Compounds comprising a hetero-fused ring structure

Abstract

The present application belongs to the field of medicinal chemistry, and relates to compounds comprising a hetero-fused ring structure, in particular to compounds of Formula I, methods for their preparation, pharmaceutical compositions containing them, and their use in the treatment of related diseases, such as cancer.

Description

Technical Field

[0001] This application relates to compounds comprising heterocyclic ring structures, methods for their preparation, pharmaceutical compositions containing such compounds, and their use in treating related diseases (e.g., cancer). Background Technology

[0002] Non-Hodgkin's lymphoma (NHL) is one of the most common malignant tumors worldwide, posing a serious threat to human health. Currently, several therapies have been approved for the treatment of NHL, such as chemotherapy drugs, antibody drugs, and small molecule targeted therapies. Clinical data indicate that existing therapies still face challenges in terms of 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 mainly expressed in B cells and myeloid cells, making it a relatively safe and effective target. However, disease progression or relapse due to primary or acquired resistance remains unavoidable.

[0003] PROTAC (proteolysis targeting chimera) molecules are bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds induce the target protein to be recognized by the cell's proteasome, causing its degradation and effectively reducing its concentration in cells. By introducing ligands that bind to different target proteins into PROTAC molecules, the application of PROTAC technology in the treatment of various diseases has become possible, and this technology 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 expression of BCL6 protein, 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. Simultaneously, BCL6 inhibits cell cycle checkpoint and differentiation-related gene and DNA damage responses. Preclinical studies have shown that the absence of BCL6 in lymphoma cells causes tumor development arrest. Therefore, BCL6 is a potentially suitable target for the treatment of various lymphomas. Novel PROTAC drugs targeting BCL6 protein and E3 ubiquitin ligase can be used to treat BCL6-related tumors.

[0005] It is necessary to develop novel PROTAC drugs for the treatment of lymphomas such as NHL, in order to address the problems of poor efficacy and drug resistance of existing therapies. Invention Details

[0007] On the one hand, this application relates to compounds of formula I, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0008] PTM-L-CLM

[0009] I

[0010] in,

[0011] CLM is selected from the E3 ubiquitin ligase binding region;

[0012] L is selected from a linking group;

[0013] PTM is selected from the portion that binds to the target protein.

[0014] In some embodiments, the target proteins of the PTM group are numerous and selected from proteins expressed in cells such that at least a portion of the sequence is found in the cell and can bind to the PTM group. The term "protein" includes oligopeptides and polypeptide sequences long enough to bind to the PTM group of this disclosure. As further described herein, any protein in a eukaryotic or microbial system comprising viruses, bacteria, or fungi is a target protein for ubiquitination mediated by the compounds according to this disclosure. Preferably, the target protein is a eukaryotic protein.

[0015] The term "target protein" is used to describe a protein or peptide that is a target that binds to the PTM according to this disclosure and is degraded by the ubiquitin ligase of this 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 some embodiments, target proteins include structural proteins, receptors, enzymes, cell surface proteins, proteins involved in cellular integration functions (including those involved in catalytic activity, aromatase activity, motility 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 (proteins, lipids, carbohydrates), receptor activity, cell movement, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, and responses to stimuli), behavioral proteins, cell adhesion proteins, proteins involved in cell death, and transport-related proteins (including protein transporter activity, nuclear transport, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular tissue and biogenetic activity, and translation regulator activity). The proteins of interest can include proteins from eukaryotes and prokaryotes (including microorganisms, viruses, fungi, and parasites, including humans, microorganisms, viruses, fungi, and parasites that are targets for drug therapy), other animals (including domesticated animals), microorganisms used to identify targets for antibiotics and other antimicrobial agents and plants, and even viruses.

[0016] More specifically, target proteins include, for example, B7.1 and B7, TINFR1m, TNFR2, NADPH oxidase, BclIBax and other mates in the apoptosis pathway, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDEI, PDEII, PDEIII, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, 5HT receptor, dopamine receptor, G protein (i.e., Gq), histamine receptor, 5-lipoxygenase, trypsin-like serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomes, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAW STAT, RXR and analogs, HIV 1 protease, HIV 1. Integrase, influenza, ceramidinase, hepatitis B reverse transcriptase, sodium channels, 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+ channels, VCAM, VLA-4 integrin, selectins, CD40 / CD40L, neurokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP kinase, RaslRaflMEWERK pathway, interleukin-1 convertase, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycine 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, 5α-reductase inhibitor, angiotensin 11, glycine receptor, norepinephrine reuptake receptor, endothelin receptor, neuropeptide Y and its receptor, estrogen receptor, androgen receptor (AR), adenosine receptor, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), farnesyltransferase, geraniol geraniol transferase, TrkA of NGF α-receptor, β-amyloid protein, tyrosine kinase Flk-IIKDR, porphyrin receptor, integrin receptor, Her-21 neutrophils, telomerase inhibitor, cytosolic phospholipase A2, and EGF receptor tyrosine kinase. Other target proteins include ecdysone 20-monooxygenase, GABA-gated chloride ion channels, acetylcholinesterase, voltage-sensitive sodium channel proteins, calcium release channels, and chloride channels. Additional target proteins include acetyl-CoA carboxylase, adenosylsuccinate synthase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.

[0017] In some embodiments, the PTM is selected from molecules (including small molecule compounds, peptides, proteins, nucleic acids, antibodies, etc.) that have anticancer, antineurodegenerative, antimicrobial, antiviral, antiHIV, or antifungal effects.

[0018] In some embodiments, the PTM is selected from molecules (including small molecule compounds, peptides, proteins, nucleic acids, antibodies, etc.) that act on AR, ER, kinases (e.g., tyrosine kinase, threonine / serine kinase), phosphatases, MDM2, proteins with human BET bromo domains, Hsp90, HDAC, human lysine methyltransferase, RAF receptor, FKBP, angiogenesis inhibitors (vascular growth factors), immunosuppression-related receptors or proteins, aryl hydrocarbon receptors (AHR), thyroid hormone receptors, HIV proteases, HIV integrase, HCV proteases, HBV proteases, or acyl protein thioesterase 1 and / or acyl protein thioesterase 2.

[0019] In some embodiments, the PTM is selected from molecules (including small molecule compounds, peptides, proteins, nucleic acids, antibodies, etc.) that act 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 scavengers.

[0020] In some embodiments, the PTM is selected from molecules (including small molecule compounds, peptides, 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.

[0021] In some embodiments, the PTM is selected from molecules (including small molecule compounds, peptides, proteins, nucleic acids, antibodies, etc.) that act on ALK, BRD4, CDK4 / 6, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEE1, 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, peptides, proteins, nucleic acids, antibodies, etc.) that act on BTK.

[0022] In some implementations, PTM is selected from the portion that binds to the target protein BCL6.

[0023] In some embodiments, PTM is selected from small molecule compounds. In some embodiments, PTM is covalently linked to L.

[0024] In some implementations, PTM also comprises a pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition thereof.

[0025] In some embodiments, the E3 ubiquitin ligase-binding moiety is selected from the cereblon E3 ubiquitin ligase-binding moiety, the VHL E3 ubiquitin ligase-binding moiety, the IAP E3 ubiquitin ligase-binding moiety, or the MDM2 E3 ubiquitin ligase-binding moiety. In some embodiments, the E3 ubiquitin ligase-binding moiety is selected from the cereblon E3 ubiquitin ligase-binding moiety. In some embodiments, the CLM is selected from small molecule compounds. In some embodiments, the CLM is covalently linked to L.

[0026] On the one hand, this application relates to compounds of formula II, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0027]

[0028] in,

[0029] Indicates a single bond or a double bond;

[0030] Ring W is selected from or ,

[0031] Ring A does not exist, or is selected from C. 3-15 Cycloalkenyl, 3-15 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl;

[0032] Ring B is selected from phenyl or 5-6-membered heteroaryl groups;

[0033] The ring C is selected from furanyl, oxazolyl, isoxazolyl, or pyrazolyl;

[0034] When ring A is absent or selected from phenyl, and ring B is selected from phenyl, ring C is selected from oxazolyl, isoxazolyl or pyrazolyl;

[0035] X a X b X c X d X e X f and X g Each of the following is independently selected from C, CH, CH2, N, NH, O, or S;

[0036] Each R 1 The following groups, each independently selected from deuterium, halogens, -OH, -NH2, -CN, and optionally substituted by 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 group, C 3-10 cycloalkyl, C 3-10 cycloalkyl C 1-3 Alkyl or 3-10 membered heterocyclic alkyl;

[0037] n is selected from 0, 1, 2, 3, 4, 5, or 6;

[0038] X 5 Selected from C(R) f ) or N;

[0039] R f C selected from H, halogens, deuterium, or optionally substituted with one or more substituents 1-6 alkyl;

[0040] L 1 Selected from -NH-, -O-, -S-, -CONH-, or -CON(C) 1-6 alkyl)-, the L 1 Connected to ring C or ring E in ring W, when L 1 When selected from the key, then X 5 Connect to ring C or ring E in ring W;

[0041] L is selected from a linking group;

[0042] PTM is selected from small molecule compounds that target BCL6.

[0043] In some embodiments, ring C is selected from furanyl, oxazolyl, or isoxazolyl, and when ring A is absent or selected from phenyl and ring B is selected from phenyl, ring C is selected from oxazolyl or isoxazolyl.

[0044] On the one hand, this application also relates to compounds of formula III or IIIA, their stereoisomers or pharmaceutically acceptable salts thereof.

[0045]

[0046] in,

[0047] Ring B, Ring W, L1 R 1 , n and X 5 The definitions are as described in this application;

[0048] L is selected from a linking group;

[0049] X 8 Selected from C(R) d ), C(R d R e ), N, N(R) d ), O or S;

[0050] X 9 Selected from C(R) g ), C(R g R h ), N, N(R) g ), O or S;

[0051] R d R e R g and R h The following groups are selected independently from hydrogen, deuterium, halogen, -CN, or optionally substituted by 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 vS(O) = N-;

[0052] Or R d and R g Together with the carbon or nitrogen atoms bonded to it, they form C 5-12 Carbocyclic or 5-12 membered heterocyclic groups, wherein the C 5-12 The carbon ring or 5- to 12-membered heterocyclic group may optionally be replaced by one or more R'';

[0053] R s and R v Selected independently from H and C respectively 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 cycloalkyl C 1-3 alkylene-, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkyl C 1-3 Alkylene-, C 3-12 Cycloalkenyl, C 3-12 Cycloalkenyl C 1-3 alkylene-, 3-12-membered heterocyclic alkenyl, 3-12-membered heterocyclic alkenyl C 1-3 Alkylene-, C 6-12 Aryl, C 6-12 Aryl C 1-3 alkylene-, 5-12 heteroaryl, or 5-12 heteroaryl C 1-3 alkylene-;

[0054] 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 group, 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-, Rj 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 heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups;

[0055] R j and R k The following groups are selected independently from H, or optionally substituted by one or more groups selected from deuterium, halogens, -OH, -NH2, or -CN: C 1-6 Alkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic alkyl;

[0056] Each R 2 and R 3 Each is independently selected from deuterium, halogens, -CN, -OH, -NH2, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, 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 heteroaryl, wherein C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, 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 The aryl or 5-12 heteroaryl group may optionally be substituted by 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;

[0057] m is selected from 0, 1, 2, or 3;

[0058] p is selected from 0, 1, 2, 3, 4 or 5;

[0059] R 4 Selected from hydrogen, -CN, -OH, -NH2, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-3 alkylene-, 3-12-membered heterocyclic alkyl C 1-3 Alkylene-, C 6-12 Aryl C 1-3 alkylene- or 5-12 heteroaryl C 1-3 alkylene-, the C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-3 alkylene-, 3-12-membered heterocyclic alkyl C 1-3 Alkylene-, C 6-12 Aryl C 1-3 alkylene- or 5-12 heteroaryl C 1-3 Alkyl groups are 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 heteroaryl groups;

[0060] X 10 X 11 X 12 X 13 X 14 X 15 X 16 and X 17 Each is independently selected from CH or N; R t Selected from H or C 1-6 alkyl.

[0061] In some implementations, the rings W and L 1 R 1 X 5 L, X 8 X 9 R d R e Rg 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 The group may independently and optionally contain one or more deuteriums (i.e., there may be no deuteriums or one, two, three, four, five, six, or more deuteriums).

[0062] In some implementations, the CLM is selected from ,in Ring W, R 1 , n, L 1 and X 5 The definition is as stated in this application.

[0063] In some implementations, the CLM is selected from ,in Ring A, Ring B, Ring C, R 1 , n, L 1 and X 5 The definition is as stated in this application.

[0064] In some implementations, CLM or Selected from , where X a X b X c X d X e X f X g R 1 , n, L 1 and X 5 The definition is as stated in this application.

[0065] In some implementations, PTM is selected from or ,in X 8 X 9 R 2 R 3 m, p, R 4 X 10 X11 X 12 X 13 X 14 X 15 X 16 X 17 and R t The definition is as stated in this application.

[0066] In some implementations, ring A is absent or selected from C. 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, C 3-12 The cycloalkenyl group is selected from C 3-8 Cycloalkenyl. In some embodiments, the 3-12 membered heterocyclic alkenyl is selected from the 4-9 membered heterocyclic alkenyl.

[0067] In some implementations, ring A is absent, or is selected from C. 5-15 Cycloalkenyl, 5-15 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0068] In some implementations, ring A is absent, or is selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0069] In some implementations, ring A is absent, or is selected from C. 5-7 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl.

[0070] 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 heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl or oxazolyl.

[0071] In some embodiments, ring A is absent, or is selected from cyclopentenyl, monocyclohexenyl, dicyclohexenyl, monocycloheptenyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydroazapyrrolyl, azaspirooctenyl, azaspirononenyl, phenyl, pyrrolyl, pyrazolyl, furanyl, oxazolyl, or dihydrooxazinyl.

[0072] In some specific implementation schemes, ring A is selected from C. 5-10 Cycloalkenyl or 5-10 membered heterocyclic alkenyl.

[0073] In some specific implementation schemes, ring A is selected from C. 5-7 Cycloalkenyl (e.g., C5, C6, or C7) or 5-10 quinone (e.g., quinone, hexaquinone, septone, octone, quinone, septone, or decone) heterocyclic alkenyl. In some specific embodiments, ring A is selected from C14. 6-7 Cycloalkenyl. In some specific embodiments, ring A is selected from 6-7 membered heterocyclic alkenyl groups.

[0074] In some specific implementation schemes, ring A is selected from C. 5-7 Cycloalkenyl or 5-7 membered heterocyclic alkenyl.

[0075] In some implementation schemes, R 1 The replacement position is selected from ring A or ring B. In some embodiments, R 1 The replacement position is selected from ring A. In some embodiments, R 1 The replacement position is selected from ring B. In some embodiments, R 1 The substitution position is selected from ring C.

[0076] In some implementations, ring A is connected to L. In some implementations, ring B is connected to L. In some implementations, ring C is connected to L.

[0077] In some embodiments, ring B is selected from phenyl or a 6-membered heteroaryl group. In some embodiments, ring B is selected from phenyl or a 6-membered heteroaryl group containing (e.g., 1, 2, 3, or 4) nitrogen-containing heteroaryl groups. In some embodiments, ring B is selected from phenyl.

[0078] In some embodiments, the ring C is selected from furanyl, oxazolyl, or isoxazolyl.

[0079] 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. In some embodiments, ring A is absent, ring B is selected from phenyl, and ring C is selected from furanyl, oxazolyl, isoxazolyl, or pyrazolyl. In some embodiments, ring A is absent, ring B is selected from phenyl, and ring C is selected from isoxazolyl or pyrazolyl.

[0080] In some implementation schemes, the structural portion Selected from or .

[0081] In some implementation schemes, the structural portion Selected from , , , , , or .

[0082] In some implementation schemes, the structural portion Selected from , , , , , or .

[0083] In some implementation schemes, the structural portion Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, the structural portion Selected from In some implementations, the structural portion Selected from .

[0084] In some implementation schemes, the structural portion Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or In some implementations, the structural portion Selected from In some implementations, the structural portion Selected from In some implementations, the structural portion Selected from , , or .

[0085] In some implementation schemes, the structural portion Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementations, the structural portion Selected from , , or In some implementations, the structural portion Selected from In some implementations, the structural portion Selected from , , , , , , , or .

[0086] In some implementation schemes, the structural portion by n R 1 Each can replace the others independently.

[0087] In some implementation schemes, X e Selected from C.

[0088] In some implementation schemes, X f and X g Each is independently selected from CH or CH2.

[0089] In some implementation schemes, X a X b X c and X d Each is independently selected from C, CH, CH2, N, or NH.

[0090] In some implementation schemes, the structural portion Selected from .

[0091] In some implementation schemes, the structural portion Selected from , , , , , or .

[0092] In some implementation schemes, the structural portion Selected from , , or .

[0093] In some implementations, each R 1 The following groups are independently selected from deuterium, halogens, -OH, -NH2, -CN, and optionally substituted by 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 group, C 3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl.

[0094] In some implementations, each R 1 The following groups are independently selected from deuterium, halogens, -OH, -NH2, -CN, and optionally substituted by one or more substituents: C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 Alkyl group. In some embodiments, the R... 1 The substituents are selected from deuterium, halogens, -OH, -NH2, -CN, -CHO or -COOH.

[0095] In some implementations, each R 1 Independently selected from deuterium, halogens, -OH, -NH2, -CN, C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl.

[0096] In some implementations, each R 1 Independently selected from deuterium, halogens, -OH, -NH2, -CN, C 1-3 Alkyl, deuterated C 1-3 Alkyl, C1-3 alkoxy or halogenated C 1-3 alkyl.

[0097] In some implementations, each R 1 Independently selected from deuterium, halogens, -OH, -NH2, -CN, C 1-3 Alkyl or deuterated C 1-3 Alkyl group. In some embodiments, each R 1 Independently selected from deuterium, halogens, and C 1-3 Alkyl or deuterated C 1-3 Alkyl group. In some embodiments, each R 1 Independently selected from deuterium, fluorine, chlorine, bromine, -OH, -NH2, or -CN. In some embodiments, each R 1 It is independently selected from deuterium, fluorine, chlorine, or bromine. In some embodiments, each R... 1 Independently selected from deuterium, fluorine, methyl, or -CD3. In some embodiments, each R 1 Selected independently from C 1-3 Alkyl group. In some embodiments, each R 1 Selected independently from methyl.

[0098] In some implementations, n is selected from 0, 1, or 2. In some implementations, n is selected from 0 or 1. In some implementations, n is selected from 0 or 1, and each R... 1 It is independently selected from fluorine.

[0099] In some specific implementation schemes, n is selected from 0.

[0100] In some implementation schemes, the structural portion Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or In some implementations, the structural portion Selected from , , , or In some implementations, the structural portion Selected from .

[0101] In some implementation schemes, X 5 Selected from C(R) f ).

[0102] In some implementation schemes, R f C selected from H, fluorine, chlorine, bromine, deuterium, or optionally substituted with one or more substituents 1-3 alkyl.

[0103] In some implementation schemes, R f Selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 Alkyl, the C 1-3 The alkyl group may optionally be substituted with one or more of the following groups: deuterium, halogen, -OH, -NH2 or -CN.

[0104] In some implementation schemes, R f Selected from H, fluorine, deuterium, or methyl. In some embodiments, R f Selected from H.

[0105] In some implementation schemes, X 5 Selected from CH or N.

[0106] In some implementation schemes, X 5Selected from CH.

[0107] In some implementation schemes, Selected from or In some implementation schemes, Selected from .

[0108] In some implementations, the L 1 Selected from the bond, -NH-, or -CONH-. In some embodiments, the L 1 Selected from key. In some implementations, the L 1 Selected from key, Selected from .

[0109] In some implementations, CLM or Selected from , or .

[0110] In some implementations, CLM or Selected from , or .

[0111] In some implementations, CLM or Selected from , or .

[0112] In some implementations, CLM or Selected from or .

[0113] In some implementations, CLM or Selected from , , , , , , , , , , , , , , , or In some implementations, CLM or Selected from , or .

[0114] In some implementations, CLM or Selected from , , , , , , , , , , , , , , , , ,or In some implementations, CLM or Selected from or In some implementations, CLM or Selected from , or .

[0115] 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 imide or C 2-50 Alkyne group, optionally, the C 1-50 Alkylene, C 2-50 imide or C 2-50 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-15 Cycloalkyl, 3-15 membered heterocyclic alkyl, 4-15 membered heterocyclic alkenyl, C 6-15 Aryl, 5-15 quinone heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S- substitution.

[0116] 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 imide or C 2-30 Alkyne group, optionally, the C 1-30 Alkylene, C 2-30 imide or C 2-30 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-12 Cycloalkyl, 3-12-membered heterocyclic alkyl, 4-12-membered heterocyclic alkenyl, C6-12 Aryl, containing 5-12 membered heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S- substitution.

[0117] 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 imide or C 2-20 Alkyne group, optionally, the C 1-20 Alkylene, C 2-20 imide or C 2-20 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-10 Cycloalkyl, 3-11 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, C 6-10 Aryl, any 5-10 heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S- substitution.

[0118] 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 imide or C 2-15 Alkyne group, optionally, the C 1-15 Alkylene, C 2-15 imide or C 2-15 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, C 6-8 Aryl, 5-8 quinone heteroaryl, -NH-, -N(C 1-4 Alkyl)- or -S- substitution.

[0119] 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 imide or C 2-10 Alkyne group, optionally, the C 1-10 Alkylene, C 2-10 imide or C 2-10 One or more -CH2- groups in the ethynyl group are independently and optionally separated 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- substitution.

[0120] In some embodiments, the L is selected from the following groups optionally substituted with one or more substituents: C 1-6 Alkylene, C2-6 imide or C 2-6 Alkyne group, optionally, the C 1-6 Alkylene, C 2-6 imide or C 2-6 One or more -CH2- groups in the ethynyl group are independently and optionally separated 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- substitution.

[0121] 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 imide or C 2-4 Alkyne group, optionally, the C 1-4 Alkylene, C 2-4 imide or C 2-4 One or more (e.g., one or two, one or three, etc.) of the ethynyl group are independently and optionally separated 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- substitution.

[0122] In some embodiments, the L is selected from C that is optionally substituted with one or more substituents. 1-10 Alkylene or C 2-10 Alkyne group, optionally, the C 1-10 Alkylene or C 2-10 One or more -CH2- groups in the ethynyl group are independently and optionally selected from -O-, C-. 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, 4-12 membered heterocyclic alkenyl, -NH-, -N(C 1-6 Alkyl)- or -S- substitution.

[0123] In some embodiments, the L is selected from C that is optionally substituted with one or more substituents. 1-6 Alkylene or C 2-6 Alkyne group, optionally, the C 1-6 Alkylene or C 2-6 One or more -CH2- groups in the ethynyl group are independently and optionally selected from -O-, C-. 3-10 Cycloalkyl, 4-11 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl, -NH-, -N(C 1-3 Alkyl)- or -S- substitution.

[0124] In some specific embodiments, the L is selected from C that is optionally substituted with one or more substituents.1-3 Alkylene, optionally, the C 1-3 One or more -CH2- atoms in the alkylene group are independently and optionally selected from C. 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, or -NH- substitution.

[0125] 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, wherein 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 group is optionally substituted with one or more halogens, -OH, -NH2 or CN.

[0126] 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 and hydroxy substituted C 1-6 Alkyl, (C 1-6 alkyl) NH- or (C 1-6 Alkyl)2N-.

[0127] 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 and hydroxy substituted C 1-4 Alkyl, (C 1-4 Alkyl) NH-, (C 1-4 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl.

[0128] 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 and hydroxy substituted C 1-6 Alkyl or C 1-6 Alkyl group.

[0129] In some embodiments, in the definition of L, the substituent is selected from halogens, =O, -OH, -NH2, -CN, or C optionally substituted with a halogen or hydroxyl group. 1-3 Alkyl group. In some embodiments, in the definition of L, the substituent is -F, =O, methyl, or HOCH2-.

[0130] 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 heterocyclic alkyl.

[0131] 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 heterocyclic alkyl.

[0132] 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 Alkyl group. In some embodiments, in the definition of L, the substituent is selected from halogen, =O, -OH, -NH2, -CN, or C. 1-3 Alkyl group. In some embodiments, in the definition of L, the substituent is methyl or =O.

[0133] In some specific embodiments, in the definition of L, the substituent is selected from C. 1-3 Alkyl (e.g., methyl).

[0134] In some implementations, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -LNK 3 -Cy 4 -LNK 4 -,in,

[0135] Cy 1Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl or 4-12 membered heterocyclic alkenyl;

[0136] LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R c The following groups are substituted: C 1-12 Alkylene, C 2-12 imidene group, C 2-12 Ethyne or C 1-12 Heteroalkylene;

[0137] Each R b and R c Each is independently selected from halogens, =O, -OH, -NH2, -CN, and 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 heterocyclic alkyl.

[0138] In some implementations, Cy 1 Cy 2 and Cy 3 They are not both keys. In some implementations, Cy 1 Cy 2 Cy 3 or Cy 4 They are not both keys. In some implementations, Cy 2 and Cy 3 As a key. In some implementations, LNK 1 and LNK 2 Selected from key. In some implementations, LNK 3 and LNK 4 Selected from key.

[0139] In some implementations, the L is selected from -Cy 1 -、-Cy 2 -、-LNK 1 -、-Cy 1 -LNK-、-Cy 1 -Cy2 -、-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 1 -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 -Cy 3 -Cy 4 -LNK 4 - In some implementations, the L is selected from -Cy 1 -LNK-.

[0140] In some implementation schemes, LNK, LNK 1 LNK2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R c The following groups are substituted: C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne or C 1-10 Heteroalkylene.

[0141] In some implementation schemes, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R c The following groups are substituted: C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne or C 1-6 Heteroalkylene.

[0142] In some implementation schemes, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R c The following groups are substituted: C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne or C 1-4 Heteroalkylene.

[0143] In some implementation schemes, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R c The following groups are substituted: C 1-6 Alkylene, C 2-6 Ethyne or C 1-6 Heteroalkylene.

[0144] In some implementation schemes, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more Rc The following groups are substituted: C 1-4 Alkylene, C 2-4 Ethyne or C 1-4 Heteroalkylene.

[0145] In some implementation schemes, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, or optionally by one or more R c The following groups are substituted: C 1-3 Alkylene, C 2-3 Ethyne or C 1-3 Heteroalkylene.

[0146] In some implementation schemes, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, or optionally by one or more R c The following groups are substituted: C 1-3 alkylene, C2-alkynyl or C 1-2 Heteroalkylene.

[0147] In some implementation schemes, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each group is independently selected from the following groups: bond, -NH-, -O-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, -C(CH3)2-, ethynyl group, -C(O)-, or -C(O)CH2-.

[0148] In some specific implementation plans, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from either the bond or -NH-.

[0149] In some implementations, the L is selected from -LNK 1 -Cy 1 -LNK-Cy 2 -LNK 2 -Cy 3 -LNK 3 -Cy 4 -LNK 4 -, where LNK 1 Cy2 LNK 2 Cy 3 LNK 3 Cy 4 and LNK 4 Selected from key, Cy 1 Selected from 6-membered heterocyclic alkyl groups, LNK is selected from -NH-. In some embodiments, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 3-11 Cycloalkyl, 4-12 membered heterocyclic alkyl or 4-11 membered heterocyclic alkenyl.

[0150] In some implementations, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-10 Cycloalkyl, 4-11 membered heterocyclic alkyl or 5-6 membered heterocyclic alkenyl.

[0151] In some implementations, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-6 Cycloalkyl, C9 cycloalkyl, 4-11 membered heterocyclic alkyl or 6 membered heterocyclic alkenyl.

[0152] In some specific implementation schemes, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-6 Cycloalkyl or 4-6 membered heterocyclic alkyl groups. In some specific embodiments, Cy 1 Cy 2 Cy 3 or Cy 4 Each molecule is independently selected from 5-6 membered heterocyclic alkyl groups. In some specific embodiments, Cy 1 It is selected from 6-membered nitrogen-containing heterocyclic alkyl groups (e.g., piperidinyl or piperazine).

[0153] In some implementations, Cy 1 Cy2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, spironyl, azircyclobutyl, pyrrolyl, piperidinyl, tetrahydropyridyl, piperazine, azirspiroheptyl, azirspirooctyl, azirspirononyl, diazirspirononyl, azirspirodecyl, diazirspirodecane, azirspiroundecyl, diazirspiroundecyl, azirbicyclohexane, octahydrocyclopentylpyrryl, pyrrylpyrryl, diazirbicyclooctyl, or azirbicyclononyl.

[0154] In some implementations, Cy 1 Cy 2 Cy 3 or Cy 4 Selected independently from keys, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0155] In some implementations, Cy 1 Cy 2 Cy 3 or Cy 4 Selected independently from keys, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0156] In some implementations, each R b and R c Each is independently selected from halogens, =O, -OH, -NH2, -CN, and 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, wherein 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 group is optionally substituted with one or more halogens, -OH, -NH2, or -CN.

[0157] In some implementations, each R b and R c Each is independently selected from halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkyl and hydroxy substituted C 1-6 Alkyl, (C 1-6 alkyl) NH- or (C 1-6 Alkyl)2N-.

[0158] In some implementations, each R b and R c Each is independently selected from halogens, =O, -OH, -NH2, -CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 alkyl and hydroxy substituted C 1-4 Alkyl, (C 1-4 Alkyl) NH-, or (C 1-4 Alkyl)2N-.

[0159] In some implementations, each R b and R c Each is independently selected from halogens (e.g., F, Cl, Br, or I), =O, -OH, -NH2, -CN, or C substituted with a halogen or hydroxyl group. 1-3 Alkyl (e.g., methyl).

[0160] In some implementations, each R b and R c Each is independently selected from -F, =O, methyl, -CF3 or HOCH2-.

[0161] In some specific implementation schemes, each R b and R c Each was independently selected from C 1-3 Alkyl (e.g., methyl).

[0162] In some embodiments, the L is selected from the following: -NHCH2-, -CH2NHCH2-, -CH2-, -C(O)CH2-, ... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0163] In some implementations, ring A or ring G is connected to L.

[0164] In some implementation schemes, X 8 Selected from C(R) d ) or C(R d R e In some implementations, X 8 Selected from C(R) d ).

[0165] In some implementation schemes, X 9 Selected from C(R)g ) or N. In some implementations, X 9 Selected from C(R) g ) or C(R g R h ).

[0166] In some implementation schemes, X 9 Selected from CH or N.

[0167] In some implementation schemes, X 8 Selected from CH or CH2. In some implementations, X 9 Selected from CH or CH2. In some implementations, X 9 Selected from CH.

[0168] In some implementation schemes, R d R e R g and R h The following groups are selected independently from hydrogen, deuterium, halogen, -CN, or optionally substituted by one or more R': R v -、R v O-, R v S- or R s R v N-.

[0169] In some implementation schemes, R s and R v Selected independently from H and C respectively 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkylene-, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkylene-, C 3-6 Cycloalkenyl, C 3-6 Cycloalkenyl C 1-3 alkylene-, 3-6 membered heterocyclic alkenyl, 3-6 membered heterocyclic alkenyl C 1-3 Alkylene-, C 6-12 Aryl, C 6-12 Aryl C 1-3 alkylene-, 5-6-membered heteroaryl or 5-6-membered heteroaryl C 1-3 Alkylene-.

[0170] In some implementation schemes, R s and R v Selected independently from H and C respectively 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-6 Cycloalkyl or 3-6 membered heterocyclic alkyl. In some embodiments, R s and R v Selected independently from H or C 1-3 Alkyl (e.g., methyl).

[0171] In some implementation schemes, R d R e R g and R h The following groups are selected independently from hydrogen, deuterium, halogen, -CN, or optionally substituted by one or more R': C 1-6 Alkyl-, C 1-6 Alkyl O-, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, C 3-6 Cycloalkyl NH- or 3-6 membered heterocyclic NH-.

[0172] In some implementation schemes, R d R e R g and R h C atoms are independently selected from hydrogen, deuterium, or optionally substituted with one or more R's. 1-4 Alkyl O-, C 1-4 Alkyl NH- or C 3-4 cycloalkyl NH-.

[0173] In some implementation schemes, R d R e R g and R h The following groups are selected independently from hydrogen or optionally substituted with one or more R' groups: C 1-3 Alkyl O-.

[0174] In some implementation schemes, R d R e R g and R h Each is independently selected from hydrogen, or CH3O- or cyclobutylNH- which is optionally substituted with one or more R'.

[0175] In some implementation schemes, R d Selected from C, which may be replaced by one or more R's. 1-3 Alkyl O-.

[0176] In some implementation schemes, R d Selected from CH3O- which may be optionally replaced by one or more R'.

[0177] In some implementation schemes, R g Selected from hydrogen.

[0178] In some implementation schemes, R d and R g Together with the carbon or nitrogen atoms bonded to it, they form C 5-10 Carbocyclic or 5-10 membered heterocyclic group, wherein the C 5-10 The carbon ring or 5- to 10-membered heterocyclic group is optionally replaced by one or more R''.

[0179] In some implementations, the R d and R g Together with the carbon or nitrogen atoms bonded to it, they form C 6-10 Carbocyclic or 6-10 membered heterocyclic group, wherein the C 6-7 The carbon ring or 6-7 membered heterocyclic group may optionally be replaced by one or more R''.

[0180] In some implementations, the R d and R g Together with the carbon or nitrogen atom attached thereto, a 7-membered heterocyclic group containing nitrogen and oxygen heteroatoms is formed, wherein the 7-membered heterocyclic group containing nitrogen and oxygen heteroatoms is optionally substituted by one or more R''.

[0181] In some implementations, 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 heteroaryl.

[0182] In some implementations, each R' or R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, R k C(O)-, R j R k NC(O)- or cyclopropyl.

[0183] In some implementations, each R' is independently selected from deuterium, halogen, -OH, -NH2, -CN, R k C(O) - or R j R k NC(O)-.

[0184] In some embodiments, each R' is independently selected from deuterium, F, -OH, -CN, CH3C(O)-, CD3C(O)-, CH3NHC(O)-, CD3NHC(O)- or cyclopropyl-NHC(O)-.

[0185] In some implementations, each R' is independently selected from R. j R k NC(O)-. In some implementations, each R' is independently selected from R. k HNC(O)-. In some embodiments, each R' is independently selected from CH3NHC(O)-. In some embodiments, each R' is independently selected from CD3NHC(O)-. In some embodiments, each R' is independently selected from cyclopropyl-NHC(O)-.

[0186] In some implementations, each R' is independently selected from R. k C(O)-. In some embodiments, each R' is independently selected from CH3C(O)-. In some embodiments, each R' is independently selected from CD3C(O)-.

[0187] In some implementation schemes, R j and R k The following groups are selected independently from H, or optionally substituted by one or more groups selected from deuterium, halogens, -OH, -NH2, or -CN: C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocyclic alkyl.

[0188] In some implementation schemes, R j and R k C elements independently selected from H, deuterium, or optionally substituted by one or more deuterium atoms. 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocyclic alkyl.

[0189] In some implementation schemes, R k Each is independently selected from C atoms that are optionally substituted with one or more deuterium atoms. 1-3 Alkyl (e.g., methyl).

[0190] In some implementation schemes, R j and R kEach is independently selected from H, deuterium, CD3, methyl, or cyclopropyl. In some embodiments, R k Each is independently selected from CD3 or methyl groups. In some embodiments, R... k Each is independently selected from CD3. In some implementations, R k Each is independently selected from methyl groups. In some embodiments, R j Each is selected independently from H.

[0191] In some implementation schemes, R e Selected from hydrogen. In some embodiments, R g and R h Selected from hydrogen.

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

[0193] In some implementation schemes, R d Each is independently selected from CH3O- that is optionally replaced by one or more R'.

[0194] In some implementation schemes, R d Selected from hydrogen, , , , , , , , , , , , or .

[0195] In some implementation schemes, R d and R g Together with the carbon or nitrogen atom attached thereto, a 7-membered heterocyclic group is formed, which is optionally substituted with one or more R''. In some embodiments, R... d and R g It forms together with the carbon or nitrogen atoms connected to it. The Optionally replaced by one or more R''. In some implementations, R d and R g It forms together with the carbon or nitrogen atoms connected to it. , , , , ,or .

[0196] In some implementations, 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 heteroaryl. In some embodiments, each R'' is independently selected from deuterium, -F, -Cl, or C. 3-4 Cycloalkyl. In some embodiments, each R'' is independently selected from deuterium, halogens (e.g., F, Cl, Br, I) or cyclopropyl.

[0197] In some implementations, each R 2 and R 3 Each is independently selected from deuterium, halogens, -CN, -OH, -NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, 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 heterocyclic alkyl, C 6-12 Aryl or 5-6 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl O-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Alkyl, 3-6 heterocyclic alkyl, C 6-12 The aryl or 5-6 heteroaryl groups may optionally be substituted by 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.

[0198] In some implementations, each R 2 and R 3 Each is independently selected from deuterium, halogens, -CN, -OH, -NH2, and C. 1-4 Alkyl, C 2-4alkenyl, C 2-4 alkynyl group, 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 group, C 1-4 Alkyl O-, C 1-4 Alkyl NH- or (C 1-4 The alkyl group (2N-) 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.

[0199] In some implementations, each R 2 Replace in X 10 X 11 or X 12 superior.

[0200] In some implementations, each R 2 and R 3 Each is independently selected from deuterium, halogens, -CN, -OH, -NH2, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl or C 1-4 Alkyl O-. In some embodiments, each R 2 and R 3 Selected independently from deuterium, halogens, -CN, and C respectively. 1-3 Alkyl, Halogenated C 1-3 Alkyl, deuterated C 1-4 Alkyl or C 1-3 Alkyl O-.

[0201] In some implementations, each R 2 and R 3 Each is independently selected from deuterium, -F, -Cl, -Br, -CN, -CF3, -CD3 or CH3O-.

[0202] In some implementations, each R 2 and R 3 Each is independently selected from deuterium, -F, -Cl, -Br, -CN, -CF3, -CD3 or CH3O-.

[0203] In some implementations, each R 2Each is independently selected from halogens (e.g., -F, -Cl, -Br or -I), -CN, -OH, -NH2 or C. 1-3 Alkyl O-. In some embodiments, each R 2 Each is independently selected from -F or CH3O-. In some embodiments, each R 2 Each is selected independently from -F.

[0204] In some implementations, each R 3 Each is independently selected from halogens, -CN, -OH, or -NH2.

[0205] In some implementations, each R 3 Each can be independently selected from -CN, -F, or -Cl.

[0206] In some implementations, each R 3 Each is independently selected from -Cl.

[0207] In some implementations, m and p are independently selected from 0, 1, or 2.

[0208] In some implementation schemes, R 4 Selected from hydrogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, 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 quinone heteroaryl, C 3-6 cycloalkyl C 1-3 alkylene-, 3-6 membered heterocyclic alkyl 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 group, 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 quinone heteroaryl, C 3-6 cycloalkyl C 1-3 alkylene-, 3-6 membered heterocyclic alkyl C 1-3 Alkylene-, C6-10 Aryl C 1-3 alkylene- or 5-6-membered heteroaryl C 1-3 Alkyl groups are 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 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-6 heteroaryl.

[0209] In some implementation schemes, R 4 Selected from hydrogen, -CN, -OH, -NH2, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl O-, C 1-4 Alkyl S-, C 1-4 Alkyl NH-, (C 1-4 Alkyl)2N- or C 3-6 Cycloalkyl.

[0210] In some implementation schemes, R 4 Selected from C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 3-6 Cycloalkyl. In some embodiments, R 4 Selected from C 1-3 Alkyl, Halogenated C 1-3 Alkyl or C 3-4 Cycloalkyl.

[0211] In some implementation schemes, R 4 Selected from methyl, ethyl, CF3CH2-, isopropyl or cyclopropyl.

[0212] In some implementation schemes, R 4 Selected from C 1-3 Alkyl (e.g., methyl, ethyl or isopropyl).

[0213] In some implementation schemes, X 10 and X 11 Selected from CH, X 12 Selected from CH or N. In some implementations, X 10 X 11 and X 12 Selected from CH.

[0214] In some implementation schemes, X 13 and X15 Selected from CH or N, X 14 X 16 and X 17 Selected from CH. In some implementations, X 13 Selected from N, X 15 Selected from CH or N, X 14 X 16 and X 17 Selected from CH. In some implementations, X 13 and X 15 Selected from N, X 14 X 16 and X 17 Selected from CH. In some implementations, X 13 Selected from N, X 14 X 15 X 16 and X 17 Selected from CH. In some implementations, X 15 Selected from N, X 13 X 14 X 16 and X 17 Selected from CH.

[0215] In some implementation schemes, R t Selected from H or C 1-3 Alkyl group. In some embodiments, R t Selected from H.

[0216] In some implementation schemes, the structural portion Selected from In some implementations, the structural portion Selected from or In some implementations, the structural portion Selected from or .

[0217] In some implementation schemes, the structural portion Selected from , , , or .

[0218] In some implementation schemes, the structural portion Selected from In some implementations, the structural portion Selected from In some implementations, the structural portion Selected from .

[0219] In some implementation schemes, the structural portion Selected from or u is selected from 0, 1, 2, 3, or 4. In some implementations, the structural portion Selected from .

[0220] In some implementation schemes, the structural portion Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or In some implementations, the structural portion Selected from , , , , , , ,or .

[0221] In some implementation schemes, the structural portion Selected from In some implementations, the structural portion Selected from In some implementations, the structural portion Selected from In some implementations, the structural portion Selected from In some implementations, the structural portion Selected from In some implementations, the structural portion Selected from In some implementations, the structural portion Selected from , ,or In some implementations, the structural portion Selected from .

[0222] In some implementation schemes, the structural portion Selected from In some implementations, the structural portion Selected from , , , , , , , , , or In some implementations, the structural portion Selected from or In some implementations, the structural portion Selected from In some implementations, the structural portion Selected from .

[0223] In some implementation schemes, PTM, structural components or Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0224] In some implementation schemes, PTM, structural components or Selected from , , , , , , , , , or .

[0225] In some implementation schemes, PTM, structural components or Selected from .

[0226] On the other hand, this application relates to compounds of formula IV, V, VI, VIII, VIIIA, VIIIB, VIIIC, or VIIID, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0227]

[0228]

[0229]

[0230] Among them, X 18 Selected from CH or N;

[0231] X 19 Selected from NH or O;

[0232] u is selected from 0, 1, 2, 3, 4, 5 or 6;

[0233] t is selected from 0, 1, 2, or 3;

[0234] 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 and R t The definition is as stated in this application.

[0235] In some implementation schemes, X 18 Selected from CH. In some implementations, X 18 Selected from N. In some implementations, X 19 Selected from NH.

[0236] In some implementations, u is selected from 1, 2, 3, or 4.

[0237] In some implementation schemes, the structural portion The definition is as shown in the structural section of this application. Definition.

[0238] In some implementations, ring B is selected from phenyl.

[0239] In some implementation schemes, the structural portion Selected from , , , or .

[0240] In some implementation schemes, the structural portion Selected from , , , , , , or .

[0241] In some implementation schemes, the structural portion Selected from , or In some implementations, the structural portion Selected from , or .

[0242] In some implementation schemes, the structural portion Selected from .

[0243] In some implementation schemes, the structural portion Selected from In some implementations, the structural portion Selected from .

[0244] This application relates to compounds of formula XI, structural moieties thereof, derivatives thereof (e.g., protac), stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0245]

[0246] in,

[0247] X 5 and L 1 The definitions are as described in this application;

[0248] Ring B is selected from phenyl or 5-6-membered heteroaryl groups;

[0249] X 18 Selected from CH or N;

[0250] X 23 Selected from bond, CH2 or NH, X 24 X 25 and X 26 Each is independently selected from CH2 or NH;

[0251] Each R 1b The following groups, each independently selected from deuterium, halogens, -OH, -NH2, -CN, and optionally substituted by 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 group, C 3-10 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0252] n is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0253] In some embodiments, ring B is selected from phenyl or 6-membered heteroaryl. In some embodiments, ring B is selected from phenyl.

[0254] In some implementation schemes, X 18 Selected from N.

[0255] In some implementation schemes, the structural portion Selected from , , , , , , or .

[0256] In some implementation schemes, X 23 X 24 X 25 and X 26 Each is independently selected from CH2. In some implementations, X 23 X 24 X 25 and X 26 One of them is selected from NH, and the others are selected from CH2.

[0257] In some implementations, each R 1b The following groups, independently selected from deuterium, halogens, -OH, -NH2, -CN, -CHO, and optionally substituted by one or more substituents: C 1-6 Alkyl, C1-6 Alkoxy, (C 1-6 Alkyl) NH-, (C 1-6 Alkyl)2N-, Halogenated C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl or C 1-6 Alkyl OC(O)-.

[0258] In some implementations, each R 1b Independently selected from deuterium, halogens, -OH, -NH2, -CN, -CHO, C 1-6 Alkyl, C 4-12 cycloalkyl (such as C) 4-10 C 4-8 Or C 4-6 ), 4-12 membered heterocyclic alkyl groups (e.g., 4-10 or 5-6 membered) 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, diC 1-4 Alkylamino, or -COOH.

[0259] In some implementations, each R 1b C is independently selected from those optionally substituted with one or more halogens, -OH, -NH2, or -CN. 1-4 Alkyl group. In some embodiments, each R 1b Selected from HOCH2-.

[0260] In some implementations, n is selected from 0 or 1.

[0261] This application relates to the following compounds, structural moieties, stereoisomers thereof, derivatives thereof (such as PROTAC), or pharmaceutically acceptable salts thereof:

[0262] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0263] On the other hand, this application relates to the use of the aforementioned compound (e.g., a general formula compound or a specific compound), its structural moiety, its isomers (e.g., stereoisomers), and its derivatives in a PROTAC molecule. On the other hand, this application relates to the use of the aforementioned compound (e.g., a general formula compound or a specific compound), its structural moiety, its isomers (e.g., stereoisomers), and its derivatives as a part of a PROTAC molecule. On the other hand, this application relates to the existence of the aforementioned compound (e.g., a general formula compound or a specific compound), its structural moiety, its isomers (e.g., stereoisomers), and its derivatives in the form of a PROTAC molecule. On the other hand, this application relates to the use of the aforementioned compound (e.g., a general formula compound or a specific compound), its structural moiety, its isomers (e.g., stereoisomers), and its derivatives in the form of a PROTAC molecule for degrading proteins, for example, the degradation of the protein by the aforementioned compound (e.g., a general formula compound or a specific compound), its structural moiety, its isomers (e.g., stereoisomers), and its derivatives in the form of a PROTAC molecule. On the other hand, this application relates to the use of the aforementioned compound (e.g., a general formula compound or a specific compound), its structural moiety, its isomers (e.g., stereoisomers), and its derivatives in the form of a PROTAC molecule for degrading proteins. This application relates to the use of the aforementioned compounds (e.g., general formula compounds or specific compounds), structural moieties, isomers (e.g., stereoisomers), and derivatives (e.g., as preparation intermediates) in the preparation of PROTAC molecules. This application also relates to the use of the aforementioned compounds (e.g., general formula compounds or specific compounds), structural moieties, isomers (e.g., stereoisomers), and derivatives (e.g., as preparation intermediates) in the preparation of protein degrading agents.

[0264] "Derivative" refers to a new compound or group of new compounds resulting from the substitution or replacement of one or more hydrogen atoms in the basic structure of a parent compound with other groups or structural parts. In this application, derivative refers to a derived compound that retains the parent structure. For example, a parent compound is derived into a PROTAC molecule, specifically a PTM-L-CLM molecule (i.e., the compound of formula I described in this application, its stereoisomer, or its pharmaceutically acceptable salt), where PTM is the protein target portion that binds to the target protein or target polypeptide (as described in this application, the portion that binds to the target protein); L is a linker group; and CLM refers to the E3 ubiquitin ligase-binding portion.

[0265] Among them, "PROTAC (proteolysis targeting chimera) molecules" are a class of bifunctional compounds capable of simultaneously binding to both the target protein and the E3 ubiquitin ligase. These compounds can induce the target protein to be recognized by the cell's proteasome, causing degradation of the protein and effectively reducing the content of the target protein in the cell. Specific examples include compounds of formula I, II, or III described in this application, their stereoisomers, or pharmaceutically acceptable salts thereof. Specifically, examples include compounds of formula I described in this application, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0266] In some embodiments, the CLM described in this application may be selected from compounds of formula XI, structural moieties, derivatives thereof (e.g., protac), or groups formed from pharmaceutically acceptable salts thereof.

[0267] In some embodiments, the CLM described in this application may be selected from the following compounds, structural moieties, and groups formed from their derivatives (e.g., protac): , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

[0268] In some embodiments, the aforementioned heterocyclic alkenyl, heteroaryl, heterocyclic alkyl, or heteroalkylene group comprises one or more heteroatoms or heteroatomic groups 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 aforementioned heterocyclic alkenyl, heteroaryl, heterocyclic alkyl, or heteroalkylene group comprises one or more heteroatoms or heteroatomic groups independently selected from -O-, -NH-, -N-, or -S-; in some embodiments, the aforementioned heterocyclic alkenyl, heteroaryl, heterocyclic alkyl, or heteroalkylene group comprises one or more heteroatoms or heteroatomic groups independently selected from -O-, -NH-, or -N-. In some embodiments, the number of said heteroatoms or heteroatomic groups 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.

[0269] In some embodiments, the heteroatom in the heterocyclic alkenyl group is selected from N, NH, O, or S. In some embodiments, the heteroatom in the heterocyclic alkenyl group is selected from N, O, or S. In some specific embodiments, the heteroatom in the heterocyclic alkenyl group is selected from N or O. In some embodiments, the number of heteroatoms in the heterocyclic alkenyl group is selected from 1, 2, 3, 4, 5, or 6. In some embodiments, the number of heteroatoms in the heterocyclic alkenyl group is selected from 1, 2, 3, or 4. In some embodiments, the number of heteroatoms in the heterocyclic alkenyl group is selected from 1, 2, or 3. In some specific embodiments, the number of heteroatoms in the heterocyclic alkenyl group is selected from 1 or 2.

[0270] In some embodiments, the halogenation is selected from fluorinated, chlorinated, or brominated compounds. In some embodiments, the halogenation is selected from fluorinated or chlorinated compounds. In some embodiments, the halogenation is selected from fluorinated compounds.

[0271] In some implementations, 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 implementations, C 1-6 Selected from C 1-4 C 1-3 or C 1-2 In some implementations, the C 1-4 Selected from C4, C3, C2, or C1. In some embodiments, C...1-3 Choose from C3, C2, or C1.

[0272] In some implementations, the C 2-10 Selected from C 2-8 C 2-6 C 2-5 C 2-4 C 2-3 In some implementations, the C 2-6 Selected from C 2-4 or C 2-3 In some implementations, the C 2-4 Choose from C4, C3, or C2.

[0273] In some implementations, the C 3-6 Selected from C 3-5 C 3-4 C 4-6 C 4-5 or C 5-6 In some implementations, the C 6-10 Selected from C 6-9 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 implementations, 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 9-12or C 9-10 In some implementations, the C 3-15 Selected from C 3-12 Or C 3-10 In some implementations, the C 3-12 Selected from C 3-10 In some implementations, the C 6-12 Selected from C 6-10 .

[0274] In some implementations, 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 implementations, 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, or 9-10 yuan. In some implementations, 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, and 9-10 yuan. In some implementations, the 3-15 yuan is selected from 3-12 yuan or 3-10 yuan. In some implementations, the 3-12 yuan is selected from 3-10 yuan. In some implementations, the 5-12 yuan is selected from 5-10 yuan.

[0275] It should be understood that any embodiment of the compounds of this application as described above and any specific ring A, ring B, ring C, R in the compounds of this application as described above are not necessarily related to this application. 1 , n, X 5 L, X 6 R 2 R 3 R 4 Any specific substituent described in the embodiments, rings G, E, etc., can be independently combined with other embodiments of this application and / or substituents of compounds to form embodiments of the invention not specifically described above. Furthermore, in the specific embodiments and / or claims, any specific ring A, ring B, ring C, R, etc., can be combined with other substituents of the compounds to form embodiments of the invention not specifically described above. 1 , n, X 5 L, X 6 R 2 R 3 R 4 In cases where the range of substituents such as ring G, ring E, etc., is disclosed, it should be understood that one or more substituents may be deleted from that range, and the remaining range of substituents should also be considered as an embodiment of this application.

[0276] In some embodiments, the VHL E3 ubiquitin ligase binding moiety is selected from:

[0277] or .

[0278] In some embodiments, the IAP E3 ubiquitin ligase binding moiety is selected from:

[0279] .

[0280] In some embodiments, the MDM2 E3 ubiquitin ligase binding moiety is selected from:

[0281] or .

[0282] In some implementations, the CLM is selected from the following structural parts:

[0283] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ,

[0284] Among them, R aEach group is independently selected from hydroxyl, halogen, amino, cyano, or C. 1-8 alkyl;

[0285] q is selected from 0, 1, 2, or 3;

[0286] X 4 Selected from N or CH which may be optionally substituted.

[0287] In some implementations, R a Each group is independently selected from hydroxyl, halogen, amino, cyano, or C. 1-6 alkyl.

[0288] In some implementations, R a Each group is independently selected from hydroxyl, halogen, amino, cyano, or C. 1-4 alkyl.

[0289] In some implementations, R a Each group is independently selected from hydroxyl, halogen, amino, cyano, or C. 1-3 alkyl.

[0290] In some implementations, R a Each group is independently selected from hydroxyl, halogen, amino, or cyano groups.

[0291] In some implementations, R a They are selected independently from halogens or amino groups.

[0292] In some implementations, q is selected from 0, 1, or 2.

[0293] In some implementation schemes, X 4 Selected from N or CH, wherein CH is optionally substituted by the following substituents: hydroxyl, halogen, amino, cyano, or C. 1-4 alkyl.

[0294] In some implementation schemes, X 4 Selected from N. In some implementations, X 4 Selected from CH.

[0295] In some implementations, the CLM is selected from the following structural parts:

[0296] , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , or .

[0297] This application does not relate to or relates to the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0298] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

[0299] , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , ,

[0300] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0301] This application also relates to the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0302] , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、

[0303] 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , ,

[0304] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

[0305] This application also relates to the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0306] , , , , , , , , , , , , , ,

[0307] , , , , , , , , , , , ,

[0308] , , ,or .

[0309] This application also covers solutions obtained by arbitrarily combining, deleting, or changing the above-described embodiments.

[0310] On the other hand, this application relates to a pharmaceutical composition containing the compounds, structural portions (compounds or derivatives containing the structural portions), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof as described above in this application. Optionally, the pharmaceutical composition of this application may further include pharmaceutically acceptable excipients.

[0311] On the other hand, this application relates to the use of the aforementioned compounds, structural moieties (compounds or derivatives containing the structural moieties), their derivatives, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases.

[0312] On the other hand, this application relates to the use of the aforementioned compounds, structural moieties (compounds or derivatives containing the structural moieties), their derivatives, their stereoisomers, or pharmaceutically acceptable salts thereof, or their pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of conditions by degrading target proteins (such as BCL6) that bind to a target ligand.

[0313] On the other hand, this application relates to the use of the aforementioned compounds, structural moieties (compounds or derivatives containing the structural moieties), their derivatives, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases by binding to cerebellar proteins in vivo.

[0314] On the other hand, this application relates to the use of the aforementioned compounds, structural moieties (compounds or derivatives containing the structural moieties), their derivatives, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for the prevention or treatment of diseases related to BCL6.

[0315] This application relates to methods for treating or preventing diseases, including administering a therapeutically effective amount of the aforementioned compound, structural portion (compound or derivative containing 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.

[0316] This application relates to a method for treating or preventing diseases in mammals by degrading target proteins (such as BCL6) that bind to a target ligand, including administering a therapeutically effective amount of the aforementioned compound, structural moiety (compound or derivative containing the structural moiety), derivative thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, of this application to a mammal (preferably a human) requiring such treatment.

[0317] This application relates to methods for treating or preventing conditions by binding to cerebellar proteins in vivo, including administering a therapeutically effective amount of the aforementioned compound, structural portion (compound or derivative containing the structural portion), derivative thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, of this application to a mammal (preferably a human) requiring such treatment.

[0318] On the other hand, this application relates to compounds, structural portions (compounds or derivatives containing the structural portion), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of diseases.

[0319] On the other hand, this application relates to a method for treating BCL6-related diseases in mammals, including administering a therapeutically effective amount of the aforementioned compound, structural portion (compound or derivative containing the structural portion), derivative thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, to a mammal (preferably a human) requiring such treatment.

[0320] On the other hand, this application relates to the aforementioned compounds, structural portions (compounds or derivatives containing the structural portion), derivatives thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the prevention or treatment of conditions by degrading target proteins (such as BCL6) that bind to target ligands.

[0321] On the other hand, this application relates to the aforementioned compounds, structural portions (compounds or derivatives containing the structural portion), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of conditions that are treated by binding to cerebellar proteins in vivo.

[0322] On the other hand, this application relates to the use of the aforementioned compounds, structural moieties (compounds or derivatives containing the structural moieties), their derivatives, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of diseases.

[0323] On the other hand, this application relates to the aforementioned compounds, structural portions (compounds or derivatives containing the structural portion), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the prevention or treatment of diseases related to BCL6.

[0324] On the other hand, this application relates to the use of the aforementioned compounds, structural moieties (compounds or derivatives containing the structural moieties), their derivatives, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of conditions treated by degradation of target proteins (such as BCL6) that bind to a target ligand.

[0325] On the other hand, this application relates to the use of the aforementioned compounds, structural portions (compounds or derivatives containing the structural portion), derivatives thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of conditions treated by binding to cerebellar proteins in vivo.

[0326] On the other hand, this application relates to the use of the aforementioned compounds, structural moieties (compounds or derivatives containing the structural moieties), their derivatives, their stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of diseases related to BCL6.

[0327] In some specific embodiments, the aforementioned disease or BCL6-related disease is selected from conditions treated by degrading and / or inhibiting the protein (BCL6) that binds to the BCL6 target protein ligand; in some specific embodiments, the aforementioned BCL6-related disease is selected from conditions treated by binding to the cerebellar protein in vivo; in some embodiments, the aforementioned disease or condition is selected from cancers, such as hematologic malignancies (lymphoma), further such as diffuse large B-cell lymphoma.

[0328] In some specific embodiments, the aforementioned diseases or conditions treated by binding to cerebellar proteins in vivo and / or by degrading target proteins that bind to target ligands are selected from BCL6-related diseases; in some specific embodiments, the aforementioned diseases or BCL6-related diseases are selected from cancer.

[0329] In some embodiments, this application includes the variables defined above and their implementation schemes, as well as any combination thereof.

[0330] Technical effect

[0331] The compounds of this application exhibit binding and degradation activities against BCL6 protein (e.g., BCL6 in OCI-LY1 cells); and also demonstrate antiproliferative activity against cells expressing BCL6. Furthermore, the compounds of this application possess good in vitro liver microsomal stability and in vivo pharmacokinetic properties in mammals (e.g., mice, rats, and humans) (specifically, parameters such as AUC), and can inhibit tumor growth in vivo, showing promising potential for drug development.

[0332] definition

[0333] Unless otherwise stated, the following terms as used in this application shall have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0334] In this document, "one or more" refers to an integer from one to ten. For example, "one or more" means one, two, three, four, five, six, seven, eight, nine, or ten; in some embodiments, "one or more" is selected from one, two, three, four, five, or six. In some embodiments, "one or more" is selected from one, two, or three. In some embodiments, "one or more" is selected from one or two.

[0335] Unless otherwise specified, Used to represent Hydrogen atoms at any position of a group can be replaced by a group connected by a "-", such as by an "L".

[0336] The term "substituted" refers to the replacement of one or more hydrogen atoms or lone pairs of electrons on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced; oxoation does not occur on aromatic groups. For example, for It can be one or more R 1 Substituent substitution, wherein the R 1 It can replace on ring G or ring E, for example, on ring X. a X b X c X d X e X fand X g and its substituents, and -NH-.

[0337] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. “Optionally substituted” includes both unsubstituted and substituted forms; for example, an ethyl group “optionally” substituted with a halogen means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0338] C in this article m-n This means that the part has an integer number of carbon atoms within 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.

[0339] When any variable (such as R) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group contains two Rs, then each R has an independent option.

[0340] When a bond cross-bonds two atoms in a ring (including monocyclic, fused, or spirocyclic rings), this bond can bond with any atom in the ring (including monocyclic, fused, or spirocyclic rings). For example, structural units. This indicates that the bonds on both sides can be connected to any two different atoms in ring A, ring B, or ring C; for example... This 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... This indicates that the bonds on both sides can be connected to any two different atoms in the four rings of the system.

[0341] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0342] The term "hydroxyl group" refers to the -OH group.

[0343] The term "amino" refers to the -NH2 group.

[0344] The term "cyano" refers to the -CN group.

[0345] The term "alkyl" refers to a compound with the general formula C1. n H 2n+1The alkyl group is a hydrocarbon group. This alkyl group can be straight-chain or branched. For example, the term "C1-6 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 groups has the same definition as above.

[0346] The term "alkylene" refers to a divalent group formed by removing a hydrogen atom from any position of an alkyl group. For example, the term "C1-6 alkyl" refers to an alkylene group containing 1 to 6 carbon atoms; the term "C1-4 alkyl" refers to an alkylene group containing 1 to 4 carbon atoms, including but not limited to -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-.

[0347] The term "alkenyl" refers to a divalent group formed by removing a hydrogen atom from any position of an alkenyl group. For example, the term "C2-6 alkenyl" refers to an alkenyl group containing 2 to 6 carbon atoms; the term "C2-4 alkenyl" refers to an alkenyl group containing 2 to 4 carbon atoms, including but not limited to -CH2CH=CH-, -CH2CH2CH=CH-, or -CH2CH=CHCH2-.

[0348] The term "acetylenol" refers to a divalent group formed by removing a hydrogen atom from any position of an acetylenic group. For example, the term "C2-6 acetylenol" refers to an acetylenol containing 2 to 6 carbon atoms; the term "C2-4 acetylenol" refers to an acetylenol containing 2 to 4 carbon atoms, including but not limited to... , , or .

[0349] The term "heteroalkyl" refers to a straight-chain or branched heteroalkyl group composed of a certain number of carbon atoms and at least one heteroatom. It preferably has 1 to 14 carbon atoms in the chain, more preferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms, wherein the heteroatom is preferably selected from S, O, and N heteroatoms, and the number is preferably 1, 2, or 3. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroatom or heteroatomic 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, thioethers, etc., 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, C1-6 Alkylamino.

[0350] The term "heteroalkylene" refers to a divalent group formed by removing a hydrogen atom from any position of a heteroalkyl group.

[0351] The term "heteroalkyl" refers to a straight-chain or branched alkyl group composed of a certain number of carbon atoms and at least one heteroatom, preferably having 1 to 14 carbon atoms in the chain, more preferably 1 to 10 carbon atoms, even more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms, and preferably having 1, 2, or 3 heteroatoms selected from S, O, and N. For example, C m A heteroalkyl group is defined as an alkyl group with heteroatoms inserted into the chain, 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. Heteroatoms or heteroatomic groups can be located at any internal position of the heteroalkyl group, including positions where the hydrocarbon group is attached to the rest of the molecule. Exemplary heteroalkyl groups include alkyl ethers, secondary and tertiary alkylamines, amides, alkyl sulfides, etc., 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.

[0352] The term "heteroalkylene" refers to a divalent group formed by removing a hydrogen atom from any position of a heteroalkyl group.

[0353] The term "alkoxy" refers to -O-alkyl.

[0354] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

[0355] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbon ring that can exist as a monocyclic, bicyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 4- to 16-membered, 4- to 12-membered, 4- to 10-membered, or 4- to 8-membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, and cycloheptadienyl. , , , , or wait.

[0356] The term "cycloalkyl" refers to a fully saturated carbon ring that can exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 16-membered ring (e.g., a 3- to 10-membered ring, or a 5- to 8-membered ring). 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.

[0357] The term "heterocyclic alkyl" refers to a fully saturated cyclic group that may exist as a monocyclic, bridged, or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3- to 16-membered ring, a 3- to 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 independently selected from sulfur, oxygen, and / or nitrogen (preferably 1 or 2 heteroatoms). Examples of 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, cyclothioethylene, and cycloazoethylene; non-limiting examples of 4-membered heterocyclic alkyl groups include, but are not limited to, acridine, oxadiazolyl, and thiobutyl; examples of 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, and tetrahydropyrazolyl; examples of 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxane, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, and 1,4-dithiaalkyl; and examples of 7-membered heterocyclic alkyl groups include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Monocyclic heterocyclic alkyl groups having 5 or 6 ring atoms are preferred.

[0358] The term "spirocyclic ring" refers to a fully saturated or partially unsaturated polycyclic system in which the individual rings share a single carbon atom (called a spiro atom), including carbon rings and heterocyclic rings. Unless otherwise indicated, the spirocyclic ring is 5 to 20 rings, preferably 6 to 14 rings, and more preferably 8 to 12 rings. When the spirocyclic ring is a heterocyclic ring, one or more ring atoms in the polycyclic ring are selected from N, O, and S(O). n P(O) n (where n is 0, 1 or 2) heteroatoms (preferably 1 or 2 heteroatoms), and the remaining ring atoms are carbon atoms.

[0359] The term "spirocycloalkyl" refers to a fully saturated polycyclic aromatic hydrocarbon sharing a single carbon atom (called a spiro atom) between its rings. Unless otherwise indicated, the spirocycloalkyl group is 5 to 20 quinary members, preferably 6 to 14 quinary members, and more preferably 8 to 12 quinary members. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups according to the number of spiro atoms shared between the rings, preferably monospirocycloalkyl and bispirocycloalkyl, more preferably 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include... , , and .

[0360] The term "spiroheteroalkyl" refers to a fully saturated polycyclic ring in which one or more ring atoms are selected from N, O, and S(O). n P(O) n (where n is 0, 1, or 2) heteroatoms (preferably 1 or 2 heteroatoms), with the remaining ring atoms being carbon atoms. Unless otherwise indicated, the spiroheteroalkyl group is 5 to 20 quinary, preferably 6 to 14 quinary, and more preferably 6 to 10 quinary. Spiroheterocycles are classified into monospiroheterocycles, bispiroheterocycles, or multispiroheterocycles according to the number of shared spiro atoms between rings, preferably monospiroheterocycles or bispiroheterocycles, more preferably 4-quinary / 4-quinary, 4-quinary / 5-quinary, 4-quinary / 6-quinary, 5-quinary / 5-quinary, or 5-quinary / 6-quinary monospiroheterocycles. Non-limiting examples of spiroheteroalkyl groups include , , , , or wait.

[0361] The term "heterocyclic alkenyl" includes cycloalkenyl groups in which one or more carbon atoms (e.g., 1-5, 1-4, 1-3, 1-2) are substituted with heteroatoms, specifically, for example, cycloalkenyl groups in which at most 3 carbon atoms, at most 2 carbon atoms in one embodiment, or in another embodiment, 1 carbon atom is independently substituted with O, S, S(O), or N, provided that at least one cycloalkenyl carbon-carbon double bond is retained. Cyclic groups that can exist as monocyclic, bridged, or spirocyclic groups can be 3 to 16-membered rings (e.g., 3 to 12-membered, 5 to 8-membered rings, specifically 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered rings). Examples of heterocyclic alkenyl groups include, but are not limited to, dihydropyrroleyl, tetrahydropyridyl, tetrahydroazapyryl, azaspirooctene, etc. , , , , , , , , , , or wait.

[0362] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic ring with 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, anthracene, and 1,2,3,4-tetrahydronaphthalene.

[0363] The term "heterocyclic group" refers to a monocyclic or fused polycyclic system containing at least one (e.g., 1-5, 1-4, 1-3, 1-2) ring atoms selected from N, O, and S, with the remaining ring atoms being C, forming an unsaturated non-aromatic ring system. It may contain no double bonds or have at least one or more double bonds. Preferred heterocyclic groups have a single 4- to 8-membered ring, particularly a 5- to 8-membered ring (e.g., 5-, 6-, 7-, or 8-membered), or multiple fused rings containing 6 to 14, particularly 6 to 10 (e.g., 6, 7, 8, 9, or 10) ring atoms.

[0364] The term "heteroaryl" refers to a monocyclic or fused polycyclic system containing at least one (e.g., 1-5, 1-4, 1-3, 1-2) ring atoms selected from N, O, and S, with the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryls have a single 4- to 8-membered ring, particularly a 5- to 8-membered ring (e.g., 5-, 6-, 7-, or 8-membered), or multiple fused rings containing 6 to 14, particularly 6 to 10 (e.g., 6, 7, 8, 9, or 10) ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothiopheneyl, indoleyl, isoindoleyl, etc.

[0365] The terms “substituent,” “optionally substituted with one or more substituents,” or “optionally substituted,” refer to substitution or substituent substitution, including all substituents mentioned in the context of this document, such as the terms “halogen,” “deuterium,” etc., mentioned below. "-NH2", "-NH(C" 1-4 Alkyl group), -N(C) 1-4 Alkyl)2”, “-OH”, “-OC” 1-4 Alkyl group, -CN, C 1-4"alkyl", "3-6 membered heterocyclic alkyl", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include mercapto, 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 The substituents include heteroaryloxy, heteroarylthio, heteroarylalkylene, heteroarylalkoxy, heteroarylalkylthio, heterocyclic, heterocyclicoxy, heterocyclicthio, heterocyclicalkylene, heterocyclicalkoxy, heterocyclicalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group, ester group, and oxo, wherein the substituents are optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, 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(O)-alkyl, -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, heterocyclic, heterocyclic alkylene, heterocyclic oxy, heterocyclic alkyl, heterocyclic alkylalkylene, heterocyclic alkyloxy, heterocyclic alkyl, heterocyclic alkyloxy, heterocyclic alkyloxy, heteroaryl, heteroaryl alkylene, heteroaryloxy, aryl, aryl alkylene or aryloxy.

[0366] In some embodiments herein, the substituents are selected from deuterium, tritium, hydroxyl, mercapto, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, Halogenated -C 1-12 Alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halogenated - C 2-12 alkenyl, 3-12-membered cycloalkenyl, halo-3-12-membered cycloalkenyl, C 2-12 Alkyne group, halogenated -C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated-8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halogenated-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12Alkylthio, 6-10 aryl, 6-10 aryloxy, 6-10 arylthio, 6-10 arylC 1-12 Alkylene, 6-10 aryl C 1-12 Alkoxy, 6-10 aryl C 1-12 Alkylthio, 5-10 heteroaryl, 5-10 heteroaryloxy, 5-10 heteroarylthio, 5-10 heteroarylalkylene, 5-10 heteroarylalkoxy, 5-10 heteroarylalkylthio, 3-12 heterocyclic, 3-12 heterocyclic oxy, 3-12 heterocyclic thio, 3-12 heterocyclic C 1-12 Alkylene, 3-12 membered heterocyclic C 1-12 Alkoxy, 3-12 membered heterocyclic C 1-12 Alkylthio, C 1-12 Acyl group, C 1-12 Acyloxy group, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 The ester group and oxo group, wherein the substituent is optionally substituted by one or more substituents selected from: oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, diC 1-12 Alkylamino, halogenated C 1-12 Alkylamino, Halogenated diC 1-12 Alkylamino, carboxyl, -C(O)O-C 1-12 Alkyl group, -OC(O)- C 1-12 Alkyl group, -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 group, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl group, -S(O)2N(C) 1-12 Alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy group, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic alkyl group, 3-12-membered heterocyclic alkyl group C 1-12Alkylene, 3-12-membered heterocyclic alkyloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryl C 1-12 alkylene, 5-10 heteroaryloxy, 6-10 aryl, 6-10 aryl C 1-12 Alkylene or 6-10 aryloxy groups.

[0367] Unless otherwise specified, the term "heteroatom" means heteroatom or heterogroup (i.e., a group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and groups containing such heteroatoms, such as heteroatoms including but not limited to oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), silicon (Si), germanium (Ge), aluminum (Al), and boron (B), and specific heteroatoms or heterogroups such as: -O-, -S-, -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 "heterogeneous" means that the heteroatom or heteroatomic group (i.e., a group containing a heteroatom) is selected from oxygen, nitrogen, or sulfur.

[0368] The term "derivative" refers to a new compound or group of new compounds that are produced through one or more chemical reactions or structural evolution, retaining the basic structure of the parent compound but changing or modifying only the side chains, functional groups or substituents.

[0369] In this application, wavy lines are used ( ) represents one of the absolute configurations of a solid center (e.g. or one, specific express or ) or one of the relative configurations (e.g. express or When the compounds described herein contain an alkene double bond or other geometrically asymmetric centers, they include E and Z geometric isomers, unless otherwise specified. Similarly, all tautomer forms are included within the scope of this application.

[0370] Groups or structural portions 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, optionally read in a left-to-right order, are respectively connected to the left and right groups of the group or fragment in the general formula, for example, in L selected from -Cy 1 -LNK- when Cy 1 Selected from Following the reading order from left to right, Cy 1 The left side is connected to the PTM segment corresponding to the left side in the general formula, and the right side is connected to the right side segment. Connect, and the resulting fragment is Optionally, groups or structural moiety such as -LNK in this application 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 from right to left, corresponding to the left and right groups of the group or fragment in the general formula, for example, L is selected from -Cy 1 -LNK- when Cy 1 Selected from Following the reading order from right to left, Cy 1 The right side is connected to the PTM segment corresponding to the left side in the general formula, and the left side is connected to the segment corresponding to the right side in the general formula. The segments formed by the connection are Other groups are the same as described above.

[0371] The term “treatment” means administering the compound or formulation described in this application to improve or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) suppressing the disease or disease state, i.e., curbing its development; (ii) alleviating the disease or disease state, even if the disease or disease state subsides.

[0372] The term “prevention” means administering the compound or formulation described in this application to prevent a disease or one or more symptoms associated with the disease, including: preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0373] The term "therapeutic effective amount" means (i) the amount of the compound of this application used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and this disclosure.

[0374] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0375] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0376] The term "pharmaceutical composition" refers to a mixture of one or more compounds of this application or their salts with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of this application to an organism.

[0377] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0378] The word “comprise” or “comprise” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0379] Unless the context clearly indicates otherwise, singular terms in this document encompass the plural referents, and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" in this document is intended to include "and".

[0380] Unless otherwise stated, all figures used herein to indicate the amount of components, measurements, or reaction conditions should be understood to be modified by the term "about" in all cases. When used with percentages, the term "about" may mean, for example, ±1%, preferably ±0.5%, more preferably ±0.1%.

[0381] The compounds and intermediates of this application may also exist in different tautomer forms, and all such forms are included within the scope of this application. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low-barrier transitions. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons. Specifically, any compound of this disclosure, such as pyrazole alone or as part of a heterocyclic group, may exist in the form of two tautomers or any mixture of two tautomers, i.e. ,or This disclosure includes all possible tautomers of the compounds disclosed herein, as a single tautomer, or any mixture of said tautomers in any proportion.

[0382] This application also includes compounds of this application that are identical to those described herein, but with one or more atoms replaced by isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into compounds of this 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, etc.

[0383] Certain isotope-labeled compounds of this application (e.g., using...) 3 H and 14 Those labeled with C can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e. 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. The isotopically labeled compounds of this application can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0384] The compounds of this application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include enantiomers and diastereomers. The compounds containing asymmetric carbon atoms of this application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized using chiral starting materials or chiral reagents.

[0385] The pharmaceutical compositions of this application can be prepared by combining the compounds of this application with suitable pharmaceutically acceptable excipients.

[0386] Typical routes of administration for the compounds of this application or their pharmaceutically acceptable salts 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.

[0387] The pharmaceutical composition of this application can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0388] In some implementations, the pharmaceutical composition is in oral form.

[0389] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation.

[0390] The pharmaceutical composition is also suitable for parenteral administration.

[0391] In all methods of administration of the compounds of general formula I described herein, the daily dose is from 0.001 to 2000 mg / kg body weight, in the form of single or separate doses.

[0392] The compounds of this application can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of this application.

[0393] In this application, under non-configurational transformation chemical reaction conditions (e.g., without the use of a chiral catalyst), the compounds of this application prepared by chiral intermediates, such as the compounds in the examples, 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 compounds in the examples.

[0394] The chemical reactions in the specific embodiments of this application are carried out in a suitable solvent, which must be suitable for the chemical changes and the reagents and materials required in this application. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0395] An important consideration in synthetic route planning in this field is selecting appropriate protecting groups for reactive functional groups (such as amino groups in this application). For example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0396] In some embodiments, the compounds of this application can be prepared by those skilled in the art of organic synthesis using the following intermediates or their salts via a one- or multi-step reaction in the following route:

[0397]

[0398] Compounds of general formula I-1 and general formula I-2 yield compound of general formula II through substitution reactions;

[0399]

[0400] Compounds of formula I-3 and I-4 are converted to compound of general formula II by reductive amination.

[0401] Among them, L a Indicates halogen. PTM, L, ring W, R 1 , n, L1 and X 5 The definition is as stated in this application.

[0402] This application uses the following abbreviations:

[0403] KOSER stands for hydroxytoluenesulfonyl iodobenzene; DCM stands for dichloromethane; NBS stands for N-bromosuccinimide; DMSO stands for dimethyl sulfoxide; EA stands for ethyl acetate; DMF stands for N,N-dimethylformamide; NMP stands for N-methylpyrrolidone; DIPEA stands for N,N-diisopropylethylamine; THF stands for tetrahydrofuran; Pd2(dba)3 stands for tris(dibenzylideneacetone)dipalladium; BINAP stands for 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); DMAP stands for 4-dimethylaminopyridine; TBS-Cl stands for tert-butyldimethylchlorosilane. MeOH represents methanol; RuPhos represents 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl; Pd(OAc)2 represents palladium acetate; DCE represents 1,2-dichloroethane; EtOH represents ethanol; AcOH represents acetic acid; Et3N represents triethylamine; Boc represents tert-butyloxycarbonyl.

[0404] For clarity, the invention is further illustrated by examples, but these 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 Implementation

[0405] Preparation Example 1: Synthesis of intermediates z39 and z40

[0406]

[0407] Steps 1 and 2: Preparation of intermediate z39b

[0408] At 0°C, a solution of intermediate z8b (69 g) and diethyl 1,3-propanone dicarboxylate (57.0 g) in DCM (350 mL) was slowly added dropwise to a mixture of tetrabutylammonium iodide (52.0 g) in sodium bicarbonate aqueous solution (1 M, 1178 mL) and DCM (500 mL) with stirring. The reaction was carried out at room temperature. After the reaction was completed, the mixture was extracted with DCM, concentrated, and then slurried with methyl tert-butyl ether. The mixture was filtered, concentrated, and then ethanol (1000 mL) and potassium hydroxide aqueous solution (1 M, 1173 mL) were added. The reaction was carried out at 85°C. After the reaction was completed, dilute hydrochloric acid was added to adjust the pH to neutral, and the mixture was extracted with DCM. The extract was purified by silica gel column chromatography to obtain intermediate z39b (24 g). 1H NMR(500 MHz, CDCl3) δ 7.16 (t, J = 7.9 Hz, 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).

[0409] Step 3: Preparation of intermediate z39c

[0410] 0 o Under C and N2 protection, a 1M, 157 mL solution of potassium tert-butoxide in THF was slowly added dropwise to a 450 mL solution of (methoxymethyl)triphenylphosphine chloride (49.7 g) in THF. After the addition was complete, the resulting mixture was heated to 0°C. o The mixture was stirred at C for 0.5 h, then intermediate Z39b (23 g) was added, and the reaction was brought to room temperature. After the reaction was complete, saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was purified by silica gel column chromatography to obtain intermediate Z39c (28.6 g). 1 H NMR (500 MHz, DMSO) δ 7.07 –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).

[0411] Step 4: Preparation of intermediate z39d

[0412] Intermediate Z39C (28.8 g), THF (200 mL), and 2M hydrochloric acid (130 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added to adjust the pH to neutral, and the mixture was extracted with ethyl acetate. The extract was concentrated to obtain intermediate Z39D (25.9 g).

[0413] 1H NMR (500 MHz, CDCl3) δ 9.66 (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).

[0414] Following the method described in Preparation Example z22 or z23 of WO2023125944, perform the following steps 5-17:

[0415] Step 5: Preparation of intermediate z39e

[0416] Following the method described in step 6 of preparation examples z22 or z23, intermediate z39e (25.6 g) was synthesized by replacing intermediate z22f with intermediate z39d.

[0417] 1 H NMR (500 MHz, CDCl3) δ 7.09 – 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).

[0418] Step 6: Preparation of intermediate Z39F

[0419] Following the method described in step 5 of preparation examples z22 or z23, intermediate z39f (14.42 g) was synthesized by replacing intermediate z22e with intermediate z39e.

[0420] MS(ESI, [MH] - m / z: 191.1.

[0421] Steps 7-16: Preparation of intermediates z39 and z40

[0422] Following the method described in steps 7-16 of preparation examples z22 or z23, intermediate z22g was replaced with intermediate z39f, and intermediate z39 (2.20g) and intermediate z40 (2.31g) were finally synthesized.

[0423] Separation conditions for intermediates z39n-1 and z39n-2:

[0424] Instrument: SFC supercritical fluid chromatograph, column: CHIRALART Amylose-SA (5μm, 30*250mm), mobile phase A: carbon dioxide, mobile phase B: methanol (0.05% ammonia + 0.1% glacial acetic acid), intermediate z39n-1 (5.21g) and intermediate z39n-2 (5.10g) were obtained sequentially.

[0425] z39n-1:MS(ESI, [M+H] + ) m / z: 304.1. z39n-2:MS(ESI, [M+H] + m / z: 304.1.

[0426] Intermediate z39: 1 H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 7.51 (d, J = 8.0Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 4.57 – 4.51 (m, 1H), 4.49 (td, J = 5.3,1.7 Hz, 1H), 3.41 – 3.34 (m, 1H), 3.24 (t, J = 5.8 Hz, 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).

[0427] Intermediate z40: 1H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.1 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 4.53 (ddd, J = 11.9, 5.0, 1.9Hz, 1H), 4.49 (td, J = 5.3, 1.7 Hz, 1H), 3.40 – 3.35 (m, 1H), 3.24 (t, J =5.8 Hz, 2H), 3.01 – 2.87 (m, 2H), 2.82 – 2.71 (m, 2H), 2.60 (dq, J = 17.3,4.1 Hz, 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).

[0428] Preparation Example 8: Synthesis of Intermediate 5h

[0429]

[0430] Step 1: Preparation of intermediate 5a

[0431] In a reaction flask, sodium hydroxide (60% wt, 31.6 g) and DMF (1000 mL) were added sequentially. Under N2 protection, the mixture was cooled to 10 °C. o For reaction C, 4-fluoroindole (89.0 g) was added dropwise, and the mixture was stirred at room temperature for 30 min. Then, 2-iodopropane (85 mL) was slowly added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 2 h. The reaction system was then cooled to 10 °C, and sodium hydrogen (60% wt, 20 g) was added in portions. The mixture was stirred at room temperature for 30 min, and then 2-iodopropane (85 mL) was slowly added dropwise to the system, and the reaction was allowed to proceed 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).

[0432] MS(ESI, [M+H)) + m / z: 178.2.

[0433] Step 2: Preparation of intermediate 5b

[0434] In a reaction flask, intermediate 5a (132 g) and DMSO (500 mL) were added sequentially. The temperature was raised to 80 °C, and a solution of tert-butyl hydroperoxide (287 g) and elemental iodine (194 g) in DMSO (900 mL) was slowly added dropwise. After the addition was complete, the reaction was maintained at 80 °C. Upon completion of the reaction, saturated sodium sulfite was added to quench the reaction. The mixture was extracted with ethyl acetate, and the extract was purified by silica gel column chromatography to obtain intermediate 5b (63.0 g). MS (ESI, [M+H)) + m / z: 208.2.

[0435] Step 3: Preparation of intermediate 5c

[0436] Intermediate 5b (60.5 g), acetonitrile (500 mL), water (1000 mL), and NBS (67.6 g) were added sequentially to a reaction flask, and the reaction was carried out 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 (500 MHz, DMSO) δ7.92 (dd, J = 8.5, 7.3 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 4.43 (hept, J = 6.9Hz, 1H), 1.40 (d, J = 6.9 Hz, 6H).

[0437] Step 4: Preparation of intermediates over 5 days

[0438] 0 o C. Under nitrogen protection, trimethylsilyldiazomethane (2M, 67.3 mL) was slowly added dropwise to an ethanol mixture (1000 mL) containing intermediate 5c (35 g) and triethylamine (33.9 mL) under stirring. The reaction was carried out at room temperature. After the reaction was completed, the reaction mixture was concentrated and subjected to silica gel column chromatography to obtain intermediate 5d (19.7 g).

[0439] MS(ESI, [M+H)) + m / z: 300.2.

[0440] Step 5: Preparation of intermediate 5e

[0441] Intermediate 5d (19 g), 2-bromo-N-methylacetamide (11.55 g), DMF (250 ml), and cesium carbonate (41.3 g) were added sequentially to a reaction flask, and the reaction was carried out at room temperature. After the reaction was complete, water was added, and the mixture was filtered. The filter cake was dried to obtain intermediate 5e (7.1 g). MS (ESI, [M+H)) + m / z: 371.1.

[0442] Step 6: Preparation of intermediate 5f

[0443] 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 sequentially to a reaction flask. The reaction was carried out at 100 °C under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, diluted with dichloromethane, filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate 5f (3.0 g). MS (ESI, [M+H)) + m / z: 472.2.

[0444] Step 7: Preparation of 5g of intermediate

[0445] Intermediate 5f (3 g), hydroxylamine hydrochloride (0.884 g), sodium acetate (1.566 g), and methanol (50 mL) were added sequentially to a reaction flask, and the reaction was carried out at room temperature. After the reaction was complete, the concentrated reaction solution was purified by silica gel column chromatography to obtain intermediate 5 g (1.0 g). MS (ESI, [M+H)) + m / z: 308.2.

[0446] Step 8: Preparation of intermediates over 5 hours

[0447] 5 g (0.6 g) of intermediate, 10 mL of DMF, 1.023 mL of DIPEA, and 466 mg of 2,4,5-trichloropyrimidine were added sequentially to a reaction flask, and the reaction was carried out at 70 °C. After the reaction was completed, the mixture was cooled to room temperature, water was added, and the mixture was filtered. The filter cake was dried to obtain 0.8 g of intermediate 5 h. MS (ESI, [M+H)) + m / z: 454.1.

[0448] Preparation Example 10: Synthesis of Intermediate Z47

[0449]

[0450] Step 1: Preparation of intermediate z47a

[0451] Sodium borohydride (25 g) was added to a methanol (1200 mL) solution of intermediate z39b (64 g) in an ice bath, and the reaction was carried out at 5 °C. After the reaction was complete, the reaction was quenched with 2 M hydrochloric acid aqueous solution, extracted with dichloromethane, and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate z47a (54 g). MS (ESI, [M+H)) + m / z: 193.12.

[0452] Step 2: Preparation of intermediate z47b

[0453] Acetic anhydride (12 g) was added dropwise to a solution of intermediate Z47a (15 g), triethylamine (15.5 g), and DMAP (0.4 g) in dichloromethane (500 mL) under ice bath conditions, and the reaction was carried out at room temperature. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate Z47b (18.6 g). MS (ESI, [M+H)) + m / z: 235.1.

[0454] Step 3: Preparation of intermediate z47c

[0455] Under ice bath conditions, 243 mL of 1 M boron tribromide DCM solution was added dropwise to 1000 mL of dichloromethane solution containing intermediate z47b (18 g), and the reaction was carried out at room temperature. After the reaction was complete, water was added to quench the reaction, followed by extraction with dichloromethane and concentration. The concentrate was purified by silica gel column chromatography to obtain intermediate z47c (15.5 g). MS (ESI, [M+H)) + m / z: 221.11.

[0456] Step 4: Preparation of intermediate z47d

[0457] 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, and the reaction was carried out at -5 °C. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with dichloromethane and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate Z47D (20 g). MS (ESI, [M+H)) + m / z: 263.12.

[0458] Step 5: Preparation of intermediate z47e

[0459] Intermediate Z47D (13 g), zirconium tetrachloride (46 g), and dichloromethane (250 mL) were added to a reaction flask and reacted at 40 °C. After the reaction was completed, 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).

[0460] MS(ESI, [M+H)) + m / z: 263.12.

[0461] Step 6: Preparation of intermediate z47f

[0462] Intermediate Z47e (7.5 g), sodium hydroxide (5.72 g), ethanol (250 mL), and water (150 mL) were added to a reaction flask, and the reaction was carried out at 25 °C. After the reaction was complete, 2 M hydrochloric acid aqueous solution was added to adjust the pH to less than 7. The mixture was extracted with dichloromethane and concentrated. The concentrate was purified by silica gel column chromatography to obtain intermediate Z47f (6.23 g). MS (ESI, [M+H) + m / z: 221.11.

[0463] Step 7: Preparation of intermediate z47g

[0464] At -5°C, TBS-Cl (5.54 g) was added in portions to a solution of intermediate z47f (6.23 g) and imidazole (5.78 g) in dichloroethane (200 mL), and the reaction was carried out at 75°C. After the reaction was complete, the reaction was quenched with water, extracted with dichloromethane, and concentrated. The concentrate was purified by silica gel column chromatography to give intermediate z47g (7.8 g). MS (ESI, [M+H)) + m / z: 335.20.

[0465] Step 8: Preparation of intermediate z47h

[0466] Intermediate Z47 g (7.8 g), diethyl carbonate (13.77 g), toluene (200 mL), and sodium hydride (4.66 g) were added to a reaction flask, and the reaction was carried out at 120 °C. After the reaction was completed, the reaction was quenched with saturated citric acid aqueous solution, extracted with ethyl acetate, and concentrated. The concentrate was purified by silica gel column chromatography to give intermediate Z47 h (9.23 g). MS (ESI, [M+H)) + m / z: 361.18.

[0467] Step 9: Preparation of intermediate z47i

[0468] Intermediate Z47H (9.14 g), 50 wt% hydroxylamine aqueous solution (41.90 g), and ethanol (100 mL) were added to a reaction flask, and the reaction was carried out at 85 °C. After the reaction was completed, the reaction was quenched with saturated citric acid aqueous solution, extracted with ethyl acetate, and concentrated to obtain intermediate Z47i (10.48 g). MS (ESI, [M+H)) + m / z: 376.19.

[0469] Step 10: Preparation of intermediate z47j

[0470] Intermediate Z47i (10.48 g), ethanol (300 mL), and concentrated sulfuric acid (13.41 g) were added to a reaction flask, and the reaction was carried out at 70 °C. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate and concentrated. The concentrate was purified by silica gel column chromatography to give intermediate Z47j (6.27 g). MS (ESI, [M+H)) + m / z: 290.13.

[0471] Step 11: Preparation of intermediate z47

[0472] At -5°C, a 1M potassium tert-butoxide solution in THF (9.33 mL) was added dropwise to an intermediate z47j (3.00 g) and an acrylamide (0.81 g) solution in THF (250 mL), and the reaction was carried out at 25°C. After the reaction was completed, a saturated ammonium chloride aqueous solution was added to quench the reaction. Ethyl acetate was used for concentration, and the concentrate was purified by silica gel column chromatography to obtain intermediate z47 (1.44 g).

[0473] MS(ESI, [M+H)) + m / z: 315.13. 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 4.74 (d, J = 4.1 Hz, 1H), 4.53 (dd, J = 11.9, 5.0 Hz, 1H), 3.85 (s, 1H), 3.27 (dd, J = 14.6, 8.9 Hz,1H), 3.17 (d, J = 5.2 Hz, 1H), 3.06 (dd, J = 14.3, 9.2 Hz, 1H), 2.74 (td, J =16.1, 10.2 Hz, 3H), 2.60 (dd, J = 17.4, 4.2 Hz, 1H), 2.17 (dd, J = 11.4, 6.7Hz, 1H), 1.93 (p, J = 10.6 Hz, 2H), 1.45 (d, J = 13.6 Hz, 2H).

[0474] Preparation Example 13: Synthesis of intermediates z13-1 and z13-2

[0475]

[0476] Step 1: Synthesis of intermediate z13b

[0477] Intermediate Z13a (100 g), diethyl carbonate (335 g), toluene (1500 mL), and sodium hydride (113 g) were added sequentially to the reaction flask. The reaction was carried out at 120 °C. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate Z13b (139 g).

[0478] MS(ESI, [M+H)) + m / z: 249.10

[0479] Step 2: Synthesis of intermediate z13c

[0480] Intermediate z13b (60 g), trifluoroacetic acid (600 mL) and triethylsilane (56 g) were added sequentially to the reaction flask. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was directly concentrated and purified by silica gel column chromatography to obtain intermediate z13c (27 g).

[0481] MS(ESI, [M+H)) + m / z: 235.13

[0482] Step 3: Synthesis of intermediate z13d

[0483] Intermediate Z13C (70 g) and tetrahydrofuran (1000 mL) were added sequentially to the reaction flask. The temperature was lowered to 0°C, and lithium aluminum hydride (18 g) was added in portions. The reaction was carried out at 25°C. After the reaction was completed, the reaction solution was quenched with water, extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate Z13D (34 g).

[0484] MS(ESI, [M+H)) + m / z: 193.12

[0485] Step 4: Synthesis of intermediate z13e

[0486] Intermediate Z13D (33 g) and dichloromethane (2000 mL) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and boron tribromide (2 M, dichloromethane solution, 257 mL) was added dropwise. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was quenched with water, extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to obtain intermediate Z13E (27 g).

[0487] MS(ESI, [M+H)) + m / z: 179.23

[0488] Step 5: Synthesis of intermediate z13f

[0489] Intermediate Z13e (33 g), dichloromethane (2500 mL), triethylamine (366 g), and 4-dimethylaminopyridine (11 g) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and acetic anhydride (256 mL) was added dropwise. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was quenched with water, extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to obtain intermediate Z13f (247 g).

[0490] MS(ESI, [M+H)) + m / z: 263.12

[0491] Step 6: Synthesis of intermediate z13g

[0492] Intermediate Z13F (216 g), ethanol (2100 mL), water (1000 mL), and sodium hydroxide (165 g) were added sequentially to the reaction flask. The reaction was carried out at 25 °C. After the reaction was completed, the mixture was extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate Z13F (181 g).

[0493] MS(ESI, [M+H)) + m / z: 263.12

[0494] Step 7: Synthesis of intermediate z13h

[0495] Intermediate z13 g (290 g), o-dichlorobenzene (1500 mL) and anhydrous aluminum chloride (295 g) were added sequentially to the reaction flask. The reaction was carried out at 150 °C. After the reaction was completed, saturated citric acid aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate, the extract was concentrated, and purified by silica gel column chromatography to obtain intermediate z13 h (216 g).

[0496] MS(ESI, [M+H)) + m / z: 221.11

[0497] Step 8: Synthesis of intermediate z13i

[0498] Intermediate Z13h (166 g), dichloromethane (1600 mL), imidazole (103 g), and tert-butyldimethylchlorosilane (284 g) were added sequentially to the reaction flask. The reaction was carried out 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 Z13i (258 g).

[0499] MS(ESI, [M+H)) + m / z: 335.20

[0500] Step 9: Synthesis of intermediate z13j

[0501] Intermediate Z13i (279 g), toluene (2900 mL), and diethyl carbonate (493 g) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and sodium hydride (167 g) was added in portions. The reaction was carried out at 120 °C. After the reaction was completed, the mixture was extracted with ethyl acetate, the extract was concentrated, and purified by silica gel column chromatography to obtain intermediate Z13j (271 g).

[0502] MS(ESI, [M+H)) + m / z: 361.18

[0503] Step 10: Synthesis of intermediate z13k

[0504] Intermediate Z13J (105 g), ethanol (800 mL), and 50% hydroxylamine aqueous solution (106 g) were added sequentially to the reaction flask. The reaction was carried out at 70 °C. After the reaction was completed, the mixture was extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate Z13K (80 g).

[0505] MS(ESI, [M+H)) + m / z: 376.19

[0506] Step 11: Synthesis of intermediates z13l, z13m-1 and z13m-2

[0507] Intermediate Z13K (105 g), ethanol (1100 mL), and sulfuric acid (41 g) were added sequentially to the reaction flask. The reaction was carried out at 70 °C. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate Z13L (80 g).

[0508] Resolution conditions of z13l: Instrument: YMC high-pressure preparative chromatograph, column: CHIRALART Amylose-SA (020, 5μm, 30*250mm), mobile phase A: ethanol, mobile phase B: n-hexane, to obtain intermediate z13m-1 (35 g) and intermediate z13m-2 (35 g) in sequence.

[0509] z13l:MS(ESI, [M+H) + m / z: 290.13

[0510] z13m-1:MS(ESI, [M+H) + m / z: 290.13

[0511] z13m-2: MS(ESI, [M+H]) +m / z: 290.13

[0512] Step 12: Synthesis of intermediate z13-1

[0513] Intermediate Z13m-1 (21 g), tetrahydrofuran (500 mL), and acrylamide (5.09 g) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and potassium tert-butoxide (1 M, tetrahydrofuran solution, 67 mL) was added dropwise. The reaction was carried out at 25 °C. After the reaction was completed, the mixture was extracted with ethyl acetate, the extract was concentrated, and purified by silica gel column chromatography to obtain intermediate Z13-1 (18 g).

[0514] MS(ESI, [M+H)) + m / z: 315.13

[0515] 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 4.60 (t, J = 5.3 Hz, 1H), 4.53 (dd, J = 11.8, 5.0Hz, 1H), 3.43 (t, J = 5.8 Hz, 2H), 3.09 – 3.01 (m, 1H), 2.95 (dd, J = 17.1,4.9 Hz, 1H), 2.89 – 2.71 (m, 2H), 2.64 – 2.53 (m, 2H), 2.46 (td, J = 12.0,4.4 Hz, 1H), 2.18 (dq, J = 13.8, 4.9 Hz, 1H), 2.07 – 2.00 (m, 1H), 1.93 –1.85 (m, 1H), 1.43 (qd, J = 11.3, 5.7 Hz, 1H).

[0516] Step 13: Synthesis of intermediate z13-2

[0517] Following the preparation process of intermediate z13-1, z13m-2 was replaced with z13m-2 to obtain intermediate z13-2 (18g).

[0518] MS(ESI, [M+H)) + m / z: 315.13

[0519] 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 4.60 (t, J = 5.3 Hz, 1H), 4.53 (dd, J = 11.8, 5.0Hz, 1H), 3.43 (t, J = 5.8 Hz, 2H), 3.09 – 3.01 (m, 1H), 2.95 (dd, J = 17.1,4.9 Hz, 1H), 2.89 – 2.71 (m, 2H), 2.62 – 2.52 (m, 2H), 2.49 – 2.42 (m, 1H),2.18 (dq, J = 13.7, 4.9 Hz, 1H), 2.04 (dt, J = 13.5, 3.6 Hz, 1H), 1.94 – 1.84(m, 1H), 1.43 (qd, J = 11.3, 5.7 Hz, 1H).

[0520] Preparation Example 14: Synthesis of Intermediate Z14

[0521]

[0522] Step 1: Synthesis of intermediate z14b

[0523] Intermediate Z14a (150 g) and methanol (30000 mL) were added sequentially to the reaction flask. The mixture was cooled to 0°C, and sodium borohydride (64 g) was added in portions. The reaction was carried out at 25°C. After the reaction was completed, the reaction solution was quenched with water and extracted with dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate Z14b (138 g).

[0524] MS(ESI, [M+H)) + m / z: 179.10

[0525] Step 2: Synthesis of intermediate z14c

[0526] Intermediate Z14b (148 g), dichloromethane (2500 mL), triethylamine (215 g), and 4-dimethylaminopyridine (5 g) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and acetic anhydride (118 mL) was added dropwise. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was quenched with water, extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to obtain intermediate Z14c (160 g).

[0527] MS(ESI, [M+H))+ m / z: 221.11

[0528] Step 3: Synthesis of intermediate z14d

[0529] Intermediate Z14C (160 g) and dichloromethane (2000 mL) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and boron tribromide (2 M, dichloromethane solution, 1400 mL) was added dropwise. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was quenched with water, extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to obtain intermediate Z14D (147 g).

[0530] MS(ESI, [M+H)) + m / z: 207.09

[0531] Step 4: Synthesis of intermediate z14e

[0532] Intermediate Z14D (147 g), dichloromethane (1500 mL), triethylamine (184 g), and 4-dimethylaminopyridine (4 g) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and acetic anhydride (101 mL) was added dropwise. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was quenched with water, extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to obtain intermediate Z14E (161 g).

[0533] MS(ESI, [M+H)) + m / z: 249.10

[0534] Steps 5-10: Synthesis of intermediate z14k

[0535] Following the method described in steps 6-11 of Preparation Example 13, z14e was replaced with z13f to prepare intermediate z14k (510 mg).

[0536] MS(ESI, [M+H)) + m / z: 276.12.

[0537] Step 11: Synthesis of intermediate z14

[0538] Following the method described in step 12 of Preparation Example 13, z14 (240 mg) was prepared by replacing z13m-1 with z14k.

[0539] MS(ESI, [M+H)) + m / z: 301.11

[0540] 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 4.92 – 4.84 (m, 1H), 4.53 (dd, J = 11.8, 5.0 Hz,1H), 4.01 (s, 1H), 3.11 – 3.01 (m, 2H), 2.89 (dt, J = 16.4, 7.2 Hz, 1H), 2.76 (ddt, J = 17.4, 11.4, 6.0 Hz, 2H), 2.60 (dt, J = 17.4, 4.2 Hz, 1H), 2.49 –2.41 (m, 1H), 2.17 (dq, J = 13.7, 4.9 Hz, 1H), 1.99 (t, J = 7.6 Hz, 1H), 1.76 (dq, J = 13.7, 7.4 Hz, 1H).

[0541] Preparation Example 15: Synthesis of Intermediate Z15

[0542]

[0543] Step 1: Preparation of intermediate z15b

[0544] Under N2 protection at 0°C, potassium tert-butoxide (89 g, 793 mL) was slowly added to a reaction solution of z15a (70 g), methyltriphenylphosphine iodide (241 g), and THF (700 mL), and the reaction was carried out at 25°C for 4 h. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution, extracted with petroleum ether, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation of the filtrate. The obtained solid was purified by column chromatography to obtain z15b (69 g).

[0545] MS(ESI, [M+H)) + m / z: 175.1

[0546] Step 2: Preparation of intermediate z15c

[0547] In a reaction flask, KOSER reagent (97 g), DCM (400 mL), and hexafluoroisopropanol (80 mL) were added sequentially. Under N2 protection, the mixture was reacted at room temperature for 30 min. Then, water (75 g, 75 mL) and z15b (33 g) were added at 0 °C, and the reaction was continued at room temperature for 4 h. After the reaction was complete, the reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with DCM, dried over anhydrous sodium sulfate, and the solvent was removed from the filtrate by evaporation. The crude product was purified by column chromatography to obtain intermediate z15c (31 g).

[0548] MS(ESI, [M+H)) + m / z: 191.0

[0549] Step 3: Preparation of intermediate z15d

[0550] Following the method described in step 1 of Preparation Example 10, intermediate z15d (4.1 g) was synthesized by replacing intermediate z39b with intermediate z15c.

[0551] MS(ESI, [M+H)) + m / z: 193.1

[0552] Step 4: Preparation of intermediate z15e

[0553] Following the method described in step 2 of Preparation Example 10, intermediate z15e (5g) was synthesized by replacing intermediate z47a with intermediate z15d.

[0554] MS(ESI, [M+H)) + m / z: 235.1

[0555] Step 5: Preparation of intermediate Z15F

[0556] Following the method described in step 3 of Preparation Example 10, intermediate z15f (3.8 g) was synthesized by replacing intermediate z47b with intermediate z15e.

[0557] MS(ESI, [M+H)) + m / z: 221.1

[0558] Step 6: Preparation of intermediate z15g

[0559] In a reaction flask, z15f (3.2 g), DCM (100 mL), diisopropylamine (0.147 g), and NBS (2.84 g) were added sequentially. Under N2 protection, the mixture was stirred at room temperature for 1.5 h. After the reaction was complete, the reaction solution was poured into water to separate the organic phase. The solution was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography to obtain z15g (3.8 g).

[0560] MS(ESI, [M+H)) + m / z: 299.1

[0561] Step 7: Preparation of intermediate z15h

[0562] In a reaction flask, 15 g (3 g), toluene (100 mL), tributyl(1-ethoxyethylene)tin (5.43 g), and bis(triphenylphosphine)palladium dichloride (0.704 g) were added sequentially. Under N2 protection, the mixture was heated to 100 °C. o C. After the reaction was complete, the reaction solution was cooled to room temperature, and hydrochloric acid aqueous solution (2.194 g, 15.04 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction was stopped, and the reaction solution was poured into a saturated sodium bicarbonate solution. EA was added for extraction, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain z15h (912 mg).

[0563] MS(ESI, [M+H)) + m / z: 263.1

[0564] Step 8: Preparation of intermediate Z15i

[0565] Following the method described in step 6 of Preparation Example 10, intermediate z15i (1.2 g) was synthesized by replacing intermediate z47e with intermediate z15h.

[0566] MS(ESI, [M+H)) + m / z: 221.1

[0567] Step 9: Preparation of intermediate Z15J

[0568] Following the method described in step 7 of Preparation Example 10, intermediate z15j (2g) was synthesized by replacing intermediate z47f with intermediate z15i.

[0569] MS(ESI, [M+H)) + m / z: 335.2

[0570] Step 10: Preparation of intermediate z15k

[0571] Following the method described in step 8 of Preparation Example 10, intermediate z15k (1.9g) was synthesized by replacing intermediate z47g with intermediate z15j.

[0572] MS(ESI, [M+H)) + m / z: 361.5

[0573] Step 11: Preparation of intermediate z15l

[0574] Following the method described in step 9 of Preparation Example 10, intermediate z15l (1.7 g) was synthesized by replacing intermediate z47h with intermediate z15k.

[0575] MS(ESI, [M+H)) + m / z: 376.1

[0576] Step 12: Preparation of intermediate z15m

[0577] Following the method described in step 10 of Preparation Example 10, intermediate z15m (1.7 g) was synthesized by replacing intermediate z47i with intermediate z15l.

[0578] MS(ESI, [M+H)) + m / z: 290.1

[0579] Step 13: Preparation of intermediate z15

[0580] Following the method described in step 10 of Preparation Example 10, intermediate z15 (0.22 g) was synthesized by replacing intermediate z47j with intermediate z15m.

[0581] MS(ESI, [M+H)) + m / z: 315.1

[0582] 1H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 4.75 (dd, J = 4.1, 1.5 Hz, 1H), 4.54 (ddd, J =11.9, 5.0, 2.1 Hz, 1H), 3.54 (s, 1H), 3.19 (dd, J = 14.5, 7.6 Hz, 1H), 3.11 –3.00 (m, 2H), 2.89 – 2.71 (m, 2H), 2.60 (dt, J = 17.3, 4.3 Hz, 1H), 2.46 (dd,J = 12.1, 4.4 Hz, 1H), 2.23 – 2.13 (m, 1H), 2.07 (dd, J = 13.6, 6.4 Hz, 1H), 1.91 (s, 1H), 1.81 – 1.70 (m, 1H), 1.47 – 1.37 (m, 1H).

[0583] Preparation Example 16: Synthesis of Intermediate Z16

[0584]

[0585] Step 1: Synthesis of intermediate z16

[0586] Deuterated methylamine hydrochloride (5.9 g), dichloromethane (150 mL), and potassium carbonate (23 g) were added sequentially to the reaction flask. The mixture was cooled to 0 °C, and bromoacetyl bromide (16.9 g) was added dropwise. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was quenched with water, extracted with dichloromethane, concentrated, and purified by silica gel column chromatography to obtain intermediate Z16 (6.4 g).

[0587] MS(ESI, [M+H)) + m / z: 155.0

[0588] 1 H NMR (500 MHz, DMSO-d6) δ 8.16 (s, 1H), 3.83 (s, 2H).

[0589] Preparation Example 17: Synthesis of Intermediate Z134

[0590]

[0591] Step 1: Preparation of intermediate z134b

[0592] Following the method described in step 1 of Preparation Example 8, intermediate 5a was prepared by replacing 4-fluoroindole with intermediate z134a and isopropyl iodine with trifluoroethyl iodine to synthesize intermediate z134b (25g).

[0593] MS(ESI, [M+H)) + m / z: 275.1.

[0594] Step 2: Preparation of intermediate z134c

[0595] In a reaction flask, z134b (20 g), diethylamine (8.00 g), and ethanol (500 mL) were added under ice bath conditions. Ethyl diazonate (12.49 g) was then slowly added dropwise. The reaction was carried out at 0°C for 10 min under N2 protection, followed by overnight reaction at room temperature. The reaction solution was purified by silica gel column chromatography to obtain intermediate z134c (5 g).

[0596] MS(ESI, [M+H)) + m / z: 389.2.

[0597] Step 3: Preparation of intermediate z134d

[0598] In the reaction flask, Z134C (4.5 g), methanol (50 mL), and boron trifluoride diethyl ether (2.467 g, 2.146 mL) were added sequentially. o The reaction proceeded for 1 hour. The reaction was then directly filtered to obtain z134d (2.3 g).

[0599] MS(ESI, [M+H)) + m / z: 361.0.

[0600] Step 4: Preparation of intermediate z134e

[0601] In a reaction flask, z134d (2.3 g), water (60 mL), and KOH (1.43 g) were added sequentially. The mixture was then poured into a container. o C reacted overnight. After the reaction was complete, 2M hydrochloric acid was added to the reaction solution, and the mixture was filtered to obtain intermediate z134e (2g).

[0602] MS(ESI, [M+H)) + m / z: 333.0

[0603] Step 5: Preparation of intermediate z134f

[0604] In a reaction flask, Z134e (2g), DMSO (30mL), water (6mL), and LiCl (0.66g) were added sequentially. The mixture was then heated to 120°C. oThe reaction was carried out at C for 4 hours. Water (250 mL) was added to the reaction solution, and the mixture was filtered to obtain intermediate z134f (0.95 g).

[0605] MS(ESI, [M+H)) + m / z: 289.2

[0606] Step 6: Preparation of intermediate z134g

[0607] In a reaction flask, z134f (0.3 g), cesium carbonate (0.678 g), DMF (10 mL), and 2-bromo-N-methylacetamide (0.158 g) were added sequentially. Under N2 protection, the mixture was reacted at room temperature for 5 h. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was filtered to obtain intermediate z134g (0.12 g).

[0608] MS(ESI, [M+H)) + m / z: 360.0

[0609] Step 7: Preparation of intermediate z134h

[0610] In a reaction flask, palladium on carbon (0.1 g) was added to a MeOH:DCM solution (v:v = 1:1, 10 mL) containing z134 g (0.12 g). The mixture was stirred overnight at room temperature under hydrogen protection. After the reaction was complete, the catalyst was removed by filtration, and the solvent was removed from the filtrate by evaporation to obtain intermediate z134h (0.1 g).

[0611] MS(ESI, [M+H)) + m / z: 330.0

[0612] Step 8: Preparation of intermediate z134

[0613] In a reaction flask, z134h (0.1 g), NMP (5 mL), DIPEA (0.101 g), and 2,4,5-trichloropyrimidine (0.073 g) were added sequentially. Under N2 protection, the mixture was poured into a container at 130 mL / min. o The reaction was carried out at C for 1 hour. After the reaction was complete, water (30 mL) was added, and the mixture was filtered to obtain intermediate Z134 (0.12 g).

[0614] MS(ESI, [M+H)) + m / z: 476.0.

[0615] 1H NMR (500 MHz, DMSO) δ 9.67 (s, 1H), 8.40 (s, 1H), 7.95 (d, J = 4.8Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.75 – 7.65 (m, 2H), 7.31 (s, 1H), 5.30(q, J = 9.0 Hz, 2H), 4.61 (s, 2H), 2.68 (d, J = 4.7 Hz, 3H).

[0616] Preparation Example 18: Synthesis of Intermediate Z140

[0617]

[0618] Referring to the method described in steps 1-8 of Preparation Example 17, intermediate Z140 was prepared by replacing trifluoroethyl iodine with iodomethane and 2-bromo-N-methylacetamide with intermediate Z16.

[0619] MS(ESI, [M+H)) + m / z: 411.1.

[0620] Preparation Example 19: Synthesis of Intermediate Z143

[0621]

[0622] Following the method described in steps 6-8 of Preparation Example 17, intermediate Z143 (0.1 g) was prepared by replacing Z134f with Z143a and 2-bromo-N-methylacetamide with bromoacetonitrile.

[0623] MS(ESI, [M+H)) + m / z: 376.0

[0624] Preparation Example 20: Synthesis of Intermediate Z161

[0625]

[0626] Following steps 6-8 of Preparation Example 17, 2-bromo-N-methylacetamide was replaced with intermediate z16 (0.35 g) to obtain intermediate z161.

[0627] z161a: MS(ESI, [M+H]+ ) m / z: 363.10

[0628] z161b:MS(ESI, [M+H]+ ) m / z:333.10

[0629] z161: MS(ESI, [M+H]+ ) m / z: 479.11.

[0630] Preparation Example 21: Synthesis of Intermediate Z133

[0631]

[0632] Step 1: Synthesis of intermediate z133b

[0633] Referring to step 4 of Preparation Example 8, intermediate 5c was replaced with intermediate z133a (10g, preparation process referred to step 1 of WO 2023141432 General Procedure for Intermediate A-60) to prepare intermediate z133b (5.18g).

[0634] MS(ESI, [M+H)) + m / z: 286.0.

[0635] Step 2: Synthesis of intermediate z133c

[0636] Referring to step 6 of Preparation Example 8, intermediate 5e was replaced with intermediate z133b to prepare intermediate z133c (4.97g).

[0637] MS(ESI, [M+H)) + m / z: 387.1.

[0638] Step 3: Synthesis of intermediate z133d

[0639] Under nitrogen protection at -20℃, boron tribromide DCM solution (1M, 18.24 mL) was slowly added dropwise to a DCM solution (150 mL) of z133c (4.7 g), and the reaction was carried out at -20℃. After the reaction was completed, the reaction solution was poured into a 1M sodium hydroxide solution (54.7 mL), extracted with dichloromethane, and the extract was concentrated and purified by silica gel column chromatography to obtain compound z133d (3.00 g).

[0640] MS(ESI, [M+H)) + m / z: 373.1.

[0641] Step 4: Synthesis of intermediate z133e

[0642] Referring to step 5 of Preparation Example 8, intermediate 5d was replaced with intermediate z133d (500 mg) to prepare intermediate z133e (595 mg).

[0643] MS(ESI, [M+H)) + m / z: 444.1.

[0644] Step 5: Synthesis of intermediate z133f

[0645] Intermediate z133e (595 mg), MeOH (10 mL), and 4M dioxane hydrochloride solution (6.71 mL) were added sequentially to the reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the mixture was concentrated and then extracted with saturated sodium bicarbonate solution and dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain compound z133f (320 mg).

[0646] MS(ESI, [M+H)) + m / z: 280.1.

[0647] Step 6: Synthesis of intermediate z133

[0648] Referring to step 8 of Preparation Example 8, intermediate 5g was replaced with intermediate z133f (320 mg) to prepare intermediate z133 (448 mg).

[0649] MS(ESI, [M+H)) + m / z: 426.1.

[0650] Preparation Example 22: Synthesis of Intermediate Z150

[0651]

[0652] Step 1: Preparation of intermediate Z150B

[0653] Z150a (10.0 g), potassium carbonate (16.8 g), and N,N-dimethylformamide (100 mL) were added sequentially to a reaction flask, followed by iodoethane (12.3 g). The reaction was carried out at room temperature for 3 h. After the reaction was complete, the reaction solution was diluted with water and EA, the organic phase was separated, washed with saturated brine, concentrated, and purified by column chromatography to obtain compound Z150b (10.2 g).

[0654] MS(ESI, [M+H)) + m / z: 193.98

[0655] Step 2: Preparation of intermediate Z150C

[0656] Intermediate Z150B (10.0 g), N,N-dimethylformamide (100 mL), and N-bromosuccinimide (10.2 g) were added sequentially to a reaction flask, and the mixture was reacted at 80 °C for 2 h. After the reaction was complete, the mixture was cooled to room temperature, the reaction solution was quenched in ice water, filtered, and the filter cake was collected and dried to obtain intermediate Z150C (12 g).

[0657] MS(ESI, [M+H]+) m / z: 271.89

[0658] Steps 3-8: Preparation of intermediate z150

[0659] Referring to steps 1-6 of Preparation Example 21, intermediate z133a was replaced with intermediate z150c (10 g), and 2-bromo-N-methylacetamide was replaced with intermediate z16 to prepare intermediate z150 (1.2 g).

[0660] MS(ESI, [M+H)) + m / z: 443.03

[0661] Preparation Example 23: Synthesis of Intermediate Z144

[0662]

[0663] Steps 1-3: Synthesis of intermediate z144

[0664] Following the method described in steps 4-6 of Preparation Example 21, intermediate z144 (590 mg) was prepared by replacing 2-bromo-N-methylacetamide with intermediate z16.

[0665] MS(ESI, [M+H)) + m / z: 429.06

[0666] Preparation Example 24: Synthesis of Intermediate Z151

[0667]

[0668] Step 1: Preparation of intermediate z151a

[0669] The following ingredients were added sequentially to a reaction flask: Z150a (12.0 g), cyclopropylboronic acid (18.8 g), copper acetate (6.6 g), cesium carbonate (47.3 g), and toluene (120 mL). The reaction was carried out at 100 °C for 12 h. After the reaction was complete, the reaction solution was purified by silica gel column chromatography to obtain Z151a (1.1 g).

[0670] MS(ESI, [M+H]+) m / z: 206.09

[0671] Steps 2-8: Preparation of intermediate z151

[0672] Referring to steps 2-8 of Preparation Example 22, intermediate z151 (0.12 g) was prepared by replacing intermediate z150b with intermediate z151a (1.1 g).

[0673] MS(ESI, [M+H]+) m / z: 455.10

[0674] Preparation Example 25: Synthesis of Intermediate Z152

[0675]

[0676] Following the method described in steps 1-8 of Preparation Example 22, iodoethane was replaced with 2,2,2-trifluoroethyltrifluoromethanesulfonate to prepare intermediate Z152 (170 mg).

[0677] MS(ESI, [M+H)) + m / z: 497.10

[0678] Preparation Example 26: Synthesis of Intermediate Z153

[0679]

[0680] Step 1: Synthesis of intermediate z153b

[0681] Following the method described in step 1 of Preparation Example 8, intermediate 5a was prepared, with intermediate z153a (10 g) replacing 4-fluoroindole and iodomethane replacing isopropyl iodine, to synthesize intermediate z153b (9.3 g). MS (ESI, [M+H]+) m / z: 230.1.

[0682] Step 2: Synthesis of intermediate z153c

[0683] Intermediate z153b (9.3 g), DMF (100 mL), and NBS (7.7 g) were added sequentially to a reaction flask, and the reaction was carried out at 80 °C. After the reaction was complete, the mixture was concentrated and extracted with saturated sodium bicarbonate solution and ethyl acetate. The extract was concentrated and purified by silica gel column chromatography to obtain compound z153c (7.3 g). MS (ESI, [M+H) + m / z: 308.1.

[0684] Step 3: Synthesis of intermediate z153d

[0685] Referring to step 4 of Preparation Example 8, intermediate 5c was replaced with intermediate z153c (7.3 g) to prepare intermediate z153d (1.6 g). MS (ESI, [M+H) + m / z: 336.1.

[0686] Step 4: Synthesis of intermediate z153e

[0687] Referring to step 6 of Preparation Example 8, intermediate 5e was replaced with intermediate z153d (preparation process refers to step 1 of WO 2023141432 General Procedure for Intermediate A-60) to prepare intermediate z153e (1.2g).

[0688] MS(ESI, [M+H)) + m / z: 437.1.

[0689] Step 5: Synthesis of intermediate z153f

[0690] Referring to step 3 of Preparation Example 21, intermediate z133c was prepared by replacing intermediate z153e (1.2 g) to obtain intermediate z153f (600 mg). MS (ESI, [M+H) + m / z: 423.1.

[0691] Step 6: Synthesis of intermediate z153g

[0692] Referring to step 5 of Preparation Example 8, intermediate 5d was replaced with intermediate z153f (350 mg), and 2-bromo-N-methylacetamide was replaced with intermediate z16 to prepare intermediate z153g (330 mg). MS (ESI, [M+H) + m / z: 497.2.

[0693] Step 7: Synthesis of intermediate z153h

[0694] Intermediate z153 g (330 mg), MeOH (10 mL), and 4M dioxane hydrochloride solution (5 mL) were added sequentially to a reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, the mixture was concentrated and extracted with saturated sodium bicarbonate solution and dichloromethane. The extract was concentrated and purified by silica gel column chromatography to obtain compound z153h (225 mg). MS (ESI, [M+H)) + m / z: 333.2.

[0695] Step 8: Synthesis of intermediate z153

[0696] Referring to step 8 of Preparation Example 8, intermediate z153 (160 mg) was prepared by replacing 5 g of intermediate z53h (225 mg). MS (ESI, [M+H) + m / z: 479.1.

[0697] Preparation Example 27: Synthesis of Intermediate Z137

[0698]

[0699] Step 1: Synthesis of intermediate z137a

[0700] Intermediate Z143a (2 g), ethyl difluorobromoacetate (3.69 g), 1,8-diazobispiro[5.4.0]undec-7-ene (4.15 g), and DMF (40 mL) were added sequentially to a reaction flask, and the reaction was carried out at 110 °C. After the reaction was complete, the reaction solution was extracted with EA (100 mL) and water (200 mL). The organic phase was separated and purified by silica gel column chromatography to obtain intermediate Z137a (840 mg). MS (ESI, [M+H)) + m / z: 343.1.

[0701] Step 2: Synthesis of intermediate z137b

[0702] Intermediate Z137a (420 mg), methylamine hydrochloride (331 mg), MeOH (10 mL), and triethylamine (497 mg) were added sequentially to a reaction flask, and the reaction was carried out at room temperature. After the reaction was complete, the reaction solution was extracted with DCM (100 mL) and water (50 mL). The organic phase was separated and purified by silica gel column chromatography to obtain intermediate Z137b (336 mg). MS (ESI, [M+H)) + m / z: 328.1.

[0703] Step 3: Synthesis of intermediate z137c

[0704] Intermediate Z137b (320 mg), ammonium chloride (262 mg), iron powder (273 mg), water (3 ml), and ethanol (20 ml) were added sequentially to a reaction flask, and the reaction was carried out at 80 °C. After the reaction was complete, the mixture was filtered, and the filtrate was extracted with DCM (100 mL) and water (50 mL). The organic phase was separated, and intermediate Z137c (290 mg) was purified by silica gel column chromatography. MS (ESI, [M+H)) + m / z: 298.1.

[0705] Step 4: Synthesis of intermediate z137

[0706] Referring to preparation example 8, step 8, intermediate z137 (330 mg) was prepared by replacing 5 g of intermediate z137 with intermediate z137c (290 mg). MS (ESI, [M+H) + m / z: 444.0

[0707] Preparation Example 28: Synthesis of intermediates z154-1 and z154-2

[0708]

[0709] Steps 1-4: Synthesis of intermediate z154d

[0710] Referring to the method described in steps 1-4 of Preparation Example 27, intermediate Z154d (330 mg) was prepared by replacing ethyl difluorobromoethyl with ethyl fluorobromoethyl and methylamine hydrochloride with deuterated methylamine hydrochloride. MS (ESI, [M+H) + m / z: 429.1.

[0711] Step 5: Preparation of intermediates z154-1 and z154-2

[0712] Z154D separation conditions: Instrument: High performance liquid chromatograph, chromatographic column: (R,R) Whelk-O1 (4.6×250mm, S-5μm), mobile phase A: dichloromethane, mobile phase D: n-hexane, mobile phase B: ethanol, yielding intermediates Z154-1 (75mg) and Z154-2 (73mg) sequentially.

[0713] z154-1: MS(ESI, [M+H]) + m / z: 429.1.

[0714] z154-2: MS(ESI, [M+H]) + m / z: 429.1.

[0715] Preparation Example 29: Synthesis of Intermediate Z156

[0716]

[0717] Referring to the method described in steps 1-4 of Preparation Example 27, intermediate z156 was prepared by replacing methylamine hydrochloride with deuterated methylamine hydrochloride. MS(ESI, [M+H] + m / z: 447.1.

[0718] Preparation Example 30: Synthesis of Intermediate Z163

[0719]

[0720] Step 1: Synthesis of intermediate z163b

[0721] Z163a (10 g), 4M hydrochloric acid aqueous solution (200 mL), and oxalic acid (11 g) were added sequentially to a reaction flask. The reaction was carried out at 120 °C. After the reaction was completed, the reaction solution was directly filtered to obtain intermediate Z163b (11 g). MS (ESI, [M+H)) + m / z: 222.04

[0722] Step 2: Synthesis of intermediate z163c

[0723] Z163b (8.5 g), DMF (150 mL), cesium carbonate (25 g), and tert-butyl bromoacetate (9 g) were added sequentially to a reaction flask. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was quenched with water, extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate Z163c (0.38 g). MS (ESI, [M+H)) + m / z: 336.11

[0724] Step 3: Synthesis of intermediate z163d

[0725] Z163C (0.21 g), dichloromethane (10 mL), and trifluoroacetic acid (10 mL) were added sequentially to a reaction flask. The reaction was carried out at 25°C. After the reaction was completed, the reaction solution was directly concentrated to obtain intermediate Z163D (0.22 g). MS (ESI, [M+H)) + m / z: 280.05

[0726] Step 4: Synthesis of intermediate z163e

[0727] Z163D (0.22 g), DMF (10 mL), deuterated methylamine hydrochloride (0.11 g), N,N-diisopropylethylamine (0.6 g), and HATU (0.6 g) were added sequentially to a reaction flask. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was quenched with water, extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate Z163E (0.15 g). MS (ESI, [M+H)) + m / z: 296.10

[0728] Steps 5-6: Synthesis of intermediate z163

[0729] Following the method described in steps 3-4 of Preparation Example 27, z137b was replaced with z163e to prepare intermediate z163 (96 mg). MS (ESI, [M+H) + m / z: 412.07

[0730] Preparation Example 31: Intermediate 17b

[0731]

[0732] The preparation process is based on Example Intermediate A10a of WO2019197842.

[0733] Preparation Example 32: Synthesis of Intermediate 13h

[0734]

[0735] The preparation process is based on Example B.7.1 of WO2018108704.

[0736] Preparation Example 33: Synthesis of Intermediate Z139

[0737]

[0738] The preparation process is based on steps 1-6 of Compound 303 in WO2021077010.

[0739] Preparation Example 34: Synthesis of Intermediate Z138

[0740]

[0741] The preparation process is based on “Synthesis of 6-((2,5-dichloropyrimidin-4-yl)amino)-l-methyl-3-(2-oxopropoxy)quinolin-2(lH)-one” in WO2021077010.

[0742] Preparation Example 35: Synthesis of Intermediate Z135

[0743]

[0744] The preparation process follows steps 1-3 of Example 1 in CN117229263.

[0745] Preparation Example 36: Synthesis of Intermediate 122a

[0746]

[0747] The preparation process is based on Intermediate A10b of WO2019197842.

[0748] Preparation Example 37: Synthesis of Intermediate 14a

[0749]

[0750] Synthesis reference WO 2018108704.

[0751] Preparation Example 38: Synthesis of Intermediate 15h

[0752]

[0753] The preparation process is based on Example 1 of WO2023244917.

[0754] Preparation Example 39: Synthesis of Intermediate Z23

[0755]

[0756] According to WO2023125944, z22 and z23 were prepared, and z23, 150 mg was obtained by step 16.

[0757] Example 106: Synthesis of Compound 106

[0758]

[0759] Step 1: Preparation of intermediate 106a

[0760] Intermediate Z40 (1 g), DMSO (20 mL), and 2-iodobenzoic acid (2.11 g) were added sequentially to a reaction flask, and the reaction was carried out 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 concentrate was added to a MeOH solution containing 1.04 g of 3-(piperidin-4-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (0.18 g), acetic acid (0.57 g), and sodium cyanoborohydride (0.57 g), and the reaction was carried out at 25 °C. After the reaction was completed, the solvent was removed by vacuum distillation, and the mixture was purified by silica gel column chromatography to obtain intermediate 106a (1.42 g). MS (ESI) m / z [M+H] + 551.3

[0761] Step 2: Preparation of intermediate 106b

[0762] To a reaction flask, 106a (1.4 g), DCM (40 mL), and dioxane hydrochloride (20 mL) were added sequentially. The mixture was stirred at room temperature. After the reaction was complete, the solvent was removed from the reaction solution under reduced pressure to obtain intermediate 106b (1.42 g). MS (ESI) m / z [M+H] + 451.3

[0763] Step 3: Preparation of Compound 106

[0764] Intermediate 106b (158 mg), intermediate 17b (90 mg), DMSO (2 mL), and DIPEA (210 mg) were added sequentially to the reaction flask, and the reaction was carried out in a microwave-assisted reaction at 140 °C. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with EA. The extract was concentrated and purified by silica gel column chromatography to obtain compound 106 (60 mg).

[0765] MS (ESI, [M+H) + m / z: 883.3

[0766] 1 H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 8.77 (s, 1H), 8.26 (d, J =2.3 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 9.1, 2.2 Hz, 1H), 7.50 (d, J = 8.0Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.16 (s, 1H), 4.57 – 4.49 (m, 1H), 4.49 – 4.31 (m, 2H), 4.00 – 3.93 (m, 2H), 3.82 – 3.73(m, 2H), 3.56 (s, 3H), 3.40 – 3.36 (m, 1H), 3.26 – 3.18 (m, 1H), 3.17 – 3.11(m, 1H), 2.97 – 2.88 (m, 2H), 2.80 – 2.72 (m, 2H), 2.64 – 2.58 (m, 1H), 2.41– 2.29 (m, 6H), 2.21 – 2.15 (m, 1H), 2.13 – 2.06 (m, 3H), 2.06 – 1.90 (m,3H), 1.33 (s, 1H), 0.98 – 0.92 (m, 2H), 0.86 – 0.82 (m, 1H), 0.75 – 0.69 (m,1H), 0.56 – 0.50 (m, 2H), 0.36 (q, J = 5.6 Hz, 1H).

[0767] Examples 107-113, 115-120, 122-140, 142-144, 147, 148, 150-158, 161-163, 168-178:

[0768] Following the method described in Example 106, compounds 107-113, 115-120, 122-140, 142-144, 147, 148, 150-158, 161-163, and 168-178 were prepared by substituting the following intermediates. See Tables 7A-7B.

[0769] Table 7A

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776] Table 7B

[0777] Example Characterization 107 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.3 Hz, 1H), 8.70 (s,1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.84 (d, J = 9.1 Hz, 1H),7.51 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 9.1 Hz, 1H), 7.17 (d, J= 8.1 Hz, 1H), 6.13 (s, 1H), 4.56 – 4.50 (m, 1H), 4.49 – 4.33(m, 2H), 3.75 (s, 1H), 3.56 (s, 3H), 3.34 (d, J = 11.0 Hz,5H), 3.25 (d, J = 8.8 Hz, 2H), 3.11 (s, 1H), 2.93 (d, J = 12.1Hz, 2H), 2.81 – 2.71 (m, 3H), 2.60 (dd, J = 17.4, 4.1 Hz, 2H),2.36 (s, 5H), 2.13 – 2.05 (m, 4H), 2.03 (s, 1H), 1.94 (s, 1H),1.74 (s, 1H), 1.33 (s, 1H), 1.23 (s, 1H), 0.95 (d, J = 12.1Hz, 2H), 0.72 (d, J = 10.0 Hz, 1H), 0.55 – 0.49 (m, 2H), 0.37(s, 1H).MS(ESI, [M+H] + ) m / z : 897.3]]> 108 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.3 Hz, 1H), 8.80 (s,1H), 8.20 (d, J = 2.3 Hz, 1H), 8.03 (s, 1H), 7.71 (dd, J =9.0, 2.2 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 9.1Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.20 (s, 1H), 4.53 (ddd, J= 11.9, 5.0, 2.5 Hz, 1H), 4.50 – 4.40 (m, 3H), 4.40 – 4.32 (m,1H), 3.57 (s, 3H), 3.37 (d, J = 7.0 Hz, 2H), 3.01 – 2.87 (m,3H), 2.84 – 2.71 (m, 5H), 2.65 – 2.56 (m, 2H), 2.50 – 2.43 (m,5H), 2.34 (s, 3H), 2.17 (tt, J = 8.3, 4.3 Hz, 2H), 2.07 (s,2H), 1.94 (s, 1H), 1.76 (s, 1H), 1.33 (t, J = 12.1 Hz, 3H),1.23 (s, 2H), 0.96 (s, 1H), 0.72 (d, J = 8.6 Hz, 1H), 0.55 –0.49 (m, 2H), 0.35 (q, J = 5.8 Hz, 1H).MS(ESI, [M+H] + ) m / z :911.3]]> 109 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.2 Hz, 1H), 8.85 (s,1H), 8.22 (d, J = 2.3 Hz, 1H), 8.04 (s, 1H), 7.69 (dd, J =9.0, 2.2 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 9.1Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 6.21 (s, 1H), 4.53 (ddd, J= 11.9, 5.0, 2.7 Hz, 1H), 4.50 – 4.33 (m, 2H), 3.57 (s, 3H),3.56 (s, 3H), 3.39 – 3.33 (m, 4H), 3.30 (s, 1H), 2.96 (s, 3H),2.77 (ddd, J = 17.2, 11.9, 5.3 Hz, 3H), 2.60 (dd, J = 17.3,3.9 Hz, 1H), 2.33 (s, 4H), 2.12 (s, 5H), 2.03 (s, 2H), 1.70(s, 2H), 1.23 (s, 3H), 1.06 (d, J = 71.9 Hz, 4H), 0.71 (q, J =5.9 Hz, 1H), 0.55 – 0.49 (m, 2H), 0.35 (q, J = 5.9 Hz, 1H).MS(ESI, [M+H] + ) m / z : 925.2 <!-- 132 -->]]> 110 <![CDATA[ 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.85 (s, 1H), 8.21(d, J = 2.3 Hz, 1H), 8.04 (s, 1H), 7.69 (dd, J = 9.0, 2.2 Hz,1H), 7.52 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.09(d, J = 8.3 Hz, 1H), 6.22 (t, J = 2.9 Hz, 1H), 4.53 (dd, J =11.8, 5.0 Hz, 1H), 4.47 – 4.31 (m, 2H), 3.57 (d, J = 12.5 Hz,7H), 3.41 (s, 1H), 3.24 – 3.17 (m, 1H), 3.07 – 2.70 (m, 7H),2.65 – 2.51 (m, 3H), 2.49 – 2.42 (m, 2H), 2.30 – 2.14 (m, 5H),2.00 (d, J = 11.9 Hz, 1H), 1.93 – 1.71 (m, 1H), 1.41 (d, J =24.9 Hz, 1H), 1.36 – 1.29 (m, 1H), 1.23 (s, 1H), 0.72 (q, J =5.8 Hz, 1H), 0.52 (p, J = 7.5 Hz, 2H), 0.35 (q, J = 6.5 Hz,1H).MS(ESI, [M+H] + ) m / z:869.34]]> 111 <![CDATA[ 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.86 (s, 1H), 8.21(d, J = 2.2 Hz, 1H), 8.05 (s, 1H), 7.69 (dd, J = 9.1, 2.2 Hz,1H), 7.52 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.09(d, J = 8.2 Hz, 1H), 6.22 (s, 1H), 4.53 (dd, J = 11.9, 5.0 Hz,1H), 4.46 – 4.33 (m, 2H), 3.57 (d, J = 12.6 Hz, 7H), 3.22 (s,2H), 3.06 – 2.71 (m, 7H), 2.63 – 2.52 (m, 3H), 2.47 (d, J =7.9 Hz, 2H), 2.21 (d, J = 34.9 Hz, 5H), 2.00 (s, 1H), 1.79 (d,J = 31.9 Hz, 1H), 1.45 (s, 1H), 1.34 (s, 1H), 1.25 (s, 1H),0.72 (d, J = 7.7 Hz, 1H), 0.52 (t, J = 6.2 Hz, 2H), 0.35 (d, J= 5.3 Hz, 1H).MS(ESI, [M+H] + ) m / z:869.34]]> 112 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.82 (s, 1H), 8.22 (d,J = 2.3 Hz, 1H), 8.04 (s, 1H), 7.69 (dd, J = 9.0, 2.2 Hz, 1H),7.51 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.10 (d, J= 8.3 Hz, 1H), 6.22 (d, J = 4.2 Hz, 1H), 4.53 (dd, J = 11.8,5.0 Hz, 1H), 4.50 – 4.32 (m, 2H), 3.56 (s, 7H), 3.00 (s, 2H),2.84 (d, J = 45.4 Hz, 3H), 2.78 – 2.71 (m, 1H), 2.65 – 2.52(m, 2H), 2.47 (d, J = 7.9 Hz, 5H), 2.24 (s, 2H), 2.20 – 2.13(m, 2H), 2.01 (s, 2H), 1.86 (d, J = 14.4 Hz, 2H), 1.71 (d, J =11.7 Hz, 2H), 1.43 (s, 3H), 1.32 (s, 1H), 1.23 (s, 1H), 0.71(q, J = 5.9 Hz, 1H), 0.52 (t, J = 6.0 Hz, 2H), 0.35 (q, J =6.3 Hz, 1H). MS(ESI, [M+H] + ) m / z:897.3 <!-- 133 -->]]> 113 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.83 (s, 1H), 8.22 (d,J = 2.3 Hz, 1H), 8.04 (s, 1H), 7.69 (dd, J = 9.1, 2.2 Hz, 1H),7.51 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 9.2 Hz, 1H), 7.10 (d, J= 8.3 Hz, 1H), 6.22 (d, J = 4.4 Hz, 1H), 4.53 (dd, J = 11.8,5.0 Hz, 1H), 4.49 – 4.33 (m, 2H), 3.62 – 3.52 (m, 7H), 3.26 –3.18 (m, 1H), 3.05 – 2.95 (m, 2H), 2.94 – 2.81 (m, 3H), 2.80 –2.72 (m, 1H), 2.63 – 2.57 (m, 1H), 2.49 – 2.43 (m, 4H), 2.29 –2.21 (m, 2H), 2.20 – 2.14 (m, 2H), 2.06 – 1.97 (m, 2H), 1.93 –1.80 (m, 2H), 1.76 – 1.66 (m, 2H), 1.50 – 1.37 (m, 3H), 1.35 –1.29 (m, 1H), 0.75 – 0.68 (m, 1H), 0.55 – 0.49 (m, 2H), 0.39 –0.32 (m, 1H).MS(ESI, [M+H] + ) m / z : 897.3]]> 115 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.4 Hz, 1H), 8.75 (s,1H), 8.19 (d, J = 2.3 Hz, 1H), 8.02 (s, 1H), 7.73 (dd, J =9.0, 2.2 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 9.2Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 6.17 (d, J = 3.9 Hz, 1H),4.53 (ddd, J = 11.9, 5.0, 2.3 Hz, 1H), 4.50 – 4.33 (m, 2H),3.62 – 3.55 (m, 6H), 3.41 – 3.34 (m, 1H), 3.26 – 3.18 (m, 1H),3.00 – 2.87 (m, 2H), 2.81 – 2.71 (m, 2H), 2.64 – 2.56 (m, 1H),2.49 – 2.43 (m, 1H), 2.38 – 2.24 (m, 4H), 2.21 – 2.14 (m, 1H),2.12 – 1.99 (m, 4H), 1.97 – 1.89 (m, 1H), 1.53 – 1.42 (m, 4H),1.41 – 1.29 (m, 5H), 1.01 – 0.89 (m, 2H), 0.75 – 0.67 (m, 1H),0.56 – 0.47 (m, 2H), 0.39 – 0.32 (m, 1H).MS(ESI, [M+H] + ) m / z :896.3]]> 116 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.4 Hz, 1H), 8.74 (s,1H), 8.04 (s, 1H), 7.99 – 7.94 (m, 1H), 7.58 (s, 1H), 7.55 –7.48 (m, 2H), 7.17 (d, J = 8.1 Hz, 1H), 6.98 (s, 1H), 4.58 –4.50 (m, 3H), 3.87 (d, J = 7.0 Hz, 6H), 3.67 (t, J = 5.6 Hz,4H), 3.41 – 3.35 (m, 1H), 2.95 (s, 2H), 2.76 (ddd, J = 17.3,11.9, 5.2 Hz, 2H), 2.67 (d, J = 4.6 Hz, 3H), 2.63 – 2.57 (m,1H), 2.46 (d, J = 13.4 Hz, 1H), 2.34 (s, 4H), 2.18 (dq, J =9.0, 4.7 Hz, 1H), 2.10 (s, 4H), 1.95 (s, 1H), 1.47 (d, J =33.3 Hz, 8H), 0.95 (s, 2H).MS(ESI, [M+H] + ) m / z:866.3 <!-- 134 -->]]> 117 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.4 Hz, 1H), 8.75 (s,1H), 8.19 (d, J = 2.3 Hz, 1H), 8.02 (s, 1H), 7.73 (dd, J =9.0, 2.2 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 9.2Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 6.17 (d, J = 3.9 Hz, 1H),4.53 (ddd, J = 11.9, 5.0, 2.3 Hz, 1H), 4.50 – 4.33 (m, 2H),3.62 – 3.55 (m, 6H), 3.41 – 3.34 (m, 1H), 3.26 – 3.18 (m, 1H),3.00 – 2.87 (m, 2H), 2.81 – 2.71 (m, 2H), 2.64 – 2.56 (m, 1H),2.49 – 2.43 (m, 1H), 2.38 – 2.24 (m, 4H), 2.21 – 2.14 (m, 1H),2.12 – 1.99 (m, 4H), 1.97 – 1.89 (m, 1H), 1.53 – 1.42 (m, 4H),1.41 – 1.29 (m, 5H), 1.01 – 0.89 (m, 2H), 0.75 – 0.67 (m, 1H),0.56 – 0.47 (m, 2H), 0.39 – 0.32 (m, 1H). MS(ESI, [M+H] + ) m / z :896.3]]> 118 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.4 Hz, 1H), 8.79 (s,1H), 8.03 (s, 1H), 7.96 (q, J = 4.6 Hz, 1H), 7.92 (d, J = 2.4Hz, 1H), 7.77 (dd, J = 9.1, 2.4 Hz, 1H), 7.49 (dd, J = 13.9,8.6 Hz, 2H), 7.17 (d, J = 8.2 Hz, 1H), 7.10 (s, 1H), 4.58 (s,2H), 4.53 (ddd, J = 11.9, 5.1, 2.4 Hz, 1H), 3.68 (s, 3H), 3.67– 3.59 (m, 4H), 3.39 – 3.34 (m, 1H), 3.00 – 2.87 (m, 2H), 2.81– 2.71 (m, 2H), 2.68 (d, J = 4.6 Hz, 3H), 2.64 – 2.56 (m, 1H),2.38 – 2.27 (m, 4H), 2.21 – 2.15 (m, 1H), 2.12 – 2.00 (m, 4H),1.99 – 1.89 (m, 1H), 1.55 – 1.46 (m, 4H), 1.45 – 1.37 (m, 4H),1.01 – 0.90 (m, 2H). MS(ESI, [M+H] + ) m / z : 836.3]]> 119 <![CDATA[ 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (d, J = 3.3 Hz, 1H), 9.03 (s,1H), 8.73 (d, J = 2.5 Hz, 1H), 8.29 (d, J = 2.5 Hz, 1H), 8.07(s, 1H), 7.96 (d, J = 4.8 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H),7.17 (d, J = 16.4 Hz, 2H), 4.62 (s, 2H), 4.53 (ddd, J = 11.8,5.0, 2.5 Hz, 1H), 3.74 (s, 3H), 3.61 (s, 3H), 3.39 – 3.33 (m,2H), 2.93 (d, J = 15.3 Hz, 2H), 2.77 (ddd, J = 17.1, 11.8, 5.3Hz, 2H), 2.68 (d, J = 4.7 Hz, 3H), 2.65 – 2.52 (m, 2H), 2.49 –2.43 (m, 1H), 2.33 (s, 3H), 2.17 (td, J = 8.7, 4.5 Hz, 1H),2.13 – 1.89 (m, 5H), 1.45 (d, J = 40.0 Hz, 8H), 0.91 (d, J =40.8 Hz, 2H). MS(ESI, [M+H] + ) m / z:837.35 <!-- 135 -->]]> 120 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.4 Hz, 1H), 8.74 (s,1H), 8.04 (s, 1H), 7.96 (q, J = 4.7 Hz, 1H), 7.58 (d, J = 2.2Hz, 1H), 7.55 – 7.48 (m, 2H), 7.17 (d, J = 8.1 Hz, 1H), 6.98(s, 1H), 4.58 – 4.49 (m, 3H), 3.87 (d, J = 7.1 Hz, 6H), 3.67(t, J = 5.7 Hz, 4H), 3.37 (dd, J = 14.3, 7.0 Hz, 1H), 2.94 (p,J = 13.9 Hz, 2H), 2.76 (ddd, J = 17.3, 12.3, 5.3 Hz, 2H), 2.67(d, J = 4.7 Hz, 3H), 2.64 – 2.56 (m, 1H), 2.49 – 2.43 (m, 1H),2.34 (s, 4H), 2.18 (dt, J = 9.1, 5.7 Hz, 1H), 2.10 (s, 4H),1.96 (s, 1H), 1.47 (d, J = 33.1 Hz, 8H), 0.96 (s, 2H). MS(ESI,[M+H] + ) m / z:866.3]]> 122 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.3 Hz, 1H), 8.80 (s,1H), 8.12 (d, J = 2.3 Hz, 1H), 8.04 (s, 1H), 7.71 (dd, J =9.1, 2.2 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 9.1Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 5.70 (d, J = 3.6 Hz, 1H),4.53 (ddd, J = 11.9, 5.1, 2.3 Hz, 1H), 4.24 (ddd, J = 11.6,7.8, 6.0 Hz, 1H), 4.16 – 4.05 (m, 1H), 3.56 (d, J = 13.9 Hz,6H), 3.40 – 3.32 (m, 2H), 3.00 – 2.91 (m, 2H), 2.91 – 2.81 (m,3H), 2.76 (ddd, J = 17.4, 11.9, 5.0 Hz, 2H), 2.65 – 2.52 (m,2H), 2.48 (d, J = 6.6 Hz, 3H), 2.19 (dtd, J = 16.7, 7.7, 4.0Hz, 3H), 2.11 – 1.91 (m, 6H), 1.84 (s, 2H), 1.70 (d, J = 11.5Hz, 2H), 1.41 (s, 2H), 1.24 (d, J = 7.5 Hz, 2H), 0.95 (s, 2H),0.60 – 0.48 (m, 2H), 0.39 (dt, J = 9.0, 4.0 Hz, 1H), 0.28 (dt,J = 10.3, 4.7 Hz, 1H). MS(ESI, [M+H] + ) m / z:875.4]]> 123 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.84 (s, 1H), 8.04 (s,1H), 7.98 – 7.91 (m, 2H), 7.75 (dd, J = 9.2, 2.4 Hz, 1H), 7.49(dd, J = 19.3, 8.7 Hz, 2H), 7.15 – 7.08 (m, 2H), 4.59 (s, 2H),4.53 (dd, J = 11.8, 5.0 Hz, 1H), 3.68 (s, 3H), 3.65 – 3.55 (m,4H), 3.06 – 2.95 (m, 2H), 2.94 – 2.81 (m, 3H), 2.80 – 2.72 (m,1H), 2.67 (d, J = 4.7 Hz, 3H), 2.63 – 2.56 (m, 1H), 2.54 –2.51 (m, 3H), 2.49 – 2.43 (m, 2H), 2.29 – 2.14 (m, 4H), 2.06 –1.97 (m, 2H), 1.94 – 1.81 (m, 2H), 1.79 – 1.69 (m, 2H), 1.51 –1.36 (m, 3H). MS(ESI, [M+H] + ) m / z : 837.3 <!-- 136 -->]]> 124 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.74 (s, 1H), 8.09 (s,1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.52 (d, J =8.2 Hz, 1H), 7.46 (d, J = 9.2 Hz, 1H), 7.14 (dd, J = 27.4,11.4 Hz, 2H), 4.61 – 4.50 (m, 3H), 3.68 (s, 3H), 3.50 (t, J =7.0 Hz, 2H), 3.33 (d, J = 4.3 Hz, 2H), 3.03 (d, J = 17.6 Hz,2H), 2.86 (s, 1H), 2.76 (td, J = 11.9, 5.9 Hz, 1H), 2.67 (d, J= 4.7 Hz, 3H), 2.60 (d, J = 17.6 Hz, 1H), 2.52 (dd, J = 4.1,2.4 Hz, 1H), 2.48 – 2.41 (m, 2H), 2.27 (s, 4H), 2.17 (dd, J =8.8, 4.4 Hz, 1H), 2.03 (s, 2H), 1.81 (s, 2H), 1.57 (s, 4H),1.42 (s, 1H), 1.23 (s, 1H).MS(ESI, [M+H] + ) m / z:808.3]]> 125 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.4 Hz, 1H), 8.79 (s,1H), 8.05 (d, J = 18.7 Hz, 2H), 7.97 (q, J = 4.7 Hz, 1H), 7.90– 7.84 (m, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 9.2 Hz,1H), 7.16 (d, J = 20.3 Hz, 2H), 4.59 (s, 2H), 4.53 (ddd, J =11.9, 5.0, 2.5 Hz, 1H), 3.69 (d, J = 7.2 Hz, 7H), 3.37 (dd, J= 14.1, 7.0 Hz, 1H), 2.95 (s, 2H), 2.77 (tt, J = 11.7, 5.5 Hz,2H), 2.67 (d, J = 4.7 Hz, 3H), 2.64 – 2.57 (m, 1H), 2.49 –2.43 (m, 1H), 2.30 (s, 3H), 2.18 (tt, J = 8.9, 4.7 Hz, 2H),2.07 (s, 4H), 1.96 (s, 1H), 1.74 (s, 4H), 0.96 (s, 2H). MS(ESI, [M+H] + ) m / z:808.3]]> 126 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.2 Hz, 1H), 8.75 (s,1H), 8.09 (s, 1H), 8.03 (s, 1H), 7.96 (d, J = 5.2 Hz, 1H),7.89 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 9.2 Hz,1H), 7.18 (d, J = 8.2 Hz, 2H), 4.61 – 4.51 (m, 3H), 3.68 (s,3H), 3.51 (t, J = 7.0 Hz, 2H), 3.37 (d, J = 19.8 Hz, 3H), 2.96(s, 2H), 2.77 (ddt, J = 17.2, 12.1, 6.2 Hz, 3H), 2.67 (d, J =4.7 Hz, 3H), 2.59 (ddd, J = 17.0, 8.6, 4.6 Hz, 2H), 2.49 –2.43 (m, 2H), 2.18 (tt, J = 8.9, 4.6 Hz, 2H), 2.05 (s, 3H),1.83 (s, 2H), 1.63 (s, 4H), 1.23 (s, 1H), 1.00 (s, 2H). MS(ESI, [M+H] + ) m / z:822.3 <!-- 137 -->]]> 127 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.6 Hz, 1H), 8.82 (s,1H), 8.04 (s, 1H), 7.99 – 7.93 (m, 1H), 7.90 (d, J = 2.4 Hz,1H), 7.77 (dd, J = 9.1, 2.5 Hz, 1H), 7.49 (dd, J = 15.0, 8.6Hz, 2H), 7.17 (d, J = 8.1 Hz, 1H), 7.11 (s, 1H), 4.59 (s, 2H),4.56 – 4.50 (m, 1H), 3.76 – 3.66 (m, 5H), 3.61 – 3.52 (m, 2H),3.40 – 3.34 (m, 2H), 2.99 – 2.88 (m, 2H), 2.81 – 2.72 (m, 2H),2.67 (d, J = 4.7 Hz, 3H), 2.63 – 2.58 (m, 1H), 2.49 – 2.44 (m,1H), 2.42 – 2.31 (m, 2H), 2.26 – 2.14 (m, 3H), 2.13 – 2.03 (m,2H), 1.94 – 1.83 (m, 1H), 1.70 – 1.58 (m, 2H), 1.57 – 1.45 (m,4H), 1.06 – 0.91 (m, 2H). MS(ESI, [M+H] + ) m / z : 822.3]]> 128 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 8.79 (s, 1H), 8.07 (d,J = 2.3 Hz, 1H), 8.02 (s, 1H), 7.97 (d, J = 4.7 Hz, 1H), 7.87(dd, J = 9.1, 2.5 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.47 (d,J = 9.2 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.14 (s, 1H), 4.60– 4.52 (m, 3H), 3.69 (d, J = 9.6 Hz, 7H), 3.23 – 3.11 (m, 2H),2.92 – 2.72 (m, 4H), 2.68 (d, J = 4.7 Hz, 3H), 2.65 – 2.57 (m,1H), 2.55 – 2.51 (m, 1H), 2.49 – 2.43 (m, 1H), 2.31 (s, 5H),2.18 (dt, J = 12.7, 4.3 Hz, 1H), 1.75 (s, 4H). MS(ESI, [M+H] + )m / z:780.3]]> 129 <![CDATA[ 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.83 (s, 1H), 8.05(s, 1H), 7.93 (s, 2H), 7.75 (d, J = 9.2 Hz, 1H), 7.53 (d, J =8.0 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.12 (d, J = 15.2 Hz,2H), 4.58 (s, 3H), 3.68 (s, 3H), 3.62 (s, 3H), 3.11 (s, 1H),2.93 (d, J = 54.1 Hz, 5H), 2.75 (d, J = 12.1 Hz, 2H), 2.67 (d,J = 4.6 Hz, 3H), 2.31 – 2.07 (m, 6H), 1.75 (d, J = 56.6 Hz,4H), 1.43 (s, 2H), 1.24 (d, J = 6.0 Hz, 5H). MS(ESI, [M+H] + ) m / z:823.34]]> 130 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.05 (s, 1H), 8.81 (s, 1H), 8.03 (s,1H), 7.96 (q, J = 4.8 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.75(dd, J = 9.1, 2.5 Hz, 1H), 7.49 (dd, J = 19.6, 8.7 Hz, 2H),7.14 – 7.07 (m, 2H), 4.59 (s, 2H), 4.53 (dd, J = 11.8, 5.0 Hz,1H), 3.68 (s, 3H), 3.59 (q, J = 5.7 Hz, 4H), 3.06 – 2.92 (m,5H), 2.86 – 2.73 (m, 2H), 2.69 (d, J = 4.7 Hz, 3H), 2.64 –2.52 (m, 3H), 2.48 – 2.41 (m, 2H), 2.17 (dt, J = 13.8, 4.9 Hz,1H), 2.05 – 1.99 (m, 1H), 1.79 (s, 1H), 1.68 (s, 4H), 1.43 (s,1H), 1.23 (s, 1H). MS(ESI, [M+H] + ) m / z:794.3 <!-- 138 -->]]> 131 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.05 (s, 1H), 8.78 (s, 1H), 8.03 (s,1H), 7.97 – 7.90 (m, 2H), 7.77 (dd, J = 9.1, 2.5 Hz, 1H), 7.49(dd, J = 17.3, 8.6 Hz, 2H), 7.14 – 7.08 (m, 2H), 4.58 (s, 2H),4.53 (dd, J = 11.8, 5.0 Hz, 1H), 3.68 (s, 3H), 3.66 – 3.60 (m,4H), 3.06 – 2.95 (m, 2H), 2.89 – 2.81 (m, 1H), 2.80 – 2.72 (m,1H), 2.68 (d, J = 4.7 Hz, 3H), 2.63 – 2.56 (m, 1H), 2.53 –2.51 (m, 1H), 2.48 – 2.44 (m, 1H), 2.43 – 2.33 (m, 4H), 2.32 –2.24 (m, 2H), 2.21 – 2.15 (m, 1H), 2.07 – 1.98 (m, 2H), 1.55 –1.48 (m, 4H), 1.45 – 1.41 (m, 4H). MS(ESI, [M+H] + ) m / z : 822.3]]> 132 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.86 (s, 1H), 8.06 (s,1H), 7.93 (dd, J = 7.0, 3.2 Hz, 2H), 7.74 (dd, J = 9.2, 2.4Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 9.1 Hz, 1H),7.11 (t, J = 4.2 Hz, 2H), 4.55 (d, J = 18.6 Hz, 3H), 3.66 (s,7H), 3.02 (d, J = 13.3 Hz, 2H), 2.88 (d, J = 10.0 Hz, 1H),2.77 (ddd, J = 17.1, 11.9, 5.3 Hz, 1H), 2.62 (d, J = 4.6 Hz,4H), 2.53 (s, 1H), 2.43 (s, 4H), 2.32 (d, J = 7.2 Hz, 2H),2.18 (dd, J = 8.6, 4.5 Hz, 1H), 2.14 (d, J = 23.1 Hz, 3H),1.46 (s, 1H). MS(ESI, [M+H] + ) m / z:754.2]]> 133 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.93 (s, 1H), 8.08 (s,1H), 7.94 (q, J = 4.7 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.70(dd, J = 17.1, 2.4 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.13 –7.07 (m, 2H), 4.60 (s, 2H), 4.53 (dd, J = 11.8, 5.0 Hz, 1H),3.82 (d, 3H), 3.70 – 3.59 (m, 4H), 3.06 – 2.95 (m, 2H), 2.95 –2.82 (m, 3H), 2.80 – 2.72 (m, 1H), 2.67 (d, J = 4.6 Hz, 3H),2.62 – 2.57 (m, 1H), 2.56 – 2.52 (m, 4H), 2.48 – 2.42 (m, 1H),2.33 – 2.14 (m, 4H), 2.08 – 1.97 (m, 2H), 1.94 – 1.82 (m, 2H),1.79 – 1.69 (m, 2H), 1.54 – 1.38 (m, 3H). MS(ESI, [M+H] + ) m / z: 855.3]]> 134 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.88 (s, 1H), 8.06 (s,1H), 7.98 (dd, J = 10.2, 3.6 Hz, 2H), 7.73 (dd, J = 9.2, 2.4Hz, 1H), 7.64 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H),7.19 (s, 1H), 7.11 (d, J = 8.3 Hz, 1H), 5.28 (q, J = 9.0 Hz,2H), 4.61 (s, 2H), 4.53 (dd, J = 11.8, 4.9 Hz, 1H), 3.62 (s,4H), 3.06 – 2.91 (m, 4H), 2.79 (d, J = 5.4 Hz, 2H), 2.78 –2.71 (m, 1H), 2.68 (d, J = 4.6 Hz, 3H), 2.65 – 2.53 (m, 4H),2.47 – 2.41 (m, 1H), 2.28 (s, 3H), 2.20 – 2.15 (m, 1H), 1.98(d, J = 50.3 Hz, 4H), 1.76 (d, J = 11.8 Hz, 2H), 1.45 (d, J =41.7 Hz, 4H).MS(ESI, [M+H] + ) m / z:905.3 <!-- 139 -->]]> 135 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.84 (s, 1H), 8.16 (d,J = 4.3 Hz, 1H), 8.05 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.75(dd, J = 9.1, 2.4 Hz, 1H), 7.49 (dd, J = 19.5, 8.7 Hz, 2H),7.10 (d, J = 8.5 Hz, 2H), 4.54 (d, J = 13.8 Hz, 3H), 3.67 (s,3H), 3.62 (s, 4H), 3.02 (d, J = 20.4 Hz, 2H), 2.97 – 2.77 (m,4H), 2.76 – 2.65 (m, 2H), 2.63 – 2.53 (m, 3H), 2.49 – 2.42 (m,2H), 2.24 (s, 2H), 2.22 – 2.14 (m, 2H), 1.81 (d, J = 71.6 Hz,7H), 1.45 (s, 3H), 0.64 (td, J = 7.0, 4.8 Hz, 2H), 0.51 – 0.44(m, 2H).MS(ESI, [M+H] + ) m / z:863.3]]> 136 <![CDATA[1H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.98 (s, 1H), 8.08 (s,1H), 7.95 (q, J = 4.7 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.71(dd, J = 9.1, 2.5 Hz, 1H), 7.50 (dd, J = 14.8, 8.6 Hz, 2H),7.14 (s, 1H), 7.10 (d, J = 8.3 Hz, 1H), 4.58 (s, 2H), 4.53(dd, J = 11.8, 5.0 Hz, 1H), 3.91 (t, J = 11.1 Hz, 2H), 3.69(s, 5H), 3.22 (d, J = 7.6 Hz, 2H), 3.16 (t, J = 5.9 Hz, 2H),3.06 – 2.92 (m, 2H), 2.87 – 2.72 (m, 2H), 2.69 (d, J = 4.7 Hz,3H), 2.63 – 2.52 (m, 2H), 2.48 – 2.42 (m, 3H), 2.17 (dq, J =13.7, 4.8 Hz, 1H), 2.06 – 1.96 (m, 3H), 1.78 (s, 1H), 1.46 –1.37 (m, 1H).MS(ESI, [M+H] + ) m / z:830.29]]> 137 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 9.06 (d, J = 5.0 Hz,1H), 8.96 (s, 1H), 8.09 – 8.02 (m, 2H), 7.90 (dd, J = 9.1, 2.5Hz, 1H), 7.86 (s, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.52 (d, J =8.2 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 4.53 (dd, J = 11.9, 5.0Hz, 1H), 3.69 (s, 3H), 3.67 – 3.55 (m, 4H), 3.06 – 2.83 (m,5H), 2.81 – 2.75 (m, 1H), 2.73 (d, J = 4.6 Hz, 3H), 2.63 –2.53 (m, 4H), 2.48 – 2.44 (m, 2H), 2.30 – 2.14 (m, 4H), 2.07 –1.98 (m, 2H), 1.94 – 1.81 (m, 2H), 1.79 – 1.68 (m, 2H), 1.51 –1.39 (m, 3H). MS(ESI, [M+H] + ) m / z : 873.3]]> 138 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.85 (s, 1H), 8.04 (s,1H), 7.90 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 9.0, 2.5 Hz, 1H),7.51 (d, J = 8.1 Hz, 1H), 7.45 (d, J = 9.1 Hz, 1H), 7.10 (d, J= 8.3 Hz, 1H), 7.06 (s, 1H), 4.92 (s, 2H), 4.53 (dd, J = 11.9,5.0 Hz, 1H), 3.67 (s, 3H), 3.60 (s, 4H), 3.09 – 2.79 (m, 6H),2.76 (td, J = 11.9, 5.9 Hz, 1H), 2.66 – 2.54 (m, 2H), 2.47(dd, J = 8.6, 3.8 Hz, 2H), 2.25 (s, 2H), 2.20 (s, 5H), 2.02(s, 2H), 1.88 (s, 2H), 1.74 (d, J = 11.6 Hz, 2H), 1.46 (d, J =17.4 Hz, 4H).MS(ESI, [M+H] + ) m / z:822.3 <!-- 140 -->]]> 139 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.84 (s, 1H), 8.05 (s,1H), 7.97 (dd, J = 6.3, 3.3 Hz, 2H), 7.74 (dd, J = 9.2, 2.5Hz, 1H), 7.52 (dd, J = 8.7, 4.1 Hz, 2H), 7.10 (d, J = 7.1 Hz,2H), 4.58 (s, 2H), 4.53 (dd, J = 11.8, 5.0 Hz, 1H), 4.32 (q, J= 7.1 Hz, 2H), 3.62 (s, 4H), 3.01 (s, 3H), 2.90 (s, 3H), 2.79– 2.73 (m, 1H), 2.67 (d, J = 4.7 Hz, 3H), 2.59 (dd, J = 17.4,4.4 Hz, 2H), 2.49 – 2.42 (m, 2H), 2.25 (s, 2H), 2.17 (dd, J =13.1, 5.2 Hz, 2H), 2.02 (s, 2H), 1.88 (s, 3H), 1.75 (s, 2H),1.47 (s, 5H), 1.26 (s, 2H).MS(ESI, [M+H] + ) m / z:851.3]]> 140 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.84 (s, 1H), 8.04 (s,1H), 7.95 – 7.90 (m, 2H), 7.75 (dd, J = 9.1, 2.5 Hz, 1H), 7.49(dd, J = 19.3, 8.6 Hz, 2H), 7.15 – 7.08 (m, 2H), 4.58 (s, 2H),4.53 (dd, J = 11.8, 5.0 Hz, 1H), 3.68 (s, 3H), 3.65 – 3.57 (m,4H), 3.08 – 2.80 (m, 6H), 2.79 – 2.71 (m, 1H), 2.67 – 2.54 (m,3H), 2.48 – 2.42 (m, 1H), 2.29 – 2.15 (m, 4H), 2.06 – 1.98 (m,2H), 1.94 – 1.82 (m, 2H), 1.79 – 1.70 (m, 2H), 1.49 – 1.36 (m,3H). MS(ESI, [M+H] + ) m / z : 840.3]]> 142 <![CDATA[ 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.84 (s, 1H), 8.04(s, 1H), 7.93 (dd, J = 12.7, 3.7 Hz, 2H), 7.73 (d, J = 9.1 Hz,1H), 7.49 (dd, J = 20.9, 8.6 Hz, 2H), 7.09 (d, J = 10.9 Hz,2H), 4.57 (s, 3H), 4.20 (s, 1H), 4.09 (d, J = 13.0 Hz, 2H),3.67 (s, 3H), 3.60 (s, 2H), 3.54 (s, 1H), 3.21 (t, J = 11.5Hz, 2H), 2.97 (dd, J = 30.6, 17.2 Hz, 2H), 2.77 (d, J = 12.4Hz, 4H), 2.66 (d, J = 4.6 Hz, 3H), 2.59 (d, J = 17.4 Hz, 1H),2.42 (s, 3H), 2.18 (s, 1H), 1.99 (s, 1H), 1.79 (s, 3H), 1.36(d, J = 10.9 Hz, 4H).MS(ESI, [M+H] + ) m / z:824.32]]> 143 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.90 (s, 1H), 8.09 –8.01 (m, 2H), 7.78 (dd, J = 9.1, 2.5 Hz, 1H), 7.51 (d, J = 8.6Hz, 2H), 7.45 (s, 1H), 7.10 (d, J = 8.3 Hz, 1H), 5.27 (s, 2H),4.53 (dd, J = 11.9, 5.0 Hz, 1H), 3.68 (s, 3H), 3.65 – 3.57 (m,4H), 3.00 (td, J = 17.3, 9.1 Hz, 2H), 2.95 – 2.82 (m, 3H),2.76 (ddd, J = 17.2, 11.9, 5.3 Hz, 1H), 2.60 (dt, J = 17.4,4.4 Hz, 1H), 2.53 (d, J = 4.9 Hz, 4H), 2.49 – 2.42 (m, 2H),2.33 – 2.24 (m, 2H), 2.17 (dq, J = 13.4, 4.6 Hz, 2H), 2.02 (d,J = 12.4 Hz, 2H), 1.89 (d, J = 16.9 Hz, 2H), 1.77 – 1.70 (m,2H), 1.44 (dt, J = 21.1, 10.9 Hz, 3H)MS(ESI, [M+H] + ) m / z:805.3 <!-- 141 -->]]> 144 <![CDATA[ 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.93 (s, 1H), 8.08(s, 1H), 7.91 (s, 1H), 7.79 (s, 1H), 7.70 (dd, J = 17.1, 2.4Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.09 (s, 2H), 4.60 (s, 2H),4.53 (dd, J = 11.8, 5.0 Hz, 1H), 3.82 (d, J = 7.8 Hz, 3H),3.63 (t, J = 4.9 Hz, 4H), 3.07 – 2.70 (m, 7H), 2.63 – 2.52 (m,5H), 2.46 (d, J = 5.5 Hz, 1H), 2.27 – 2.14 (m, 4H), 2.02 (s,2H), 1.88 (d, J = 12.9 Hz, 2H), 1.74 (d, J = 11.8 Hz, 2H),1.44 (dd, J = 31.1, 13.1 Hz, 3H).MS(ESI, [M+H] + ) m / z:858.36]]> 147 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.5 Hz, 1H), 8.90 (s,1H), 8.06 (s, 1H), 7.98 (q, J = 4.7 Hz, 1H), 7.95 – 7.85 (m,2H), 7.51 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.14– 7.06 (m, 1H), 4.60 (s, 2H), 4.56 – 4.50 (m, 1H), 3.83 (d, J= 7.8 Hz, 3H), 3.72 (s, 4H), 3.01 – 2.89 (m, 2H), 2.82 – 2.73(m, 2H), 2.68 (d, J = 4.6 Hz, 3H), 2.65 – 2.56 (m, 2H), 2.49 –2.44 (m, 1H), 2.43 – 2.15 (m, 5H), 2.13 – 2.02 (m, 4H), 2.00 –1.92 (m, 1H), 1.85 – 1.68 (m, 4H), 1.04 – 0.91 (m, 2H). MS(ESI, [M+H] + ) m / z : 826.3]]> 148 <![CDATA[ 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.90 (s, 1H), 8.06(s, 1H), 7.95 (q, J = 4.7 Hz, 1H), 7.78 – 7.72 (m, 2H), 7.51(d, J = 8.2 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.06 (d, J =1.4 Hz, 1H), 4.59 (s, 2H), 4.53 (dd, J = 11.7, 5.0 Hz, 1H),3.82 (d, J = 7.9 Hz, 3H), 3.66 (t, J = 5.7 Hz, 4H), 3.01 (t, J= 19.2 Hz, 2H), 2.86 (d, J = 10.6 Hz, 1H), 2.76 (td, J = 11.9,5.8 Hz, 1H), 2.67 (d, J = 4.6 Hz, 3H), 2.60 (d, J = 17.3 Hz,1H), 2.46 (d, J = 4.0 Hz, 1H), 2.34 (d, J = 45.3 Hz, 6H), 2.20– 2.15 (m, 1H), 2.04 (d, J = 11.6 Hz, 2H), 1.52 (s, 5H), 1.45(s, 5H).MS(ESI, [M+H] + ) m / z:840.33]]> 150 <![CDATA[1H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.94 (s, 1H), 8.08 (s,1H), 7.93 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.73 (dd, J =17.7, 2.4 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.13 – 7.07 (m,2H), 4.59 (s, 2H), 4.53 (dd, J = 11.8, 5.0 Hz, 1H), 4.42 –4.33 (m, 2H), 3.64 (s, 4H), 3.07 – 2.80 (m, 6H), 2.59 – 2.53(m, 4H), 2.47 – 2.42 (m, 1H), 2.35 – 2.13 (m, 5H), 2.06 – 1.99(m, 2H), 1.76 (d, J = 11.6 Hz, 2H), 1.45 (d, J = 35.5 Hz, 4H),1.30 (t, J = 7.0 Hz, 3H).MS(ESI, [M+H] + ) m / z:872.64<!-- 142 --> ]]> 151 <![CDATA[1H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.93 (s, 1H), 8.08 (s,1H), 7.93 (s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.68 (dd, J =17.3, 2.4 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.14 – 7.08 (m,2H), 6.02 (ddt, J = 15.4, 9.7, 4.6 Hz, 1H), 5.11 (dd, J =10.5, 1.6 Hz, 1H), 5.02 – 4.91 (m, 3H), 4.61 (s, 2H), 4.53(dd, J = 11.8, 5.0 Hz, 1H), 3.64 (s, 4H), 3.08 – 2.73 (m, 7H),2.56 (d, J = 17.4 Hz, 4H), 2.46 (d, J = 3.8 Hz, 1H), 2.33 –2.14 (m, 4H), 2.02 (s, 2H), 1.89 (s, 2H), 1.75 (s, 2H), 1.45(d, J = 34.4 Hz, 4H).MS(ESI, [M+H] + ) m / z:884.61]]> 152 <![CDATA[1H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.99 (s, 1H), 8.09 (s,1H), 7.95 (s, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.75 (dd, J =17.8, 2.4 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.19 (s, 1H),7.11 (d, J = 8.3 Hz, 1H), 5.29 (d, J = 9.4 Hz, 2H), 4.63 (s,2H), 4.53 (dd, J = 11.8, 5.0 Hz, 1H), 3.64 (s, 4H), 3.11 –2.71 (m, 7H), 2.58 (d, J = 35.0 Hz, 5H), 2.46 (d, J = 4.3 Hz,1H), 2.31 – 2.13 (m, 4H), 2.02 (s, 2H), 1.89 (s, 2H), 1.75 (d,J = 11.3 Hz, 2H), 1.45 (d, J = 33.1 Hz, 3H).MS(ESI, [M+H] + ) m / z:926.3]]> 153 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 9.14 (s, 1H), 8.33 (d,J = 2.4 Hz, 1H), 8.23 – 8.03 (m, 2H), 7.92 (s, 1H), 7.51 (d, J= 8.1 Hz, 1H), 7.24 – 7.02 (m, 2H), 4.62 (s, 2H), 4.53 (dd, J= 11.8, 5.1 Hz, 1H), 3.62 (d, J = 7.8 Hz, 8H), 3.09 – 2.70 (m,7H), 2.66 – 2.56 (m, 2H), 2.46 (d, J = 5.8 Hz, 1H), 2.32 –2.12 (m, 4H), 2.10 – 1.96 (m, 2H), 1.88 (q, J = 12.7 Hz, 2H),1.73 (d, J = 11.7 Hz, 2H), 1.58 – 1.36 (m, 3H). MS(ESI, [M+H] + )m / z : 908.3]]> 154 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.92 (s, 1H), 8.53 (s,1H), 8.06 (s, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.86 (dd, J =9.2, 2.6 Hz, 1H), 7.66 (s, 1H), 7.53 (dd, J = 18.2, 8.6 Hz,2H), 7.11 (d, J = 8.2 Hz, 1H), 6.30 (d, J = 58.9 Hz, 1H), 4.53(dd, J = 11.9, 5.0 Hz, 1H), 3.70 (s, 3H), 3.65 – 3.57 (m, 4H),3.05 – 2.82 (m, 5H), 2.81 – 2.71 (m, 1H), 2.63 – 2.51 (m, 4H),2.49 – 2.42 (m, 2H), 2.30 – 2.15 (m, 4H), 2.06 – 1.97 (m, 2H),1.94 – 1.83 (m, 2H), 1.77 – 1.69 (m, 2H), 1.51 – 1.37 (m, 3H).MS(ESI, [M+H] + ) m / z : 858.3 <!-- 143 -->]]> 155 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.92 (s, 1H), 8.53 (s,1H), 8.06 (s, 1H), 7.98 (d, J = 2.6 Hz, 1H), 7.86 (dd, J =9.2, 2.4 Hz, 1H), 7.66 (s, 1H), 7.53 (dd, J = 17.4, 8.7 Hz,2H), 7.11 (d, J = 8.4 Hz, 1H), 6.24 (s, 1H), 4.53 (dd, J =11.7, 5.0 Hz, 1H), 3.70 (s, 3H), 3.65 – 3.56 (m, 4H), 3.05 –2.84 (m, 5H), 2.80 – 2.71 (m, 1H), 2.67 – 2.52 (m, 4H), 2.49 –2.42 (m, 2H), 2.31 – 2.14 (m, 4H), 2.06 – 1.98 (m, 2H), 1.95 –1.80 (m, 2H), 1.79 – 1.68 (m, 2H), 1.53 – 1.36 (m, 3H). MS(ESI, [M+H] + ) m / z : 858.3]]> 156 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 9.03 (s, 1H), 8.95 (s,1H), 8.06 (s, 1H), 8.04 (d, J = 2.6 Hz, 1H), 7.90 (dd, J =9.2, 2.4 Hz, 1H), 7.86 (s, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.51(d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 4.53 (dd, J =12.0, 5.0 Hz, 1H), 3.69 (s, 3H), 3.64 – 3.57 (m, 4H), 3.05 –2.82 (m, 5H), 2.79 – 2.71 (m, 1H), 2.66 – 2.53 (m, 2H), 2.47 –2.35 (m, 3H), 2.28 – 2.15 (m, 4H), 2.04 – 1.98 (m, 2H), 1.94 –1.81 (m, 2H), 1.77 – 1.69 (m, 2H), 1.51 – 1.39 (m, 3H). MS(ESI, [M+H] + ) m / z : 876.3]]> 157 <![CDATA[1H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 9.02 (s, 1H), 8.96 (s,1H), 8.07 (d, J = 2.5 Hz, 1H), 8.06 (s, 1H), 7.90 – 7.80 (m,2H), 7.54 (dd, J = 20.8, 8.6 Hz, 2H), 7.09 (d, J = 8.2 Hz,1H), 4.53 (dd, J = 11.8, 5.0 Hz, 1H), 4.23 (s, 1H), 4.10 (d, J= 12.9 Hz, 2H), 3.69 (s, 4H), 3.56 (s, 1H), 3.20 (ddd, J =13.2, 9.6, 3.2 Hz, 2H), 3.07 – 2.92 (m, 3H), 2.88 – 2.71 (m,3H), 2.65 – 2.53 (m, 3H), 2.45 (dt, J = 12.4, 6.4 Hz, 2H),2.18 (dt, J = 13.2, 4.6 Hz, 1H), 2.00 (d, J = 12.8 Hz, 1H),1.79 (d, J = 12.7 Hz, 3H), 1.49 – 1.33 (m, 4H).MS(ESI, [M+H] + )m / z:863.3]]> 158 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 9.04 (s, 1H), 8.92 (s,1H), 8.10 – 8.03 (m, 2H), 7.90 (dd, J = 9.2, 2.5 Hz, 1H), 7.82(s, 1H), 7.57 (d, J = 9.3 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H),7.12 (d, J = 8.2 Hz, 1H), 4.53 (dd, J = 11.9, 5.0 Hz, 1H),3.69 (s, 3H), 3.67 – 3.59 (m, 4H), 3.07 – 2.96 (m, 2H), 2.91 –2.82 (m, 1H), 2.79 – 2.71 (m, 1H), 2.65 – 2.53 (m, 2H), 2.48 –2.22 (m, 7H), 2.20 – 2.15 (m, 1H), 2.08 – 1.98 (m, 2H), 1.60 –1.48 (m, 4H), 1.45 – 1.38 (m, 4H). MS(ESI, [M+H] + ) m / z : 861.3 <!-- 144 -->]]> 161 <![CDATA[1H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.87 (s, 1H), 8.06 (s,1H), 8.02 – 7.93 (m, 2H), 7.73 (dd, J = 9.2, 2.5 Hz, 1H), 7.64(d, J = 9.2 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.20 (s, 1H),7.10 (d, J = 8.3 Hz, 1H), 5.28 (q, J = 9.1 Hz, 2H), 4.61 (s,2H), 4.53 (dd, J = 11.8, 5.0 Hz, 1H), 3.68 – 3.58 (m, 4H),3.11 – 2.71 (m, 7H), 2.64 – 2.52 (m, 5H), 2.46 (q, J = 7.3 Hz,1H), 2.34 – 2.15 (m, 5H), 2.09 – 1.99 (m, 2H), 1.75 (d, J =11.8 Hz, 2H), 1.45 (d, J = 29.7 Hz, 3H).MS(ESI, [M+H] + ) m / z:908.3]]> 162 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.83 (s, 1H), 8.04 (s,1H), 7.93 (d, J = 2.2 Hz, 2H), 7.74 (dd, J = 9.1, 2.4 Hz, 1H),7.51 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 9.1 Hz, 1H), 7.11 (d, J= 5.8 Hz, 2H), 4.58 (s, 2H), 4.53 (dd, J = 11.9, 5.0 Hz, 1H),4.07 (d, J = 12.7 Hz, 2H), 3.68 (s, 4H), 3.49 (d, J = 14.9 Hz,1H), 3.25 (d, J = 10.6 Hz, 2H), 2.99 (d, J = 18.1 Hz, 2H),2.86 (d, J = 9.7 Hz, 1H), 2.73 (s, 3H), 2.63 – 2.56 (m, 1H),2.46 (d, J = 4.1 Hz, 1H), 2.26 (s, 2H), 2.19 – 2.14 (m, 1H),2.03 (s, 4H), 1.81 (s, 4H), 1.43 (d, J = 39.9 Hz, 6H).MS(ESI,[M+H] + ) m / z:855.3]]> 163 <![CDATA[ 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.85 (s, 1H), 8.06(s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.85 (s, 1H), 7.79 (dd, J =9.0, 2.5 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 9.1Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 4.82 (s, 2H), 4.53 (dd, J =11.8, 5.0 Hz, 1H), 3.64 (d, J = 6.6 Hz, 7H), 3.02 – 2.71 (m,6H), 2.63 – 2.51 (m, 5H), 2.49 – 2.42 (m, 2H), 2.28 – 2.14 (m,4H), 2.02 (s, 2H), 1.89 (d, J = 14.6 Hz, 2H), 1.75 (d, J =10.8 Hz, 2H), 1.49 (s, 1H), 1.47 – 1.37 (m, 2H).MS(ESI, [M+H] + )m / z:841.37]]> 168 <![CDATA[ 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.88 (s, 1H), 8.04 (s,1H), 7.96 – 7.89 (m, 2H), 7.74 (dd, J = 9.1, 2.4 Hz, 1H), 7.50(dd, J = 17.1, 8.6 Hz, 2H), 7.15 – 7.07 (m, 2H), 4.87 – 4.73(m, 1H), 4.59 (s, 2H), 4.53 (dd, J = 11.9, 5.0 Hz, 1H), 4.27(s, 1H), 4.09 (q, J = 5.5 Hz, 1H), 3.69 (s, 3H), 3.49 – 3.37(m, 1H), 3.16 (t, J = 6.6 Hz, 3H), 3.09 – 2.92 (m, 4H), 2.88 –2.72 (m, 2H), 2.66 – 2.52 (m, 3H), 2.45 (dt, J = 11.5, 5.9 Hz,2H), 2.17 (dq, J = 13.7, 4.8 Hz, 1H), 2.02 (d, J = 12.5 Hz,1H), 1.95 – 1.87 (m, 1H), 1.74 (d, J = 14.6 Hz, 2H), 1.41 (s,1H).MS(ESI, [M+H] + ) m / z:815.3]]> 169 <![CDATA[MS(ESI, [M+H] + ) m / z:869.3<!-- 145 --> ]]> 170 <![CDATA[MS(ESI, [M+H] + ) m / z:829.3]]> 171 <![CDATA[MS(ESI, [M+H] + ) m / z:815.3]]> 172 <![CDATA[MS(ESI, [M+H] + ) m / z:840.3]]> 173 <![CDATA[MS(ESI, [M+H] + ) m / z:842.3]]> 174 <![CDATA[MS(ESI, [M+H] + ) m / z:870.3]]> 175 <![CDATA[MS(ESI, [M+H] + ) m / z:890.3]]> 176 <![CDATA[MS(ESI, [M+H] + ) m / z:847.3]]> 177 <![CDATA[MS(ESI, [M+H] + ) m / z:833.3]]> 178 <![CDATA[MS(ESI, [M+H] + ) m / z:891.3]]>

[0778] Example 114: Synthesis of Compound 114

[0779]

[0780] Step 1: Preparation of intermediate 114b

[0781] 114a (5 g), 4-hydroxypyridine (1.89 g), potassium carbonate (8.25 g), and DMF (200 mL) were added sequentially to a reaction flask, and the reaction was carried out at 100 °C for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and extracted with ethyl acetate. The organic phases were separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate 114b (4.32 g). MS (ESI) m / z [M+H] + 291.1

[0782] Step 2: Preparation of intermediate 114c

[0783] Intermediate 114b (1 g), platinum oxide (0.498 g), p-toluenesulfonic acid (0.688 g), and ethanol (15 mL) were added sequentially to a reaction flask. The reaction was carried out overnight at 50°C under hydrogen atmosphere. After the reaction was complete, the mixture was filtered, and DIPEA (1.37 mL) was added to the filtrate. The filtrate was then concentrated under reduced pressure to obtain intermediate 114c (1.8 g).

[0784] Step 3: Preparation of intermediate 114d

[0785] Intermediate 114c (1.8 g), intermediate 5h (0.4 g), DIPEA (2.2 mL), and DMF (10 mL) were added sequentially to the reaction flask, and the reaction was carried out at 80 °C for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution, and extracted with DCM (50 mL). The organic phases were separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate 114d (0.49 g). MS (ESI) m / z [M+H] + 714.3

[0786] Step 4: Preparation of intermediate 114e

[0787] Intermediate 114d (0.49 g), trifluoroacetic acid (1 mL), and DCM (10 mL) were added sequentially to a reaction flask, and the reaction was carried out at room temperature for 2 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain intermediate 114e (0.9 g). MS (ESI) m / z [M+H) + 614.3

[0788] Step 5: Preparation of Compound 114

[0789] Intermediate Z47 (50 mg), DMSO (1 mL), and 2-iodobenzoic acid (138 mg) were added sequentially to a reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, water and saturated sodium bicarbonate solution were added to quench the reaction, followed by extraction with ethyl acetate and concentration. The resulting concentrate was added to a DCE / i-PrOH solution (v:v=5:1, 2 mL) containing intermediate 114e (130 mg), sodium acetate (48 mg), and sodium triacetoxyborohydride (42 mg), and the reaction was carried out at room temperature. After the reaction was completed, the solvent was removed by vacuum distillation, and the solution was purified by silica gel column chromatography to give compound 114 (48 mg). MS (ESI, [M+H)) + m / z:910.3

[0790] 1H NMR (500 MHz, DMSO) δ 11.09 – 11.05 (m, 1H), 8.74 (s, 1H), 8.06 –7.96 (m, 2H), 7.60 – 7.52 (m, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.2Hz, 1H), 7.12 (s, 1H), 5.32 (t, J = 4.9 Hz, 1H), 4.60 (s, 2H), 4.53 (dd, J =11.8, 5.0 Hz, 1H), 3.95 (p, J = 7.1 Hz, 2H), 3.43 (tt, J = 8.3, 3.8 Hz, 2H),3.34 (s, 4H), 3.12 – 3.01 (m, 4H), 2.75 (ddt, J = 23.4, 15.7, 8.2 Hz, 4H),2.67 (d, J = 4.6 Hz, 3H), 2.64 – 2.53 (m, 2H), 2.49 – 2.42 (m, 1H), 2.35 (s,2H), 2.17 (td, J = 9.3, 5.2 Hz, 1H), 1.93 (dt, J = 10.5, 5.8 Hz, 2H), 1.80(s, 1H), 1.69 (dd, J = 11.0, 6.3 Hz, 2H), 1.57 (d, J = 6.9 Hz, 6H), 1.30 –1.22 (m, 3H).

[0791] Example 121: Synthesis of Compound 121

[0792]

[0793] Step 1: Preparation of intermediate 121a

[0794] Under nitrogen protection, dimethylchlorosilane (10.03 g) was slowly added dropwise to a mixture of methyl cis-3-hydroxycyclobutanecarboxylate (4.6 g) and 1-Cbz-4-piperidinone (16.49 g) in acetonitrile (150 ml) with stirring. After the addition was complete, the mixture was stirred at 50 °C. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, and the extract was purified by silica gel column chromatography to obtain intermediate 121a (6.1 g).

[0795] Step 2: Preparation of intermediate 121b

[0796] Intermediate 121a (6.1 g), di-tert-butyl dicarbonate (5.75 g), palladium on carbon (1.869 g), and methanol (120 ml) were added sequentially to a reaction flask, and the reaction was carried out at room temperature under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate 121b (5.08 g).

[0797] Step 3: Preparation of intermediate 121c

[0798] Under nitrogen protection at -78°C, diisobutylaluminum hydride (1.5M THF solution, 6.38 mL) was slowly added dropwise to anhydrous THF (50 mL) of intermediate 121b (2.50 g) with stirring. After the addition was complete, the mixture was stirred at -78°C. After the reaction was complete, saturated ammonium chloride aqueous solution was added dropwise to quench the reaction, followed by extraction with ethyl acetate. The extract was purified by silica gel column chromatography to obtain intermediate 121c (1.8 g).

[0799] Step 4: Preparation of intermediate 121d:

[0800] Intermediate 121c (207 mg), intermediate z4 (150 mg, synthesis procedure referred to CN118852177 Preparation Example 4, compound z4), anhydrous sodium acetate (40 mg), sodium cyanoborohydride (77 mg), and methanol (20 mL) were added sequentially to a reaction flask. The reaction was carried out 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 121d (197 mg). MS (ESI, [M+H)) + m / z: 553.3.

[0801] Steps 5 and 6: Preparation of compound 121:

[0802] Following the method described in steps 2-3 of Example 106, intermediate 121 was prepared by replacing intermediate 106a with intermediate 121d and intermediate 17b with intermediate 14a.

[0803] 1H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 8.76 (s, 1H), 8.04 (s, 1H), 7.94 (d, J = 4.8 Hz, 1H), 7.59 – 7.50 (m, 3H), 7.08 (d, J = 8.3 Hz, 1H), 6.99(s, 1H), 4.59 – 4.51 (m, 3H), 4.11 (ddt, J = 16.5, 10.5, 5.4 Hz, 2H), 3.97(p, J = 7.2 Hz, 1H), 3.86 (d, J = 8.7 Hz, 6H), 3.67 (s, 2H), 3.54 (dq, J =8.5, 4.3 Hz, 1H), 3.26 (td, J = 9.6, 4.7 Hz, 2H), 2.96 (t, J = 5.9 Hz, 2H), 2.76 (dt, J = 17.7, 6.1 Hz, 3H), 2.66 (d, J = 4.7 Hz, 3H), 2.59 (dt, J =25.7, 5.9 Hz, 3H), 2.48 – 2.35 (m, 3H), 2.18 (dq, J = 13.4, 4.8 Hz, 1H), 2.08 (p, J = 8.6 Hz, 1H), 1.85 – 1.76 (m, 2H), 1.56 (q, J = 9.5 Hz, 2H), 1.37 (qd,J = 8.9, 4.3 Hz, 2H). MS(ESI, [M+H] + m / z:854.3

[0804] Example 141: Synthesis of Compound 141

[0805]

[0806] Step 1: Preparation of intermediate 141a

[0807] Z15M (1.44 g), 2-iodobenzoic acid (3.21 g), and acetonitrile (80 mL) were added sequentially to the reaction flask, and the mixture was stirred at 70 °C. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the extract was concentrated to obtain intermediate 141a (1.27 g).

[0808] Step 2: Preparation of intermediate 141b

[0809] 1-Boc-4-(piperidin-4-yl)-piperazine (340 mg), intermediate 141a (250 mg), methanol (50 mL), sodium acetate (53 mg), and sodium cyanoborohydride (68 mg) were added sequentially to a reaction flask, and the reaction was carried out at 60 °C. After the reaction was completed, the mixture was quenched with water, extracted with dichloromethane, and the extract was concentrated and purified by silica gel column chromatography to obtain compound 141b (290 mg).

[0810] MS(ESI, [M+H)) + m / z: 541.3.

[0811] Step 3: Preparation of intermediates 141c and 141c'

[0812] Intermediate 141b was prepared and resolved (chromatographic column: IG, 30*250 mm, 10 μm; mobile phase: dichloromethane: methanol), yielding intermediate 141c (385 mg) and intermediate 141c' (395 mg).

[0813] Intermediate 141c: MS(ESI, [M+H]) + m / z: 541.3

[0814] Intermediate 141c': MS(ESI, [M+H] + m / z: 541.3

[0815] Step 4: Preparation of intermediate 141d'

[0816] Referring to step 13 of Preparation Example 15, intermediate z15 was prepared by replacing intermediate z15m with intermediate 141c' to obtain intermediate 141d' (220mg).

[0817] MS(ESI, [M+H)) + m / z: 566.3.

[0818] Steps 5 and 6: Preparation of compound 141

[0819] Following the method described in steps 2-3 of Example 106, intermediate 106a was replaced with intermediate 141d' and intermediate 17b was replaced with intermediate 13h to prepare compound 141 (45 mg).

[0820] 1H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.0 Hz, 1H), 8.84 (s, 1H), 8.05 (s, 1H), 7.98 – 7.91 (m, 2H), 7.75 (dd, J = 9.1, 2.4 Hz, 1H), 7.52 (d, J= 8.1 Hz, 1H), 7.47 (d, J = 9.1 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.13 (s,1H), 4.59 (s, 2H), 4.53 (ddd, J = 12.0, 5.1, 2.2 Hz, 1H), 3.68 (s, 2H), 3.62 (s, 4H), 3.31 – 3.24 (m, 2H), 3.00 (s, 2H), 2.88 (s, 1H), 2.77 (dd, J = 17.1,11.4 Hz, 3H), 2.67 (d, J = 4.7 Hz, 3H), 2.59 (dt, J = 17.3, 4.4 Hz, 2H), 2.47– 2.27 (m, 3H), 2.18 (ddt, J = 12.8, 8.3, 5.1 Hz, 3H), 2.05 (s, 2H), 1.90 (s,2H), 1.77 (s, 2H), 1.53 – 1.29 (m, 4H), 1.23 (s, 1H).

[0821] MS(ESI, [M+H)) + m / z: 837.4.

[0822] Example 145 Synthesis of Compound 145

[0823] Referring to the method described in steps 1-6 of Example 141, intermediate Z15m was replaced by intermediate Z47j, intermediate 13h was replaced by intermediate Z144, and intermediate 145b was separated by the following method (chromatographic column: IG, 30*250 mm, 10um; mobile phase: dichloromethane: ethanol: n-hexane; intermediates 145c and 145c' were obtained successively) to prepare compound 145 (24 mg).

[0824] 1H NMR (500 MHz, DMSO-d6) δ 11.07 (d, J = 3.9 Hz, 1H), 8.93 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 17.1, 2.4Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.08 (s, 1H), 4.59 (s, 2H), 4.55 – 4.50 (m, 1H), 3.81 (d, J = 7.8 Hz, 3H), 3.62 (s, 4H), 3.38 (dd, J = 14.3, 7.0 Hz, 1H), 3.01 – 2.94 (m, 1H), 2.85 – 2.70 (m, 5H), 2.69 – 2.56 (m, 3H), 2.30 – 1.93 (m, 7H), 1.74 (d, J = 12.3 Hz, 2H), 1.35 (d,J = 13.6 Hz, 5H), 1.24 (d,J = 7.7 Hz, 2H).

[0825] MS(ESI, [M+H)) + m / z: 858.36.

[0826] Example 146: Synthesis of Compound 146

[0827]

[0828] Referring to step 6 of Example 141, the preparation process of compound 141 involved replacing intermediate z144 with intermediate 13h to prepare compound 146 (36mg).

[0829] 1H NMR (500 MHz, DMSO-d6) δ 11.07 (d, J = 3.0 Hz, 1H), 8.93 (s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 17.1, 2.4Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 1.4Hz, 1H), 4.60 (s, 2H), 4.53 (ddd, J = 11.9, 5.0, 2.2 Hz, 1H), 3.82 (d, J =7.8 Hz, 3H), 3.63 (t, J = 4.9 Hz, 4H), 3.28 (d, J = 20.1 Hz, 1H), 2.94 (d, J= 53.7 Hz, 3H), 2.75 (q, J = 12.5 Hz, 3H), 2.65 – 2.52 (m, 5H), 2.49 – 2.31(m, 3H), 2.25 – 2.13 (m, 3H), 2.08 – 1.86 (m, 3H), 1.76 (d, J = 10.5 Hz, 2H), 1.42 – 1.28 (m, 3H).

[0830] MS(ESI, [M+H)) + m / z: 858.36.

[0831] Example 149: Synthesis of Compound 149

[0832]

[0833] Referring to the method described in steps 1-6 of Example 121, methyl cis-3-hydroxycyclobutanecarboxylate was replaced with trans-3-hydroxycyclobutanecarboxylate, and intermediate 14a was replaced with intermediate z133 to prepare compound 149.

[0834] 1H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 8.93 (s, 1H), 8.07 (s, 1H), 7.93 (t, J = 4.8 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 17.2, 2.4Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.11 – 7.04 (m, 2H), 4.59 (s, 2H), 4.55(dd, J = 11.9, 5.0 Hz, 1H), 4.27 (p, J = 6.8 Hz, 1H), 4.11 (d, J = 12.5 Hz, 2H), 3.81 (d, J = 7.9 Hz, 3H), 3.67 (s, 2H), 3.56 – 3.49 (m, 1H), 3.25 (dd, J= 12.7, 9.0 Hz, 2H), 3.00 – 2.94 (m, 2H), 2.75 (td, J = 6.6, 3.6 Hz, 3H), 2.69 – 2.56 (m, 6H), 2.49 – 2.42 (m, 2H), 2.22 – 2.15 (m, 1H), 2.03 (t, J =6.6 Hz, 4H), 1.82 (d, J = 11.6 Hz, 2H), 1.38 (d, J = 9.3 Hz, 2H).

[0835] MS(ESI, [M+H)) + m / z: 842.3.

[0836] Example 159: Synthesis of Compound 159

[0837]

[0838] Step 1: Preparation of intermediate 159a

[0839] Referring to the preparation process of compound 160 in step 5 of Example 160, intermediate 160d was replaced with intermediate 160b to prepare compound 159a (40mg).

[0840] MS(ESI, [M+H)) + m / z: 584.3.

[0841] Step 2: Preparation of intermediate 159b

[0842] Referring to the preparation process of intermediate 160d in step 4 of Example 160, intermediate 160c was replaced with intermediate 159a to prepare compound 159b (40mg).

[0843] MS(ESI, [M+H)) + m / z: 484.3.

[0844] Step 3: Preparation of Compound 159

[0845] Referring to the preparation process of intermediate 160c in step 3 of Example 160, intermediate 160b was replaced with intermediate 159b to prepare compound 159 (20mg).

[0846] 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.96 (s, 1H), 8.07 (s, 1H), 7.91 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 16.9, 2.4 Hz, 1H), 7.51(d, J = 8.1 Hz, 1H), 7.13 – 7.06 (m, 2H), 5.10 (d, J = 49.2 Hz, 1H), 4.83 (s,1H), 4.65 (s, 1H), 4.59 (s, 2H), 4.53 (dd, J = 11.8, 5.0 Hz, 1H), 3.82 (d, J= 7.8 Hz, 3H), 3.14 – 2.98 (m, 3H), 2.88 (dd, J = 16.2, 9.4 Hz, 3H), 2.79 –2.71 (m, 1H), 2.69 – 2.54 (m, 6H), 2.48 – 2.31 (m, 5H), 2.26 (d, J = 7.1 Hz, 2H), 2.18 (dt, J = 13.4, 4.6 Hz, 1H), 2.03 (s, 2H), 1.79 – 1.68 (m, 2H), 1.42 (d, J = 11.8 Hz, 1H).

[0847] MS(ESI, [M+H)) + m / z: 876.3.

[0848] Example 160: Synthesis of Compound 160

[0849]

[0850] Step 1: Preparation of intermediate 160a

[0851] Benzyl-1-piperazine carbonate (4.06 g), tert-butyl 3-fluoro-4-oxopiperidin-1-carboxylate (2 g), MeOH (30 mL), acetic acid (2.76 g), and sodium triacetoxyborohydride (5.85 g) were added sequentially to a reaction flask, and the mixture was heated to 50 °C and reacted for 4 h. After the reaction was complete, the solvent was evaporated from the reaction solution, and the mixture was purified by column chromatography to obtain intermediate 160a (2.3 g).

[0852] MS(ESI, [M+H)) + m / z: 422.2.

[0853] Step 2: Preparation of intermediate 160b

[0854] In a reaction flask, Pd / C (0.2 g) was added to a 10 mL solution of MeOH (organic solvent) containing 160a (0.7 g). The reaction solution was first purged with nitrogen, then with hydrogen, and stirred at 25 °C for 1 h. After the reaction was complete, the reaction solution was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain intermediate 160b (0.5 g). MS (ESI, [M+H)) + m / z: 288.2.

[0855] Step 3: Preparation of intermediate 160c

[0856] 160b (60.3 mg), Z144 (60 mg), DMSO (2 mL), and DIPEA (90 mg) were added sequentially to a microwave tube. After stirring for 1 minute, the tube was placed in a microwave reactor and heated to 140°C at 400 watts. o The reaction was carried out at C for 120 minutes. After the reaction was complete, the reaction solution was poured into water, a solid precipitated, and filtered. The filter cake yielded intermediate 160c (0.1 g). MS (ESI, [M+H]) + m / z: 680.2.

[0857] Step 4: Preparation of intermediate 160d

[0858] In the reaction flask, 160 mg (100 mg), HCl (2 mL), and DCM (5 mL) were added sequentially. o React at C for 1 hour. After the reaction is complete, the reaction solution is directly concentrated to obtain intermediate 160d (0.1 g). MS (ESI, [M+H)) + m / z: 580.2.

[0859] Step 5: Preparation of Compound 160

[0860] Intermediate Z13-2 (40.5 mg), DMSO (20 mL), and 2-iodobenzoic acid (90 mg) were added sequentially to a reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate and concentrated. The resulting concentrate was added to 160d (80 mg), sodium cyanoborohydride (20.39 mg), sodium acetate (21.29 mg), and MeOH (25 mL), 25 o The reaction was carried out at C for 1.5 h. After the reaction was completed, the reaction solution was cooled to room temperature, the solvent was removed by evaporation, and the solution was purified by silica gel column chromatography to obtain compound 160 (65 mg).

[0861] 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.95 (s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.71 (dd, J = 17.1, 2.3 Hz, 1H), 7.51(d, J = 8.1 Hz, 1H), 7.10 (dd, J = 8.8, 2.9 Hz, 2H), 5.03 – 4.89 (m, 1H), 4.59 (s, 2H), 4.53 (dd, J = 11.9, 5.0 Hz, 1H), 3.82 (d, J = 7.9 Hz, 3H), 3.64(s, 4H), 3.12 (d, J = 10.0 Hz, 1H), 2.98 (d, J = 21.4 Hz, 3H), 2.85 (s, 1H), 2.78 – 2.71 (m, 1H), 2.67 – 2.56 (m, 5H), 2.47 (d, J = 10.3 Hz, 2H), 2.29 (s,3H), 2.21 – 2.09 (m, 2H), 2.03 (d, J = 13.6 Hz, 3H), 1.65 (d, J = 11.6 Hz,1H), 1.42 (s, 1H), 1.17 (s, 1H).

[0862] MS(ESI, [M+H)) + m / z: 877.3.

[0863] Example 164: Synthesis of Compound 164

[0864]

[0865] Referring to the method described in steps 4-6 of Example 141, intermediate 141c' was replaced with intermediate 141c, and intermediate 13h was replaced with intermediate 17b to prepare compound 164 (20 mg).

[0866] 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (d, J = 2.9 Hz, 1H), 8.83 (s, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.04 (s, 1H), 7.70 (dd, J = 9.0, 2.2 Hz, 1H), 7.52(d, J = 8.0 Hz, 1H), 7.44 (d, J = 9.1 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 6.22(d, J = 4.4 Hz, 1H), 4.53 (ddd, J = 11.9, 5.1, 2.2 Hz, 1H), 4.41 (dtd, J =29.9, 13.5, 7.3 Hz, 2H), 3.56 (s, 7H), 3.29 – 3.15 (m, 4H), 3.11 – 2.67 (m,7H), 2.62 – 2.57 (m, 1H), 2.48 (s, 4H), 2.24 – 1.73 (m, 8H), 1.43 – 1.29 (m,4H), 0.71 (q, J = 6.1 Hz, 1H), 0.53 (q, J = 6.6 Hz, 2H), 0.35 (q, J = 6.3 Hz,1H).

[0867] MS(ESI, [M+H)) + m / z: 897.37

[0868] Example 165: Synthesis of Compound 165

[0869]

[0870] Step 1: Synthesis of intermediate 165b

[0871] Add 165a (2.0 g) and methanol (30 mL) to the reaction flask in sequence, cool to 0°C, add sodium borohydride (0.4 g) in portions, react at 25°C, monitor the reaction until completion, quench the reaction solution with water, extract with ethyl acetate, concentrate the extract, and purify by silica gel column chromatography to obtain intermediate 165b (1.98 g).

[0872] MS(ESI, [M+H)) + m / z: 188.12

[0873] Step 2: Synthesis of intermediates 165c, 165d, and 165d1

[0874] 165b (1.9 g), toluene (30 mL), 4-hydroxypyridine (2.0 g), and cyanomethylenetributylphosphine (4.5 g) were added sequentially to the reaction flask. The reaction was carried out at 110 °C. After the reaction was completed, the reaction solution was quenched with water, extracted with ethyl acetate, and the extract was concentrated to obtain 165c (2.87 g).

[0875] Intermediate 165c was separated by silica gel column chromatography and then further separated under the following conditions: instrument: YMC preparative chromatograph, column: CHIRALART Amylose-SA (020, 5μm, 30*250mm), mobile phase A: ethanol, mobile phase B: n-hexane, yielding intermediate z165d (0.74 g) and intermediate 165d1 (0.78 g) sequentially.

[0876] 165c: MS(ESI, [M+H]) + m / z: 265.13

[0877] 165d: MS(ESI, [M+H]) + m / z: 265.13

[0878] 165d1: MS(ESI, [M+H]) + m / z: 265.13

[0879] Step 3: Synthesis of intermediate 165e

[0880] 165d (0.7 g), methanol (20 mL), and palladium on carbon (0.35 g) were added sequentially to the reaction flask. The reaction was carried out at 25 °C. After the reaction was completed, the reaction solution was quenched with water, extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain 165e (0.54 g).

[0881] MS(ESI, [M+H)) + m / z: 271.13

[0882] Step 4: Synthesis of intermediate 165f

[0883] Add 165e (60.3 mg), Z140 (60 mg), DMSO (2 mL), and DIPEA (90 mg) sequentially to a microwave tube. After stirring for 1 minute, place the tube in a microwave reactor and heat at 400 watts to 140°C.o The reaction was carried out for 120 minutes. After the reaction was completed, the reaction solution was poured into water, and a solid precipitated out. The solid was filtered, and the filter cake yielded intermediate 165f (0.1 g).

[0884] MS(ESI, [M+H)) + m / z: 645.20

[0885] Step 5: Synthesis of 165g of intermediate

[0886] Add 165f (0.1 g), dichloromethane (10 mL), and trifluoroacetic acid (3 mL) sequentially to the reaction flask. React at 25°C. After the reaction is completed, concentrate the solvent to obtain 165 g (0.11 g).

[0887] Step 6: Synthesis of Compound 165

[0888] Intermediate Z13-2 (45.5 mg), DMSO (10 mL), and 2-iodobenzoic acid (90 mg) were added sequentially to a reaction flask, and the reaction was carried out at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate and concentrated. The resulting concentrate was added to 165 g (80 mg), sodium cyanoborohydride (22.39 mg), sodium acetate (25.29 mg), and MeOH (25 mL), 25 o The reaction was carried out at C for 1.5 h. After the reaction was completed, the reaction solution was cooled to room temperature, the solvent was evaporated, and the solution was purified by silica gel column chromatography to obtain compound 165 (65 mg).

[0889] MS(ESI, [M+H)) + m / z: 841.21

[0890] 1H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.83 (s, 1H), 8.04 (s, 1H), 7.92 (d, J = 2.5 Hz, 2H), 7.73 (dd, J = 9.0, 2.4 Hz, 1H), 7.49 (dd, J = 21.8,8.7 Hz, 2H), 7.15 – 7.06 (m, 2H), 4.60 – 4.50 (m, 3H), 4.08 (dt, J = 9.5, 4.3Hz, 2H), 3.73 (s, 1H), 3.67 (s, 4H), 3.54 (d, J = 8.4 Hz, 1H), 3.26 – 3.19(m, 2H), 3.03 – 2.93 (m, 2H), 2.91 – 2.70 (m, 4H), 2.61 (t, J = 4.2 Hz, 1H), 2.59 – 2.54 (m, 2H), 2.47 – 2.43 (m, 1H), 2.30 (s, 1H), 2.17 (dq, J = 13.4,4.7 Hz, 1H), 2.06 – 1.99 (m, 1H), 1.80 (d, J = 10.6 Hz, 3H), 1.42 – 1.32 (m,3H), 1.16 (d, J = 6.0 Hz, 3H).

[0891] Example 166: Synthesis of Compound 166

[0892]

[0893] Steps 1-5: Synthesis of intermediate z152

[0894] Following the method described in steps 3-6 of Example 165, 165d was replaced with 165d1 to prepare compound 166 (54 mg).

[0895] MS(ESI, [M+H)) + m / z: 841.21

[0896] 1H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.84 (s, 1H), 8.04 (s, 1H), 7.97 – 7.86 (m, 2H), 7.73 (dd, J = 9.0, 2.5 Hz, 1H), 7.49 (dd, J = 21.7, 8.5Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 4.62 – 4.50 (m, 3H), 4.08 (dt, J = 12.1,5.9 Hz, 2H), 3.73 (s, 1H), 3.67 (s, 4H), 3.55 (s, 1H), 3.27 – 3.20 (m, 2H),3.06 – 2.94 (m, 2H), 2.92 – 2.69 (m, 4H), 2.60 (dt, J = 17.2, 4.3 Hz, 2H), 2.46 (dd, J = 11.9, 7.4 Hz, 2H), 2.31 (s, 1H), 2.21 – 2.13 (m, 1H), 2.02 (s,1H), 1.81 (s, 3H), 1.37 (s, 3H), 1.16 (d, J = 6.0 Hz, 3H).

[0897] Example 167: Synthesis of Compound 167

[0898]

[0899] Steps 1-2: Synthesis of intermediate 167b

[0900] Referring to the method described in steps 3-4 of Example 160, z144 was replaced with z140 and 160b was replaced with 1-Boc-3-(4-piperidinoxy)pyrrolidine to prepare intermediate 167b (203 mg).

[0901] MS(ESI, [M+H)) + m / z: 545.24.

[0902] Step 3: Preparation of intermediate 167a

[0903] Referring to the preparation process of compound 160 in step 5 of Example 160, intermediate 160d was replaced with intermediate 167b to prepare compound 167 (76mg).

[0904] 1H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.83 (s, 1H), 8.04 (s, 1H), 7.93 (d, J = 2.8 Hz, 2H), 7.76 – 7.70 (m, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.47(d, J = 9.2 Hz, 1H), 7.10 (s, 2H), 4.57 (s, 2H), 4.53 (dd, J = 11.8, 5.0 Hz,1H), 4.22 (s, 1H), 4.13 – 4.07 (m, 2H), 3.67 (s, 3H), 3.56 (s, 1H), 3.24 –3.16 (m, 3H), 3.05 – 2.99 (m, 2H), 2.91 – 2.71 (m, 4H), 2.63 – 2.59 (m, 1H), 2.39 (s, 2H), 2.20 – 2.16 (m, 1H), 2.08 – 1.82 (m, 6H), 1.65 (s, 1H), 1.46 –1.32 (m, 5H).

[0905] MS(ESI, [M+H)) + m / z: 841.36

[0906] Example 179: Synthesis of Compound 179

[0907]

[0908] Compound 179 was prepared by replacing intermediate z144 with intermediate z154-1, following the method described in Example 146.

[0909] MS(ESI, [M+H)) + m / z: 858.3

[0910] Example 180: Synthesis of Compound 180

[0911]

[0912] Compound 180 was prepared by replacing intermediate z144 with intermediate z156, following the method described in Example 146. MS (ESI, [M+H]) + m / z: 876.3

[0913] Example 181: Synthesis of Compound 181

[0914]

[0915] Step 1: Preparation of intermediate 181b

[0916] Intermediate 181a (500 mg), 2,4,5-trichloropyrimidine (526 mg), DIPEA (1484 mg), and NMP (5 mL) were added sequentially to a microwave tube and placed in a microwave reactor. The mixture was heated to 140°C at 150 watts. o The reaction was carried out at C for 120 minutes. After the reaction was complete, 10 mL of water was added to the microwave tube, and a solid precipitated. The solid was filtered, the filter cake was washed with water, collected, and dried to obtain intermediate 181b (0.9 g).

[0917] MS (ESI) m / z [M+H] + 321.1

[0918] Step 2: Preparation of Compound 181

[0919] Intermediate 181b (664 mg), 181c (400 mg) (preparation process referred to Synthesis of Intermediate i-5 in WO2025096706), DIPEA (805 mg), and DMSO (20 mL) were added sequentially to a microwave tube, which was then placed in a microwave reactor and heated to 140°C at 200 watts. o The reaction was carried out at C for 120 minutes. The reaction solution was cooled to room temperature and purified by reverse column chromatography to give compound 181 (0.404 g).

[0920] MS (ESI) m / z [M+H] + 640.2

[0921] 1H NMR (500 MHz, DMSO) δ 10.81 (s, 1H), 8.91 (s, 1H), 8.09 – 8.02 (m,2H), 7.88 (dd, J = 9.2, 2.5 Hz, 1H), 7.79 (d, J = 9.5 Hz, 1H), 7.51 (d, J =9.2 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 6.62 (d, J = 9.5 Hz, 1H), 6.51 (d, J =8.8 Hz, 1H), 6.44 (s, 1H), 5.69 (d, J = 8.9 Hz, 1H), 4.57 – 4.38 (m, 2H),4.17 (dd, J = 8.8, 5.1 Hz, 1H), 3.81 (s, 3H), 3.61 (s, 3H), 3.29 (s, 1H), 3.05 (t, J = 12.4 Hz, 1H), 2.72 (t, J = 12.1 Hz, 1H), 2.61 (q, J = 9.6 Hz,2H), 2.26 (dt, J = 14.7, 7.1 Hz, 1H), 2.19 – 2.06 (m, 2H), 1.61 (t, J = 6.6Hz, 1H), 1.22 (dd, J = 18.8, 9.8 Hz, 1H), 0.96 (d, J = 6.5 Hz, 3H).

[0922] Example 182 Synthesis of Compound 182

[0923]

[0924] Referring to the method described in steps 1-2 of Example 181, 181a was replaced with 182a (the preparation process is described in Synthesis Example 9 of WO 2016034512) to prepare compound 182.

[0925] MS(ESI, [M+H)) + m / z: 654.2.

[0926] 1H NMR (500 MHz, DMSO) δ 10.81 (s, 1H), 8.90 (s, 1H), 8.12 – 8.03 (m,2H), 7.87 (dd, J = 9.2, 2.5 Hz, 1H), 7.78 (d, J = 9.5 Hz, 1H), 7.56 (d, J =9.2 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 6.60 (d, J = 9.5 Hz, 1H), 6.51 (dd, J= 8.8, 1.8 Hz, 1H), 6.44 (d, J = 1.8 Hz, 1H), 5.69 (d, J = 9.0 Hz, 1H), 4.49(s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 4.17 (dd, J = 8.8, 5.1 Hz, 1H), 3.81 (s,3H), 3.34 (s, 1H), 3.17 (d, J = 5.3 Hz, 1H), 3.05 (t, J = 12.3 Hz, 1H), 2.71(dd, J = 13.3, 11.0 Hz, 1H), 2.60 (q, J = 5.8 Hz, 2H), 2.25 (dq, J = 14.4,8.0 Hz, 1H), 2.19 – 2.06 (m, 2H), 1.64 – 1.56 (m, 1H), 1.20 (t, J = 7.0 Hz,3H), 0.95 (d, J = 6.5 Hz, 3H).

[0927] Example 183: Synthesis of Compound 183

[0928]

[0929] Step 1: Synthesis of intermediate 183a

[0930] 6-nitro-2(1H)-quinolinone (2 g), N,N-dimethylformamide (100 mL), NaH (1.70 g) and 2-iodopropane (10.73 g) were added sequentially to the reaction flask. The reaction was carried out at 25 °C. After the reaction was completed, saturated ammonium chloride aqueous solution was added to quench the reaction. The mixture was extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate 183a (58 mg).

[0931] MS(ESI, [M+H]+) m / z: 233.08.

[0932] Step 2: Synthesis of intermediate 183b

[0933] 183a (58 mg), ethanol (15 mL), water (2 mL), ammonium chloride (27 mg) and iron powder (70 mg) were added sequentially to the reaction flask. The reaction was carried out at 60 °C. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and purified by silica gel column chromatography to obtain intermediate 183b (53 mg).

[0934] MS(ESI, [M+H)) + m / z: 203.11

[0935] Step 3: Synthesis of intermediate 183c

[0936] 183b (53 mg), N-methylpyrrolidone (2 mL), 2,4,5-trichloropyrimidine (96 mg) and N,N-diisopropylethylamine (135 mg) were added sequentially to a microwave tube and reacted in a microwave oven at 140 °C. After the reaction was completed, the reaction solution was quenched with water, extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain intermediate 183c (162 mg).

[0937] MS(ESI, [M+H)) + m / z: 349.05

[0938] Step 4: Synthesis of Compound 183

[0939] 183c (123 mg), DMSO (2 mL), intermediate 181c (100 mg), and N,N-diisopropylethylamine (185 mg) were added sequentially to a microwave tube. The reaction was carried out in a microwave oven at 140 °C. After the reaction was completed, the reaction solution was quenched with water, extracted with ethyl acetate, concentrated, and purified by silica gel column chromatography to obtain compound 183 (29 mg).

[0940] MS(ESI, [M+H)) + m / z: 668.28

[0941] 1H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.89 (s, 1H), 8.07 (s, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 2.6 Hz, 1H), 7.72 (dd, J = 9.4, 4.9Hz, 2H), 7.31 (d, J = 8.7 Hz, 1H), 6.56 – 6.48 (m, 2H), 6.44 (d, J = 1.8 Hz,1H), 5.69 (d, J = 9.0 Hz, 1H), 5.33 (s, 1H), 4.49 (s, 2H), 4.20 – 4.14 (m,1H), 3.81 (s, 3H), 3.06 (t, J = 12.7 Hz, 1H), 2.71 (dd, J = 13.3, 11.1 Hz, 1H), 2.60 (t, J = 4.7 Hz, 2H), 2.26 (dt, J = 14.5, 7.1 Hz, 1H), 2.18 – 2.07(m, 2H), 1.60 (q, J = 8.5 Hz, 1H), 1.53 (d, J = 6.9 Hz, 6H), 1.24 (d, J = 7.6Hz, 2H), 0.95 (d, J = 6.5 Hz, 3H).

[0942] Example 184: Synthesis of Compound 184

[0943]

[0944] Following the method described in steps 3-4 of Example 183, 183b was replaced with intermediate 181a and 2,4,5-trichloropyrimidine was replaced with 2,5,6-trichloropyridin-3-carboxynitrile to prepare compound 184 (96 mg).

[0945] MS(ESI, [M+H)) + m / z: 664.25

[0946] 1H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.08 (s, 1H), 8.00 (d, J =2.6 Hz, 1H), 7.96 (s, 1H), 7.84 (d, J = 9.2 Hz, 2H), 7.51 (d, J = 9.1 Hz,1H), 7.30 (d, J = 8.7 Hz, 1H), 6.60 (d, J = 9.4 Hz, 1H), 6.50 (dd, J = 8.8,1.8 Hz, 1H), 6.42 (d, J = 1.8 Hz, 1H), 5.72 (d, J = 9.0 Hz, 1H), 4.30 – 4.23(m, 1H), 4.19 (ddt, J = 17.9, 8.7, 4.4 Hz, 2H), 3.80 (s, 3H), 3.60 (s, 3H), 3.30 – 3.23 (m, 1H), 3.18 (t, J = 12.7 Hz, 1H), 2.80 (dd, J = 13.5, 11.0 Hz, 1H), 2.60 (s, 2H), 2.25 (tt, J = 14.1, 6.8 Hz, 1H), 2.19 – 2.11 (m, 1H), 2.08 (d, J = 12.9 Hz, 1H), 1.75 – 1.65 (m, 1H), 1.30 (q, J = 14.2 Hz, 1H), 0.88 (d, J = 6.5 Hz, 3H).

[0947] Example 185: Synthesis of Compound 185

[0948]

[0949] Compound 185 was prepared by replacing 2,5,6-trichloropyridine-3-carboxynitrile with 3-cyano-2,6-dichloro-5-fluoropyridine.

[0950] MS(ESI, [M+H)) + m / z: 648.2.

[0951] 1H NMR (500 MHz, DMSO) δ 10.81 (s, 1H), 9.59 (d, J = 1.9 Hz, 1H), 8.16 (d, J = 2.5 Hz, 1H), 7.89 (dd, J = 9.1, 2.5 Hz, 1H), 7.82 (t, J = 10.2Hz, 2H), 7.51 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.61 (d, J = 9.5Hz, 1H), 6.51 (dd, J = 8.8, 1.8 Hz, 1H), 6.44 (d, J = 1.7 Hz, 1H), 5.75 (d, J= 9.0 Hz, 1H), 4.23 – 4.12 (m, 3H), 3.81 (s, 3H), 3.60 (s, 3H), 3.24 – 3.16(m, 1H), 2.85 (dd, J = 13.3, 10.9 Hz, 1H), 2.64 – 2.58 (m, 2H), 2.30 – 2.21(m, 1H), 2.18 – 2.09 (m, 2H), 1.82 – 1.72 (m, 1H), 1.42 – 1.33 (m, 1H), 0.95(d, J = 6.5 Hz, 3H).

[0952] Example 186: Synthesis of Compound 186

[0953]

[0954] Steps 1-2: Synthesis of Compound 186

[0955] Following the method described in steps 3-4 of Preparation Example 183, 186 (102 mg) was prepared by replacing 183b with 186a and 2,5,6-trichloropyridin-3-carboxynitrile with 2,5,6-trichloropyrimidine.

[0956] MS(ESI, [M+H)) + m / z: 666.26

[0957] 1H NMR (500 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.08 (s, 1H), 8.00 (d, J =2.6 Hz, 1H), 7.96 (s, 1H), 7.84 (d, J = 9.2 Hz, 2H), 7.51 (d, J = 9.1 Hz,1H), 7.30 (d, J = 8.7 Hz, 1H), 6.60 (d, J = 9.4 Hz, 1H), 6.50 (dd, J = 8.8,1.8 Hz, 1H), 6.42 (d, J = 1.8 Hz, 1H), 5.72 (d, J = 9.0 Hz, 1H), 4.30 – 4.23(m, 1H), 4.19 (ddt, J = 17.9, 8.7, 4.4 Hz, 2H), 3.80 (s, 3H), 3.60 (s, 3H), 3.30 – 3.23 (m, 1H), 3.18 (t, J = 12.7 Hz, 1H), 2.80 (dd, J = 13.5, 11.0 Hz, 1H), 2.60 (s, 2H), 2.25 (tt, J = 14.1, 6.8 Hz, 1H), 2.19 – 2.11 (m, 1H), 2.08 (d, J = 12.9 Hz, 1H), 1.75 – 1.65 (m, 1H), 1.30 (q, J = 14.2 Hz, 1H), 0.88 (d, J = 6.5 Hz, 3H).

[0958] Example 187: Synthesis of Compound 187

[0959]

[0960] Compound 187 was prepared by replacing 2,5,6-trichloropyridine-3-carboxynitrile with 3-cyano-2,6-dichloro-5-fluoropyridine.

[0961] MS(ESI, [M+H)) + m / z: 650.2.

[0962] 1H NMR (500 MHz, DMSO) δ 10.81 (s, 1H), 9.40 – 9.36 (m, 1H), 7.78 (d,J = 10.9 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.59 (dd, J = 8.7, 2.5 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.52 (dd, J = 8.8, 1.8Hz, 1H), 6.46 – 6.42 (m, 1H), 5.76 (d, J = 9.0 Hz, 1H), 4.23 – 4.12 (m, 3H),3.81 (s, 3H), 3.31 – 3.27 (m, 1H), 3.23 (s, 3H), 3.20 – 3.17 (m, 1H), 2.88 –2.80 (m, 3H), 2.64 – 2.57 (m, 2H), 2.55 – 2.52 (m, 1H), 2.30 – 2.21 (m, 1H), 2.18 – 2.08 (m, 2H), 1.82 – 1.72 (m, 1H), 1.42 – 1.33 (m, 1H), 0.97 (d, J =6.5 Hz, 3H).

[0963] Example 188: Synthesis of Compound 188

[0964]

[0965] Step 1: Synthesis of intermediate 188a

[0966] 6-bromo-8-methoxyquinoline (3 g), dichloromethane (50 mL), and methyl trifluoromethanesulfonate (2.4 mL) were added sequentially to the reaction flask. The reaction was carried out at 25 °C. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 188a (3.85 g).

[0967] MS(ESI, [M+H]+) m / z: 252.1.

[0968] Step 2: Synthesis of intermediate 188b

[0969] Intermediate 188a (2 g), acetonitrile (80 ml), dimethyl phosphite (550 mg) and potassium tert-butoxide (1.67 g) were added sequentially to the reaction flask. The reaction was carried out in an open container at room temperature. After the reaction was completed, saturated brine was added, and the mixture was extracted with ethyl acetate. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 188b (0.45 g).

[0970] MS(ESI, [M+H]+) m / z: 268.1.

[0971] Steps 3-6: Synthesis of Compound 188

[0972] Compound 188 was prepared by replacing intermediate 191a with intermediate 188b according to the method described in steps 1-4 of Example 191.

[0973] MS(ESI, [M+H)) + m / z: 670.2.

[0974] Example 189 Synthesis of Compound 189

[0975]

[0976] Compound 189 was prepared by replacing intermediate 191a with intermediate 189a (the preparation process is described in steps 1-4 of Example 191, which is based on intermediate 022-2 of Example 22 in WO2024235165).

[0977] MS (ESI) m / z [M+H] + 641.3

[0978] Example 190 Synthesis of Compound 190

[0979]

[0980] Step 1: Preparation of intermediate 190b

[0981] 190a (1.50 g, intermediate 6-bromo-5-fluoroquinoline-2(1H)-one, prepared according to the procedure in Example 130 of WO2022192431), iodomethane (1.32 g), cesium carbonate (4.05 g), and DMF (20 mL) were mixed and reacted at 80°C for 2 h. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, and purified by column chromatography to obtain intermediate 190b (0.18 g).

[0982] MS (ESI) m / z [M+H] + 256.3

[0983] Steps 2-5: Preparation of Compound 190

[0984] Referring to the method described in steps 1-4 of Example 191, intermediate 191a was replaced with intermediate 190b to prepare compound 190.

[0985] MS (ESI) m / z [M+H] + 658.3

[0986] Example 191 Synthesis of Compound 191

[0987]

[0988] Step 1: Preparation of intermediate 191b

[0989] Referring to step 2 of Preparation Example 21, intermediate z133b was replaced with intermediate 191a (10g, preparation process referred to WO 2024235165 Example 14 018a) to prepare intermediate 191b (5.18g).

[0990] MS(ESI, [M+H)) + m / z: 357.1

[0991] Step 2: Preparation of intermediate 191c

[0992] Referring to step 5 of Preparation Example 21, intermediate 191c (5.18g) was prepared by replacing intermediate z133e with intermediate 191b (5g).

[0993] MS(ESI, [M+H]+ ) m / z:193.0

[0994] Steps 3-4: Preparation of compound 191

[0995] Referring to the method described in steps 1-2 of Example 181, 181a was replaced with 191c to prepare compound 191.

[0996] MS(ESI, [M+H)) + m / z: 658.2

[0997] Example 192: Synthesis of Compound 192

[0998]

[0999] Step 1: Synthesis of intermediate 192b

[1000] Intermediate 192a (3 g, preparation process as described in WO2022262782, intermediate BB-2-B from Example 2) was added sequentially to a reaction flask, along with dichloromethane (50 mL) and dioxane hydrochloride solution (4 M, 50 mL). The reaction was carried out at 25 °C. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and saturated sodium bicarbonate solution was added. The mixture was extracted with ethyl acetate, and the extract was concentrated and purified by silica gel column chromatography to obtain intermediate 192b (1.85 g).

[1001] MS(ESI, [M+H)) + m / z: 221.1.

[1002] Step 2: Synthesis of intermediate 192c

[1003] Intermediate 192b (1.8 g), (R)-3-methyl-4-oxopiperidin-1-carboxylic acid tert-butyl ester (2.61 g), toluene (100 ml), and p-toluenesulfonic acid (0.211 g) were added sequentially to the reaction flask. The mixture was refluxed for 8 h, and the solvent was removed by concentration under reduced pressure. 1,2-dichloroethane and sodium triacetoxyborohydride (5.20 g) were added, and the mixture was reacted at 50 °C. After the reaction was completed, saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was concentrated and purified by silica gel column chromatography to obtain intermediate 192c (1.60 g).

[1004] MS(ESI, [M+H)) + m / z: 418.2.

[1005] Step 3: Splitting intermediates 192d-1 and 192d-2

[1006] Intermediate 192c was prepared and separated (chromatographic column: CHIRALART Cellulose-SC, 10μm, 30*250mm; mobile phase: A = ethanol: dichloromethane 1:1-0.1% ammonia, B = n-hexane) to obtain intermediate 192d-1 (350mg) and intermediate 192d-2 (330mg).

[1007] Intermediate 192d-1: MS(ESI, [M+H]) + m / z: 418.2

[1008] Intermediate 192d-2: MS(ESI, [M+H]) + m / z: 418.2

[1009] Step 4: Synthesis of intermediate 192e

[1010] Referring to the method described in step 11 of Preparation Example 10, intermediate 192e was prepared by replacing intermediate z47j with intermediate 192d-1.

[1011] MS(ESI, [M+H)) + m / z: 443.2.

[1012] Step 5: Synthesis of intermediate 192f

[1013] Intermediate 192e (350 mg), dichloromethane (5 mL), and dioxane hydrochloride solution (4 M, 5 mL) were added sequentially to the reaction flask. The reaction was carried out at 25 °C. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain intermediate 192f (345 mg).

[1014] MS(ESI, [M+H]+) m / z: 343.2.

[1015] Step 6: Synthesis of Compound 192

[1016] Compound 192 was prepared by replacing intermediate 181b with 5-((2,5-dichloropyrimidin-4-yl)amino)-1-methylindole-2-one and intermediate 181c with intermediate 192f.

[1017] MS(ESI, [M+H)) + m / z: 615.2.

[1018] 1H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 8.72 (s, 1H), 8.01 (s, 1H), 7.56 – 7.48 (m, 2H), 7.40 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.80(dd, J = 8.7, 1.8 Hz, 1H), 6.72 (d, J = 1.8 Hz, 1H), 6.36 (d, J = 8.3 Hz,1H), 4.37 (dd, J = 11.2, 5.0 Hz, 1H), 3.96 (s, 1H), 3.89 (dd, J = 13.3, 6.3Hz, 1H), 3.75 (s, 1H), 3.54 (s, 3H), 3.47 – 3.43 (m, 1H), 3.10 (s, 3H), 2.73(ddd, J = 16.9, 11.3, 5.3 Hz, 1H), 2.57 (dt, J = 17.3, 4.6 Hz, 1H), 2.40 (s,1H), 2.16 (dq, J = 8.5, 4.9 Hz, 2H), 1.66 (d, J = 20.7 Hz, 2H), 0.82 (d, J =6.9 Hz, 3H).

[1019] Example 193: Synthesis of Compound 193

[1020]

[1021] Compound 193 was prepared by replacing intermediate 192d-1 with intermediate 192d-2 according to the method described in steps 4-6 of Example 192.

[1022] MS(ESI, [M+H)) + m / z: 615.2.

[1023] 1H NMR (500 MHz, DMSO) δ 11.01 (s, 1H), 8.80 (s, 1H), 8.02 (s, 1H), 7.56 – 7.48 (m, 2H), 7.41 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.80(dd, J = 8.8, 1.9 Hz, 1H), 6.73 (d, J = 1.8 Hz, 1H), 6.45 – 6.26 (m, 1H), 4.37 (dd, J = 11.3, 5.0 Hz, 1H), 4.06 – 3.85 (m, 2H), 3.80 – 3.71 (m, 1H),3.54 (s, 3H), 3.49 – 3.44 (m, 1H), 3.11 (s, 3H), 2.78 – 2.68 (m, 1H), 2.62 –2.53 (m, 1H), 2.45 – 2.34 (m, 1H), 2.20 – 2.11 (m, 2H), 1.73 – 1.60 (m, 2H), 0.82 (d, J = 6.9 Hz, 3H).

[1024] Example 194: Synthesis of Compound 194

[1025]

[1026] Compound 194 was prepared by replacing intermediate 192a with intermediate 194a, according to the method described in Example 192.

[1027] MS(ESI, [M+H)) + m / z: 615.2

[1028] Example 195: Synthesis of Compound 195

[1029]

[1030] Compound 195 was prepared by replacing intermediate 192d-2 with intermediate 195a according to the method described in Example 193.

[1031] MS(ESI, [M+H)) + m / z: 615.2.

[1032] Example 196: Synthesis of Compound 196

[1033]

[1034] Referring to the method described in Example 106, intermediate z40 was replaced with intermediate z13-2, tert-butyl 3-(piperidin-4-yl)azacyclobutane-1-carboxylate was replaced with intermediate z162a, and intermediate 17b was replaced with intermediate z154-1 to prepare compound 196.

[1035] MS(ESI, [M+H)) + m / z: 873.3.

[1036] 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.91 (s, 1H), 8.53 (s,1H), 8.05 (s, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 9.2, 2.4 Hz, 1H),7.62 (s, 1H), 7.53 (dd, J = 15.8, 8.8 Hz, 2H), 7.11 (d, J = 8.2 Hz, 1H), 6.29(d, J = 58.9 Hz, 1H), 4.53 (dd, J = 11.8, 5.0 Hz, 1H), 4.15 – 4.04 (m, 2H),3.72 – 3.64 (m, 4H), 3.49 – 3.42 (m, 1H), 3.29 – 3.21 (m, 2H), 3.06 – 2.94(m, 2H), 2.89 – 2.80 (m, 1H), 2.80 – 2.66 (m, 3H), 2.63 – 2.55 (m, 1H), 2.48– 2.43 (m, 1H), 2.25 (d, J = 7.3 Hz, 2H), 2.21 – 2.14 (m, 1H), 2.10 – 1.97(m, 4H), 1.85 – 1.76 (m, 4H), 1.49 – 1.33 (m, 5H).

[1037] Example 197: Synthesis of Compound 197

[1038]

[1039] Referring to the method described in Example 106, tert-butyl 3-(piperidin-4-yl)-piperazine was replaced with tert-butyl 1-(piperidin-4-yl)azacyclobutane-1-carboxylate, and intermediate 17b was replaced with intermediate z156, to prepare compound 197.

[1040] MS(ESI, [M+H)) + m / z: 890.3

[1041] 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (d, J = 3.4 Hz, 1H), 9.03 (s, 1H), 8.95 (s, 1H), 8.08 – 8.02 (m, 2H), 7.90 (dd, J = 9.2, 2.6 Hz, 1H), 7.86 (s,1H), 7.57 (d, J = 9.2 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.17 (d, J = 8.2 Hz,1H), 4.53 (ddd, J = 11.7, 5.0, 2.4 Hz, 1H), 3.69 (s, 3H), 3.60 (s, 4H), 3.40– 3.33 (m, 2H), 3.00 – 2.90 (m, 2H), 2.89 – 2.82 (m, 2H), 2.81 – 2.71 (m,2H), 2.63 – 2.57 (m, 1H), 2.54 – 2.52 (m, 1H), 2.48 – 2.43 (m, 1H), 2.23 – 2.13 (m, 2H), 2.11 – 1.98 (m, 4H), 1.96 – 1.80 (m, 3H), 1.76 – 1.68 (m, 2H), 1.50 – 1.36 (m, 2H), 1.00 – 0.89 (m, 2H).

[1042] Example 198: Synthesis of Compound 198

[1043]

[1044] Step 1: Synthesis of intermediate 198a

[1045] In a reaction flask, 1-Boc-3,5-dimethylpiperazine (11.50 g), 1,4-dioxane (100 mL), 4-iodopyridine (10 g), RuPhos (4.55 g), Cs₂CO₃ (31.8 g), and Pd(OAc)₂ (1.095 g) were added sequentially. Under N₂ protection, the mixture was heated to 100 °C and reacted for 18 h. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate 198a (5 g).

[1046] MS (ESI) m / z [M+H] + 292.2

[1047] Step 2: Synthesis of intermediate 198b

[1048] In a reaction flask, intermediate 198a (2 g), DCE (20 mL), and benzyl chloride (8.69 g, 7.90 mL) were added sequentially. Under N2 protection, the mixture was heated to 60 °C and reacted for 2 h. After the reaction was complete, the solvent was removed from the reaction solution by vacuum distillation, and petroleum ether (20 mL) was added to the residue. A solid precipitated, was filtered, and the filter cake was collected to obtain intermediate 198b (2.5 g).

[1049] Step 3: Synthesis of intermediate 198c

[1050] In a reaction flask, intermediate 198b (2 g) and EtOH (50 mL) were added sequentially at 0 °C, followed by sodium borohydride (0.989 g) in portions. After the addition was complete, the reaction mixture was allowed to react at room temperature for 3.5 h. Upon completion of the reaction, the reaction solution was poured into ice water, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, yielding intermediate 198c (2 g).

[1051] MS (ESI) m / z [M+H] + 388.3

[1052] Step 4: Synthesis of intermediate 198d

[1053] In a reaction flask, intermediate 198c (2g), MeOH (15 mL), and 10% palladium on carbon (300mg) were added sequentially. The mixture was then purged with hydrogen and heated to 60°C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and palladium on carbon was removed by filtration. The filtrate was purified by column chromatography to obtain intermediate 198d (300mg).

[1054] Step 5: Synthesis of intermediate 198e

[1055] Referring to the method described in step 1 of Example 159, intermediate 160b was replaced with intermediate 198d to prepare intermediate 198e (200 mg).

[1056] MS(ESI, [M+H)) + m / z: 594.3

[1057] Step 6: Synthesis of intermediate 198f

[1058] Referring to the method described in step 2 of Example 159, intermediate 159a was replaced with intermediate 198e to prepare intermediate 198f (200 mg).

[1059] MS(ESI, [M+H)) + m / z: 494.3

[1060] Step 7: Synthesis of Compound 198

[1061] Referring to the method described in step 3 of Example 159, intermediate 159b was replaced with intermediate 198f, and intermediate z144 was replaced with intermediate z154-1 to prepare compound 198 (60 mg).

[1062] MS(ESI, [M+H)) + m / z: 886.4

[1063] 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.87 (s, 1H), 8.52 (s,1H), 8.17 (d, J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.88 (dd, J = 9.2, 2.5 Hz, 1H), 7.63 (s, 1H), 7.53 (dd, J = 13.9, 8.6 Hz, 2H), 7.11 (d, J = 8.2 Hz, 1H), 6.27(d, J = 59.0 Hz, 1H), 4.53 (dd, J = 11.8, 5.0 Hz, 1H), 3.70 (s, 3H), 3.61 (d,J = 27.9 Hz, 2H), 3.50 (d, J = 11.7 Hz, 2H), 3.21 – 3.13 (m, 3H), 3.01 (s,2H), 2.92 (s, 3H), 2.79 – 2.66 (m, 2H), 2.64 – 2.56 (m, 1H), 2.46 (d, J = 5.7Hz, 1H), 2.25 (d, J = 7.0 Hz, 2H), 2.21 – 2.14 (m, 1H), 2.02 (s, 2H), 1.90(d, J = 12.2 Hz, 2H), 1.69 (d, J = 11.4 Hz, 2H), 1.46 (dd, J = 51.6, 10.5 Hz, 3H), 0.99 (d, J = 6.2 Hz, 6H).

[1064] Example 200: Synthesis of Compound 200

[1065]

[1066] Compound 200 was prepared by replacing intermediate z156 with intermediate z133, referring to the method described in Example 197.

[1067] MS(ESI, [M+H)) + m / z: 869.3

[1068] 1 H NMR (500 MHz, DMSO) δ 11.07 (d, J = 3.4 Hz, 1H), 8.94 (s, 1H), 8.08 (s, 1H), 7.94 (t, J = 4.8 Hz, 1H), 7.80 (d, J = 2.9 Hz, 1H), 7.70 (dd, J= 17.1, 2.4 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 1.4 Hz, 1H), 4.60 (s, 2H), 4.53 (ddd, J = 11.9, 5.0, 2.4 Hz, 1H),3.82 (d, J = 7.9 Hz, 3H), 3.63 (d, J = 5.6 Hz, 3H), 3.36 (dd, J = 14.6, 8.1Hz, 2H), 2.99 – 2.84 (m, 4H), 2.76 (ddd, J = 17.1, 12.1, 5.4 Hz, 2H), 2.67(d, J = 4.7 Hz, 3H), 2.60 (dd, J = 17.0, 3.9 Hz, 1H), 2.54 (d, J = 4.6 Hz, 4H), 2.48 – 2.43 (m, 1H), 2.25 – 2.14 (m, 2H), 2.07 (s, 4H), 1.86 (s, 3H), 1.74 (d, J = 9.8 Hz, 2H), 1.45 (d, J = 11.3 Hz, 2H), 0.97 – 0.92 (m, 1H).

[1069] Example 201: Synthesis of Compound 201

[1070]

[1071] Step 1: Preparation of intermediate 201a

[1072] Referring to step 1 of Preparation Example 27, intermediate 201a was prepared by replacing z143a with z133d and ethyl difluorobromoacetone with 1-bromo-2-propanone.

[1073] Steps 2-3: Preparation of intermediate 201c

[1074] Referring to steps 7-8 of Preparation Example 26, intermediate 201c was prepared by replacing intermediate z153g with intermediate 201a.

[1075] Step 4: Preparation of Compound 201

[1076] Referring to step 3 of Example 106, intermediate 17b was replaced with intermediate 201c, and intermediate 106b was replaced with intermediate 203f to prepare compound 201. MS (ESI, [M+H]) + m / z: 840.3

[1077] 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.94 (s, 1H), 8.07 (s, 1H), 7.80 – 7.71 (m, 1H), 7.71 – 7.61 (m, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.10 (d,J = 8.2 Hz, 1H), 7.04 (s, 1H), 4.94 (s, 1H), 4.53 (dd, J = 11.8, 5.1 Hz, 1H), 3.81 (d, J = 7.7 Hz, 3H), 3.65 – 3.59 (m, 3H), 3.07 – 2.79 (m, 6H), 2.78 –2.71 (m, 1H), 2.61 (td, J = 12.7, 6.1 Hz, 1H), 2.54 (s, 3H), 2.46 (d, J = 4.9Hz, 1H), 2.25 (d, J = 21.2 Hz, 3H), 2.20 (s, 3H), 2.16 (q, J = 4.4 Hz, 1H), 2.08 – 1.83 (m, 5H), 1.75 (d, J = 11.9 Hz, 2H), 1.69 – 1.62 (m, 1H), 1.48 (d,J = 12.3 Hz, 2H), 1.23 (s, 1H).

[1078] Example 202: Synthesis of Compound 202

[1079]

[1080] Step 1: Preparation of intermediate 202a

[1081] Referring to the method described in step 1 of Example 106, intermediate 202a (0.43 g) was prepared by replacing z40 with intermediate z13-2 and replacing 3-(piperidin-4-yl)azacyclobutane-1-carboxylic acid tert-butyl ester with 67a.

[1082] MS(ESI, [M+H)) + m / z: 551.3

[1083] Step 2: Preparation of intermediate 202b

[1084] Add 0.62 g of 202a, 10 mL of dichloromethane, and 10 mL of 4 M dioxane hydrochloride to the reaction flask in sequence, and react at room temperature for 1 h. After the reaction is complete, remove the solvent by rotary evaporation under reduced pressure to obtain intermediate 202b (0.51 g).

[1085] MS(ESI, [M+H)) + m / z: 451.2

[1086] Steps 3-4: Preparation of intermediate 202d

[1087] Following the method described in steps 1-2 of Preparation Example 28, intermediate 202d was prepared by replacing z143a with intermediate z133d.

[1088] MS(ESI, [M+H)) + m / z: 465.1

[1089] Steps 5-6: Preparation of intermediate 202f

[1090] Following the method described in steps 7-8 of Preparation Example 26, z153g was replaced with 202d to prepare intermediate 202f.

[1091] MS(ESI, [M+H)) + m / z: 447.0

[1092] Step 7: Preparation of intermediates 202g-1 and 202g-2

[1093] Separation conditions: Instrument: High performance liquid chromatograph, chromatographic column: (R,R) Whelk-O1 (4.6×250mm, S-5μm), mobile phase A: dichloromethane, mobile phase D: n-hexane, mobile phase B: ethanol, yielding intermediates 202g-1 and 202g-2 sequentially.

[1094] 202g-1 : MS(ESI, [M+H] + m / z: 447.0

[1095] 202g-2 : MS(ESI, [M+H] + m / z: 447.0

[1096] Step 8: Preparation of Compound 202

[1097] Following the method described in step 3 of Example 106, 17b was replaced with 202g-1 and 106b was replaced with 202b to prepare compound 202 (0.08g).

[1098] MS(ESI, [M+H)) + m / z: 861.2

[1099] 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.99 (s, 1H), 8.54 (s, 1H), 8.07 (s, 1H), 7.84 (ddd, J = 10.2, 7.3, 2.4 Hz, 2H), 7.59 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.32 (d, J = 58.6 Hz, 1H), 4.53 (dd,J = 11.8, 5.0 Hz, 1H), 3.83 (d, J = 7.8 Hz, 3H), 3.65 (d, J = 6.8 Hz, 4H),3.01 (t, J = 19.4 Hz, 2H), 2.86 (d, J = 10.0 Hz, 1H), 2.77 (td, J = 11.9, 6.0Hz, 1H), 2.60 (d, J = 17.6 Hz, 1H), 2.49 – 2.45 (m, 2H), 2.42 – 2.25 (m, 6H), 2.21 – 2.15 (m, 1H), 2.03 (s, 2H), 1.48 (d, J = 37.9 Hz, 9H).

[1100] Example 203: Synthesis of Compound 203

[1101]

[1102] Referring to the method described in Example 202, referring to steps 1-2, intermediate 203f was prepared by replacing intermediate 67a with 1-Boc-4-(piperidin-4-yl)-piperazine; referring to steps 3-6, intermediate 203d was prepared by replacing ethyl difluorobromoacetate with ethyl fluorobromoacetate; referring to step 8, intermediate 202b was replaced with intermediate 203f, and intermediate 202g-1 was replaced with intermediate 203d to prepare compound 203.

[1103] MS(ESI, [M+H)) + m / z: 894.3

[1104] 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 9.05 (d, J = 9.8 Hz, 2H), 8.10 (s, 1H), 7.92 – 7.89 (m, 1H), 7.86 (d, J = 16.9 Hz, 2H), 7.52 (d, J =8.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 4.53 (dd, J = 11.8, 5.0 Hz, 1H), 3.83(d, J = 7.9 Hz, 3H), 3.73 – 3.54 (m, 4H), 3.07 – 2.81 (m, 5H), 2.80 – 2.71(m, 1H), 2.63 – 2.52 (m, 4H), 2.49 – 2.42 (m, 2H), 2.29 – 2.14 (m, 3H), 2.08 – 1.97 (m, 2H), 1.95 – 1.64 (m, 4H), 1.57 – 1.35 (m, 3H).

[1105] Example 204: Synthesis of Compound 204

[1106]

[1107] Step 1: Preparation of intermediate 204a

[1108] In a reaction flask, 1-Boc-2,2-dimethylpiperidin-4-one (1.22 g), benzyl-1-piperazine carbonate (0.6 g), methanol (20 mL), and acetic acid (0.08 g) were added sequentially, followed by sodium cyanoborohydride (0.5 g). The mixture was then heated to 60°C. oThe reaction proceeded at C for 3 hours. After the reaction was complete, EA 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 solvent was removed from the filtrate by vacuum distillation to obtain intermediate 204a (1.02 g).

[1109] MS(ESI, [M+H)) + m / z: 432.3

[1110] Step 2: Preparation of intermediate 204b

[1111] In a reaction flask, 1.02 g of 204a, 20 mL of methanol, and 0.3 g of 10% palladium on carbon were added sequentially. The mixture was then heated to 60 °C. o The reaction was carried out at C for 10 hours. After the reaction was complete, the mixture was filtered, and the solvent was removed from the filtrate by vacuum distillation to obtain intermediate 204b (0.55 g).

[1112] MS(ESI, [M+H)) + m / z: 298.2

[1113] Step 3: Preparation of intermediate 204d

[1114] Referring to the method described in step 2 of Example 181, intermediate 204d (0.62 g) was prepared by replacing 181b with intermediate z154-1 and 181c with 204b.

[1115] MS(ESI, [M+H)) + m / z: 690.3

[1116] Step 4: Preparation of intermediate 204e

[1117] In a reaction flask, 0.62 g of 204d, 10 mL of dichloromethane, and 10 mL of 4 M dioxane hydrochloride were added sequentially, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the solvent was removed by vacuum distillation to obtain intermediate 204e (0.51 g).

[1118] MS(ESI, [M+H)) + m / z: 590.3

[1119] Step 5: Preparation of Compound 204

[1120] Referring to the method described in step 1 of Example 106, Z40 was replaced by intermediate Z13-2, and tert-butyl 3-(piperidin-4-yl)azacyclobutane-1-carboxylic acid was replaced by intermediate 204e to prepare compound 204.

[1121] MS(ESI, [M+H)) +m / z: 886.2

[1122] 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.93 (s, 1H), 8.54 (s, 1H), 8.06 (s, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.86 (dd, J = 9.1, 2.5 Hz, 1H), 7.66(s, 1H), 7.53 (dd, J = 16.7, 8.7 Hz, 2H), 7.10 (dd, J = 11.8, 8.2 Hz, 1H), 6.31 (d, J = 58.8 Hz, 1H), 4.53 (dd, J = 11.8, 5.0 Hz, 1H), 3.70 (s, 3H), 3.61 (s, 3H), 3.05 (d, J = 17.4 Hz, 2H), 2.94 – 2.71 (m, 4H), 2.59 (dd, J =17.6, 4.5 Hz, 3H), 2.48 – 2.41 (m, 2H), 2.32 – 2.14 (m, 3H), 1.93 (s, 3H), 1.66 (d, J = 77.9 Hz, 3H), 1.34 (s, 4H), 1.20 – 0.99 (m, 5H), 0.91 (s, 2H).

[1123] Example 205: Synthesis of Compound 205

[1124]

[1125] Step 1: Preparation of intermediates z154c-1 and z154c-2

[1126] Intermediate Z154C was prepared and resolved (instrument: SFC supercritical fluid chromatograph; column: CHIRALARTCellulose-SB (5μm, 20*100mm); mobile phase A: carbon dioxide, mobile phase B: ethanol). Intermediate Z154C-1 (350mg) and intermediate Z154C-2 (330mg) were obtained.

[1127] Intermediate z154c-1: MS(ESI, [M+H]) + m / z: 283.1

[1128] Intermediate z154c-2: MS(ESI, [M+H])+ m / z: 283.1

[1129] Step 2: Preparation of intermediate 205a

[1130] In a reaction flask, 2,6-difluoropyridine (2 g), piperazine-1-carboxylic acid tert-butyl acetate (3.56 g), DMSO (30 mL), and N,N-diisopropylethylamine (3.37 g) were added sequentially. The mixture was then heated to 70°C. o The reaction proceeds at C for 3 hours. After the reaction is complete, EA and water are added to the reaction solution for extraction. The organic phase is separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent is removed from the filtrate by vacuum distillation to obtain intermediate 205a (5 g).

[1131] MS(ESI, [M+H)) + m / z: 282.1

[1132] Step 3: Preparation of intermediate 205b

[1133] In a reaction flask, intermediate 205a (3 g), DMF (30 mL), and NCS (1.424 g) were added sequentially, and the mixture was heated to 70°C. o The reaction proceeds at C for 3 hours. The reaction solution is poured into water, alkalized with sodium bicarbonate solution, and then extracted with EA. The organic phase is separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent is removed from the filtrate by vacuum distillation to obtain intermediate 205b (4 g).

[1134] MS(ESI, [M+H)) + m / z: 316.1

[1135] Step 4: Preparation of intermediate 205c

[1136] In a reaction flask, intermediate 205b (3 g), THF (150 mL), pentamethyldiethylenetriamine (3.62 g), and n-butyllithium (1.339 g, 13.06 mL) were added sequentially at -78°C. Under N2 protection, the mixture was stirred at -78°C for 120 min. Then, a solution of iodine (4.82 g) in THF (10 mL) was added dropwise, and the mixture was gradually allowed to return to room temperature overnight. After the reaction was complete, the reaction solution was poured into an aqueous sodium thiosulfate solution, and the residue was 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 205c (1.35 g).

[1137] MS(ESI, [M+H)) + m / z: 442.0

[1138] Step 5: Preparation of intermediate 205d

[1139] In a reaction flask, intermediates 205c (0.639 g), z154c-1 (1 g), Pd2(dba)3 (0.104 g), BINAP (0.066 g), cesium carbonate (1.475 g), and toluene (100 mL) were added sequentially. Under N2 protection, the mixture was heated to 100°C. o The reaction was carried out at C for 8 hours. The reaction solution was filtered, and the filtrate was purified by silica gel column chromatography to obtain intermediate 205d (0.250 g).

[1140] MS(ESI, [M+H)) + m / z: 596.1

[1141] Step 6: Preparation of intermediate 205e

[1142] In a reaction flask, intermediate 205d (150 mg), DCM (2 mL), and hydrochloric acid (284 mg, 1.947 mL) were added sequentially, and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the solvent was removed from the reaction solution by vacuum distillation to obtain intermediate 205e (0.1 g).

[1143] MS(ESI, [M+H)) + m / z: 496.1

[1144] Step 7: Preparation of intermediate 205f

[1145] In a reaction flask, intermediate 205e (150 mg), N-tert-butyloxycarbonyl-4-piperidinone (112 mg), sodium acetate (46.2 mg), MeOH (30 mL), and sodium cyanoborohydride (53.1 mg) were added sequentially. The mixture was then heated to 60°C. o The reaction was carried out overnight at C. After the reaction was complete, the reaction solution was directly concentrated and purified by silica gel column chromatography to obtain intermediate 205f (0.15 g).

[1146] MS(ESI, [M+H)) + m / z: 679.2

[1147] Step 8: Preparation of 205g of intermediate

[1148] In a reaction flask, intermediate 205f (50 mg), hydrochloric acid (293 mg, 2.009 mL), and DCM (2 mL) were added sequentially, and the mixture was reacted at room temperature for 1 h. The solvent was removed from the reaction solution by vacuum distillation to obtain intermediate 205 g (0.05 g).

[1149] MS(ESI, [M+H)) + m / z: 579.2

[1150] Step 9: Preparation of Compound 205

[1151] In the reaction flask, 205 g (0.05 g) of intermediate, Z13-2 (27.6 mg), sodium acetate (12.08 mg), sodium cyanoborohydride (11.57 mg), MeOH (10 mL), and 25 mL of solvent were added sequentially. o The reaction was carried out at C for 5 hours. After the reaction was completed, the reaction solution was poured into a container to remove the solvent under reduced pressure, and then purified by silica gel column chromatography to obtain compound 205 (0.043 g).

[1152] MS(ESI, [M+H)) + m / z: 875.3

[1153] 1 H NMR (500 MHz, DMSO) δ 11.06 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 7.77 (s, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 9.1 Hz, 1H), 7.56 – 7.48(m, 2H), 7.10 (d, J = 8.3 Hz, 1H), 6.28 (d, J = 59.0 Hz, 1H), 5.98 (s, 1H), 4.53 (dd, J = 11.9, 5.0 Hz, 1H), 3.70 (s, 3H), 3.28 – 3.19 (m, 4H), 3.16 (s, 1H), 3.00 (s, 2H), 2.88 (s, 3H), 2.79 – 2.71 (m, 1H), 2.61 (d, J = 4.5 Hz,2H), 2.47 (d, J = 14.4 Hz, 4H), 2.24 (s, 2H), 2.20 – 2.12 (m, 2H), 2.01 (s,2H), 1.86 (s, 2H), 1.71 (s, 2H), 1.42 (s, 3H).

[1154] Experimental Example 1: Assay of BCL6 Degradation Activity in In Vitro Cells

[1155] 1.1 BCL6 degradation activity in OCI-LY1 cells

[1156] Collect OCI-LY1 cells in good growth condition into centrifuge tubes and adjust the cell density to 3×10⁻⁶. 5 Cells were seeded at a concentration of 50 μL / well in pre-coated 384-well plates, with compound additions made using a nanoparticle pipette to achieve a final concentration of 100 nM - 0.0061 nM. Two replicates were performed, and a control was also included. After culturing for 8 hours, the supernatant was discarded, and 40 μL / well of 4% paraformaldehyde was added and incubated at room temperature for 20 min. Then, 40 μL / well of ice-cold methanol was added and incubated at 4°C for 10 min, followed by washing with PBST. After blocking with 20 μL / well of 5% BSA blocking buffer at room temperature for 1 hour, a mixture of BCL6 and GAPDH antibodies (20 μL / well) was added and incubated overnight at 4°C, followed by washing with PBST. Finally, a mixture of 800 nm and 680 nm fluorescent antibodies (20 μL / well) was added and incubated at room temperature in the dark for 45 min, followed by washing with PBST. Fluorescence values ​​were detected using an Azure multispectral laser imager, and four-parameter analysis was performed to fit a dose-response curve and calculate DC. 50 The experimental results are shown in Table 1.

[1157] 1.2 BCL6 degradation activity in OCI-LY1-BCL6-HIBIT cells

[1158] Collect OCI-LY1-BCL6-HIBIT cells in good growth condition into centrifuge tubes and adjust the cell density to 1×10⁻⁶. 5 Cells were seeded at a concentration of 100 nM to 0.0061 nM using a nanoparticle pipette, with two replicates. A control was also included. After 6 hours of cell culture, Nano-GLo HiBiT Lytic (Promega, 25 μL / well) was added. The cells were shaken at 400 rpm for 10 minutes at room temperature. The luminescence value was then measured using a PerkinElmer Envision Lumi 384 microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and DC was calculated. 50 The experimental results are shown in Table 2.

[1159] Table 1

[1160]

[1161] Table 2

[1162]

[1163] Experimental Example 2: Determination of CRBN Protein Binding Activity

[1164] Dilute the Human Cereblon WT GST-tagged protein stock solution to 1X using the binding buffer from the kit (cisbio, 64BDCRBNPEG). Add 5 μL / well of Human Cereblon WT GST-tagged protein diluent to each well of a 384-well plate. Add 5 μL / well of the 1X compound diluent and use a nanoparticle pipette to add the compounds to a final concentration of 50,000 nM–69 nM. Perform two replicates for each concentration. Include a control. Centrifuge to mix and incubate at room temperature for 20 minutes. Dilute the GST Eu cryptate antibody and Thalidomide-Red reagent to 1X using the binding buffer from the kit (cisbio, 64BDCRBNPEG). Mix the GST Eu cryptate antibody and Thalidomide-Red reagent diluent at a 1:1 volume ratio. Add 10 μL / well of the antibody mixture to the 384-well plate, centrifuge to mix, and incubate at room temperature for 3 hours. Fluorescence values ​​were detected at 665nm / 620nm using an Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and IC50 was calculated. 50 The experimental results showed that the compound of this application has CRBN protein-binding activity.

[1165] Experimental Example 3: In vitro liver microsomal metabolic stability

[1166] Liver microsomal incubation samples (species: human, monkey, dog, rat, and mouse) were prepared as a mixture of PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), the test compound, and NADPH + MgCl2 solution, and incubated at 37°C and 300 rpm for 1 hour. Samples at 0 hours were prepared as a mixture of PBS buffer (pH 7.4), liver microsomal solution (0.5 mg / mL), and the test compound. Acetonitrile solution containing an internal standard was added to the samples, and the supernatant was prepared by protein precipitation, diluted, and used for LC / MS / MS analysis. The results showed that the compound of this application possesses in vitro liver microsomal metabolic stability. The results are shown in Table 3.

[1167] Table 3

[1168]

[1169] Experimental Example 4: Pharmacokinetics in Mice

[1170] ICR mice, weighing 18-22 g, were randomly divided into groups of 6 mice each after acclimatization for 3-5 days. The gavage group was administered the test compound solution by gavage at a dose of 10 mg / kg, while the intravenous injection group was administered the test compound solution by intravenous injection at a dose of 1 mg / kg.

[1171] Blood samples were collected at the following time points: 15 min, 1 h, 4 h, 6 h, 8 h, 10 h, and 24 h after administration. Blood samples were collected at the following time points: 5 min, 0.25 h, 2 h, 4 h, 8 h, 10 h, and 24 h after administration. Blood was collected from the orbital cavity to prepare plasma samples for testing.

[1172] Take 30 µL of the plasma sample to be tested and the standard curve sample, add acetonitrile solution containing internal standard, and obtain the supernatant by protein precipitation. After dilution, use it for LC / MS / MS determination.

[1173] Pharmacokinetic parameters were fitted using a non-compartmental model. The experimental results are shown in Table 4.

[1174] Table 4

[1175]

[1176] The experimental results showed that the compound of this application has good in vivo pharmacokinetic properties, such as at AUC, t 1 / 2 C max And F, etc. For example, some compounds in the embodiments of this application have AUC > 2000 ng*h / mL, C max >200 ng / mL.

[1177] Experimental Example 5: Assay of In Vitro Cell Proliferation Inhibition Activity

[1178] Collect OCI-LY1 cells in good growth condition into centrifuge tubes and adjust the cell density to 5 × 10⁻⁶. 3 The compound was seeded at a concentration of 100 μL / well in 96-well plates, and simultaneously added using a nanoparticle pipette to achieve a final concentration of 100 nM - 0.0061 nM. Two replicates were performed, and a control was also included. After culturing for 7 days in a cell incubator, the assay reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL / well) was added. After incubation for 2 hours in a cell incubator, the absorbance was measured at 450 nm using a PerkinElmer Envision microplate reader. Four-parameter analysis was performed, a dose-response curve was fitted, and the IC50 was calculated. 50 The experimental results are shown in Table 5.

[1179] Table 5

[1180] Compound numbering <![CDATA[IC 50 (nM)]]> Compound numbering <![CDATA[IC 50 (nM)]]> 181 ＜5 197 ＜5 182 ＜5 198 ＜5 183 ＜5 200 ＜5 184 ＜5 201 ＜5 185 ＜5 202 ＜5 186 ＜5 203 ＜5 187 ＜5 204 ＜5 196 ＜5 205 ＜5

[1181] .

Claims

1. A compound of formula II, its stereoisomers, or a pharmaceutically acceptable salt thereof, in, Indicates a single bond or a double bond; Ring W is selected from or , A ring 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 groups; The ring C is selected from furanyl, oxazolyl, isoxazolyl, or pyrazolyl; When ring A is absent or selected from phenyl, and ring B is selected from phenyl, ring C is selected from oxazolyl, isoxazolyl or pyrazolyl; X a X b X c X d X e X f and X g Each of the following is independently selected from C, CH, CH2, N, NH, O, or S; Each R 1 The following groups, each independently selected from deuterium, halogens, -OH, -NH2, -CN, and optionally substituted by 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 group, C 3-10 cycloalkyl, C 3-10 cycloalkyl C 1-3 Alkyl or 3-10 membered heterocyclic alkyl; n is selected from 0, 1, 2, 3, 4, 5, or 6; X 5 Selected from C(R) f ) or N; R f C selected from H, halogens, deuterium, or optionally substituted with one or more substituents 1-6 alkyl; L 1 Selected from -NH-, -O-, -S-, -CONH-, or -CON(C) 1-6 alkyl)-, the L 1 Connected to ring C or ring E in ring W, when L 1 When selected from the key, then X 5 Connect to ring C or ring E in ring W; L is selected from a linking group; PTM is selected from small molecule compounds that target BCL6.

2. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, selected from compounds of formula III or IIIA, their stereoisomers, or pharmaceutically acceptable salts 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 C(R) g ), C(R g R h ), N, N(R) g ), O or S; R d R e R g and R h The following groups are selected independently from hydrogen, deuterium, halogen, -CN, or optionally substituted by 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 atoms bonded to it, they form C 5-12 Carbocyclic or 5-12 membered heterocyclic groups, wherein the C 5-12 The carbon ring or 5- to 12-membered heterocyclic group may optionally be replaced by one or more R''; R s and R v Selected independently from H and C respectively 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 cycloalkyl, C 3-12 cycloalkyl C 1-3 alkylene-, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkyl C 1-3 Alkylene-, C 3-12 Cycloalkenyl, C 3-12 Cycloalkenyl C 1-3 alkylene-, 3-12-membered heterocyclic alkenyl, 3-12-membered heterocyclic alkenyl C 1-3 Alkylene-, C 6-12 Aryl, C 6-12 Aryl C 1-3 alkylene-, 5-12 heteroaryl, or 5-12 heteroaryl C 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 group, 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 heterocyclic alkyl, C 6-10 Aryl or 5-10 heteroaryl groups; R j and R k The following groups are selected independently from H, or optionally substituted by one or more groups selected from deuterium, halogens, -OH, -NH2, or -CN: C 1-6 Alkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic alkyl; Each R 2 and R 3 Each is independently selected from deuterium, halogens, -CN, -OH, -NH2, and C. 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, 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 heteroaryl, wherein C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, 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 The aryl or 5-12 heteroaryl group may optionally be substituted by 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 group, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-3 alkylene-, 3-12-membered heterocyclic alkyl C 1-3 Alkylene-, C 6-12 Aryl C 1-3 alkylene- or 5-12 heteroaryl C 1-3 alkylene-, the C 1-12 Alkyl, C 2-12 alkenyl, C 2-12 alkynyl group, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl, 5-12 heteroaryl, C 3-12 cycloalkyl C 1-3 alkylene-, 3-12-membered heterocyclic alkyl C 1-3 Alkylene-, C 6-12 Aryl C 1-3 alkylene- or 5-12 heteroaryl C 1-3 Alkyl groups are 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 heteroaryl groups; X 10 X 11 X 12 X 13 X 14 X 15 X 16 and X 17 Each is independently selected from CH or N; R t Selected from H or C 1-6 alkyl.

3. The compound of claim 1 or 2, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein ring A is absent or selected from C. 3-12 Cycloalkenyl, 3-12 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A does not exist, or it is selected from C. 5-15 Cycloalkenyl, 5-15 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A does not exist, or it is selected from C. 5-10 Cycloalkenyl, 5-10 membered heterocyclic alkenyl, phenyl or 5-6 membered heteroaryl; Alternatively, ring A does not exist, or it is selected from C. 5-7 Cycloalkenyl, 5-9 membered heterocyclic alkenyl, 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 heterocyclic alkenyl, phenyl, pyrroleyl, pyrazolyl, furanyl or oxazolyl; Alternatively, ring A is absent, or is selected from cyclopentenyl, monocyclohexenyl, dicyclohexenyl, monocycloheptenyl, dihydropyrroleyl, tetrahydropyridyl, tetrahydroazapyryl, azaspirooctenyl, azaspirononenyl, phenyl, pyrroleyl, pyrazolyl, furanyl, oxazolyl, or dihydrooxazinyl. Optionally, ring B is selected from phenyl or 6-membered heteroaryl; or, ring B is selected from phenyl. Optionally, the ring C is selected from furanyl, oxazolyl, or isoxazolyl; Alternatively, ring C is selected from furanyl or isoxazolyl; or ring C is selected from oxazolyl or isoxazolyl. Alternatively, when ring A is absent or selected from phenyl, and ring B is selected from phenyl, ring C is selected from oxazolyl or isoxazolyl; Optionally, each R 1 The following groups are independently selected from deuterium, halogens, -OH, -NH2, -CN, and optionally substituted by 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 group, C 3-6 cycloalkyl or 3-6 membered heterocyclic alkyl; Or, each R 1 The following groups are independently selected from deuterium, halogens, -OH, -NH2, -CN, and optionally substituted by one or more substituents: C 1-6 Alkyl, C 1-6 alkoxy or halogenated C 1-6 alkyl; Or, the R 1 The substituents are selected from deuterium, halogens, -OH, -NH2, -CN, -CHO, or -COOH; Or, each R 1 Independently selected from deuterium, halogens, -OH, -NH2, -CN, C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl; Or, each R 1 Independently selected from deuterium, halogens, -OH, -NH2, -CN, C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 alkoxy or halogenated C 1-3 alkyl; Or, each R 1 Independently selected from deuterium, halogens, -OH, -NH2, -CN, C 1-3 Alkyl or deuterated C 1-3 alkyl; Or, each R 1 Independently selected from deuterium, halogens, and C 1-3 Alkyl or deuterated C 1-3 alkyl; Or, each R 1 Independently selected from deuterium, fluorine, methyl, or -CD3; Optional, structural part Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or ; Structural parts Selected from , , , , , , , , , , , , , , , or .

4. The compound according to any one of claims 1-3, its stereoisomers, or its pharmaceutically acceptable salts, R f C selected from H, fluorine, chlorine, bromine, deuterium, or optionally substituted with one or more substituents 1-3 alkyl; Or, R f Selected from H, fluorine, chlorine, bromine, deuterium or C 1-3 Alkyl, the C 1-3 The alkyl group may optionally be substituted with one or more of the following groups: deuterium, halogen, -OH, -NH2 or -CN; Or, R f Selected from H, fluorine, deuterium or methyl.

5. The compound of claims 1-4, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the L is selected from the following groups optionally substituted with one or more substituents: C 1-50 Alkylene, C 2-50 imide or C 2-50 Alkyne group, optionally, the C 1-50 Alkylene, C 2-50 imide or C 2-50 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-15 Cycloalkyl, 3-15 membered heterocyclic alkyl, 4-15 membered heterocyclic alkenyl, C 6-15 Aryl, 5-15 quinone heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-30 Alkylene, C 2-30 imide or C 2-30 Alkyne group, optionally, the C 1-30 Alkylene, C 2-30 imide or C 2-30 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-12 Cycloalkyl, 3-12-membered heterocyclic alkyl, 4-12-membered heterocyclic alkenyl, C 6-12 Aryl, containing 5-12 membered heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-20 Alkylene, C 2-20 imide or C 2-20 Alkyne group, optionally, the C 1-20 Alkylene, C 2-20 imide or C 2-20 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-10 Cycloalkyl, 3-11 membered heterocyclic alkyl, 4-10 membered heterocyclic alkenyl, C 6-10 Aryl, any 5-10 heteroaryl, -NH-, -N(C 1-6 Alkyl)- or -S-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-15 Alkylene, C 2-15 imide or C 2-15 Alkyne group, optionally, the C 1-15 Alkylene, C 2-15 imide or C 2-15 One or more -CH2- groups in the ethynyl group are independently and optionally separated by -O-, C 3-9 Cycloalkyl, 3-11 membered heterocyclic alkyl, 4-8 membered heterocyclic alkenyl, C 6-8 Aryl, 5-8 quinone heteroaryl, -NH-, -N(C 1-4 Alkyl)- or -S-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-10 Alkylene, C 2-10 imide or C 2-10 Alkyne group, optionally, the C 1-10 Alkylene, C 2-10 imide or C 2-10 One or more -CH2- groups in the ethynyl group are independently and optionally separated 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-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-6 Alkylene, C 2-6 imide or C 2-6 Alkyne group, optionally, the C 1-6 Alkylene, C 2-6 imide or C 2-6 One or more -CH2- groups in the ethynyl group are independently and optionally separated 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-replacement; Alternatively, the L is selected from the following groups optionally substituted with one or more substituents: C 1-4 Alkylene, C 2-4 imide or C 2-4 Alkyne group, optionally, the C 1-4 Alkylene, C 2-4 imide or C 2-4 One or more (e.g., one or two, one or three, etc.) of the ethynyl group are independently and optionally separated 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-replacement; Alternatively, the L is selected from C that is optionally substituted with one or more substituents. 1-10 Alkylene or C 2-10 Alkyne group, optionally, the C 1-10 Alkylene or C 2-10 One or more -CH2- groups in the ethynyl group are independently and optionally selected from -O-, C-. 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl, 4-12 membered heterocyclic alkenyl, -NH-, -N(C 1-6 Alkyl)- or -S-replacement; Alternatively, the L is selected from C that is optionally substituted with one or more substituents. 1-6 Alkylene or C 2-6 Alkyne group, optionally, the C 1-6 Alkylene or C 2-6 One or more -CH2- groups in the ethynyl group are independently and optionally selected from -O-, C-. 3-10 Cycloalkyl, 4-11 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl, -NH-, -N(C 1-3 Alkyl)- or -S-replacement; Optionally, in the definition of L, the substituent is selected from halogens, =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, wherein 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 group is optionally substituted with one or more halogens, -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 and 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 and hydroxy substituted C 1-4 Alkyl, (C 1-4 Alkyl) NH-, (C 1-4 Alkyl)2N-, C 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl groups; 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 and hydroxy substituted C 1-6 Alkyl or C 1-6 Alkoxy; Alternatively, in the definition of L, the substituent is selected from halogens, =O, -OH, -NH2, -CN, or C optionally substituted with a halogen or hydroxyl group. 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 halogens, =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 heterocyclic alkyl; 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 heterocyclic alkyl.

6. The compound of any one of claims 1-5, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein the 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 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 3-12 Cycloalkyl, 4-12 membered heterocyclic alkyl or 4-12 membered heterocyclic alkenyl; LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R c The following groups are substituted: C 1-12 Alkylene, C 2-12 imidene group, C 2-12 Ethyne or C 1-12 Heteroalkylene; Each R b and R c Each is independently selected from halogens, =O, -OH, -NH2, -CN, and 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 heterocyclic alkyl; Or, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R c The following groups are substituted: C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Ethyne or C 1-10 Heteroalkylene; Or, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R c The following groups are substituted: C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne or C 1-6 Heteroalkylene; Or, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R c The following groups are substituted: C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne or C 1-4 Heteroalkylene; Or, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R c The following groups are substituted: C 1-6 Alkylene, C 2-6 Ethyne or C 1-6 Heteroalkylene; Or, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, -S-, or optionally by one or more R c The following groups are substituted: C 1-4 Alkylene, C 2-4 Ethyne or C 1-4 Heteroalkylene; Or, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, or optionally by one or more R c The following groups are substituted: C 1-3 Alkylene, C 2-3 Ethyne or C 1-3 Heteroalkylene; Or, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each is independently selected from the bond, -NH-, -O-, or optionally by one or more R c The following groups are substituted: C 1-3 alkylene, C2-alkynyl or C 1-2 Heteroalkylene; Or, LNK, LNK 1 LNK 2 LNK 3 and LNK 4 Each group is independently selected from the following groups: bond, -NH-, -O-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, -C(CH3)2-, ethynyl group, -C(O)-, or -C(O)CH2-. Or, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 3-11 Cycloalkyl, 4-12 membered heterocyclic alkyl or 4-11 membered heterocyclic alkenyl; Or, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-10 Cycloalkyl, 4-11 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl; Or, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-6 Cycloalkyl, C9 cycloalkyl, 4-11 membered heterocyclic alkyl or 6 membered heterocyclic alkenyl; Or, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups are substituted: C 4-6 cycloalkyl or 4-6 membered heterocyclic alkyl; Or, Cy 1 Cy 2 Cy 3 or Cy 4 Each is independently selected from a key, or optionally selected by one or more R keys. b The following groups may be substituted: cyclobutyl, cyclopentyl, cyclohexyl, spironyl, azircyclobutyl, pyrrolyl, piperidinyl, tetrahydropyridyl, piperazine, azirspiroheptyl, azirspirooctyl, azirspirononyl, diazirspirononyl, azirspirodecyl, diazirspirodecane, azirspiroundecyl, diazirspiroundecyl, azirbicyclohexane, octahydrocyclopentylpyrryl, pyrrylpyrryl, diazirbicyclooctyl, or azirbicyclononyl.

7. The compound of claim 6, its stereoisomers, or pharmaceutically acceptable salts thereof, each R b and R c Each is independently selected from halogens, =O, -OH, -NH2, -CN, and 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, wherein 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 group is optionally substituted with one or more halogens, -OH, -NH2 or -CN; Or, each R b and R c Each is independently selected from halogens, =O, -OH, -NH2, -CN, and C. 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkyl and 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 is independently selected from halogens, =O, -OH, -NH2, -CN, and C. 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 alkyl and hydroxy substituted C 1-4 Alkyl, (C 1-4 Alkyl) NH-, or (C 1-4 Alkyl)2N-; Or, each R b and R c Each C is independently selected from halogens, =O, -OH, -NH2, -CN, or optionally substituted with a halogen or hydroxyl group. 1-3 alkyl; Or, each R b and R c Each is independently selected from -F, =O, methyl, -CF3, or HOCH2-; Alternatively, L or -LNK 1 - Selected from -O-, -NH-, -NHCH2-, -CH2NHCH2-, -CH2-, -CH2CH2-, -C(CH3)2-, ethynyl group, -C(O)- or -C(O)CH2-.

8. The compound according to any one of claims 1-7, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein the L is selected from the group consisting of -NHCH2-, -CH2NHCH2-, -CH2-, -C(O)CH2-, ... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 9. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 2-8, R d R e R g and R h The following groups are selected independently from hydrogen, deuterium, halogen, -CN, or optionally substituted by one or more R': R v -、R v O-, R v S- or R s R v N-; Or, R s and R v Selected independently from H and C respectively 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkylene-, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl C 1-3 Alkylene-, C 3-6 Cycloalkenyl, C 3-6 Cycloalkenyl C 1-3 alkylene-, 3-6 membered heterocyclic alkenyl, 3-6 membered heterocyclic alkenyl C 1-3 Alkylene-, C 6-12 Aryl, C 6-12 Aryl C 1-3 alkylene-, 5-6-membered heteroaryl or 5-6-membered heteroaryl C 1-3 alkylene-; Or, R s and R v Selected independently from H and C respectively 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl or 3-6 membered heterocyclic alkyl; Or, R s and R v Selected independently from H or C 1-3 alkyl; Or, R d R e R g and R h The following groups are selected independently from hydrogen, deuterium, halogen, -CN, or optionally substituted by one or more R': C 1-6 Alkyl-, C 1-6 Alkyl O-, C 1-6 Alkyl S-, C 1-6 Alkyl NH-, C 3-6 cycloalkyl NH- or 3-6 membered heterocyclic alkyl NH-; Or, R d R e R g and R h C atoms are independently selected from hydrogen, deuterium, or optionally substituted with one or more R's. 1-4 Alkyl O-, C 1-4 Alkyl NH- or C 3-4 cycloalkyl NH-; Or, R d R e R g and R h The following groups are selected independently from hydrogen or optionally substituted with one or more R' groups: C 1-3 Alkyl O-; Or, R d R e R g and R h Each is independently selected from hydrogen, or CH3O- or cyclobutylNH- optionally substituted with one or more R'; Or, R d and R g Together with the carbon or nitrogen atoms bonded to it, they form C 5-10 Carbocyclic or 5-10 membered heterocyclic group, wherein the C 5-10 The carbocyclic or 5- to 10-membered heterocyclic group may optionally be replaced by one or more R''; Or, the R mentioned above d and R g Together with the carbon or nitrogen atoms bonded to it, they form C 6-10 Carbocyclic or 6-10 membered heterocyclic group, wherein the C 6-7 The carbocyclic or 6-7 membered heterocyclic group is optionally replaced by one or more R''; Or, the R mentioned above d and R g The carbon or nitrogen atom connected thereto forms a 7-membered heterocyclic group containing nitrogen and oxygen heteroatoms, wherein the 7-membered heterocyclic group containing nitrogen and oxygen heteroatoms is optionally substituted by one or more R''; Or, R d Each is independently selected from CH3O- that is optionally substituted by one or more R'; Or, R d Selected from hydrogen, , , , , , , , , , , , or ; Or, R d and R g The carbon or nitrogen atom attached thereto forms a 7-membered heterocyclic group, which is optionally substituted by one or more R''; Or, R d and R g It forms together with the carbon or nitrogen atoms connected to it. The Optionally replaced by one or more R''; Or, R d and R g It forms together with the carbon or nitrogen atoms connected to it. , , , , ,or ; Optionally, 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 quinone heteroaryl; Alternatively, each R' or R'' is independently selected from deuterium, halogen, -OH, -NH2, -CN, R k C(O)-、R j R k NC(O)- or cyclopropyl; Alternatively, each R' can be independently selected from deuterium, halogens, -OH, -NH2, -CN, R k C(O) - or R j R k NC(O)- ; Alternatively, each R' may be independently selected from deuterium, F, -OH, -CN, CH3C(O)-, CH3NHC(O)-, CD3NHC(O)- or cyclopropyl-NHC(O)-; Alternatively, each R'' can be independently selected from deuterium, halogens, -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 quinone heteroaryl; Alternatively, each R'' can be independently selected from deuterium, -F, -Cl, or C. 3-4 cycloalkyl; Alternatively, each R'' may be independently selected from deuterium, halogen, or cyclopropyl; Optional, R j and R k The following groups are selected independently from H, or optionally substituted by one or more groups selected from deuterium, halogens, -OH, -NH2, or -CN: C 1-3 Alkyl, C 3-4 cycloalkyl or 3-4 membered heterocyclic alkyl; Optional, R j and R k C elements independently selected from H, deuterium, or optionally substituted by one or more deuterium atoms. 1-3 Alkyl, C 3-4 cycloalkyl or 3-4 membered heterocyclic alkyl; Optional, R j and R k Each is independently selected from H, deuterium, CD3, methyl or cyclopropyl.

10. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 2-9, each R 2 and R 3 Each is independently selected from deuterium, halogens, -CN, -OH, -NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, 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 heterocyclic alkyl, C 6-12 Aryl or 5-6 heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl O-, C 1-6 Alkyl NH-, (C 1-6 Alkyl)2N-, C 3-6 Alkyl, 3-6 heterocyclic alkyl, C 6-12 The aryl or 5-6 heteroaryl groups may optionally be substituted by 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; Or, each R 2 and R 3 Each is independently selected from deuterium, halogens, -CN, -OH, -NH2, and C. 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, 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 group, C 1-4 Alkyl O-, C 1-4 Alkyl NH- or (C 1-4 The alkyl group (2N-) 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; Or, each R 2 and R 3 Each is independently selected from deuterium, halogens, -CN, -OH, -NH2, and C. 1-4 Alkyl, Halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl or C 1-4 Alkyl O-; Or, each R 2 and R 3 Selected independently from deuterium, halogens, -CN, and C respectively. 1-3 Alkyl, Halogenated C 1-3 Alkyl, deuterated C 1-4 Alkyl or C 1-3 Alkyl O-; Or, each R 2 and R 3 Each of the following is independently selected from deuterium, -F, -Cl, -Br, -CN, -CF3, -CD3, or CH3O-; Or, each R 2 and R 3 Each of the following is independently selected from deuterium, -F, -Cl, -Br, -CN, -CF3, -CD3, or CH3O-; Or, each R 3 Each was independently selected from Cl; Optional, R 4 Selected from hydrogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, 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 quinone heteroaryl, C 3-6 cycloalkyl C 1-3 alkylene-, 3-6 membered heterocyclic alkyl 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 group, 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 quinone heteroaryl, C 3-6 cycloalkyl C 1-3 alkylene-, 3-6 membered heterocyclic alkyl C 1-3 Alkylene-, C 6-10 Aryl C 1-3 alkylene- or 5-6-membered heteroaryl C 1-3 Alkyl groups are 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 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-6 quinone heteroaryl; Or, R 4 Selected from hydrogen, -CN, -OH, -NH2, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkyl O-, C 1-4 Alkyl S-, C 1-4 Alkyl NH-, (C 1-4 Alkyl)2N- or C 3-6 cycloalkyl; Or, R 4 Selected from C 1-6 Alkyl, Halogenated C 1-6 Alkyl or C 3-6 cycloalkyl; Or, R 4 Selected from C 1-3 Alkyl, Halogenated C 1-3 Alkyl or C 3-4 cycloalkyl; Or, R 4 Selected from methyl, ethyl, CF3CH2-, isopropyl, or cyclopropyl; Optional, structural part Selected from or u is selected from 0, 1, 2, 3 or 4; Or, structural parts Selected from or ; Or, structural parts Selected from or ; Or, structural parts Selected from , , , or .

11. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, as described in any one of claims 1-10, wherein the compound is selected from compounds of formula IV, V, VI, VIII, VIIIA, VIIIB, VIIIC, or VIIID, their stereoisomers, or a pharmaceutically acceptable salt thereof. in, X 18 Selected from CH or N; X 19 Selected from NH or O; u is selected from 0, 1, 2, 3, 4, 5 or 6; t is selected from 0, 1, 2 or 3.

12. A pharmaceutical composition comprising the compound of any one of claims 1-11, its stereoisomer, or a pharmaceutically acceptable salt thereof.

13. Use of the compound of any one of claims 1-11, its stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 12 in the preparation of a medicament for the prevention or treatment of a disease; optionally, the disease is selected from cancer.

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