.2Hz,1H),6.22(d,J=4.4Hz,1H),4.53(dd,J=11.9,5.0Hz,1H),4.41(ddt,J=29.3,13.0,6.2Hz,2H),3.56(s,7 H),3.39(d,J=16.6Hz,2H),3.24–3.15(m,1H),3.13–3.04(m,1H),2.76(ddd,J=24.4,20.4,12.8Hz,6H),2.62–2.56(m,1H),2.48–2.34(m,2H), 2.25(s,4H),2.17(dq,J=8.7,4.3Hz,1H),1.79(s,2H),1.37–1.21(m,4H),0.71(p,J=6.2Hz,1H),0.53(q,J=6.8Hz,2H),0.36(q,J=6.9Hz,1H).

[0771] Example 36: Synthesis of Compound 36

[0772] Following the procedure of Example 34, 35b was used to replace 30b, and the reaction temperature was changed from 25°C to 50°C to obtain compound 36 (65 mg). MS (ESI, [M+H] + )m / z:883.35. 1 H NMR (500MHz, DMSO-d6) δ11.07(d,J=3.2Hz,1H),8.84(s,1H),8.21(d,J=2.3Hz,1H),8.04(s,1H),7.69(dd,J=9.1,2.2Hz,1H),7.50(d,J =7.9Hz,1H),7.43(d,J=9.1Hz,1H),7.17(d,J=8.1Hz,1H),6.22(d,J=4.3Hz,1H),4.53(ddd,J=11.9,5.0,2.3Hz,1H),4.39(ddt,J=34.4, 13.2,7.3Hz,2H),3.57(d,J=10.9Hz,8H),3.35(s,1H),3.24–3.19(m,1H),2.76(d,J=5.7Hz,8H),2.63–2.57(m,1H),2.48–2.42(m,1H),2 .22(s,7H),2.00(d,J=28.8Hz,2H),1.71(s,1H),1.35–1.29(m,1H),1.00(s,2H),0.74–0.67(m,1H),0.52(s,2H),0.35(q,J=6.5Hz,1H).

[0773] Example 37: Synthesis of Compound 37

[0774] Referring to the method of Example 35, N-BOC-piperidinone was substituted for 1-Boc-3-azetidinone to prepare compound 37. MS (ESI, [M+H] + )m / z:897.4. 1H NMR (500MHz, DMSO) δ11.07(d,J=4.0Hz,1H),8.82(s,1H),8.21(d,J=2.3Hz,1H),8.03(s,1H),7.69(dd,J=9.1,2.1Hz,1H),7.52 (d,J=8.0Hz,1H),7.43(d,J=9.1Hz,1H),7.19(d,J=8.0Hz,1H),6.21(s,1H),4.57–4.49(m,1H),4.47–4.33(m,2H),3.62–3.50(m ,8H),3.43–3.35(m,2H),3.25–3.18(m,1H),3.02–2.94(m,1H),2.81–2.72(m,4H),2.64–2.57(m,2H),2.45–2.41(m,3H),2.23– 2.14(m,3H),2.12–1.96(m,3H),1.76–1.64(m,2H),1.39–1.27(m,5H),0.75–0.66(m,1H),0.55–0.47(m,2H),0.39–0.31(m,1H).

[0775] Example 38: Synthesis of Compound 38

[0776] Referring to the method of Example 36, intermediate 37b was substituted for intermediate 35b to prepare compound 38. MS (ESI, [M+H] + )m / z:911.4. 1H NMR (500MHz, DMSO) δ11.07(d,J=3.4Hz,1H),8.83(s,1H),8.22(d,J=2.3Hz,1H),8.04(s,1H),7.70(dd,J=9.0,2.2Hz,1H),7.51(d,J=8.0Hz,1H),7. 44(d,J=9.1Hz,1H),7.17(d,J=8.1Hz,1H),6.24–6.20(m,1H),4.57–4.50( m,1H),4.49–4.33(m,2H),3.65–3.50(m,7H),3.40–3.34(m,1H),3.27–3.1 8(m,1H),3.00–2.82(m,4H),2.80–2.72(m,2H),2.64–2.57(m,1H),2.49–2 .44(m,3H),2.23–2.13(m,2H),2.11–1.98(m,4H),1.97–1.90(m,1H),1.89 –1.77(m,2H),1.77–1.64(m,2H),1.50–1.36(m,2H),1.35–1.30(m,1H),1. 02–0.90(m,2H),0.76–0.68(m,1H),0.55–0.49(m,2H),0.39–0.33(m,1H).

[0777] Example 39: Synthesis of Compound 39

[0778] Step 1: Preparation of intermediate 39a

[0779] 6m (918 mg), z1 (350 mg), MeCN (50 mL), and DIPEA (735 mg) were added to the reaction flask in sequence and reacted at 25°C for 2 h. After the reaction was complete, the reaction solution was concentrated and the concentrate was purified by silica gel column chromatography to obtain intermediate 39a (340 mg). MS (ESI, [M+H] + )m / z:525.26.

[0780] Step 2: Preparation of intermediate 39b

[0781] 39a (340 mg) and hydrochloric acid (10 mL, 4 M dioxane solution) were added to the reaction flask in sequence and stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to obtain intermediate 39b (398 mg). MS (ESI, [M+H] + )m / z:425.21.

[0782] Step 3: Preparation of compound 39

[0783] Refer to the procedure of step 3 of Example 1, replace 1b with intermediate 39b, and extract with ethyl acetate after the reaction to obtain compound 39 (37 mg). MS (ESI, [M+H] + )m / z:824.32. 1 H NMR (500MHz, DMSO-d6) δ11.09(s,1H),8.82(s,1H),8.04(s,1H),7.95(s,2H),7.74–7.67(m,3H),7.30(d,J=8.1Hz,1H),7.03 (s,1H),5.31(s,1H),4.60(dd,J=11.9,5.0Hz,1H),4.54(s,2H),4.36–4.29(m,1H),4.11(s,4H),4.00(s,2H),3.55(dd,J=8. 6,4.5Hz,1H),3.30–3.20(m,3H),2.77(ddd,J=17.3,12.0,5.4Hz,1H),2.67(d,J=4.6Hz,3H),2.61(dt,J=17.2,4.1Hz,1H),2 .35(d,J=11.4Hz,2H),2.23–2.17(m,1H),2.06(s,2H),1.84(d,J=12.7Hz,2H),1.57(d,J=6.9Hz,6H),1.39(d,J=9.4Hz,2H).

[0784] Example 40: Synthesis of Compound 40

[0785] Step 1: Preparation of intermediate 40a

[0786] Refer to the procedure of step 1 of Example 39, and replace z1 with z4 to obtain intermediate 40a (580 mg). MS (ESI, [M+H] + )m / z:539.30.

[0787] Step 2: Preparation of intermediate 40b

[0788] 40a (580 mg), DCM (50 ml), and hydrochloric acid (20 mL, 4 M dioxane solution) were added to the reaction flask in sequence and stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to obtain intermediate 40b (560 mg). MS (ESI, [M+H] + )m / z:439.30.

[0789] Step 3: Synthesis of compound 40

[0790] Refer to the procedure of step 3 of Example 1, replace 1b with intermediate 40b, and extract with ethyl acetate after the reaction to obtain compound 40 (81 mg). MS (ESI, [M+H] + )m / z:838.34. 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.82(s,1H),8.04(s,1H),7.94(d,J=5.2Hz,2H),7.68(d,J=1.5Hz,2H),7.57(d,J=8.1Hz,1H),7. 11(d,J=8.4Hz,1H),7.02(s,1H),4.58–4.54(m,1H),4.54(s,2H),4.23(s,1H),4.12(d,J=13.3Hz,2H),3.62(s,2H),3.55(s,1H),3.23(t ,J=10.6Hz,3H),3.01(d,J=22.8Hz,3H),2.80–2.74(m,1H),2.67(t,J=3.8Hz,5H),2.60(dd,J=17.3,4.2Hz,1H),2.46(dd,J=12.3,4.2Hz ,1H),2.31–2.25(m,2H),2.21–2.16(m,1H),2.08(d,J=4.7Hz,2H),1.83(d,J=12.3Hz,2H),1.57(d,J=6.9Hz,6H),1.39(d,J=9.2Hz,2H).

[0791] Example 41 Synthesis of Compound 41

[0792] Step 1: Preparation of intermediate 41a

[0793] To the reaction flask were added 6m (350 mg), z48 (943 mg), MeCN (20 mL), and DIPEA (529 mg) in sequence. Under nitrogen protection, the resulting mixture was reacted at 70°C for 2 h. After completion of the reaction, the reaction solution was purified by silica gel column chromatography to obtain intermediate 41a (0.2 g). MS (ESI) m / z [M+H] + :553.1.

[0794] Step 2: Preparation of intermediate 41b

[0795] 41a (500 mg) and hydrochloric acid (10 mL, 4 M) were added to the reaction flask in sequence, and the resulting mixture was stirred at room temperature. After the reaction was complete, 10 mL of DCM was added to the reaction solution, and the solvent was evaporated under reduced pressure to obtain intermediate 41b (0.5 g). MS (ESI) m / z [M+H] +:453.2.

[0796] Step 3: Preparation of compound 41

[0797] Referring to the procedure of step 3 of Example 1, intermediate 41b was substituted for 1b to obtain compound 41 (0.1 g). MS (ESI) m / z [M+H] + :852.3. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.81(s,1H),8.03(s,1H),7.94(d,J=4.8Hz,2H),7.68(d,J=1.4Hz,2H),7.54(d,J=7.8Hz,1H),7.19–7.14(m ,1H),7.01(s,1H),5.32(s,1H),4.59–4.54(m,1H),4.54(s,2H),4.08(s ,3H),3.89(d,J=8.5Hz,2H),3.49(td,J=8.0,3.9Hz,2H),3.19(ddd,J=1 9.1,9.8,6.0Hz,4H),3.00(d,J=40.8Hz,3H),2.77(ddd,J=17.2,11.9,5.3Hz,1H),2.65(d,J=4.6Hz,3H),2.61(dt,J=17.3,4.1Hz,1H),2.19(d q,J=8.6,4.6Hz,1H),2.12(s,2H),1.93(s,2H),1.78(d,J=11.9Hz,2H), 1.74–1.64(m,2H),1.56(d,J=6.8Hz,6H),1.33(dt,J=11.0,3.7Hz,2H).

[0798] Example 42: Synthesis of Compound 42

[0799] Step 1: Preparation of intermediate 42a:

[0800] Intermediate 45c (207 mg), intermediate z1 (150 mg), anhydrous sodium acetate (40 mg), sodium cyanoborohydride (77 mg) and methanol (20 mL) were added to the reaction flask in sequence and reacted at 25°C. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 42a (197 mg). MS (ESI, [M+H] + )m / z:539.28.

[0801] Step 2: Preparation of intermediate 42b

[0802] Referring to the procedure of step 2 of Example 39, 39a was replaced with 42a to obtain intermediate 42b (229 mg). MS (ESI, [M+H] + )m / z:439.23.

[0803] Step 3: Preparation of compound 42

[0804] Refer to the procedure of step 3 of Example 1, replace 1b with intermediate 42b, and extract with ethyl acetate after the reaction to obtain compound 42 (52 mg). MS (ESI, [M+H] + )m / z:838.34. 1 H NMR (500MHz, DMSO-d6) δ11.08(s,1H),8.82(s,1H),8.04(s,1H),7.94(s,2H),7.69(d,J=3.6Hz,3H),7.29(d,J=8.1Hz,1H), 7.02(s,1H),5.31(s,1H),4.59(dd,J=11.9,5.0Hz,1H),4.54(s,2H),4.27(p,J=6.7Hz,1H),4.12(s,4H),4.01(s,2H),3.56 –3.50(m,1H),3.24(t,J=11.0Hz,2H),2.81(d,J=7.9Hz,2H),2.78–2.73(m,1H),2.68(d,J=4.7Hz,3H),2.60(dd,J=17.4,4. 3Hz,1H),2.40(s,1H),2.23–2.16(m,1H),2.06(s,4H),1.82(d,J=12.4Hz,2H),1.57(d,J=6.8Hz,6H),1.38(d,J=9.9Hz,2H).

[0805] Example 43 Synthesis of Compound 43

[0806] Step 1: Preparation of intermediate 43a

[0807] Following the procedure of step 1 of Example 42, z1 was replaced with z4 to obtain intermediate 43a (230 mg). MS (ESI) m / z [M+H] + :553.2.

[0808] Step 2: Preparation of intermediate 43b

[0809] Following the procedure of step 2 of Example 41, 43a was substituted for 41a to obtain intermediate 43b (0.2 g). MS (ESI) m / z [M+H] + :453.1.

[0810] Step 3: Preparation of compound 43

[0811] Referring to step 3 of Example 1, intermediate 43b was substituted for 1b to obtain compound 43 (0.1 g). MS (ESI) m / z [M+H] + :852.3. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.81(s,1H),8.04(s,1H),7.94(s,2H),7.68(s,2H),7.57(d,J=8.2Hz,1H),7.08(d,J=8.3Hz,1H) ,7.02(s,1H),5.33(s,1H),4.55(d,J=13.2Hz,3H),4.27(q,J=6.8Hz,1H),4.10(dd,J=11.8,6.2Hz,2H),3.67(s,2H),3.54–3.48(m, 1H),3.27–3.19(m,2H),2.97(t,J=6.0Hz,2H),2.75(p,J=5.5Hz,3H),2.67(d,J=4.6Hz,3H),2.60(dd,J=16.8,5.8Hz,3H),2.46(dd, J=12.1,4.9Hz,1H),2.22–2.14(m,1H),2.03(t,J=6.5Hz,4H),1.82(dd,J=9.7,4.8Hz,2H),1.56(d,J=6.8Hz,6H),1.40–1.32(m,2H).

[0812] Example 44: Synthesis of Compound 44

[0813] Referring to the method described in Steps 4-6 of Example 45, intermediate z3 was substituted for intermediate z5 to prepare compound 44 (45 mg). MS (ESI, [M+H] + )m / z:852.4. 1H NMR(500MHz,DMSO)δ11.07(s,1H),8.82(s,1H),8.04(s,1H),7.99–7.92(m,2H),7.68(s,2H),7.58(d,J=8.2Hz,1H), 7.13(d,J=8.2Hz,1H),7.02(s,1H),5.74–4.92(m,1H),4.59–4.51(m,3H),4.28(p,J=6.7Hz,1H),4.14–4.07(m,2H),3 .77(s,2H),3.57–3.48(m,1H),3.27–3.19(m,2H),2.98–2.90(m,2H),2.80–2.71(m,3H),2.67(d,J=4.7Hz,3H),2.64 –2.57(m,3H),2.22–2.14(m,1H),2.04(t,J=6.7Hz,4H),1.85–1.78(m,2H),1.56(d,J=6.8Hz,6H),1.42–1.34(m,2H).

[0814] Example 45: Synthesis of Compound 45

[0815] Step 1: Preparation of intermediate 45a

[0816] Under nitrogen, dimethylmonochlorosilane (10.03 g) was slowly added dropwise to a mixture of methyl trans-3-hydroxycyclobutanecarboxylate (4.6 g) and 1-Cbz-4-piperidone (16.49 g) in acetonitrile (150 mL). After the addition was complete, the resulting mixture was stirred at 50°C. After completion, the reaction was quenched with water and extracted with ethyl acetate. The extract was purified by silica gel column chromatography to yield intermediate 45a (6.1 g).

[0817] Step 2: Preparation of intermediate 45b

[0818] To a reaction flask, intermediate 45a (6.1 g), di-tert-butyl dicarbonate (5.75 g), palladium on carbon (1.869 g), and methanol (120 ml) were added sequentially and reacted at room temperature under a hydrogen atmosphere. After completion of the reaction, the mixture was filtered and the filtrate was purified by silica gel column chromatography to afford intermediate 45b (5.08 g). 1H NMR (500MHz, DMSO) δ4.26–4.16(m,1H),3.67–3.62(m,2H),3.61(s,3H),3.47–3.39(m,1H),3.02–2. 93(m,3H),2.43–2.34(m,2H),2.21–2.11(m,2H),1.76–1.67(m,2H),1.38(s,9H),1.32–1.21(m,2H).

[0819] Step 3: Preparation of intermediate 45c

[0820] Under nitrogen at -78°C, diisobutylaluminum hydride (1.5 M in THF, 6.38 mL) was slowly added dropwise to a solution of intermediate 45b (2.50 g) in anhydrous THF (50 mL) at -78°C. After the addition was complete, the resulting mixture was stirred at -78°C. After completion of the reaction, saturated aqueous ammonium chloride was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was purified by silica gel column chromatography to afford intermediate 45c (1.8 g).

[0821] Steps 4-6: Preparation of compound 45

[0822] Referring to the method described in steps 1-3 of Example 42, intermediate z5 was substituted for intermediate z1 to prepare compound 45 (40 mg). MS (ESI, [M+H] + )m / z:866.4. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.82(s,1H),8.04(s,1H),7.99–7.93(m,2H),7.69(s,2H),7.53(d,J=8.0Hz,1H),7.17(d,J= 8.1Hz,1H),7.02(s,1H),5.71–4.88(m,1H),4.57–4.50(m,3H),4.25(p,J=6.7Hz,1H),4.14–4.06(m,2H),3.55–3.48(m,1H),3. 27–3.19(m,2H),3.16–3.09(m,2H),3.05–2.98(m,2H),2.81–2.72(m,1H),2.68(d,J=4.6Hz,3H),2.66–2.57(m,5H),2.57–2.51 (m,3H),2.43–2.34(m,1H),2.22–2.14(m,1H),2.05–1.98(m,4H),1.85–1.79(m,2H),1.57(d,J=6.9Hz,6H),1.43–1.32(m,2H).

[0823] Examples 46 and 47: Synthesis of Compounds 46 and 47

[0824] Step 1: Preparation of Compound 46 and Compound 47

[0825] Compound 35 was subjected to preparative separation (chromatographic column: CHIRALPAK IK; mobile phase, dichloromethane:ethanol:n-hexane) to obtain compound 46 (17 mg) and compound 47 (14 mg).

[0826] Among them, the retention time of compound 46 in the chiral chromatographic column is shorter than that of compound 47, and the retention time of compound 47 in the chiral chromatographic column is longer than that of compound 46.

[0827] Compound 46: MS (ESI, [M+H] + )m / z:869.34. 1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.85(s,1H),8.21(s,1H),8.05(s,1H),7.70(dd,J=9.1,2.2Hz,1H),7.51(s,1H) ,7.43(d,J=9.1Hz,1H),7.18(s,1H),6.23(s,1H),4.53(dd,J=11.8,4.9Hz,1H),4.43–4.34(m,2H),3.58(d,J=14.0Hz, 7H),3.42–3.37(m,2H),3.22(s,1H),2.93–2.69(m,6H),2.62–2.58(m,1H),2.40(d,J=6.3Hz,2H),2.27(s,4H),2.19–2 .16(m,1H),1.77–1.70(m,2H),1.34(d,J=8.0Hz,4H),0.75–0.68(m,1H),0.52(t,J=6.1Hz,2H),0.35(d,J=5.4Hz,1H).

[0828] Compound 47: MS (ESI, [M+H] + )m / z:869.34. 1H NMR (500MHz, DMSO-d6)-δ11.07(s,1H),8.84(s,1H),8.21(d,J=2.4Hz,1H),8.05(s,1H),7.70(dd,J=9.0,2.2Hz,1H),7.51(d,J=8.0Hz,1H),7. 43(d,J=9.1Hz,1H),7.17(d,J=8.2Hz,1H),6.22(d,J=4.4Hz,1H),4.53(dd,J=11.9,5.0Hz,1H),4.41(ddt,J=29.3,13.0,6.2Hz,2H),3.56(s,7 H),3.39(d,J=16.6Hz,2H),3.24–3.15(m,1H),3.13–3.04(m,1H),2.76(ddd,J=24.4,20.4,12.8Hz,6H),2.62–2.56(m,1H),2.48–2.34(m,2H), 2.25(s,4H),2.17(dq,J=8.7,4.3Hz,1H),1.79(s,2H),1.37–1.21(m,4H),0.71(p,J=6.2Hz,1H),0.53(q,J=6.8Hz,2H),0.36(q,J=6.9Hz,1H).

[0829] Example 48: Synthesis of Compound 48

[0830] Step 1: Preparation of compound 48

[0831] Referring to the procedure of Example 34, z39 was substituted for z40, and 35b was substituted for 30b to obtain compound 48 (67 mg). MS (ESI, [M+H] + )m / z:883.35. 1H NMR (500MHz, DMSO-d6) δ11.07(d,J=3.2Hz,1H),8.84(s,1H),8.21(d,J=2.3Hz,1H),8.04(s,1H),7.69(dd,J=9.1,2.2Hz,1H),7.50(d,J=7.9Hz, 1H),7.43(d,J=9.1Hz,1H),7.17(d,J=8.1Hz,1H),6.22(d,J=4.1Hz,1H),4.53(ddd,J=12.0,5.0,2.3Hz,1H),4.40(ddt,J=29.6,13.1,6.2Hz,2H ),3.57(d,J=8.1Hz,7H),3.24–3.17(m,1H),2.96–2.71(m,7H),2.65–2. 52(m,2H),2.47(d,J=3.3Hz,1H),2.22(t,J=5.2Hz,7H),2.00(d,J=29.9 Hz,2H),1.73(d,J=22.9Hz,1H),1.33(d,J=6.2Hz,1H),0.99(d,J=12.3Hz,2H),0.72(q,J=6.1Hz,1H),0.56–0.47(m,2H),0.35(q,J=6.3Hz,1H).

[0832] Example 49: Synthesis of Compound 49

[0833] Referring to the method of Example 48, intermediate 37b was substituted for intermediate 35b to prepare compound 49. MS (ESI, [M+H] + )m / z:911.4. 1H NMR(500MHz,DMSO)δ11.07(d,J=3.5Hz,1H),8.83(s,1H),8.24(d,J=2.3Hz,1H ),8.04(s,1H),7.71(dd,J=9.1,2.2Hz,1H),7.51(d,J=8.0Hz,1H),7.44(d,J= 9.2Hz,1H),7.17(d,J=8.1Hz,1H),6.24(s,1H),4.54(ddd,J=11.9,5.0,2.6Hz ,1H),4.48–4.33(m,2H),3.60–3.53(m,7H),3.38–3.36(m,1H),3.26–3.19(m, 1H),2.97–2.90(m,2H),2.89–2.82(m,2H),2.80–2.73(m,2H),2.65–2.56(m,2 H),2.48–2.45(m,3H),2.21–2.14(m,2H),2.10–2.00(m,4H),1.96–1.89(m,1H ),1.88–1.79(m,2H),1.74–1.67(m,2H),1.45–1.37(m,2H),1.34–1.31(m,1H) ,1.00–0.89(m,2H),0.75–0.68(m,1H),0.55–0.49(m,2H),0.40–0.32(m,1H).

[0834] Examples 50, 51: Synthesis of Compounds 50, 51

[0835] Step 1: Preparation of intermediate 50a

[0836] Refer to the preparation process of intermediate 35c in step 3 of Example 35, and replace intermediate z47 with intermediate z47j to prepare intermediate 50a (1.02g).

[0837] MS (ESI, [M+H] + )m / z:288.2.

[0838] Step 2: Preparation of intermediate 50b

[0839] Refer to the preparation process of compound 35 in step 4 of Example 35, replace intermediate 35c with intermediate 50a, and replace intermediate 35b with 1-Boc-4-(piperidin-4-yl)-piperazine to prepare intermediate 50b (1.30 g). MS (ESI, [M+H] + )m / z:541.3.

[0840] Step 3: Preparation of Intermediates 50c and 51a

[0841] Intermediate 50b was subjected to preparative separation (chromatographic column: IG, 30*250 mm, 10 μm; mobile phase, dichloromethane:ethanol:n-hexane) to obtain Intermediate 50c (650 mg) and Intermediate 51a (700 mg).

[0842] Among them, the retention time of intermediate 50c in the chiral chromatographic column is shorter than that of intermediate 51a, and the retention time of intermediate 51a in the chiral chromatographic column is longer than that of intermediate 50c.

[0843] Intermediate 50c: MS (ESI, [M+H] + )m / z:541.3.

[0844] Intermediate 51a: MS (ESI, [M+H] + )m / z:541.3.

[0845] Step 4: Preparation of Intermediate 50d

[0846] Refer to the preparation process of intermediate 66c in step 3 of Example 66, and replace intermediate z39m with intermediate 50c to prepare intermediate 50d (220 mg). MS (ESI, [M+H] + )m / z:566.3.

[0847] Step 5: Preparation of Intermediate 50e

[0848] Refer to the preparation process of intermediate 45e in step 5 of Example 45, and replace intermediate 45d with intermediate 50d to prepare intermediate 50e (210 mg).

[0849] MS (ESI, [M+H] + )m / z:466.3.

[0850] Step 6: Preparation of compound 50

[0851] Referring to the preparation process of compound 45 in step 6 of Example 45, intermediate 50e was substituted for intermediate 45e, and intermediate 17b was substituted for intermediate 6i to prepare compound 50 (110 mg). MS (ESI, [M+H] + )m / z:897.4. 1H NMR (500MHz, DMSO) δ11.07(d,J=4.0Hz,1H),8.81(s,1H),8.21(d,J=2.3Hz,1H),8.03(s,1H),7.69(dd,J=9.1,2.2Hz,1H),7.52(d ,J=7.9Hz,1H),7.43(d,J=9.1Hz,1H),7.19(d,J=8.1Hz,1H),6.20(d,J=4.2Hz,1H),4.57–4.49(m,1H),4.49–4.32(m,2H),3.59–3. 51(m,7H),3.41–3.35(m,1H),3.26–3.18(m,1H),3.02–2.95(m,1H),2.83–2.69(m,5H),2.68–2.56(m,3H),2.47–2.41(m,4H),2.2 5–2.14(m,3H),2.12–1.96(m,3H),1.74–1.63(m,2H),1.39–1.28(m,5H),0.74–0.67(m,1H),0.54–0.48(m,2H),0.38–0.31(m,1H).

[0852] Steps 7-9: Preparation of compound 51

[0853] Referring to the method described in Steps 4-6 above, intermediate 51a was substituted for intermediate 50c to prepare compound 51 (105 mg). MS (ESI, [M+H] + )m / z:897.4. 1H NMR (500MHz, DMSO) δ11.07(d,J=4.0Hz,1H),8.82(s,1H),8.21(d,J=2.3Hz,1H),8.03(s,1H),7.69(dd,J=9.0,2.2Hz,1H),7.52(d ,J=8.0Hz,1H),7.43(d,J=9.2Hz,1H),7.19(d,J=8.1Hz,1H),6.21(d,J=4.3Hz,1H),4.57–4.49(m,1H),4.49–4.31(m,2H),3.62–3. 48(m,7H),3.42–3.35(m,1H),3.26–3.17(m,1H),3.04–2.93(m,1H),2.84–2.71(m,4H),2.70–2.55(m,3H),2.47–2.40(m,4H),2.2 6–2.14(m,3H),2.13–1.96(m,3H),1.76–1.64(m,2H),1.41–1.27(m,5H),0.74–0.67(m,1H),0.56–0.48(m,2H),0.38–0.31(m,1H).

[0854] Example 52 Synthesis of Compound 52

[0855] Step 1: Preparation of compound 52

[0856] Referring to step 1 of Example 17, intermediate 2b was substituted for 7f to obtain compound 52 (0.1 g). MS (ESI) m / z [M+H] + :828.3. 1H NMR (500MHz, DMSO) δ11.07(s,1H),8.76(s,1H),8.18(d,J=2.3Hz,1H),8.03(s,1H),7.75(dd,J=9.0,2.3Hz,1H),7.53(d,J=8. 0Hz,1H),7.44(d,J=9.1Hz,1H),7.17(d,J=8.1Hz,1H),6.19–6.14(m,1H),4.54(dd,J=11.9,5.0Hz,1H),4.51–4.25(m,5H),3. 56(s,3H),3.13(s,2H),3.02(s,2H),2.85–2.74(m,3H),2.66–2.56(m,5H),2.49–2.43(m,1H),2.29(d,J=6.6Hz,2H),2.21–2. 15(m,1H),1.75(d,J=12.7Hz,3H),1.04(d,J=12.5Hz,2H),0.72(q,J=5.8Hz,1H),0.52(q,J=6.7Hz,2H),0.36(q,J=5.9Hz,1H).

[0857] Example 53 Synthesis of Compound 53

[0858] Step 1: Preparation of intermediate 53b

[0859] To the reaction flask were added z4 (150 mg), 53a (119 mg), sodium acetate (38.2 mg), DCE (3.5 mL), isopropanol (3.5 mL), and sodium triacetoxyborohydride (296 mg, 1.399 mmol) in sequence and allowed to react at room temperature overnight. After the reaction, the reaction mixture was extracted with water and DCM, washed with saturated brine, dried, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain intermediate 53b (200 mg). MS (ESI) m / z [M+H] + :483.2.

[0860] Step 2: Preparation of intermediate 53c

[0861] 53b (200 mg) and hydrochloric acid (10 mL, 4 M) were added to the reaction flask in sequence and stirred at room temperature. After the reaction was complete, 10 mL of DCM was added to the reaction solution and the solvent was evaporated to obtain intermediate 53c (0.2 g). MS (ESI) m / z [M+H] + :383.1.

[0862] Step 3: Preparation of compound 53

[0863] Referring to Example 17, step 1, intermediate 53c was substituted for 7f to obtain compound 53 (0.1 g). MS (ESI) m / z [M+H] + :814.2. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.75(s,1H),8.15(d,J=2.3Hz,1H),8.02(s,1H),7.74(dd,J=9.1,2.2Hz,1H),7.57(d,J=8.2Hz,1H),7.42(d,J=9. 1Hz,1H),7.08(d,J=8.3Hz,1H),6.18–6.14(m,1H),4.55(dd,J=11.9,5.0H z,1H),4.47–4.28(m,4H),3.68(s,2H),3.54(s,3H),3.25–3.18(m,1H),2. 97(d,J=6.1Hz,2H),2.85–2.71(m,5H),2.60(dt,J=17.3,4.4Hz,1H),2.46 (dd,J=12.1,4.5Hz,1H),2.35(d,J=7.2Hz,2H),2.19(dt,J=13.2,4.7Hz,1 H),1.89(s,1H),1.74(d,J=12.7Hz,2H),1.31(s,1H),1.05(d,J=12.5Hz,2 H),0.74–0.66(m,1H),0.51(dd,J=8.2,4.7Hz,2H),0.34(q,J=5.2Hz,1H).

[0864] Example 54: Synthesis of Compound 54

[0865] Step 1: Preparation of intermediate 54a

[0866] Referring to the procedure of step 2 of Example 40, 21a was used to replace 40a to obtain intermediate 54a (189 mg). MS (ESI, [M+H] + )m / z:466.3.

[0867] Step 2: Synthesis of compound 54

[0868] Intermediate 54a (160 mg), intermediate 17b (80 mg), DMSO (9 mL) and N,N-diisopropylethylamine (222 mg) were added to the reaction flask in sequence and reacted at 100°C. After the reaction was completed, the reaction solution was quenched with water and extracted with ethyl acetate. The extract was concentrated and purified by silica gel column chromatography to obtain compound 54 (49 mg). MS (ESI, [M+H] + )m / z:897.38.1 H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.83(s,1H),8.19(d,J=2.3Hz,1H),8.04(s,1H),7.71(dd,J=9.0,2.2Hz,1H),7.57(d,J=8.2Hz,1H),7. 44(d,J=9.1Hz,1H),7.08(d,J=8.3Hz,1H),6.23(s,1H),4.55(dd,J=11.9,5.0Hz,2H),4.45(d,J=5.5Hz,2H),4.44–4.29(m,2H),3.67(s,2H),3 .56(s,3H),3.27–3.18(m,2H),2.98(t,J=5.9Hz,3H),2.76(dq,J=17.5,6.7Hz,6H),2.60(dt,J=17.4,4.3Hz,2H),2.45(dd,J=11.9,4.3Hz,1H ),2.35(s,2H),2.25–2.11(m,2H),1.91(s,5H),1.45(s,3H),1.33(s,1H),0.71(q,J=6.0Hz,1H),0.51(t,J=6.1Hz,2H),0.35(q,J=6.8Hz,1H).

[0869] Example 55: Synthesis of Compound 55

[0870] Referring to the procedure of Example 34, z55 (i.e., a mixture of intermediates z23 and z22 prepared in WO2023 / 125944 in equal proportions) was substituted for z40, intermediate 57e was substituted for 30b, and sodium triacetoxyborohydride was substituted for sodium cyanoborohydride to obtain compound 55 (78 mg). MS (ESI, [M+H] + )m / z:838.35. 1H NMR (500MHz, DMSO-d6) δ11.07(s,1H),8.82(s,1H),8.04(s,1H),7.94(h,J=4.1Hz,2H),7.68(d,J=1.5Hz,2H),7.59(d,J=8.1Hz ,1H),7.23(d,J=8.1Hz,1H),7.02(s,1H),5.31(s,1H),4.55(d,J=10.6Hz,3H),4.21(s,1H),4.11(d,J=12.8Hz,2H),3.59(d,J= 35.2Hz,3H),3.34(s,1H),3.22(p,J=5.6Hz,2H),3.11(dd,J=16.4,7.8Hz,1H),2.88–2.72(m,5H),2.67(d,J=4.6Hz,3H),2.60( dt,J=17.6,4.5Hz,2H),2.45(dd,J=12.0,4.4Hz,1H),2.20–2.15(m,1H),1.81(s,2H),1.57(d,J=6.9Hz,6H),1.39–1.33(m,2H).

[0871] Example 56: Synthesis of Compound 56

[0872] Intermediate 35c (80 mg), intermediate 57e (230 mg), methanol (50 mL), sodium acetate (126 mg), acetic acid (154 mg), and sodium cyanoborohydride (40 mg) were added to the reaction flask in sequence and reacted at 60°C. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain compound 56 (146 mg). MS (ESI, [M+H] + )m / z:852.35. 1H NMR (500MHz, DMSO-d6) δ11.07(d,J=1.4Hz,1H),8.82(s,1H),8.05(s,1H),7.99–7.93(m,2H),7.69(d,J=1.5Hz,2H),7.50(d,J =8.0Hz,1H),7.17(d,J=8.2Hz,1H),7.03(s,1H),5.31(s,1H),4.56–4.50(m,3H),4.19–4.07(m,3H),3.57(ddd,J=11.9,8.3,3 .7Hz,3H),3.30–3.20(m,3H),3.08(dd,J=14.3,9.2Hz,1H),2.84–2.67(m,8H),2.60(dt,J=17.3,4.3Hz,1H),2.49–2.31(m,2H ), 2.18(tt,J=8.6,4.0Hz,1H),1.83(d,J=11.9Hz,4H),1.57(d,J=6.8Hz,6H),1.38(tdd,J=14.9,9.1,4.7Hz,2H),1.23(s,2H).

[0873] Example 57 Synthesis of Compound 57

[0874] Step 1: Preparation of intermediate 57b

[0875] To the reaction flask were added 57a (5 g), 4-hydroxypyridine (1.89 g), potassium carbonate (8.25 g), and DMF (200 mL) in sequence and reacted at 100°C for 4 h. After the reaction was complete, the reaction solution was cooled to room temperature, quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate 57b (3.54 g). MS (ESI) m / z [M+H] + :251.2. 1 H NMR (500MHz, DMSO-d6) δ8.44–8.39(m,2H),6.90–6.85(m,2H),5.09(tt,J=6. 4,3.9Hz,1H),4.40–4.28(m,2H),3.81(dd,J=10.1,3.9Hz,2H),1.39(s,9H).

[0876] Step 2: Preparation of intermediate 57c

[0877] To a reaction flask, intermediate 57b (1 g), platinum oxide (0.498 g), p-toluenesulfonic acid (0.688 g), and ethanol (15 mL) were added sequentially and reacted at 50°C overnight under hydrogen. After completion, the reaction was filtered, and DIPEA (1.37 mL) was added to the filtrate, which was then concentrated under reduced pressure to afford intermediate 57c (1.8 g).

[0878] Step 3: Preparation of Intermediate 57d

[0879] Intermediate 57c (1.8 g), intermediate 6i (0.4 g), DIPEA (2.2 mL), and DMF (10 mL) were added to the reaction flask in sequence and reacted at 80°C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with saturated aqueous ammonium chloride, and extracted with DCM (50 mL). The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate 57d (0.49 g). MS (ESI) m / z [M+H] + :656.4.

[0880] Step 4: Preparation of intermediate 57e

[0881] Intermediate 57d (0.49 g), TFA (1 mL), and DCM (10 mL) were added to the reaction flask in sequence and reacted at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain Intermediate 57e (0.9 g). MS (ESI) m / z [M+H] + :556.2.

[0882] Step 5: Preparation of compound 57

[0883] To the reaction flask, intermediate 66c (50 mg, i.e., a 1:1 mixture of intermediates z39 and z40), DMSO (1 mL), and 2-iodobenzoic acid (138 mg) were added sequentially and allowed to react at room temperature. After completion, the reaction was quenched by adding water and saturated sodium bicarbonate solution, extracted with ethyl acetate, and concentrated. The resulting concentrate was added to a solution of intermediate 57e (130 mg), sodium acetate (48 mg), and sodium triacetoxyborohydride (42 mg) in DCE / i-PrOH = 5:1 (2 mL) and allowed to react at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure and the mixture was purified by silica gel column chromatography to yield compound 57 (72 mg). HR-MS ([M+H] + )m / z:866.3756. 1H NMR (500MHz, DMSO-d6) δ11.07(d,J=3.3Hz,1H),8.82(s,1H),8.04(s,1H),7.98–7.93(m,2H),7.68(d,J=1.5Hz,2H),7.50(d,J=8.0Hz,1H),7.17( d,J=8.2Hz,1H),7.02(s,1H),4.54(s,2H),4.54–4.49(m,1H),4.18(s,1H) ),4.11(d,J=6.5Hz,1H),3.56(s,2H),3.22(ddd,J=13.2,9.6,3.2Hz,2H) ,2.93(td,J=16.6,9.3Hz,2H),2.82–2.69(m,4H),2.68(d,J=4.6Hz,3H), 2.63–2.57(m,1H),2.49–2.42(m,1H),2.26(s,2H),2.17(tt,J=8.0,4.3H z,1H),2.06–1.95(m,2H),1.80(d,J=12.1Hz,2H),1.70(s,1H),1.57(d,J =6.9Hz, 6H), 1.36 (dtd, J = 12.9, 9.0, 3.9Hz, 2H), 0.99 (d, J = 12.6Hz, 2H).

[0884] Example 58: Synthesis of Compound 58

[0885] According to the method described in Example 81, intermediate 43b was substituted for intermediate 42b to prepare compound 58. MS (ESI, [M+H] + )m / z:884.3.

[0886] Example 59: Synthesis of Compound 59

[0887] Step 1: Preparation of intermediate 59a

[0888] 5-Chloro-2-fluoro-4-iodopyridine (1 g), DMF (20 mL), DIPEA (1.51 g) and tert-butyl piperazine-1-carboxylate acetate (1.44 g) were added to the reaction flask in sequence and reacted at 100°C. After completion of the reaction, water was added to quench the reaction, and the product was extracted with ethyl acetate and concentrated. The resulting concentrate was purified by silica gel column chromatography to obtain Intermediate 59a (804 mg). MS (ESI, [M+H] + )m / z:424.02.

[0889] Step 2: Preparation of intermediate 59b

[0890] Tris(dibenzylideneacetone)palladium (114 mg), DMF (20 mL), toluene (10 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (180 mg), cesium carbonate (608 mg), intermediate 59a (343 mg), and intermediate 61a (200 mg) were added to the reaction flask in sequence and reacted at 80°C. After completion of the reaction, water was added to quench the reaction, and the product was extracted with ethyl acetate and concentrated. The resulting concentrate was purified by silica gel column chromatography to obtain intermediate 59b (321 mg). MS (ESI, [M+H] + )m / z:617.24.

[0891] Step 3: Preparation of intermediate 59c

[0892] Following the procedure of step 2 of Example 39, 59b was substituted for 39a to give intermediate 59c (383 mg). MS (ESI, [M+H] + )m / z:517.19.

[0893] Step 4: Preparation of Intermediate 59d

[0894] Referring to the procedure of step 1 of Example 35, intermediate 59c was used to replace 30b to obtain intermediate 59d (293 mg). MS (ESI, [M+H] + )m / z:672.28.

[0895] Step 5: Preparation of intermediate 59e

[0896] Referring to the above step 3, 59b was replaced with 59d to obtain intermediate 59e (34 mg). MS (ESI, [M+H] + )m / z:572.23.

[0897] Step 6: Preparation of compound 59

[0898] Referring to the procedure of Example 34, intermediate z39 was substituted for intermediate z40, and intermediate 59e was substituted for intermediate 30b to obtain compound 59 (83 mg). MS (ESI, [M+H] + )m / z:882.36. 1H NMR (500MHz, DMSO-d6) δ11.06(d,J=3.3Hz,1H),8.05(s,2H),7.93(s,1H),7.48(s,3H),7.16(d,J=8.1Hz,1H),6.44 –6.39(m,1H),6.09(s,1H),4.58–4.34(m,3H),3.57(s,3H),3.34(d,J=8.7Hz,3H),3.25(d,J=5.5Hz,5H),2.98–2.69 (m,7H),2.63–2.56(m,1H),2.49–2.42(m,1H),2.25(d,J=4.9Hz,7H),1.99(d,J=30.2Hz,2H),1.71(s,1H),1.32(dd, J=12.7,6.7Hz,1H),0.98(d,J=12.4Hz,2H),0.71(dq,J=12.2,5.8Hz,1H),0.50(q,J=5.5Hz,2H),0.34–0.25(m,1H).

[0899] Example 60: Synthesis of Compound 60

[0900] Referring to the procedure of Example 34, intermediate 59e was used to replace intermediate 30b to obtain compound 60 (92 mg). MS (ESI, [M+H] + )m / z:882.36. 1 H NMR (500MHz, DMSO-d6) δ11.07(d,J=3.2Hz,1H),8.08–8.03(m,2H),7.93(s,1H),7.53–7.43(m,3H),7.16(d,J= 8.1Hz,1H),6.44–6.39(m,1H),6.09(s,1H),4.56–4.31(m,3H),3.57(s,3H),3.34(d,J=5.8Hz,3H),3.26(q,J=5 .1Hz,5H),2.99–2.68(m,7H),2.61(d,J=4.1Hz,1H),2.48(d,J=1.6Hz,1H),2.25(s,7H),1.99(d,J=29.3Hz,2H ),1.74(d,J=19.7Hz,1H),1.34(s,1H),0.99(s,2H),0.72(s,1H),0.50(d,J=6.3Hz,2H),0.30(d,J=5.6Hz,1H).

[0901] Examples 61, 62 Synthesis of Compounds 61, 62

[0902] Step 1: Preparation of intermediate 61b

[0903] 61a (200 mg), 2,4-dichloro-5-fluoropyrimidine (104 mg), DIPEA (322 mg), and NMP (3 mL) were added to a microwave tube in sequence and heated to 140°C at 150 W for 120 minutes. After the reaction was complete, 10 mL of water was added to the residue, which was filtered and the filter cake was collected to obtain intermediate 61b (0.153 g). MS (ESI) m / z [M+H] + :452.1.

[0904] Step 2: Preparation of intermediate 61c

[0905] Intermediate 61b (153 mg), DMSO (4 mL), DIPEA (219 mg), and tert-butyl piperazine-1-carboxylate acetate (76 mg) were added sequentially to a microwave tube and heated to 140°C at 150 W for 120 minutes. After completion of the reaction, the mixture was extracted with EA and water. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to yield Intermediate 61c (0.448 g). MS (ESI) m / z [M+H] + :602.2.

[0906] Step 3: Preparation of intermediate 61d

[0907] Intermediate 61c (150 mg), DCM (1 mL), and dioxane hydrochloride solution (145 mg, 4 M) were added to the reaction flask in sequence and allowed to react at room temperature for 1 h. After completion of the reaction, 20 mL of DCM was added to the reaction solution, and the solvent was evaporated under reduced pressure to obtain Intermediate 61d (0.13 g). MS (ESI) m / z [M+H] + :502.1.

[0908] Step 4: Preparation of intermediate 61e

[0909] 61d (130 mg), MeOH (20 mL), 1-Boc-3-azetidinone (89 mg) and sodium acetate (42.5 mg) were added to the reaction flask in sequence, stirred at room temperature for 30 minutes, and sodium cyanoborohydride (32.6 mg) was added. After reacting at 65°C for 30 minutes, 1-Boc-3-azetidinone (89 mg) and sodium cyanoborohydride (32.6 mg) were added and repeated three times. After the reaction was completed, DCM and water were added to the reaction solution for extraction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate 61e (0.15 g). MS (ESI) m / z [M+H] + :657.3.

[0910] Step 5: Preparation of intermediate 61f

[0911] 61e (150 mg), DCM (2 mL), and trifluoroacetic acid (1 mL) were added to the reaction flask in sequence, and the resulting mixture was reacted at room temperature. After the reaction, the solvent was evaporated under reduced pressure, and 20 mL of DCM was added to the residue, and the solvent was evaporated under reduced pressure to obtain intermediate 61f (0.15 g). MS (ESI) m / z [M+H] + :557.3.

[0912] Step 6: Preparation of compound 61

[0913] Referring to the procedure of Example 31, z23 was replaced with z39, and 30b was replaced with 61f to obtain compound 61 (60 mg). MS (ESI) m / z [M+H] + :867.3. 1 H NMR (500MHz, DMSO) δ11.07(d,J=3.2Hz,1H),9.33(s,1H),8.25(d,J=2.3Hz,1H),8.01(d,J=3.7Hz,1H),7.73(dd,J=9.1,2.2Hz,1H),7.50(d,J= 7.9Hz,1H),7.44(d,J=9.1Hz,1H),7.17(d,J=8.1Hz,1H),6.10–6.06(m,1H),4.53(ddd,J=11.9,5.0,2.2Hz,1H),4.47–4.33(m,2H),3.58(s,4H) ,3.55(s,3H),3.36(s,2H),3.00–2.81(m,4H),2.76(dq,J=12.5,6.6Hz, 4H),2.65–2.58(m,1H),2.48–2.43(m,1H),2.30–2.20(m,6H),2.17(td, J=7.6,4.0Hz,1H),1.98(s,2H),1.70(s,1H),1.32(s,2H),0.99(d,J=12 .8Hz,2H),0.75–0.68(m,1H),0.53(q,J=6.7Hz,2H),0.41–0.33(m,1H).

[0914] Step 7: Preparation of compound 62

[0915] Referring to the procedure of Example 31, z23 was replaced by z40 and 30b was replaced by 61f to obtain compound 62 (60 mg). MS (ESI) m / z [M+H] + :867.3. 1H NMR (500MHz, DMSO) δ11.07(d,J=3.2Hz,1H),9.34(s,1H),8.25(d,J=2.4Hz,1H),8. 02(d,J=3.6Hz,1H),7.73(dd,J=9.1,2.2Hz,1H),7.51(d,J=8.0Hz,1H),7.43(d,J= 9.1Hz,1H),7.17(d,J=8.1Hz,1H),6.15–6.02(m,1H),4.53(ddd,J=11.9,5.0,2.5H z,1H),4.41(dtd,J=29.9,13.6,7.3Hz,2H),3.57(d,J=16.1Hz,7H),3.34(s,2H),3 .30–3.19(m,2H),2.99–2.85(m,3H),2.76(ddd,J=16.8,11.1,4.3Hz,3H),2.60(dd ,J=17.4,4.1Hz,1H),2.48–2.43(m,1H),2.26(s,5H),2.16(tt,J=9.3,4.8Hz,1H), 2.00(dt,J=21.6,9.9Hz,2H),1.72(d,J=33.4Hz,1H),1.32(dt,J=12.3,6.9Hz,2H) ,1.02(s,2H),0.72(p,J=6.6Hz,1H),0.52(t,J=6.2Hz,2H),0.37(p,J=6.2Hz,1H).

[0916] Example 63 Synthesis of Compound 63

[0917] Step 1: Preparation of intermediate 63b

[0918] Referring to the procedure of step 1 of Example 35, 1-Boc-3-azetidinone was replaced with 63a, and intermediate 30b was replaced with tert-butyl piperazine-1-carboxylate acetate to obtain intermediate 63b (0.4 g). MS (ESI) m / z [M+H] + :422.2.

[0919] Step 2: Preparation of intermediate 63c

[0920] Pd / C (40.4 mg, 10%) was added to a solution of 63b (160 mg) in MeOH (10 mL) and stirred at room temperature under a hydrogen atmosphere overnight. After completion of the reaction, the catalyst was removed by filtration to obtain intermediate 63c (0.1 g).

[0921] Step 3: Preparation of intermediate 63d

[0922] Referring to step 2 of Example 61, intermediate 63c was substituted for tert-butyl piperazine-1-carboxylate acetate, and intermediate 17b was substituted for intermediate 61b to obtain intermediate 63d (0.1 g). MS (ESI) m / z [M+H] + :719.2.

[0923] Step 4: Preparation of intermediate 63e

[0924] Refer to Example 61, step 3, intermediate 63d replaced 61c to obtain intermediate 63e (0.1 g). MS (ESI) m / z [M+H] + :619.1.

[0925] Step 5: Preparation of compound 63

[0926] Referring to step 6 of Example 61, intermediate 63e was substituted for 61f to obtain compound 63 (0.1 g). MS (ESI) m / z [M+H] + :929.3. 1 H NMR (500MHz, DMSO) δ11.07(d,J=3.4Hz,1H),8.83(d,J=7.2Hz,1H),8.17(d,J=14.9Hz, 1H),8.03(d,J=3.8Hz,1H),7.74–7.68(m,1H),7.50(d,J=8.0Hz,1H),7.45(dd,J=9.1, 2.8Hz,1H),7.17(d,J=8.1Hz,1H),6.16(d,J=48.9Hz,1H),5.02(d,J=49.1Hz,1H),4.7 9(s,1H),4.60(s,1H),4.53(ddd,J=11.8,5.0,2.3Hz,1H),4.48–4.33(m,2H),3.57(d, J=1.1Hz,3H),3.40–3.34(m,1H),3.28–3.20(m,1H),3.02–2.88(m,3H),2.82–2.71(m, 3H),2.64–2.53(m,5H),2.49–2.43(m,1H),2.34(s,4H),2.17(dq,J=8.8,4.2Hz,1H),2 .07(s,4H),1.94(s,1H),1.69(d,J=35.9Hz,2H),1.34(d,J=5.0Hz,1H),1.24(d,J=7.4 Hz,1H),0.95(d,J=12.5Hz,2H),0.71(s,1H),0.58–0.47(m,2H),0.36(d,J=6.1Hz,1H).

[0927] Example 64: Synthesis of Compound 64

[0928] Referring to the method described in steps 1-5 of Example 69, 1-BOC-2-hydroxymethylpiperazine was substituted for N-1-Boc-2-methylpiperazine to prepare compound 64. MS (ESI, [M+H] + )m / z:913.4. 1 H NMR (500MHz, DMSO) δ11.07(d,J=3.2Hz,1H),8.80(s,1H),8.17(s,1H),8.03(s,1H),7.77(s,1H),7.50(d,J=7.9Hz,1H),7.41(d,J=9 .1Hz,1H),7.17(d,J=8.1Hz,1H),6.19(s,1H),4.56–4.49(m,2H),4.48–4.32(m,2H),4.05–3.88(m,1H),3.84–3.69(m,1H),3.56(s,3 H),3.47–3.34(m,4H),3.26–3.12(m,4H),2.98–2.85(m,2H),2.80–2.67(m,4H),2.64–2.56(m,2H),2.47(s,1H),2.31–2.15(m,4H),2 .10–1.94(m,3H),1.76–1.65(m,1H),1.37–1.31(m,1H),1.05–0.93(m,2H),0.76–0.68(m,1H),0.56–0.48(m,2H),0.39–0.33(m,1H).

[0929] Example 65: Synthesis of Compound 65

[0930] Referring to the method described in steps 1-5 of Example 69, 1-BOC-3-hydroxymethylpiperazine was substituted for N-1-Boc-2-methylpiperazine to prepare compound 65. MS (ESI, [M+H] + )m / z:913.4. 1H NMR (500MHz, DMSO) δ11.07(d,J=3.2Hz,1H),8.80(d,J=5.2Hz,1H),8.20(d,J=2.6Hz,1H),8.04(d,J=1.9Hz,1H),7.81–7.67(m,1H),7.50(d ,J=8.0Hz,1H),7.41(dd,J=9.2,1.4Hz,1H),7.17(d,J=8.2Hz,1H),6.22(d,J=11.2Hz,1H),4.85–4.64(m,1H),4.56–4.15(m,5H),3.73–3.62 (m,1H),3.55(d,J=1.5Hz,3H),3.43–3.34(m,3H),3.25–3.15(m,1H),2.99–2.84(m,4H),2.83–2.71(m,5H),2.67–2.56(m,2H),2.31–2.13(m ,3H),2.09–1.93(m,2H),1.83–1.65(m,3H),1.38–1.30(m,1H),1.05– 0.93(m,2H),0.77–0.67(m,1H),0.58–0.45(m,2H),0.39–0.29(m,1H).

[0931] Example 66: Synthesis of Compound 66

[0932] Step 1: Preparation of intermediate 66a

[0933] To the reaction flask, intermediate 61a (120 mg), 2-tert-butyloxycarbonyl-2,7-diazaspiro[3.5]nonane (87 mg), DMSO (10 mL), and N,N-diisopropylethylamine (166 mg) were added sequentially and reacted at 140°C in a microwave oven for 2 h. After completion of the reaction, the reaction solution was quenched with water and extracted with ethyl acetate. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 66a (206 mg). MS (ESI, [M+H] + )m / z:658.26.

[0934] Step 2: Preparation of intermediate 66b

[0935] Referring to step 2 of Example 35, 35a was replaced with 66a to obtain intermediate 66b (171 mg). MS (ESI, [M+H] + )m / z:558.21.

[0936] Step 3: Preparation of intermediate 66c

[0937] Referring to the procedure of step 11 of Preparation Example 10, z47j was replaced with z39m to obtain intermediate 66c (1.44 g). MS (ESI, [M+H] + )m / z:329.14.

[0938] Step 4: Preparation of intermediate 66d

[0939] Intermediate 66c (100 mg), DMSO (20 mL), and 2-iodobenzoic acid (277 mg) were added to a reaction flask in sequence and reacted at room temperature. After completion of the reaction, water and saturated sodium bicarbonate solution were added to quench the reaction, and the mixture was extracted with ethyl acetate and concentrated to afford Intermediate 66d (105 mg).

[0940] Step 5: Preparation of compound 66

[0941] Referring to the procedure of step 1 of Example 42, intermediate 66b was substituted for intermediate z1, and intermediate 66d was substituted for intermediate 45c to obtain compound 66 (68 mg). MS (ESI, [M+H] + )m / z:868.34. 1 H NMR (500MHz, DMSO-d6) δ11.07(d,J=3.4Hz,1H),8.79(s,1H),8.17(d,J=2.3Hz,1H),8.02(s,1H),7.72(dd,J=9.0,2.2Hz,1H),7.50(d,J=8.0Hz,1 H),7.44(d,J=9.1Hz,1H),7.17(d,J=8.1Hz,1H),6.19(d,J=4.4Hz,1H), 4.57–4.32(m,3H),3.57(s,7H),3.35(d,J=7.5Hz,1H),3.27–3.20(m,1H) ,2.99–2.84(m,5H),2.76(qd,J=12.6,6.3Hz,2H),2.60(dd,J=17.3,4.2 Hz,1H),2.45(s,1H),2.35–2.10(m,3H),2.03(dd,J=30.1,15.9Hz,2H),1 .77–1.56(m,5H),1.36–1.30(m,1H),1.24(d,J=7.5Hz,1H),0.97(d,J=2 0.2Hz, 2H), 0.75–0.66 (m, 1H), 0.55–0.48 (m, 2H), 0.35 (q, J = 5.4Hz, 1H).

[0942] Example 67: Synthesis of Compound 67

[0943] Step 1: Preparation of intermediate 67b

[0944] Referring to the procedure of Example 34, z40 was replaced by 66c and 30b was replaced by 67a to obtain intermediate 67b (119 mg). MS (ESI, [M+H] + )m / z:565.3.

[0945] Step 2: Preparation of intermediate 67c

[0946] Following the procedure of step 2 of Example 40, 40a was replaced with 67b to obtain intermediate 67c (112 mg). MS (ESI, [M+H] + )m / z:465.3.

[0947] Step 3: Synthesis of compound 67

[0948] Referring to the procedure of step 2 of Example 54, 54a was replaced with 67c to obtain compound 67 (39 mg). MS (ESI, [M+H] + )m / z:896.44. 1 H NMR (500MHz, DMSO-d6) δ11.07(d,J=3.4Hz,1H),8.76(s,1H),8.19(d,J=2.3Hz,1H),8.02(s,1H),7.73(dd,J=9.0,2.2Hz,1H),7.50(d,J=8.0Hz,1 H),7.44(d,J=9.1Hz,1H),7.17(d,J=8.2Hz,1H),6.17(s,1H),4.53(ddd, J=11.8,5.0,2.4Hz,1H),4.48–4.34(m,2H),3.57(d,J=6.3Hz,7H),3.40– 3.35(m,1H),3.29–3.18(m,2H),2.98–2.88(m,2H),2.80–2.72(m,2H),2 .63–2.57(m,1H),2.46(t,J=6.8Hz,1H),2.32(s,3H),2.17(dt,J=9.2,4. 4Hz,1H),2.08(s,4H),1.95(s,1H),1.46(s,3H),1.42–1.28(m,6H),0.95 (s,2H),0.71(q,J=5.8Hz,1H),0.55–0.48(m,2H),0.35(q,J=5.7Hz,1H).

[0949] Example 68 Synthesis of Compound 68

[0950] Step 1: Preparation of intermediate 68a

[0951] Referring to Example 57, step 3, intermediate 17b (100 mg) was substituted for 6i to give intermediate 68a (120 mg). MS (ESI, [M+H] + )m / z:688.1.

[0952] Step 2: Preparation of intermediate 68b

[0953] Referring to step 4 of Example 57, intermediate 68a (120 mg) was substituted for 57d to obtain intermediate 68b (360 mg). MS (ESI, [M+H] + )m / z:588.2.

[0954] Step 3: Synthesis of compound 68

[0955] Referring to step 5 of Example 57, intermediate 68b (340 mg) was substituted for 57e to give compound 68 (50 mg). HR-MS ([M+H] + )m / z:898.3639. 1 H NMR (500MHz, DMSO-d6) δ11.07(d,J=3.3Hz,1H),8.80(s,1H),8.18(d,J=2.3Hz,1H),8.03(s,1H),7.70(dd,J=9.0,2.2Hz,1H),7.50(d,J=8.0Hz,1H ),7.43(d,J=9.1Hz,1H),7.16(d,J=8.1Hz,1H),6.21(s,1H),4.53(ddd,J =11.9,5.0,2.3Hz,1H),4.47–4.33(m,2H),4.13(s,1H),4.05(s,2H),3.5 6(s,6H),3.22(t,J=5.4Hz,1H),3.18–3.10(m,2H),2.92(td,J=17.3,9.8 Hz,2H),2.82–2.64(m,4H),2.63–2.57(m,1H),2.32–2.14(m,3H),1.99(d ,J=31.2Hz,2H),1.74(d,J=12.8Hz,3H),1.32(d,J=10.5Hz,3H),0.98(d, J=12.3Hz,2H),0.74–0.67(m,1H),0.56–0.48(m,2H),0.39–0.33(m,1H).

[0956] Example 69: Synthesis of Compound 69

[0957] Step 1: Preparation of intermediate 69a

[0958] Refer to the procedure of step 2 of Example 54, and replace 54a with N-1-Boc-2-methylpiperazine to obtain intermediate 69a (114 mg). MS (ESI, [M+H] + )m / z:632.25.

[0959] Step 2: Preparation of intermediate 69b

[0960] Referring to the procedure of step 2 of Example 39, 39a was replaced with 69a to obtain intermediate 69b (105 mg). MS (ESI, [M+H] + )m / z:532.20.

[0961] Step 3: Preparation of intermediate 69c

[0962] Referring to the procedure of step 3 of Example 30, intermediate 69b was substituted for 30b, and 1-Boc-3-azetidinone was substituted for 9d to obtain intermediate 69c (57 mg). MS (ESI, [M+H] + )m / z:687.298.

[0963] Step 4: Preparation of Intermediate 69d

[0964] Referring to step 2 of Example 39, 39a was replaced with 69c to obtain intermediate 69d (60 mg). MS (ESI, [M+H] + )m / z:587.24.

[0965] Step 5: Preparation of compound 69

[0966] Referring to the procedure of Example 34, z40 was replaced by z39, and 30b was replaced by 69d to obtain compound 69 (23 mg). MS (ESI, [M+H] + )m / z:897.37. 1H NMR (500MHz, DMSO-d6) δ11.07(d,J=3.2Hz,1H),8.83(s,1H),8.19(s,1H),8.03(s,1H),7.70(d,J=9.1Hz,1H),7.50(d,J=7.9Hz,1H),7.43(d,J= 9.1Hz,1H),7.17(d,J=8.1Hz,1H),6.23(d,J=6.8Hz,1H),4.53(ddd,J=12.0,5.0,2.5Hz,1H),4.49–4.33(m,2H),3.88(s,2H),3.56(s,4H),3.21 (s,2H),3.04–2.86(m,4H),2.75(dt,J=13.4,6.8Hz,3H),2.59(d,J=19. 0Hz,3H),2.49–2.45(m,1H),2.35–2.11(m,4H),1.96(s,3H),1.72(t,J= 16.4Hz,1H),1.30(s,1H),1.24(d,J=7.2Hz,2H),1.00(s,2H),0.85(d,J=6.1Hz,3H),0.71(d,J=9.6Hz,1H),0.52(d,J=8.6Hz,2H),0.35(s,1H).

[0967] Example 70: Synthesis of Compound 70

[0968] Step 1: Preparation of intermediate 70b

[0969] Referring to step 2 of Example 54, 54a was replaced with 70a to obtain compound 70b (126 mg). MS (ESI, [M+H] + )m / z:632.3.

[0970] Step 2: Preparation of intermediate 70c

[0971] Referring to the procedure of step 2 of Example 40, 70b was used to replace 40a to obtain intermediate 70c (106 mg). MS (ESI, [M+H] + )m / z:532.3.

[0972] Step 3: Preparation of Intermediate 70d

[0973] To the reaction flask, a solution of intermediate 70c (100 mg), sodium cyanoborohydride (63 mg), 1-Boc-3-azetidinone (440 mg), and sodium acetate (79 mg) in dichloroethane-isopropanol = 5:1 (50 mL) was added sequentially and reacted at 25°C. After completion of the reaction, the solvent was evaporated under reduced pressure and the product was purified by silica gel column chromatography to obtain compound 70d (96 mg). MS (ESI, [M+H] + )m / z:687.3.

[0974] Step 4: Preparation of intermediate 70e

[0975] Referring to the procedure of step 2 of Example 40, 40a was replaced with 70d to obtain intermediate 70e (99 mg). MS (ESI, [M+H] + )m / z:587.3.

[0976] Step 5: Synthesis of compound 70

[0977] Referring to the procedure of step 5 of Example 57, 66c was replaced by z39 and 57e was replaced by 70e to obtain compound 70 (47 mg). MS (ESI, [M+H] + )m / z:897.38. 1H NMR (500MHz, DMSO-d6) δ11.07(d,J=3.2Hz,1H),8.80(d,J=6.9Hz,1H),8.19(dd,J=14.4 ,2.3Hz,1H),8.04(s,1H),7.71(ddd,J=15.4,9.0,2.2Hz,1H),7.50(d,J=8.0Hz,1H),7. 42(dd,J=9.1,2.9Hz,1H),7.16(d,J=8.1Hz,1H),6.20(s,1H),4.60–4.50(m,2H),4.40( ddd,J=31.1,15.8,6.8Hz,2H),3.56(d,J=1.8Hz,3H),3.36(d,J=10.8Hz,3H),3.23(s,1 H),3.03–2.83(m,4H),2.82–2.69(m,5H),2.67(d,J=10.5Hz,1H),2.63–2.58(m,1H),2. 53(s,2H),2.27(s,2H),2.17(dd,J=8.4,3.9Hz,1H),2.04(s,1H),1.97(s,1H),1.91(dd ,J=8.8,5.8Hz,1H),1.77–1.68(m,2H),1.32(s,1H),1.12(dd,J=6.7,2.6Hz,3H),0.99( d,J=12.3Hz,2H),0.72(dt,J=8.0,5.2Hz,1H),0.52(q,J=5.3Hz,2H),0.38–0.33(m,1H).

[0978] Example 71 Synthesis of Compound 71

[0979] Step 1: Preparation of intermediate 71a

[0980] To the reaction flask were added intermediate 71ab (50 mg), 71aa (128 mg), DIPEA (78 mg), and MeCN (2 mL) in sequence. Under N2 protection, the mixture was heated to 80°C and allowed to react overnight. After completion of the reaction, DCM and water were added to the reaction solution for extraction. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate 71a (0.14 g). MS (ESI) m / z [M+H] + :470.2.

[0981] Step 2: Preparation of intermediate 71b

[0982] Pd / C (40.4 mg, 10%) was added to a solution of 71a (160 mg) in MeOH (10 mL) and stirred at room temperature under a hydrogen atmosphere overnight. After the reaction was complete, the catalyst was removed by filtration to obtain intermediate 71b (0.12 g). MS (ESI) m / z [M+H] + :336.2.

[0983] Step 3: Preparation of intermediate 71c

[0984] Referring to Example 63, step 3, intermediate 71b was substituted for intermediate 63c to obtain intermediate 71c (0.1 g). MS (ESI) m / z [M+H] + :767.3.

[0985] Step 4: Preparation of Intermediate 71d

[0986] Intermediate 71c (0.1 g) and DCE (10 mL) were added sequentially to the reaction flask. 1-Chloroethyl chloroformate (55.9 mg) was added dropwise at 0°C under N2 protection. The resulting mixture was reacted at 80°C for 1 h. The reaction solution was concentrated, methanol (10 mL) was added, and the resulting mixture was reacted at 80°C. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain Intermediate 71d (0.08 g). MS (ESI) m / z [M+H] + :601.2.

[0987] Step 5: Preparation of compound 71

[0988] Refer to Example 63, step 5, intermediate 71d replaced 63e to obtain compound 71 (0.06 g). MS (ESI) m / z [M+H] + :911.3. 1H NMR (500MHz, DMSO) δ11.07(d,J=3.3Hz,1H),8.79(s,1H),8.16–8.11(m,1H),8.02(s,1H),7.79–7.72(m,1H),7.51(d,J=7.9Hz,1H),7.43 (d,J=9.0Hz,1H),7.17(d,J=8.1Hz,1H),6.19(s,1H),4.53(ddd,J=12.1,5.1,2.6Hz,1H),4.47–4.32(m,2H),3.85(s,2H),3.56(s,3H),3. 48(s,2H),3.23(d,J=12.1Hz,3H),3.03–2.84(m,3H),2.76(tt,J=12.3,5.7Hz,4H),2.62(s,2H),2.47(s,1H),2.38–2.13(m,3H),2.05–1 .96(m,2H),1.75(s,1H),1.38–1.26(m,2H),1.02(s,3H),0.94–0.81(m,6H),0.72(d,J=8.1Hz,1H),0.57–0.48(m,2H),0.39–0.31(m,1H).

[0989] Example 72 Synthesis of Compound 72

[0990] Step 1: Preparation of intermediate 72b

[0991] To a reaction flask, 72a (1 g), tert-butyl piperazine-1-carboxylate acetate (1.31 g), sodium cyanoborohydride (0.63 g), DCE / i-PrOH = 5:1 (20 mL), and acetic acid (0.29 mL) were added sequentially and reacted at room temperature. After completion of the reaction, the solvent was evaporated and the product was purified by silica gel column chromatography to obtain intermediate 72b (1.37 g). MS (ESI) m / z [M+H] + :374.2.

[0992] Step 2: Preparation of intermediate 72c

[0993] In step 2 of reference example 63, intermediate 72b was substituted for 63b to give intermediate 72c (0.1 g).

[0994] Step 3: Preparation of Intermediate 72d

[0995] Refer to Example 63, step 3, intermediate 72c was substituted for 63c to obtain intermediate 72d (0.1 g). MS (ESI) m / z [M+H] + :715.3.

[0996] Step 4: Preparation of intermediate 72e

[0997] Refer to Example 63, step 4, intermediate 72d was substituted for 63d to obtain intermediate 72e (0.08 g). MS (ESI) m / z [M+H] + :615.3.

[0998] Step 5: Preparation of compound 72

[0999] Refer to Example 63, step 5, intermediate 72e was substituted for 63e to obtain compound 72 (0.1 g). MS (ESI) m / z [M+H] + :925.4. 1 H NMR (500MHz, DMSO) δ11.07(d,J=3.4Hz,1H),8.76(d,J=10.1Hz,1H),8.16(s,1H),8.00(d,J=1.1Hz,1H),7.75(dd,J=8.9,2. 5Hz,1H),7.51(d,J=8.0Hz,1H),7.44(d,J=9.2Hz,1H),7.17(d,J=8.1Hz,1H),6.20(s,1H),4.57–4.31(m,5H),3.56(s,3H),3 .40–3.34(m,1H),3.27–3.19(m,1H),2.94(s,2H),2.84–2.73(m,3H),2.60(dd,J=17.2,3.8Hz,3H),2.43–2.21(m,6H),2.20 –1.90(m,10H),1.71(s,1H),1.32(d,J=18.5Hz,2H),0.96(s,2H),0.74(d,J=6.5Hz,4H),0.52(d,J=6.3Hz,2H),0.36(s,1H).

[1000] Example 73 Synthesis of Compound 73

[1001] Step 1: Preparation of intermediate 73b

[1002] Referring to Example 74, step 1, intermediate 73a was substituted for 74a to obtain intermediate 73b (0.1 g). MS (ESI) m / z [M+H] + :418.2.

[1003] Step 2: Preparation of intermediate 73c

[1004] In step 2 of reference example 63, intermediate 73b was substituted for 63b to give intermediate 73c (0.1 g).

[1005] Step 3: Preparation of intermediate 73d

[1006] Referring to Example 63, step 3, intermediate 73c was substituted for 63c to obtain intermediate 73d (0.1 g). MS (ESI) m / z [M+H] + :715.3.

[1007] Step 4: Preparation of intermediate 73e

[1008] Referring to step 4 of Example 63, intermediate 73d was substituted for 63d to obtain intermediate 73e (0.08 g). MS (ESI) m / z [M+H] + :615.2.

[1009] Step 5: Preparation of compound 73

[1010] Referring to step 5 of Example 63, intermediate 73e was substituted for 63e to obtain compound 73 (0.1 g). MS (ESI) m / z [M+H] + :925.4. 1 H NMR (500MHz, DMSO) δ11.07(d,J=3.4Hz,1H),8.80(s,1H),8.21(dd,J=5.5,2.3Hz,1H),8.03(s,1H),7.74–7.68(m,1H),7.50(d,J=8.0Hz, 1H),7.44(d,J=9.1Hz,1H),7.17(d,J=8.2Hz,1H),6.21(s,1H),4.60–4.33(m,5H),3.57(s,3H),3.40–3.32(m,2H),3.23(s,2H),2.94(s,3 H),2.76(td,J=15.7,5.2Hz,4H),2.60(dd,J=17.1,3.8Hz,2H),2.48–2.27(m,2H),2.18(td,J=8.9,4.3Hz,2H),2.04(s,4H),1.94(s,2H), 1.60(d,J=82.6Hz,3H),1.34(s,2H),1.24(d,J=7.3Hz,2H),0.98(s,4H),0.72(q,J=6.1Hz,1H),0.55–0.46(m,2H),0.36(t,J=6.0Hz,1H).

[1011] Example 74 Synthesis of Compound 74

[1012] Step 1: Preparation of intermediate 74b

[1013] 74a (1 g), 1-Cbz-4-piperidone (1.75 g), sodium cyanoborohydride (0.63 g), DCE / i-PrOH = 5:1 (20 mL), and acetic acid (0.29 mL) were added to the reaction flask in sequence and reacted at room temperature. After completion of the reaction, the solvent was evaporated and the product was purified by silica gel column chromatography to obtain compound 74b (1.37 g). MS (ESI, [M+H] + )m / z:418.2.

[1014] Step 2: Preparation of intermediate 74c

[1015] In step 2 of reference example 63, intermediate 74c was substituted for 63b to give intermediate 74c (0.92 g).

[1016] Step 3: Preparation of intermediate 74d

[1017] Referring to step 3 of Example 57, intermediate 17b (100 mg) was substituted for 6i, and intermediate 74c (110 mg) was substituted for 57c to obtain intermediate 74d (150 mg). MS (ESI, [M+H] + )m / z:715.1.

[1018] Step 4: Preparation of intermediate 74e

[1019] Referring to step 4 of Example 57, intermediate 74d (150 mg) was substituted for 57d to give intermediate 74e (230 mg). MS (ESI, [M+H] + )m / z:615.4.

[1020] Step 5: Synthesis of Compound 74

[1021] Referring to the procedure of Example 34, z40 was replaced by z39, and 30b was replaced by 74e to obtain compound 74 (43 mg). HR-MS ([M+H] + )m / z:925.4116. 1H NMR(500MHz,DMSO-d6)δ11.07(d,J=3.5Hz,1H),8.82(s,1H),8.21(s,1H),8.04(s,1H),7.71(d,J=9.0Hz,1H),7 .51(d,J=8.0Hz,1H),7.44(d,J=9.1Hz,1H),7.17(d,J=8.2Hz,1H),6.21(s,1H),4.60–4.35(m,5H),3.57(s,3H) ,3.22(s,2H),2.92(d,J=32.0Hz,3H),2.84–2.70(m,5H),2.66–2.58(m,2H),2.26–2.13(m,3H),1.82(d,J=76.4 Hz,7H),1.45–1.16(m,6H),0.89(d,J=35.6Hz,5H),0.74–0.69(m,1H),0.52(t,J=6.4Hz,2H),0.39–0.33(m,1H).

[1022] Example 75 Synthesis of Compound 75

[1023] Step 1: Preparation of intermediate 75a

[1024] Referring to step 4 of Example 61, tert-butyl 3-formylazetidine-1-carboxylate was substituted for 1-Boc-3-azetidinone, and 30b was substituted for 61d to obtain intermediate 75a (0.1 g). MS (ESI) m / z [M+H] + :687.2.

[1025] Step 2: Preparation of intermediate 75b

[1026] Referring to Example 30, step 2, intermediate 75a was substituted for 30a to give intermediate 75b. MS (ESI) m / z [M+H] + :587.1.

[1027] Step 3: Preparation of compound 75

[1028] Referring to the procedure of Example 31, intermediate 75b was substituted for 30b, and 66c was substituted for z23 to obtain compound 75. MS (ESI) m / z [M+H] + :897.3. 1H NMR (500MHz, DMSO) δ11.07(d,J=3.4Hz,1H),8.84(s,1H),8.21(d,J=2.3Hz,1H),8.04(s,1H),7.68(dd,J=9.0,2.2Hz,1H),7.51(d,J=7.9Hz,1H),7.43 (d,J=9.1Hz,1H),7.18(d,J=8.1Hz,1H),6.24(d,J=4.4Hz,1H),4.53(ddd, J=11.9,5.0,2.9Hz,1H),4.49–4.31(m,2H),3.55(d,J=8.3Hz,8H),3.21(dq ,J=11.3,6.0Hz,2H),3.02–2.85(m,3H),2.76(ddd,J=17.0,11.9,5.4Hz,3 H),2.64–2.57(m,2H),2.48–2.42(m,2H),2.31(s,5H),2.17(ddq,J=13.6,9 .0,4.9Hz,2H),2.05–1.94(m,2H),1.37–1.27(m,2H),1.02(s,2H),0.72(dd d,J=11.9,7.2,3.8Hz,1H),0.56–0.49(m,2H),0.34(dt,J=8.9,4.8Hz,1H).

[1029] Example 76: Synthesis of Compound 76

[1030] Compound 76 was prepared by following the method described in steps 1-3 of Example 77, substituting intermediate 35c for intermediate 9d. MS (ESI, [M+H] + )m / z:842.3.

[1031] Example 77 Synthesis of Compound 77

[1032] Step 1: Preparation of intermediate 77a

[1033] Referring to step 3 of Example 57, intermediate 36h (100 mg) was substituted for 6i to give intermediate 77a (100 mg). MS (ESI, [M+H] + )m / z:646.2.

[1034] Step 2: Preparation of intermediate 77b

[1035] Referring to step 4 of Example 57, intermediate 77a (100 mg) was substituted for 57d to obtain intermediate 77b (300 mg). MS (ESI, [M+H] +)m / z:546.2.

[1036] Step 3: Synthesis of compound 77

[1037] To the reaction flask, a solution of intermediate 77b (300 mg), intermediate 9d (60 mg), sodium acetate (30 mg), and sodium triacetoxyborohydride (78 mg) in DCE / i-PrOH = 5:1 (2 mL) was added in sequence and reacted at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure and the reaction solution was purified by silica gel column chromatography to obtain compound 77 (40 mg). HR-MS ([M+H] + )m / z:814.2802. 1 H NMR (500MHz, DMSO) δ11.07(s,1H),8.74(s,1H),8.03(s,1H),7.92(q,J=4.8Hz,1H),7.73(d,J=8.2Hz,1H),7.60(d,J= 8.1Hz,1H),7.47(d,J=12.6Hz,1H),7.23(d,J=9.9Hz,2H),4.56(d,J=9.6Hz,3H),4.09(s,1H),3.97(s,2H),3.66(s,3H ),3.57(s,2H),3.48(s,1H),3.33(s,2H),3.07(d,J=12.7Hz,3H),2.84(s,1H),2.77(ddd,J=22.9,10.8,5.0Hz,3H),2. 66(d,J=4.6Hz,3H),2.59(ddd,J=22.1,8.1,4.4Hz,2H),2.21–2.14(m,1H),1.71(d,J=12.2Hz,2H),1.32–1.25(m,3H).

[1038] Example 78 Synthesis of Compound 78

[1039] Step 1: Preparation of intermediate 78a

[1040] Referring to Example 30, step 1, intermediate 57c was substituted for piperazine-1-carboxylic acid tert-butyl ester acetate to obtain intermediate 78a (0.1 g). MS (ESI) m / z [M+H] + :688.2.

[1041] Step 2: Preparation of intermediate 78b

[1042] Referring to Example 30, step 2, intermediate 78a was substituted for 30a to give intermediate 78b. MS (ESI) m / z [M+H] + :588.1.

[1043] Step 3: Preparation of Compound 78

[1044] Referring to step 4 of Example 35, intermediate 78b was substituted for 35b to give compound 78. MS (ESI) m / z [M+H] + :884.3. 1 H NMR(500MHz,DMSO)δ11.07(d,J=1.5Hz,1H),8.81(s,1H),8.19(d,J=2.3Hz,1 H),8.03(s,1H),7.70(dd,J=9.0,2.2Hz,1H),7.51(d,J=8.0Hz,1H),7.44(d,J =9.2Hz,1H),7.17(d,J=8.2Hz,1H),6.22(d,J=4.4Hz,1H),4.53(dd,J=11.9, 5.0Hz,1H),4.48–4.32(m,2H),4.13(s,1H),4.09(q,J=5.3Hz,2H),3.59(s,1H ),3.52(s,1H),3.30–3.20(m,3H),3.16–3.00(m,3H),2.86–2.67(m,5H),2.6 0(dt,J=17.3,4.2Hz,1H),2.53(d,J=3.7Hz,1H),2.48–2.42(m,1H),2.36(s,1 H),2.20–2.13(m,1H),1.76(d,J=11.1Hz,4H),1.40–1.28(m,4H),1.24(s,3H ),0.71(dq,J=12.4,5.6Hz,1H),0.53(q,J=6.7Hz,2H),0.35(q,J=5.8Hz,1H).

[1045] Example 79 Synthesis of Compound 79

[1046] Step 1: Preparation of compound 79

[1047] Referring to step 3 of Example 78, intermediate 9d was substituted for 35c to obtain compound 79. MS (ESI) m / z [M+H] + :856.3. 1H NMR (500MHz, DMSO) δ11.07(s,1H),8.80(s,1H),8.18(d,J=2.3Hz,1H),8.03(s,1H),7.70(dd,J=9.1,2.2Hz,1H),7.63–7.58(m, 1H),7.43(d,J=9.1Hz,1H),7.23(d,J=8.1Hz,1H),6.21(s,1H),4.56(dd,J=11.8,5.0Hz,1H),4.50–4.31(m,2H),4.06(s,3H),3 .56(s,3H),3.49(s,3H),3.28–3.17(m,2H),3.09(d,J=41.8Hz,4H),2.88–2.70(m,5H),2.60(dd,J=17.3,3.6Hz,1H),2.49–2.4 3(m,1H),2.21–2.15(m,1H),1.75(d,J=11.7Hz,2H),1.33(s,3H),0.74–0.68(m,1H),0.55–0.49(m,2H),0.35(q,J=6.0Hz,1H).

[1048] Example 80: Synthesis of Compound 80

[1049] Step 1: Preparation of compound 80

[1050] Referring to step 2 of Example 54, 54a was replaced with 42b, and 17b was replaced with 36h to obtain compound 80 (52 mg). MS (ESI, [M+H] + )m / z:828.30. 1H NMR(500MHz,DMSO-d6)δ11.08(s,1H),8.73(s,1H),8.03(s,1H),7.92(s,1H),7.72(dd,J=15.1,8.5Hz,2H),7 .47(d,J=12.4Hz,1H),7.29(d,J=8.2Hz,1H),7.24(s,1H),4.59(d,J=16.3Hz,1H),4.55(s,2H),4.22(d,J=9. 9Hz,1H),4.11(s,1H),4.00(s,3H),3.65(s,3H),3.45(s,1H),3.08(s,2H),2.77(d,J=25.0Hz,3H),2.66(d,J =4.6Hz,3H),2.38(s,1H),2.20(d,J=13.5Hz,1H),2.04–1.99(m,3H),1.72(s,2H),1.23(s,6H),0.85(s,1H).

[1051] Example 81: Synthesis of Compound 81

[1052] Referring to step 2 of Example 54, 54a was replaced with 42b to obtain compound 81 (52 mg). MS (ESI, [M+H] + )m / z:870.3. 1H NMR(500MHz,DMSO-d6)δ11.08(s,1H),8.80(s,1H),8.18(d,J=2.3Hz,1H), 8.03(s,1H),7.75–7.65(m,2H),7.43(d,J=9.0Hz,1H),7.29(d,J=8.1Hz,1H ),6.19(d,J=4.2Hz,1H),4.60(dd,J=11.9,4.9Hz,1H),4.50–4.31(m,2H),4 .22(p,J=6.8Hz,1H),4.14–3.99(m,5H),3.56(s,3H),3.49(d,J=9.1Hz,1H) ,3.30(s,1H),3.19(ddd,J=37.1,12.9,7.9Hz,3H),2.77(ddd,J=17.4,12.6 ,5.3Hz,3H),2.61(dt,J=17.4,4.3Hz,1H),2.53(d,J=14.7Hz,1H),2.39(s, 1H),2.24–2.15(m,1H),2.04(d,J=7.5Hz,3H),1.80–1.73(m,2H),1.34(s,3 H),1.23(s,1H),0.71(q,J=6.0Hz,1H),0.52(s,2H),0.35(q,J=6.2Hz,1H).

[1053] Example 82: Synthesis of Compound 82

[1054] Step 1: Synthesis of Intermediates 82a and 82b

[1055] Intermediate 50a (800 mg), tert-butyl 4-(3-azetidinyloxy)piperidine-1-carboxylate (928 mg), methanol (30 mL), and sodium cyanoborohydride (437 mg) were added sequentially to a reaction flask and reacted at 50°C. After completion of the reaction, the mixture was quenched with water and extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography and preparative separation (chromatographic column: CHIRALPAK IK mobile phase, dichloromethane:ethanol:n-hexane) to obtain Intermediate 82a (550 mg) and Intermediate 82b (530 mg).

[1056] The retention time of intermediate 82a in the chiral chromatographic column is shorter than that of intermediate 82b, and the retention time of intermediate 82b in the chiral chromatographic column is longer than that of intermediate 82a.

[1057] Intermediate 82a: MS (ESI, [M+H] + )m / z:528.30

[1058] Intermediate 82b: MS (ESI, [M+H] + )m / z:528.30

[1059] Step 2: Preparation of Intermediate 82c

[1060] A 1M solution of potassium tert-butoxide in THF (0.853 mL) was added dropwise to a solution of intermediate 82a (500 mg) and acrylamide (74 mg) in THF (50 mL) at -5°C and allowed to react at 25°C. After completion of the reaction, saturated aqueous ammonium chloride was added to quench the reaction, and the product was concentrated with ethyl acetate. The resulting concentrate was purified by column chromatography to afford intermediate 82c (244 mg). MS (ESI, [M+H] + )m / z:553.29.

[1061] Step 3: Preparation of compound 82

[1062] 82c (120 mg) and DCM (5 mL) were added to the reaction flask in sequence, followed by trifluoroacetic acid (2 mL), and the reaction was allowed to proceed at room temperature. After the reaction was complete, the solvent was evaporated under reduced pressure, and intermediate 6i (80 mg), DMSO (1 mL), and DIPEA (97 mg) were added and the reaction was continued at 70°C. After the reaction was complete, the mixture was extracted with ethyl acetate and purified by silica gel column chromatography to obtain compound 82 (30 mg). MS (ESI) m / z [M+H] + :852.35.

[1063] Example 83: Synthesis of Compound 83

[1064] Referring to the procedure of Step 2-3 of Example 82, intermediate 82a was replaced with 82b to give compound 83 (20 mg).

[1065] Intermediate 83a: MS (ESI, [M+H] + )m / z:553.29.

[1066] Compound 83:MS (ESI) m / z [M+H] + :852.35.

[1067] Examples 84 and 86: Referring to the method of Example 82, compounds 84 and 86 were prepared by substituting the following intermediates for intermediate 6i.

[1068] Table 2A

[1069] Examples 85 and 87: Referring to the method of Example 83, compounds 85 and 87 were prepared by replacing intermediate 6i with the following intermediates, as shown in Table 3A.

[1070] Table 3A

[1071] Examples 88-91: Referring to the method described in Example 45, intermediate z5 and 6i (or 6i) were replaced by the following intermediates to prepare compounds 88-91, as shown in Tables 4A and 4B.

[1072] Table 4A

[1073] Table 4B

[1074] Example 92: Synthesis of Compound 92

[1075] Step 1: Preparation of intermediate 92a

[1076] To the reaction flask, intermediate z39 (1 g), DMSO (20 mL) and 2-iodobenzoic acid (2.11 g) were added in sequence and reacted at room temperature. After the reaction was completed, water and saturated sodium bicarbonate solution were added to quench the reaction, and the mixture was extracted with ethyl acetate and concentrated. The resulting concentrate was added to a solution of 1-Boc-4-(piperidin-4-yl)-piperazine (1.06 g), acetic acid (0.18 g) and sodium cyanoborohydride (0.57 g) in MeOH (20 mL) and reacted at 25°C. After the reaction was completed, the solvent was evaporated under reduced pressure and the mixture was purified by silica gel column chromatography to obtain intermediate 92a (1.71 g). MS (ESI) m / z [M+H] + :580.36

[1077] Step 2: Preparation of intermediate 92b

[1078] To the reaction flask were added 92a (1.4 g) and DCM (34 mL), followed by dioxane hydrochloride (14.5 mL), and the resulting mixture was stirred at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure to yield intermediate 92b (1.5 g). MS (ESI) m / z [M+H] + :480.35

[1079] Step 3: Preparation of compound 92

[1080] Intermediate 92b (158 mg), intermediate 14a (90 mg), DMSO (2 mL), and DIPEA (210 mg) were added to a reaction flask in sequence and reacted under microwave at 140°C. After completion of the reaction, the product was quenched with water and extracted with EA. The extract was concentrated and purified by silica gel column chromatography to give compound 92 (82 mg).

[1081] MS (ESI, [M+H] +)m / z:881.25. 1 H NMR (500MHz, DMSO) δ11.07(d,J=3.5Hz,1H),8.78(s,1H),8.06(s,1H),7.95(q,J=4.7Hz,1H),7.58(d,J=2.3Hz,1H),7.53–7 .49(m,2H),7.17(d,J=8.1Hz,1H),7.01(s,1H),4.57(s,2H),4.55–4.51(m,1H),3.88(s,3H),3.86(s,3H),3.65(s,4H),3.39 –3.35(m,1H),2.98–2.84(m,4H),2.76(dq,J=11.8,6.6Hz,2H),2.66(d,J=4.6Hz,3H),2.61(t,J=3.9Hz,1H),2.56(d,J=23.7 Hz,3H),2.47(dd,J=4.9,3.0Hz,1H),2.18(tt,J=8.7,4.4Hz,2H),2.06(s,4H),1.94–1.71(m,5H),1.45(s,2H),0.95(s,2H).

[1082] Examples 94, 96, 98, 100, and 102: Referring to the method of Example 92, the following intermediates were substituted for intermediate 14a to prepare compounds 94, 96, 98, 100, and 102, as shown in Tables 5A-5B.

[1083] Table 5A

[1084] Table 5B

[1085] Example 93: Synthesis of Compound 93

[1086] By following the procedure of Step 1-3 of Example 92 and substituting z40 for z39, Compound 93 (98 mg) (1.5 g) was obtained.

[1087] Intermediate 93a: MS (ESI) m / z [M+H] + :580.35.

[1088] Intermediate 93b: MS (ESI) m / z [M+H] + :480.37.

[1089] Compound 93: MS (ESI, [M+H] + )m / z:881.33.

[1090] 1 H NMR (500MHz, DMSO) δ11.07(d,J=3.5Hz,1H),8.78(s,1H),8.06(s,1H),7.96(q,J=4.8Hz,1H),7.58(d,J=2.3Hz,1H),7.53–7. 49(m,2H),7.17(d,J=8.1Hz,1H),7.01(s,1H),4.57(s,2H),4.55–4.51(m,1H),3.88(s,3H),3.86(s,3H),3.65(s,4H),3.39– 3.35(m,1H),2.98–2.84(m,4H),2.80–2.73(m,2H),2.66(d,J=4.7Hz,3H),2.62(d,J=3.8Hz,1H),2.58(d,J=3.7Hz,3H),2.47 (s,1H),2.23–2.15(m,2H),2.06(s,4H),1.89(d,J=42.7Hz,3H),1.74(d,J=12.0Hz,2H),1.44(d,J=11.8Hz,2H),0.95(s,2H).

[1091] Examples 95, 97, 99, 101, and 103: Referring to the method of Example 93, the following intermediates were substituted for intermediate 14a to prepare compounds 95, 97, 99, 101, and 103, as shown in Tables 6A-6B.

[1092] Table 6A

[1093] Table 6B

[1094] Example 104: Synthesis of Compound 104

[1095] Compound 104 was prepared by following the procedure described in steps 1-6 of Example 45, substituting cis-methyl 3-hydroxycyclobutanecarboxylate for trans-methyl 3-hydroxycyclobutanecarboxylate, intermediate z1 for intermediate z5, and intermediate 5h for intermediate 6i. MS (ESI, [M+H]+) m / z: 856.3. 1H NMR (500MHz, DMSO) δ11.08(s,1H),8.73(s,1H),8.01(d,J=19.0Hz,2H),7.70(d,J=8.0Hz,1H),7.59–7.50(m,2H),7.28(d, J=8.2Hz,1H),7.12(s,1H),4.59(d,J=15.4Hz,3H),4.09(s,2H),4.02–3.90(m,5H),3.47(td,J=8.3,4.0Hz,1H),3.08(t,J= 10.2Hz,2H),2.79–2.71(m,3H),2.67(d,J=4.6Hz,3H),2.61(dt,J=17.3,4.3Hz,1H),2.55–2.52(m,1H),2.39(q,J=9.1Hz, 2H),2.20(dt,J=13.3,4.6Hz,1H),2.02(q,J=8.2Hz,1H),1.72(d,J=11.7Hz,2H),1.57(d,J=6.9Hz,8H),1.33–1.22(m,3H).

[1096] Example 105: Synthesis of Compound 105

[1097] Step 1: Preparation of intermediate 105a

[1098] To the reaction flask, intermediate 5h (120 mg), tert-butyl 3-(piperidin-4-yloxy)azetidine-1-carboxylate (67 mg), DMSO (10 mL), and N,N-diisopropylethylamine (171 mg) were added sequentially and reacted at 130°C in a microwave oven for 2 h. After completion of the reaction, the reaction solution was quenched with water and extracted with ethyl acetate. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 105a (187 mg). MS (ESI, [M+H] + )m / z:674.28.

[1099] Step 2: Preparation of Intermediate 105b

[1100] 105a (187 mg) and hydrochloric acid (10 mL, 4 M dioxane solution) were added to the reaction flask in sequence and stirred at room temperature. After the reaction was completed, the reaction solution was concentrated to obtain intermediate 105b (240 mg). MS (ESI, [M+H] + )m / z:574.23.

[1101] Step 3: Preparation of compound 105

[1102] To the reaction flask, intermediate 9d (111 mg), intermediate 105b (187 mg), sodium acetate (53 mg), sodium cyanoborohydride (51 mg), acetic acid (98 mg) and MeOH (40 mL) were added in sequence and reacted at 25°C. After the reaction was completed, the solvent was evaporated under reduced pressure and the reaction solution was purified by silica gel column chromatography to obtain compound 105 (90 mg). MS (ESI, [M+H] + )m / z:842.31. 1 H NMR(500MHz,DMSO-d6)δ11.07(s,1H),8.74(s,1H),8.03(s,2H),7.55(s,3H),7.23(d,J=8.1Hz,1H), 7.12(s,1H),5.31(s,1H),4.60(s,2H),4.56(dd,J=11.8,5.0Hz,1H),4.12–4.05(m,1H),3.95(s,2H) ,3.55(s,2H),3.47(s,1H),3.07(d,J=12.9Hz,4H),2.85–2.72(m,5H),2.67(d,J=4.6Hz,3H),2.60(d d,J=17.3,3.3Hz,1H),2.21–2.14(m,1H),1.70(d,J=11.9Hz,2H),1.58(d,J=6.9Hz,6H),1.23(s,4H).

[1103] Experimental Example 1: In vitro cell BCL6 degradation activity assay

[1104] Take OCI-LY1 cells that are in good growth condition, collect them into a centrifuge tube, and adjust the cell density to 3×10 5 / mL, inoculated on a 384-well plate pre-coated with fibronectin solution (50μL / well), and simultaneously used a nanoliter pipette to add the compound to a final concentration of 1000nM-0.0061nM, with 2 replicates for each concentration, and a control was set up at the same time. After continuing to culture in the cell culture incubator for 24 hours, the supernatant was discarded, 4% paraformaldehyde (40μL / well) was added and incubated at room temperature for 20 minutes, then ice methanol (40μL / well) was added and incubated at 4°C for 10 minutes, and washed with PBST. After adding 5% BSA blocking buffer (20μL / well) and blocking at room temperature for 1 hour, a mixture of BCL6 antibody and GAPDH antibody (20μL / well) was added and incubated at 4°C overnight, and washed with PBST. A mixture of 800nm ​​and 680nm fluorescent antibodies (20μL / well) was added and incubated at room temperature in the dark for 45 minutes, and washed with PBST. The fluorescence value was detected by Azure multispectral laser imager, and the four-parameter analysis was performed to fit the dose-effect curve and calculate DC 50 The test results are shown in Table 1.

[1105] Table 1

[1106] The test results show that the compound of the present application has BCL6 degradation activity in in vitro cells.

[1107] Experimental Example 2: CRBN protein binding activity assay

[1108] Dilute the Human Cereblon WT GST-tagged protein stock solution to 1X using the binding buffer provided in the kit (cisbio, 64BDCRBNPEG). Add 5 μL / well of the Human Cereblon WT GST-tagged protein dilution to a 384-well plate. Add 5 μL / well of the 1X compound dilution and pipette the compounds using a nanoliter pipette to a final concentration of 50,000 nM to 69 nM. In duplicate wells are added for each concentration, along with a control. Centrifuge to mix thoroughly, and incubate at room temperature for 20 minutes. Dilute the GST Eu cryptate antibody and Thalidomide-Red reagent to 1X using the binding buffer provided in the kit (cisbio, 64BDCRBNPEG). Mix the GST Eu cryptate antibody and Thalidomide-Red reagent dilutions at a 1:1 volume ratio. Add 10 μL / well of the antibody mixture to the 384-well plate, centrifuge to mix thoroughly, and incubate at room temperature for 3 hours. The fluorescence value was detected by Envision microplate reader at 665nm / 620nm, and four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 . See Table 2.

[1109] Table 2

[1110] The test results show that the compound of the present application has CRBN protein binding activity.

[1111] Test Example 3: In vitro liver microsome metabolic stability

[1112] Liver microsomal samples (species: human, monkey, dog, rat, and mouse) were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), test compound, and NADPH + MgCl₂ solution. The mixture was incubated at 37°C and 300 rpm for 1 hour. At 0 hours, samples were prepared by mixing PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and test compound. Protein precipitation was performed with acetonitrile containing an internal standard to prepare the supernatant, which was diluted and analyzed by LC / MS / MS. The results are shown in Tables 3-4.

[1113] Table 3

[1114] Table 4

[1115] The test results show that the compound of the present application has the property of stable metabolism in liver microsomes in vitro.

[1116] Test Example 4: In vitro cell proliferation inhibitory activity assay

[1117] Take OCI-LY1 cells that are in good growth condition, collect them into a centrifuge tube, and adjust the cell density to 1×10 5 Cells were plated at 100 μL / well in a 96-well plate. Compounds were added using a nanoliter pipette to a final concentration of 5000 nM to 0.31 nM, with two replicates per well. A control was also included. After 9 days of incubation in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After 3 hours of incubation in a cell culture incubator, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 The test results are shown in Table 5.

[1118] Table 5

[1119] Test Example 5: Pharmacokinetics in mice

[1120] ICR mice weighing 18-22 g were randomly divided into groups of 6 after acclimation for 3-5 days. The oral administration group was given a 10 mg / kg dose of the test compound solution, while the intravenous administration group was given a 1 mg / kg dose of the test compound solution intravenously.

[1121] The blood samples for the oral administration group were collected at 15 min, 1 h, 4 h, 6 h, 8 h, 10 h, and 24 h after administration, and the blood samples for the intravenous administration group were collected at 5 min, 0.25 h, 2 h, 4 h, 8 h, 10 h, and 24 h after administration. Blood was collected from the eye sockets to prepare plasma samples for testing.

[1122] 30 μL of plasma sample to be tested and standard curve sample were taken, and acetonitrile solution containing internal standard was added to obtain protein precipitation to obtain supernatant, which was diluted and used for LC / MS / MS determination.

[1123] The non-compartmental model was used to fit the pharmacokinetic parameters.

[1124] The test results show that the compounds of the present invention have good in vivo pharmacokinetic properties, such as AUC, t 1 / 2 、C maxFor example, some compounds in the examples of this application have AUC>4000ng*h / mL, C max >200ng / mL.

[1125] Here are the results:

[1126] Experimental Example 6: Pharmacodynamic Evaluation of OCI-LY1 in a Subcutaneous Xenograft Tumor Model of Human Diffuse Large B-Cell Lymphoma in NOD-SCID Mice

[1127] OCI-LY1 cells were subcutaneously inoculated in the right axilla of SPF female NOD-SCID mice (source: Shanghai Lingchang Biotechnology Co., Ltd.) at a rate of 1×10 7 cells / mouse (PBS:Matrigel=1:1 resuspended cells). 3 The animals were randomly divided into groups.

[1128] The day of grouping was designated Day 0. Starting from Day 0, the test compound was administered orally once daily (10-60 mg / kg). The vehicle control group received an equal volume of vehicle. Tumor volume was measured 2-3 times per week, and mice were weighed and recorded. General performance of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.

[1129] The detection indicators and calculation formulas are as follows:

[1130] Tumor volume, TV (mm 3 )=1 / 2×(a×b 2 ), where a is the long diameter of the tumor and b is the short diameter of the tumor.

[1131] Relative tumor volume, RTV = TV t / TV0; TV0 is the tumor volume on day 0, TV t is the tumor volume at each measurement.

[1132] Relative tumor growth rate, T / C (%) = T RTV / C RTV ×100%; where T RTV RTV for the treatment group; C RTV The vehicle control group was RTV.

[1133] Tumor growth inhibition rate, TGI (%) = (1-TW / TW0) × 100%; wherein, TW is the tumor weight of the treatment group, and TW0 is the tumor weight of the vehicle control group.

[1134] Body weight change rate, WCR (%) = (Wt t -Wt0) / Wt0×100%; where Wt0 is the weight of mice on day 0, Wtt is the weight of the mice at each measurement.

[1135] The test results show that the compounds of the examples of the present application can have a good tumor-suppressing effect in vivo (eg, about 21 days, TGI>60%).

Claims

1. A compound of formula II, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, represents a single bond or a double bond; Ring W is selected from Ring A is absent or selected from C 3-15 Cycloalkenyl, 3-15 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Ring B is selected from phenyl or 5-6 membered heteroaryl; Ring C is selected from furyl, oxazolyl, isoxazolyl or pyrazolyl; When ring A is absent or selected from phenyl, ring B is selected from phenyl, and ring C is selected from oxazolyl, isoxazolyl or pyrazolyl; X a 、X b 、X c 、X d 、X e 、X f and X g are independently selected from C, CH, CH2, N, NH, O or S; X 19 、X 20 、X 21 , and X 22 are independently selected from CH or N; X h Selected from CH2 or NH; Each R 1 are independently selected from deuterium, halogen, -OH, -NH2, -CN, the following groups optionally substituted with one or more substituents: C 1-10 Alkyl, C 1-10 Alkoxy, (C 1-10 Alkyl)NH-, (C 1-10 Alkyl) 2N-, halogenated C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl; n is selected from 0, 1, 2, 3, 4, 5 or 6; X 5 Selected from C(R f ) or N; R f is selected from H, halogen, deuterium or C optionally substituted by one or more substituents 1-6 alkyl; L 1 is selected from a bond, -NH-, -O-, -S-, -CONH- or -CON(C 1-6 alkyl)-, said L 1 Connected to ring C or ring E in ring W, when L 1 When selected from the bond, then X 5 Connected to ring C or ring E in ring W; L is selected from a linking group; The PTMs were selected from small molecule compounds targeting BCL6.

2. The compound according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, wherein ring W is selected from Ring C is selected from furyl, oxazolyl or isoxazolyl. When ring A is absent or selected from phenyl and ring B is selected from phenyl, ring C is selected from oxazolyl or isoxazolyl.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from the compound of formula III, its stereoisomer or a pharmaceutically acceptable salt thereof, in, L is selected from a linking group; X 8 Selected from C(R d )、C(R d R e )、N、N(R d ), O or S; X 9 Selected from bonds, C(R g )、C(R g R h )、N、N(R g ), O or S; R d 、R e 、R g and R h are independently selected from hydrogen, deuterium, halogen, -CN, or the following groups optionally substituted with one or more R': R v -、R v O-、R v S-、R s R v N-、R v C(O)-、R v S(O)2-、R v S(O)-、R v =N-、R v OC(O)-、R v C(O)O-、R v S(O)O-、R v OS(O)-、R v S(O)2O-、R v OS(O)2-、R s R v NC(O)-、R v C(O)NH-、R v OC(O)NH-、R s R v NC(O)O-、R v S(O)NH-、R s R v NS(O)-、R v S(O)2NH-、R s R v NS(O)2-or R s R v S(O)=N-; or R d and R g Together with the carbon or nitrogen atom to which it is connected, it forms a C 5-12 Carbocyclic or 5-12 membered heterocyclic, the C 5-12 Carbocyclyl or 5-12 membered heterocyclyl is optionally substituted by one or more R"; R s and R v are independently selected from H, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkyl C 1-3 Alkylene-, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkyl C 1-3 Alkylene-, C 3-12 Cycloalkenyl, C 3-12 Cycloalkenyl C 1-3 Alkylene-, 3-12 membered heterocycloalkenyl, 3-12 membered heterocycloalkenyl C 1-3 Alkylene-, C 6-12 Aryl, C 6-12 Aryl C 1-3 Alkylene-, 5-12 membered heteroaryl, or 5-12 membered heteroarylC 1- 3-alkylene-; Each R' or R" is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, R k O-、R k S-、R j R k N-、R k C(O)-、R k S(O)2-、R k S(O)-、R k OC(O)-、R k C(O)O-、R k S(O)O-、R k OS(O)-、R k S(O)2O-、R k OS(O)2-、R j R k NC(O)-、R k C(O)NH-、R k OC(O)NH-、R j R k NC(O)O-、R k S(O)NH-、R j R k NS(O)-、R k S(O)2NH-、R j R k NS(O)2-、C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; R j and R k are independently selected from H, C optionally substituted with one or more groups selected from deuterium, halogen, -OH, -NH2 or -CN 1- 6-alkyl; Each R 2 and R 3 are independently selected from deuterium, halogen, -CN, -OH, -NH2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O-, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl or 5-12 membered heteroaryl is optionally substituted with one or more of the following groups: deuterium, halogen, -CN, -OH, -NH2 or C 1-6 Alkyl, each R 2 Replace in X 10 、X 11 or X 12 superior; m is selected from 0, 1, 2, or 3; p is selected from 0, 1, 2, 3, 4 or 5; R 4 Selected from hydrogen, -CN, -OH, -NH2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O-, C 1-12 Alkyl S-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl C 1-3 Alkylene-, 3-12 membered heterocycloalkyl C 1-3 Alkylene-, C 6-12 Aryl C 1-3 Alkylene-, or 5-12 membered heteroaryl C 1-3 Alkylene-, the C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkyl O-, C 1-12 Alkyl NH-, (C 1-12 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6- 12 Aryl, 5-12 membered heteroaryl, C 3-12 Cycloalkyl C 1-3 Alkylene-, 3-12 membered heterocycloalkyl C 1-3 Alkylene-, C 6-12 Aryl C 1-3 Alkylene-, or 5-12 membered heteroaryl C 1-3 Alkylene - optionally substituted with one or more of the following groups: deuterium, halogen, -CN, -OH, -NH2, C 1-6 Alkyl O-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl; X 10 、X 11 、X 12 、X 13 、X 14 、X 15 、X 16 and X 17 are independently selected from CH or N; R t Selected from H or C 1-6 alkyl.

4. The compound according to any one of claims 1 to 3, its stereoisomer or pharmaceutically acceptable salt thereof, wherein Ring A is absent or selected from C 3- 12 Cycloalkenyl, 3-12 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, Ring A is absent or selected from C 5-15 Cycloalkenyl, 5-15 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, Ring A is absent or selected from C 5-10 Cycloalkenyl, 5-10 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, Ring A is absent or selected from C 5-7 Cycloalkenyl, 5-9 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, Ring A is absent or is selected from C5 cycloalkenyl, C6 cycloalkenyl, C7 cycloalkenyl, 5-membered, 6-membered, 7-membered, 8-membered or 9-membered heterocycloalkenyl, phenyl, pyrrolyl, pyrazolyl, furanyl or oxazolyl; Alternatively, ring A is absent or is selected from cyclopentenyl, monocyclohexenyl, bicyclohexenyl, monocycloheptenyl, dihydropyrrolyl, tetrahydropyridinyl, tetrahydroazepine 1-Hydroxy, ...

5. The compound according to any one of claims 1 to 4, its stereoisomer or pharmaceutically acceptable salt thereof, wherein ring B is selected from phenyl or 6-membered heteroaryl; or, ring B is selected from phenyl.

6. The compound according to any one of claims 1 to 5, its stereoisomer or pharmaceutically acceptable salt thereof, wherein Ring C is selected from furyl, oxazolyl or isoxazolyl; Alternatively, ring C is selected from furanyl or isoxazolyl; Alternatively, ring C is selected from oxazolyl or isoxazolyl; Alternatively, when ring A is absent or selected from phenyl, ring B is selected from phenyl, and ring C is selected from oxazolyl or isoxazolyl.

7. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from 8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from Or, the structural part Selected from 9. The compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 1 independently selected from deuterium, halogen, -OH, -NH2, -CN, the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-10 Alkyl)NH-, (C 1-10 Alkyl) 2N-, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; Or, each R 1 independently selected from deuterium, halogen, -OH, -NH2, -CN, the following groups optionally substituted with one or more substituents: C 1-6 Alkyl, C 1-6 Alkoxy or halogenated C 1-6 alkyl; Alternatively, the R 1 The substituents in are selected from halogen, -OH, -NH2, -CN, -CHO or -COOH; Or, each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy or halogenated C 1-4 alkyl; Or, each R 1 independently selected from halogen, -OH, -NH2, -CN, C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 alkyl; Or, each R 1 independently selected from halogen, -OH, -NH2, -CN or C 1-3 alkyl; Or, each R 1 independently selected from fluorine, chlorine, bromine, -OH, -NH2 or -CN; Or, each R 1 independently selected from fluorine, chlorine or bromine; Or, each R 1 independently selected from fluoro or methyl; and / or, n is selected from 0, 1 or 2; Alternatively, n is selected from 0 or 1; Alternatively, n is selected from 0.

10. The compound according to any one of claims 1 to 9, its stereoisomer or a pharmaceutically acceptable salt thereof, CLM or Selected from 11. The compound according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is selected from the following groups optionally substituted with one or more substituents: C 1-50 Alkylene, C 2-50 Alkenylene or C 2-50 Alkynylidene, optionally, the C 1-50 Alkylene, C 2-50 Alkenylene or C 2-50 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-15 Cycloalkyl, 3-15 membered heterocycloalkyl, 4-15 membered heterocycloalkenyl, C 6-15 Aryl, 5-15 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted; Alternatively, said L is selected from the following groups optionally substituted by one or more substituents: C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 Alkynylidene, optionally, the C 1-30 Alkylene, C 2-30 Alkenylene or C 2-30 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3- 12 Cycloalkyl, 3-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted; Alternatively, said L is selected from the following groups optionally substituted by one or more substituents: C 1-20 Alkylene, C 2-20 Alkenylene or C 2-20 Alkynylidene, optionally, the C 1-20 Alkylene, C 2-20 Alkenylene or C 2-20 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3- 10 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl, C 6-10 Aryl, any 5-10 membered heteroaryl, -NH-, -N(C 1-6 alkyl)- or -S-substituted; Alternatively, said L is selected from the following groups optionally substituted by one or more substituents: C 1-15 Alkylene, C 2-15 Alkenylene or C 2-15 Alkynylidene, optionally, the C 1-15 Alkylene, C 2-15 Alkenylene or C 2-15 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-8 membered heterocycloalkenyl, C 6-8 Aryl, 5-8 membered heteroaryl, -NH-, -N(C 1-4 alkyl)- or -S-substituted; Alternatively, said L is selected from the following groups optionally substituted by one or more substituents: C 1-10 Alkylene, C 2-10 Alkenylene or C 2-10 Alkynylidene, optionally, the C 1-10 Alkylene, C 2-10 Alkenylene or C 2-10 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-substituted; Alternatively, said L is selected from the following groups optionally substituted by one or more substituents: C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene, optionally, the C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 One or more -CH2- in the alkynylene group are independently optionally replaced by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-substituted; Alternatively, said L is selected from the following groups optionally substituted by one or more substituents: C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 Alkynylidene, optionally, the C 1-4 Alkylene, C 2-4 Alkenylene or C 2-4 One or more (e.g., one or two, one or three, etc.) -CH2- in the alkynylene group are independently optionally replaced by -O-, C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, 4-6 membered heterocycloalkenyl, C6 aryl, 5-6 membered heteroaryl, -NH-, -N(C 1-3 alkyl)- or -S-substituted; Alternatively, said L is selected from C optionally substituted by one or more substituents 1-10 Alkylene or C 2-10 Alkynylidene, optionally, the C 1-10 Alkylene or C 2-10 One or more -CH2- in the alkynylene group are independently optionally selected from -O-, C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl, 4-12 membered heterocycloalkenyl, -NH-, -N(C 1-6 alkyl)- or -S-substituted; Alternatively, said L is selected from C optionally substituted by one or more substituents 1-6 Alkylene or C 2-6 Alkynylidene, optionally, the C 1-6 Alkylene or C 2-6 One or more -CH2- in the alkynylene group are independently optionally selected from -O-, C 3-10 Cycloalkyl, 4-11 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, -NH-, -N(C 1-3 alkyl)- or -S-substituted; Optionally, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl is optionally substituted with one or more halogen, -OH, -NH2 or -CN; Alternatively, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, (C 1-6 alkyl)NH- or (C 1-6 Alkyl)2N-; Alternatively, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, (C 1-4 Alkyl)NH-, (C 1-4 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl; Alternatively, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl or C 1-6 alkoxy; Alternatively, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN or C optionally substituted by halogen or hydroxyl. 1-3 alkyl; Alternatively, in the definition of L, the substituent is -F, =O, methyl or HOCH2-; Optionally, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl; Alternatively, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, (C 1-4 Alkyl)NH-, (C 1-4 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl.

12. The compound according to any one of claims 1 to 11, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -LNK 3 -Cy 4 -LNK 4 -,in, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 3-12 Cycloalkyl, 4-12 membered heterocycloalkyl or 4-12 membered heterocycloalkenyl; LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-12 Alkylene, C 2-12 Alkenylene, C 2-12 Alkynylidene or C 1-12 heteroalkylene; Each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-12 Cycloalkyl or 4-12 membered heterocycloalkyl; Or, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene or C 1-10 heteroalkylene; Or, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene or C 1-6 heteroalkylene; Or, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkynylidene or C 1-4 heteroalkylene; Or, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-6 Alkylene, C 2-6 Alkynylidene or C 1-6 heteroalkylene; Or, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, -S-, or optionally substituted by one or more R c Substituted with the following groups: C 1-4 Alkylene, C 2-4 Alkynylidene or C 1-4 heteroalkylene; Or, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, or optionally substituted by one or more R c Substituted with the following groups: C 1-3 Alkylene, C 2-3 Alkynylidene or C 1-3 heteroalkylene; Or, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 are independently selected from a bond, -NH-, -O-, or optionally substituted by one or more R c Substituted with the following groups: C 1-3 Alkylene, C2 alkynylene or C 1-2 heteroalkylene; Or, LNK, LNK 1 、LNK 2 、LNK 3 and LNK 4 Each is independently selected from a bond, -NH-, -O-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, -C(CH3)2-, ethynylene, -C(O)- or -C(O)CH2-; Alternatively, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 3-11 Cycloalkyl, 4-12 membered heterocycloalkyl or 4-11 membered heterocycloalkenyl; Alternatively, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 4-10 Cycloalkyl, 4-11 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl; Alternatively, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 4-6 Cycloalkyl, C9 cycloalkyl, 4-11 membered heterocycloalkyl or 6 membered heterocycloalkenyl; Alternatively, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, or optionally substituted by one or more R b Substituted with the following groups: C 4-6 Cycloalkyl or 4-6 membered heterocycloalkyl; Alternatively, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, or optionally substituted by one or more R b Substituted cyclobutyl, cyclopentyl, cyclohexyl, spironanyl, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyridinyl, piperazinyl, monoazaspiroheptanyl, monoazaspirooctanyl, monoazaspironanyl, diazaspironanyl, monoazaspirodecanyl, diazaspirodecanyl, monoazaspiroundecyl, diazaspiroundecyl, monoazaspiroundecyl, monoazabicyclohexane, octahydrocyclopentapyrrolyl, diazabicyclooctanyl or monoazabicyclononanyl; Alternatively, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, Alternatively, Cy 1 、Cy 2 、Cy 3 or Cy 4 are independently selected from a bond, 13. The compound according to claim 12, its stereoisomer or pharmaceutically acceptable salt thereof, wherein each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, (C 1-6 Alkyl)NH-, (C 1-6 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocycloalkyl is optionally substituted with one or more halogen, -OH, -NH2 or -CN; Or, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, (C 1-6 alkyl)NH- or (C 1-6 Alkyl)2N-; Or, each R b and R c Each independently selected from halogen, =O, -OH, -NH2, -CN, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, (C 1-4 Alkyl)NH-, or (C 1-4 Alkyl)2N-; Or, each R b and R c are each independently selected from halogen, =O, -OH, -NH2, -CN or C optionally substituted by halogen or hydroxyl 1-3 alkyl; Or, each R b and R c Each is independently selected from -F, =O, methyl or HOCH2-; Alternatively, L or -LNK 1 - is selected from a bond, -O-, -NH-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, -C(CH3)2-, ethynylene, -C(O)- or -C(O)CH2-.

14. The compound according to any one of claims 1 to 13, its stereoisomer or pharmaceutically acceptable salt thereof, wherein L is selected from a bond, -NHCH2-, -CH2NHCH2-, -CH2-, -C(O)CH2-, 15. The compound according to any one of claims 3 to 14, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R d 、R e 、R g and R h are independently selected from hydrogen, halogen, -CN, or the following groups optionally substituted with one or more R': R v -、R v O-、R v S- or R s R v N-; optionally, R s and R v are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl C 1-3 Alkylene-, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl C 1-3 Alkylene-, C 3-6 Cycloalkenyl, C 3-6 Cycloalkenyl C 1-3 Alkylene-, 3-6 membered heterocycloalkenyl, 3-6 membered heterocycloalkenyl C 1-3 Alkylene-, C 6-12 Aryl, C 6-12 Aryl C 1-3 Alkylene-, 5-6 membered heteroaryl or 5-6 membered heteroarylC 1-3 Alkylene-; Or, R s and R v are independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl.

16. The compound according to any one of claims 3 to 15, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R d 、R e 、R g and R h are independently selected from hydrogen, halogen, -CN, or the following groups optionally substituted with one or more R': C 1-6 Alkyl-, C 1-6 Alkyl O-, C 1- 6-alkyl S- or C 1-6 Alkyl NH-; Or, R d 、R e 、R g and R h are independently selected from hydrogen, or C optionally substituted by one or more R' 1-4 Alkyl O-; Or, R d 、R e 、R g and R h are independently selected from hydrogen, or CH3O- optionally substituted with one or more R'; Or, R d and R g Together with the carbon or nitrogen atom to which it is connected, it forms a C 5-10 Carbocyclic or 5-10 membered heterocyclic, the C 5-10 The carbocyclyl or 5- to 10-membered heterocyclyl is optionally substituted with one or more R"; Alternatively, the R d and R g Together with the carbon or nitrogen atom to which it is connected, it forms a C 6-10 Carbocyclic or 6-10 membered heterocyclic, the C 6-7 The carbocyclyl or 6-7 membered heterocyclyl is optionally substituted with one or more R"; Alternatively, the R d and R g Together with the carbon atom or nitrogen atom to which it is attached, it forms a 7-membered heterocyclic group containing nitrogen and oxygen heteroatoms, and the 7-membered heterocyclic group containing nitrogen and oxygen heteroatoms is optionally substituted by one or more R".

17. The compound according to any one of claims 3 to 16, its stereoisomer or pharmaceutically acceptable salt thereof, wherein each R' or R" is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, R k O-、R k S-、R j R k N-、R k C(O)-、R k S(O)2-、R k S(O)-、R k OC(O)-、R k OS(O)-、R k OS(O)2-、R j R k NC(O)-、R j R k NS(O)-、R j R k NS(O)2-、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl; Alternatively, each R' is independently selected from R j R k NC(O)-; or, each R' is independently selected from CH3NHC(O)-; Optionally, R j and R k are independently selected from H, C optionally substituted with one or more groups selected from halogen, -OH, -NH2 or -CN 1-3 alkyl; Or, R j and R k are independently selected from H or C 1-3 alkyl; Or, R j and R k are independently selected from H or methyl.

18. The compound according to any one of claims 3 to 17, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R d Selected from hydrogen or Or, R d and R g Together with the carbon atom or nitrogen atom to which it is attached, it forms a 7-membered heterocyclic group, which is optionally substituted with one or more R"; Or, R d and R g Together with the carbon or nitrogen atom to which it is attached, described is optionally substituted with one or more R"; or, R d and R g Together with the carbon or nitrogen atom to which it is attached, 19. The compound according to any one of claims 3 to 18, its stereoisomer or pharmaceutically acceptable salt thereof, wherein each R" is independently selected from deuterium, halogen, -OH, -NH2, -CN, =O, R k O-、R k S-、R j R k N-、C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl; or, each R" is independently selected from -F, -Cl or C 3-4 Cycloalkyl.

20. The compound according to any one of claims 3 to 19, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R 2 and R 3 are independently selected from halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl O-, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Alkyl, 3-6 heterocycloalkyl, C 6-12 Aryl or 5-6 heteroaryl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkyl O-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Alkyl, 3-6 heterocycloalkyl, C 6-12 Aryl or 5-6 heteroaryl are optionally substituted by one or more of the following groups: halogen, -CN, -OH, -NH2 or C 1-6 Alkyl, each R 2 Replace in X 10 、X 11 or X 12 superior; Or, each R 2 and R 3 are independently selected from halogen, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl O-, C 1-4 Alkyl S-, C 1-4 Alkyl NH- or (C 1-4 Alkyl) 2N-, the C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl O-, C 1-4 Alkyl NH- or (C 1-4 alkyl)2N- is optionally substituted with one or more of the following groups: halogen, -CN, -OH, -NH2 or C 1-6 Alkyl, each R 2 Replace in X 10 、X 11 or X 12 superior; Optionally, each R 2 Replace in X 10 、X 11 or X 12 superior; Or, each R 2 and R 3 are independently selected from halogen, -CN, -OH, -NH2, C 1-4 Alkyl or C 1-4 Alkyl O-; or, each R 2 and R 3 are independently selected from halogen, -CN, C 1-3 Alkyl or C 1-3 Alkyl O-; Or, each R 2 and R 3 Each is independently selected from -F, -Cl, -Br, -CN or CH3O-.

21. The compound according to any one of claims 3 to 20, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl O-, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl C 1-3 Alkylene-, 3-6 membered heterocycloalkyl C 1-3 Alkylene-, C 6-10 Aryl C 1-3 Alkylene- or 5-6 membered heteroaryl C 1-3 Alkylene-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl O-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl C 1-3 Alkylene-, 3-6 membered heterocycloalkyl C 1-3 Alkylene-, C 6-10 Aryl C 1-3 Alkylene- or 5-6 membered heteroaryl C 1-3 Alkylene - optionally substituted with one or more of the following groups: halogen, -CN, -OH, -NH2, C 1-6 Alkyl O-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-6 membered heteroaryl; Or, R 4 Selected from hydrogen, -CN, -OH, -NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkyl O-, C 1-4 Alkyl S-, C 1- 4-alkyl NH- or (C 1-4 Alkyl)2N-; Or, R 4 Selected from C 1-6 alkyl; Or, R 4 Selected from C 1-3 alkyl; Or, R 4 is selected from methyl or isopropyl.

22. The compound according to any one of claims 3 to 21, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural part Selected from Or, the structural part Selected from Optionally, the structural part Selected from Or, the structural part Selected from 23. A compound according to any one of claims 1 to 22, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, a PTM, or a structural portion thereof Selected from 24. A compound according to any one of claims 1 to 23, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from a compound of Formula IV, Formula V, Formula VIA, Formula VIB, Formula VIC, Formula VIIA, Formula VIIB, Formula VIIC, Formula VIID, Formula VIIE, or Formula VIIF, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, X 18 selected from CH or N; u is selected from 0, 1, 2, 3, 4, 5 or 6.

25. The following compound, its stereoisomer or a pharmaceutically acceptable salt thereof:

26. A pharmaceutical composition comprising the compound, structural portion, derivative, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, and optionally further comprising a pharmaceutically acceptable excipient.

27. Use of the compound according to any one of claims 1 to 25, its stereoisomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 26 in the preparation of a medicament for preventing or treating a disease; optionally, the disease is selected from cancer.

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