Heterocyclic compound, pharmaceutical composition thereof and use thereof

Abstract

Disclosed in the present invention are a heterocyclic compound, a pharmaceutical composition thereof and a use thereof. Specifically, disclosed in the present invention are a compound shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The heterocyclic compound of the present invention has good inhibitory activity or degradation activity against STAT6.

Description

Heterocyclic compounds, their pharmaceutical compositions and their applications

[0001] This application claims priority to Chinese patent application 2025103511204, filed March 24, 2025; Chinese patent application 2025114070525, filed September 29, 2025; Chinese patent application 2026102168809, filed February 14, 2026; and Chinese patent application 2026103301836, filed March 17, 2026. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to heterocyclic compounds, pharmaceutical compositions thereof, and their applications. Background Technology

[0003] Protein degradation target chimeric molecules (PROTACs) are a new class of drugs that can degrade various proteins associated with human diseases, exhibiting advantages such as high efficiency, high selectivity, and targeting of "undruggable" proteins. PROTAC technology can be used to target various cancer targets, including different targets against solid tumors and hematologic malignancies, and has shown highly efficient killing of certain tumor cells in a target-dependent manner. Scientists have discovered more than 600 E3 ligases in the human genome. The main E3 ligases used in PROTACs are CRBN, VHL, cIAP, and MDM2, with CRBN and VHL being the most effective and frequently used.

[0004] The signal transducer and activator of transcription (STAT) protein family consists of transcription factors that play important roles in the regulation of cellular processes such as proliferation, differentiation, apoptosis, and angiogenesis. Seven STAT genes have been identified in the human genome: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6.

[0005] STAT6 has received particular attention, and recent studies have shown that STAT6 signaling is crucial for IL-4 and IL-13-induced epithelial-mesenchymal transition (EMT) and the invasiveness of colorectal cancer cells (CRC). STAT6 (Signal transducer and activator of transcription 6) is involved in intracellular signaling of IL-4 and IL-13. It has been reported that STAT6 deficiency prevents Thrp cells from differentiating into Th2 cells (immunity, 4, 313-319, 1996), and in a mouse model of asthma with STAT6 deficiency, IgE production, increased airway responsiveness, and suppressed eosinophil infiltration of the airways and lungs are observed (J. Exp. Med, 187, 9, 1537-1542, 1998), suggesting that STAT6 is associated with inflammatory respiratory diseases such as asthma.

[0006] Furthermore, reports indicate that administering antigens to patients with allergic rhinitis increases the levels of STAT6 and IL-4 mRNA in the nasal mucosa (Clin. Exp. Allergy 30, 86-93, 1709-1716, 2000). Additionally, overexpression of IL-4 in mice induces dermatitis symptoms such as inflammatory cell infiltration of the skin (J. Invest. Dermatol. 117.4, 977-983 (2001)), suggesting a link between STAT6 and allergic rhinitis and dermatitis. STAT6 binds to the GYKXF motif of the IL-4 receptor α chain (IL-4Ra), a component of both the IL-4 and IL-13 receptors (Science 165, 1265-1267, 1994). These receptors also bind to JAK family kinases. When IL-4 or IL-13 binds to its receptor, STAT6 undergoes tyrosine phosphorylation via JAK family kinases, forming a dimer that translocates to the nucleus to function as a transcription factor (Science 165, 1265-1267, 1994). Therefore, inhibiting any of these processes, such as tyrosine phosphorylation of STAT6, would suppress its function as a transcription factor, potentially offering therapeutic potential for various diseases associated with the aforementioned IL-4 and IL-13.

[0007] STAT6 is involved in multiple aspects of inflammatory diseases and other related conditions. Given its role in the regulation of cellular processes, regulating one or more STAT proteins, specifically the activity of STAT6, is a key area of ​​research for the treatment of cancer, inflammatory conditions, and other therapeutic needs, such as atopic dermatitis, sinusitis, asthma, esophageal diseases, chronic obstructive pulmonary disease, Alzheimer's disease, and peripheral nervous system diseases.

[0008] Published patent applications for STAT6 inhibitors or degraders include: WO2023192960A1, WO2023250058A1, WO2024030628A1, WO2024064080A1, WO2025049820A1 and WO2025049821A1. Summary of the Invention

[0009] The technical problem this invention aims to solve is to address the deficiency in the variety of STAT6 inhibitors or degraders in existing technologies by providing a novel cyclic compound, its pharmaceutical composition, and its applications. The heterocyclic compound of this invention exhibits good inhibitory or degradative activity against STAT6.

[0010] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0011] This invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0012] in, Indicates a single bond or a double bond;

[0013] Ring B is a saturated or partially unsaturated C3-C ring. 18 Carbon rings, saturated or partially unsaturated 3-18 membered heterocycles, C6-C 18 Aromatic rings or 5-18 membered heteroaromatic rings; in the 3-18 membered heterocycles, the heteroatom is selected from one or more of N, O, S, Si, and P, and the number of heteroatoms is 1, 2, 3, 4, or 5; in the 5-18 membered heteroaromatic rings, the heteroatom is selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 18 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-18 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0014] n is 0, 1, 2, 3, 4 or 5;

[0015] R B Independently for R A-2 R B-1 Hydrogen, halogen, cyano, nitro, oxo (=O), =NR A-1 =S, -OR A-1 -SR A-1 -N(R) A-1 )2、-Si(R A-13. -S(=O)R A-1 -S(=O)2R A-1 -S(=O)(=NR) A-1 )R A-1 -S(=NR) A-1 )2R A-1 -S(=O)2N(R) A-1 )2、-C(=O)R A-1 -C(=O)OR A-1 -C(=O)N(R) A- 1 )2、-C(=O)N(R A-1 OR A-1 -OC(=O)R A-1 -OC(=O)N(R) A-1 )2、-P(=O)(R A-1 )2、-P(=O)(OR A-1 )2、-OP(=O)(R A-1 )2、-OP(=O)(OR A- 1 )2、-NR A-1 C(=O)OR A-1 -NR A-1 C(=NR A-1 OR A-1 -NR A-1 C(=O)R A-1 -NR A-1 C(=NR A-1 )R A-1 -NR A-1 C(=O)N(R A-1 )2、-NR A- 1 C(=NR A-1 )N(R A-1 )2、-NR A-1 C(=NOR A-1 )N(R A-1 )2、-NR A-1 C(=NR A-1 )NH(OR A-1 ) or -NR A-1 S(=O)2R A-1 ;

[0016] R A-2 Independently for C1-C 12 Alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 12 cycloalkyl, C3-C 12Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C1-C 12 Alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 aryl or 5-14 heteroaryl groups are optionally surrounded by one or more R groups. A-2-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0017] R B-1 -L B -H, -L B -Cy B1’ or -L B -Cy B11 -Cy B2’ ;

[0018] L B Independently C1-C4 alkylene groups, wherein 0, 1, 2, 3, or 4 methylene groups are independently replaced by the following groups: -O-, -C(=O)-, -C(=S)-, -C(=NR)-. A-1 -, -CF2-, -CR A-1 F-、-CR A-1 R A-1 -、-CR A-1 (OR A-1 )-、-NR A-1 -, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR A-1 )-、-CR A-1 CR A-1 -or

[0019] Cy B11 Independently for C3-C 12 Cycloalkylene, C3-C 12Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene or 5-14 quinone heteroarylene; wherein the C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene or 5-14 heteroarylene, optionally enclosed by one or more R A-1-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 member heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0020] Cy B1’ and Cy B2’ Each independently constitutes C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 aryl or 5-14 heteroaryl groups are optionally surrounded by one or more R groups. A-1-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0021] R A-1 Independently hydrogen, C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 aryl or 5-14 heteroaryl groups are optionally surrounded by one or more R groups. A-1-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0022] Alternatively, two R atoms on the same atom or two adjacent atoms A-1 Together with the atoms bonded to them, they form saturated or partially unsaturated C3-C atoms. 12 Carbon rings, or saturated or partially unsaturated 3-12 membered heterocycles; wherein the C3-C 12 The carbon ring or 3-12 membered heterocycle is optionally separated by one or more R A-1-1 The 3-12 membered heterocycles are replaced by heteroatoms selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0023] R A-1-1 and R A-2-1 Each independently for Cy X1 Halogen, -(CH2) 0-4 R A-1-1-1 -(CH2) 0-4 OR A-1-1-1 -O(CH2) 0-4 R A-1-1-1 -O(CH2) 0-4 -C(=O)OR A- 1-1-1 -(CH2) 0-4 CH(OR A-1-1-1 2、-(CH2) 0-4 SR A-1-1-1 -(CH2) 0-4 Ph、-(CH2) 0-4O(CH₂) 0-1 Ph, -(CH₂) 0-4 Py, -(CH₂) 0-4 O(CH₂) 0-1 Py, -CH=CHPh, nitro, cyano, azido, -(CH₂) 0-4 N(R A-1-1-1 )₂, -(CH₂) 0-4 N(R A-1-1-1 )C(=O)R A-1-1-1 , -N(R A-1-1-1 )C(=S)R A-1-1-1 , -(CH₂) 0- ₄N(R A-1-1-1 )C(=O)N(R A-1-1-1 )₂, -N(R A-1-1-1 )C(=S)N(R A-1-1-1 )₂, -(CH₂) 0-4 N(R A-1-1-1 )C(=O)OR A-1-1-1 , -N(R A-1-1-1 )N(R A-1-1-1 )C(=O)R A- 1-1-1 , -N(R A-1-1-1 )N(R A-1-1-1 )C(=O)N(R A-1-1-1 )₂, -N(R A-1-1-1 )N(R A-1-1-1 )C(=O)OR A-1-1-1 , -(CH₂) 0-4 C(=O)R A-1-1-1 , -C(=S)R A-1-1-1 , -(CH₂) 0-4 -C(=O)OR A-1-1-1 , -(CH₂) 0-4 -C(=O)SR A-1-1-1 , -(CH₂) 0-4 -C(=O)OSi(R A-1-1-1 )₃, -(CH₂) 0-4 OC(=O)R A-1-1-1 , -OC(=O)(CH₂) 0- ₄SR A-1-1-1 , -(CH₂) 0-4 SC(=O)R A-1-1-1 , -(CH₂) 0-4 C(=O)N(R A-1-1-1 )₂, -C(=S)N(R A-1-1-1 )₂, -C(=S)SR A-1-1-1 , -SC(=S)SR A-1-1-1, -(CH2) 0- 4OC(=O)N(R A-1-1-1 )2, -C(=O)N(OR A-1-1-1 )R A-1-1-1 , -C(=O)C(=O)R A-1-1-1 , -C(=O)CH2C(=O)R A-1-1-1 , -C(=NOR A-1-1-1 )R A-1-1-1 , -(CH2) 0-4 SSR A-1-1-1 , -(CH2) 0-4 S(=O)2R A-1-1-1 , -(CH2) 0-4 S(=O)2OR A-1-1-1 , -(CH2) 0-4 OS(=O)2OR A-1-1-1 , -S(=O)2N(R A-1-1-1 )2, -(CH2) 0- 4S(=O)R A-1-1-1 , -N(R A-1-1-1 )S(=O)2N(R A-1-1-1 )2, -N(R A-1-1-1 )S(=O)2R A-1-1-1 , -N(OR A-1-1-1 )R A-1-1-1 , -C(=NH)N(R A-1-1-1 )2, -(CH2) 0- 4P(=O)(R A-1-1-1 )2, -(CH2) 0-4 OP(=O)(R A-1-1-1 )2, -(CH2) 0-4 OP(=O)(OR A-1-1-1 )2, -Si(R A-1-1-1 )3, -(CH CH) 0-4 O-N(R A-1-1-1 )2, -(CH CH) 0-4 C(=O)O-N(R A-1-1-1 )2, =O, =S, =NR A-1-1-1 , =NN(R A-1-1-1 )2, =NNHC(=O)R A-1-1-1 , =NNHC(=O)OR A-1-1-1 , =NNHS(=O)2R A-1-1-1 , =NR A-1-1-1 or =NOR A-1-1-1 ;

[0024] Cy X1 is independently C3-C 12cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl, 5-14 heteroaryl, optionally bounded by one or more R Z1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0025] R Z1 Independently for R Z1-1 Oxygenation (=O), =NR Z1-1 =S, hydrogen, halogen, cyano, nitro, -OR Z1-1 -SR Z1-1 -N(R) Z1-1 )2、-Si(R Z1-1 3. -S(=O)R Z1-1 -S(=O)2R Z1-1 -S(=O)(=NR) Z1-1 )R Z1-1 -S(=O)2N(R) Z1-1 )2、-S(=NR Z1-1 )2R Z1-1 -C(=O)R Z1-1 -C(=O)OR Z1-1 -C(=O)N(R) Z1-1 )2、-C(=O)N(R Z1-1 OR Z1-1 -OC(=O)R Z1-1 -OC(=O)N(R) Z1-1 )2、-P(=O)(R Z1-1 )2、-P(=O)(OR Z1-1 )2、-OP(=O)(R Z1- 1 )2、-OP(=O)(OR Z1-1 )2、-NRZ1-1 C(=O)OR Z1-1 -NR Z1-1 C(=O)R Z1-1 -NR Z1-1 C(=NR Z1-1 OR Z1-1 -NR Z1-1 C(=NR Z1-1 )R Z1-1 -NR Z1- 1 C(=NR Z1-1 )N(R Z1-1 )2、-NR Z1-1 C(=NOR Z1-1 )N(R Z1-1 )2、-NR Z1-1 C(=NR Z1-1 )NH(OR Z1-1 -NR Z1-1 C(=O)N(R Z1-1 )2 or -NR Z1- 1 S(=O)2R Z1-1 ;

[0026] R Z1-1 Independently hydrogen, C1-C 12 Alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C1-C 12 Alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 aryl or 5-14 heteroaryl groups are optionally surrounded by one or more R groups. Z1-1-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0027] Alternatively, two R atoms on the same atom or two adjacent atoms Z1-1 Together with the atoms bonded to them, they form saturated or partially unsaturated C3-C atoms. 12 Carbon rings, or saturated or partially unsaturated 3-12 membered heterocycles; wherein the C3-C 12 The carbon ring or 3-12 membered heterocycle is optionally separated by one or more R Z1-1-1 The 3-12 membered heterocycles are replaced by heteroatoms selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0028] R Z1-1-1 Independently halogenated, -(CH2) 0-4 R Z1-1-1-1 -(CH2) 0-4 OR Z1-1-1-1 -O(CH2) 0-4 R Z1-1-1-1 -O(CH2) 0-4 -C(=O)OR Z1-1-1-1 -(CH2) 0- 4CH(OR Z1-1-1-1 2、-(CH2) 0-4 SR Z1-1-1-1 -(CH2) 0-4 Ph、-(CH2) 0-4 O(CH2) 0-1 Ph、-(CH2) 0-4 Py, -(CH2) 0-4 O(CH2) 0-1 Py, -CH CHPh, nitro, cyano, azide, -(CH2) 0-4 N(R Z1-1-1-1 2、-(CH2) 0-4 N(R Z1-1-1-1 )C(=O)R Z1-1-1-1 -N(R) Z1-1-1-1 )C(=S)R Z1-1-1-1 -(CH2) 0-4 N(R Z1- 1-1-1 )C(=O)N(R Z1-1-1-1 )2、-N(R Z1-1-1-1 )C(=S)N(R Z1-1-1-1 2、-(CH2) 0-4 N(R Z1-1-1-1 )C(=O)OR Z1-1-1-1 -N(R) Z1-1-1-1 )N(R Z1-1-1-1 )C(=O)R Z1- 1-1-1、-N(R Z1-1-1-1 )N(R Z1-1-1-1 )C(=O)N(R Z1-1-1-1 )2、-N(R Z1-1-1-1 )N(R Z1-1-1-1 )C(=O)OR Z1-1-1-1 、-(CH2) 0-4 C(=O)R Z1-1-1-1 、-C(=S)R Z1-1- 1-1 、-(CH2) 0-4 -C(=O)OR Z1-1-1-1 、-(CH2) 0-4 -C(=O)SR Z1-1-1-1 、-(CH2) 0-4 -C(=O)OSi(R Z1-1-1-1 )3、-(CH2) 0-4 OC(=O)R Z1-1-1-1 、-OC(=O)(CH2) 0-4 SR Z1-1-1-1 、-(CH2) 0-4 SC(=O)R Z1-1-1-1 、-(CH2) 0-4 C(=O)N(R Z1-1-1-1 )2、-C(=S)N(R Z1-1-1-1 )2、-C(=S)SR Z1-1-1-1 、-SC(=S)SR Z1-1-1-1 、-(CH2) 0-4 OC(=O)N(R Z1-1-1-1 )2、-C(=O)N(OR Z1-1-1-1 )R Z1-1-1-1 、-C(=O)C(=O)R Z1-1-1-1 、-C(=O)CH2C(=O)R Z1-1-1- 1 、-C(=NOR Z1-1-1-1 )R Z1-1-1-1 、-(CH2) 0-4 SSR Z1-1-1-1 、-(CH2) 0-4 S(=O)2R Z1-1-1-1 、-(CH2) 0-4 S(=O)2OR Z1-1-1-1 、-(CH2) 0-4 OS(=O)2OR Z1- 1-1-1 、-S(=O)2N(R Z1-1-1-1 )2、-(CH2) 0-4 S(=O)R Z1-1-1-1 、-N(R Z1-1-1-1)S(=O)2N(R Z1-1-1-1 )2、-N(R Z1-1-1-1 )S(=O)2R Z1-1-1-1 -N(OR) Z1-1-1- 1 )R Z1-1-1-1 -C(=NH)N(R) Z1-1-1-1 2、-(CH2) 0-4 P(=O)(R Z1-1-1-1 2、-(CH2) 0-4 OP(=O)(R Z1-1-1-1 2、-(CH2) 0-4 OP(=O)(OR Z1-1-1-1 )2、-Si(R Z1- 1-1-1 3、-(CH CH) 0-4 ON(R Z1-1-1-1 )2、-(CH CH) 0-4 C(=O)ON(R Z1-1-1-1 )2、=O、=S、=NR Z1-1-1-1 =NN(R) Z1-1-1-1 )2、=NNHC(=O)R Z1- 1-1-1 =NNHC(=O)OR Z1-1-1-1 =NNHS(=O)2R Z1-1-1-1 =NR Z1-1-1-1 or = NOR Z1-1-1-1 ;

[0029] R Z1-1-1-1 Independently -(CH2) 0-2 R Z1-1-1-1-1 -(CH2) 0-2 OH, -(CH2) 0-2 OR Z1-1-1-1-1 -(CH2) 0-2 CH(OR Z1-1-1-1-1 2. Cyano, azide, nitro, -(CH2) 0-2 C(=O)R Z1-1-1-1-1 -(CH2) 0-2 C(=O)OH, -(CH2) 0-2 C(=O)OR Z1-1-1-1-1 -(CH2) 0-2 SR Z1-1-1-1-1 -(CH2) 0-2 SH, -(CH2) 0-2 NH2、-(CH2) 0-2 NHR Z1-1-1-1-1 -(CH2) 0-2 N(R Z1-1-1-1-1)2、-Si(R Z1-1-1-1-1 3. -C(=O)SR Z1-1-1-1-1 -(CH=CH) 0-4 C(=O)OR Z1-1-1-1-1 or -SSR Z1-1- 1-1-1 ;

[0030] R Z1-1-1-1-1 Independently hydrogen, halogen, benzyl, C1-C6 alkyl, -O(CH2) 0-2 Ph, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl; wherein the heteroatom in the 3-6 membered heterocyclic alkyl is selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2 or 3;

[0031] R A-1-1-1 Independently -(CH2) 0-2 R A-1-1-1-1 -(CH2) 0-2 OH, -(CH2) 0-2 OR A-1-1-1-1 -(CH2) 0-2 CH(OR A-1-1-1-1 2. Cyano, azide, nitro, -(CH2) 0-2 C(=O)R A-1-1-1-1 -(CH2) 0-2 C(=O)OH, -(CH2) 0-2 C(=O)OR A-1-1-1-1 -(CH2) 0-2 SR A-1-1-1-1 -(CH2) 0-2 SH, -(CH2) 0-2 NH2、-(CH2) 0- 2NHR A-1-1-1-1 -(CH2) 0-2 N(R A-1-1-1-1 )2、-Si(R A-1-1-1-1 3. -C(=O)SR A-1-1-1-1 -(CH=CH) 0-4 C(=O)OR A-1-1-1-1 or -SSR A-1-1-1-1 ;

[0032] R A-1-1-1-1 Independently hydrogen, halogen, benzyl, C1-C6 alkyl, -O(CH2) 0-2 Ph, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl; wherein the heteroatom in the 3-6 membered heterocyclic alkyl is selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2 or 3;

[0033] Ring A is a saturated or partially unsaturated C3-C ring. 20 Carbon rings, saturated or partially unsaturated 3-20 membered heterocycles, C6-C 20 Aromatic rings or 5-20 membered heteroaromatic rings; in the 3-20 membered heterocycles, the heteroatom is selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5; in the 5-20 membered heteroaromatic rings, the heteroatom is selected from one or more of N, O, S and Se, and the number of heteroatoms is 1, 2, 3, 4 or 5; the C6-C 20 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-20 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; in the 3-20 membered heterocycle, 0, 1, or more -CH2- groups on the ring are independently replaced by the following groups: -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A-1 )-、-Si(=NR A- 1 )-、 -P(=O)R A-1 -、 -NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -、-NR A-1 OC(=O)-, -CHF-, -CF2-, -S(=O)(=NR A-1 )-or

[0034] m can be 0, 1, 2, 3, 4, or 5;

[0035] Y is hydrogen, halogen, or...

[0036] q can be 0, 1, 2, 3, 4, or 5;

[0037] Ring Z is independently saturated or partially unsaturated C3-C 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 14Aromatic rings or 5-14 membered heteroaromatic rings; in the 3-12 membered heterocycles, the heteroatom is selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5; in the 5-14 membered heteroaromatic rings, the heteroatom is selected from one or more of N, O, S and Se, and the number of heteroatoms is 1, 2, 3, 4 or 5; the C6-C 14 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; in the 3-12 membered heterocycle, 0, 1, or more -CH2- groups on the ring are independently replaced by the following groups: -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A-1 )-、-Si(=NR A-1 )-、 -P(=O)R A-1 -、 -NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -、-NR A-1 OC(=O)-, -CHF-, -CF2-, -S(=O)(=NR A-1 )-or

[0038] R A and R Z Each independently as R A-2 R A-1 Oxygenation (=O), =NR A-1 =S, hydrogen, halogen, cyano, nitro, -OR A-1 -SR A-1 -N(R) A-1 )2、-Si(R A-1 )3\-S(=O)R A-1 -S(=O)2R A-1 -S(=O)(=NR) A-1 )R A-1 -S(=NR) A-1 )2R A-1 -S(=O)2N(R) A-1 )2、-C(=O)R A-1 -C(=O)OR A-1 -C(=O)N(R)A-1 )2、-C(=O)N(R A-1 OR A-1 -OC(=O)R A-1 -OC(=O)N(R) A-1 )2、-P(=O)(R A-1 )2、-P(=O)(OR A-1 )2、-OP(=O)(R A-1 )2、-OP(=O)(OR A-1 )2、-NR A-1 C(=NR A-1 OR A-1 -NR A-1 C(=NR A-1 )R A-1 -NR A-1 C(=NR A-1 )N(R A-1 )2、-NR A-1 C(=NOR A-1 )N(R A-1 )2、-NR A-1 C(=NR A-1 )NH(OR A-1 -NR A-1 C(=O)OR A-1 -NR A-1 C(=O)R A-1 -NR A-1 C(=O)N(R A-1 )2 or -NR A-1 S(=O)2R A-1 ;

[0039] L A It is a C1-C5 alkylene group, wherein 0, 1, or more methylene groups are independently replaced by the following groups: -Cy X -, -O-, -C(=O)-, -C(=S)-, -C(=NR A- 1 -, -CF2-, -CR A-1 F-、-CR A-1 R A-1 -、-CR A-1 (OR A-1 )-、-NR A-1 -, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR A-1 )-、-CR A-1 =CR A-1 -or

[0040] CyX Independently for C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene or 5-14 quinone heteroarylene; wherein the C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene, 5-14 arylene heteroarylene, optionally enclosed by one or more R Z The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 member heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0041] L a For C1-C 15 Alkylene, wherein 0, 1, or more methylene groups are independently replaced with -NR B -、-O-、-S-、 -CR B CR B -、 Saturated or partially unsaturated C3-C 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings; wherein the C1-C 15 Alkylene, C3-C 12 Carbon rings, 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings are optionally surrounded by one or more R B The substituted 3-12 membered heterocycles have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5. The 5-14 membered heteroaromatic rings have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5. The C6-C 14The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0042] L b For covalent bonds, -O-, -S-, or -NL 11 -;

[0043] L 11 H, C1-C6 alkyl, C3-C 16 Cycloalkyl, 3-16 membered heterocycloalkyl, C3-C 16 Cycloalkenyl, 3-16 membered heterocyclic alkenyl, phenyl or 6 membered heteroaryl, wherein the C1-C6 alkyl, C3-C 16 Cycloalkyl, 3-16 membered heterocycloalkyl, C3-C 16 Cycloalkenyl, 3-16-membered heterocyclic alkenyl, phenyl or 6-membered heteroaryl, optionally separated by one or more R A-1 The substituted 3-16-membered heterocyclic alkyl or 3-16-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5; the 6-membered heteroaryl group has heteroatoms selected from one or more of N, O, S and Se, and the number of heteroatoms is 1, 2 or 3.

[0044] L X Covalent bond or C1-C 20 Alkylene, the C1-C 20 In the alkylene group, 0, 1, or more methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -NR. A-1 -、-C(R A-1 )2-、-CR A-1 =CR A-1 -、 -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A-1 )-、-Si(=NR A-1 )-、 -P(=O)R A-1 -、 -NR A-1 C(=O)-、-C(=O)NR A- 1 -、-OC(=O)NR A-1 -、-NR A-1OC(=O)-, -CHF-, -CF2-, -S(=O)(=NR A-1 )-、 M can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 independently;

[0045] With L X Connect any point on the [structure / structure];

[0046] L X When it is a covalent bond, -L a -L b - Connect to any point on ring X;

[0047] Or L X Independently for -L X1 -L X2 -L X3 -L X4 -;

[0048] L X1 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 -、 -NR A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -or-NR A-1 OC(=O)-;

[0049] L X2 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 -、 -NR A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NRA-1 -、-NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -or-NR A-1 OC(=O)-;

[0050] L X3 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 -、 -NR A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -or-NR A-1 OC(=O)-;

[0051] L X4 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 -、 -NR A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -or-NR A-1 OC(=O)-;

[0052] Cy is independently saturated or partially unsaturated C3-C 14 Carbon rings, saturated or partially unsaturated 3-14 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings; wherein the C3-C 14 Carbon rings, 3-14 membered heterocycles, C6-C14 Aromatic rings or 5-14 membered heteroaryl rings are optionally surrounded by one or more R Z The substituted 3-14 membered heterocycles are selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14 membered heteroaromatic rings are selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, or 3; the C6-C 14 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0053] for

[0054] X 5 and X 6 Independently covalent bond, -C(R) A-3 )2-, -SO2-, -S(=O)-, -P(=O)R A-3 -、-P(=O)OR A-3 -、-P(=O)N(R A-3 -, -C(=O)- or -C(=S)-;

[0055] X 2 For N, CR 2-1 Si-R 2-1 Or P = O;

[0056] It can be a single bond or a double bond;

[0057] when When it is a single bond, X 3 and X 4 Independently covalent bond, -C(R) A-3 -2-, -CF2-, -O-, or -S-; X 3 When it is a covalent bond, X 2 and X 4 Directly connected; X 4 When it is a covalent bond, X 3 and X 5 Directly connected; X 3 and X 4 When all are covalent bonds, X 2 and X 5 Directly connected;

[0058] when When it is a double bond, For -CR A-3 CRA-3 -;

[0059] R A-3 Independently hydrogen, C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 aryl or 5-14 heteroaryl groups are optionally surrounded by one or more R groups. A-1-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0060] Alternatively, two R atoms on the same atom or two adjacent atoms A-3 Together with the atoms bonded to them, they form saturated or partially unsaturated C3-C atoms. 12 Carbon rings, or saturated or partially unsaturated 3-12 membered heterocycles; wherein the C3-C 12 The carbon ring or 3-12 membered heterocycle is optionally separated by one or more R A-1-1 The 3-12 membered heterocycles are replaced by heteroatoms selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0061] R 2-1 Independently hydrogen, -OR A-1 -SR A-1 -S(=O)R A-1 -SO2R A-1 -N(R) A-1 2. Or optionally by one or more R A-1-1 Replacement C1-C 12 alkyl:

[0062] Or R2-1 and R A-3 Together with the atoms bonded to them, they form saturated or partially unsaturated C3-C atoms. 12 Carbon rings, or saturated or partially unsaturated 3-12 membered heterocycles; wherein the C3-C 12 The carbon ring or 3-12 membered heterocycle is optionally separated by one or more R A-1-1 The 3-12 membered heterocycles are replaced by heteroatoms selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0063] Ring E3 is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the heteroatom in the 5-6 membered heteroaromatic ring is selected from one or more of N, O, S and Se, and the number of heteroatoms is 1, 2 or 3;

[0064] Cycle E4 is a C4-C7 cycloene or a 4-7 membered heterocyclic alkene, wherein the heteroatom in the 4-7 membered heterocyclic alkene is selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3 or 4.

[0065] n1 is 1, 2, 3, or 4; R 3 Substituents on ring E3 or ring E4;

[0066] R 3 It can be hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 alkyl substituted with one or more halogens, or C1-C6 alkoxy substituted with one or more halogens.

[0067] In certain preferred embodiments of the present invention, certain groups of the compound represented by formula (I), its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention").

[0068] In one aspect of the present invention,

[0069] Indicates a single bond or a double bond;

[0070] Ring B is a saturated or partially unsaturated C3-C ring. 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaromatic rings; in the 3-12 membered heterocycles, the heteroatom is selected from one or more of N, O, S, Si, and P, and the number of heteroatoms is 1, 2, 3, 4, or 5; in the 5-14 membered heteroaromatic rings, the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0071] n is 0, 1, 2, 3, 4 or 5;

[0072] R B Independently for R A-2 R B-1 Hydrogen, halogen, cyano, nitro, oxo (=O), =NR A-1 =S, -OR A-1 -SR A-1 -N(R) A-1 )2、-Si(R A-1 3. -S(=O)R A-1 -S(=O)2R A-1 -S(=O)(=NR) A-1 )R A-1 -S(=O)2N(R) A-1 )2、-C(=O)R A-1 -C(=O)OR A-1 -C(=O)N(R) A-1 )2、-C(=O)N(R A- 1 OR A-1 -OC(=O)R A-1 -OC(=O)N(R) A-1 )2、-P(=O)(R A-1 )2、-P(=O)(OR A-1 )2、-OP(=O)(R A-1 )2、-OP(=O)(OR A-1 )2、-NR A-1 C(=O)OR A- 1 -NR A-1 C(=O)R A-1 -NR A-1 C(=O)N(R A-1 )2 or -NR A-1 S(=O)2R A-1 ;

[0073] R A-2 Independently for C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14Aryl or 5-14 heteroaryl; wherein the C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 aryl or 5-14 heteroaryl groups are optionally surrounded by one or more R groups. A-2-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0074] R B-1 -L B -Cy B1 -H or -L B -Cy B1 -Cy B2 -H;

[0075] L B Independently C1-C3 alkylene groups, wherein 0, 1, 2 or 3 methylene groups are independently replaced by the following groups: -O-, -C(=O)-, -C(=S)-, -C(=NR)-. A-1 -, -CF2-, -CR A-1 F-、-CR A-1 R A-1 -、-CR A-1 (OR A-1 )-、-NR A-1 -, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR A-1 )-、-CR A- 1 CR A-1 -or

[0076] R A-1 Independently hydrogen, C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C1-C12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 aryl or 5-14 heteroaryl groups are optionally surrounded by one or more R groups. A-1-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0077] Alternatively, two R atoms on the same atom or two adjacent atoms A-1 Together with the atoms bonded to them, they form saturated or partially unsaturated C3-C atoms. 12 Carbon rings, or saturated or partially unsaturated 3-12 membered heterocycles; wherein the C3-C 12 The carbon ring or 3-12 membered heterocycle is optionally separated by one or more R A-1-1 The 3-12 membered heterocycles are replaced by heteroatoms selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5.

[0078] R A-1-1 and R A-2-1 Each is independently a halogen, -(CH2) 0-4 R A-1-1-1 -(CH2) 0-4 OR A-1-1-1 -O(CH2) 0-4 R A-1-1-1 -O(CH2) 0-4 -C(=O)OR A-1-1-1 -(CH2) 0-4 CH(OR A-1-1-1 2、-(CH2) 0-4 SR A-1-1-1 -(CH2) 0-4 Ph、-(CH2) 0-4 O(CH2) 0-1 Ph、-(CH2) 0-4 Py, -(CH2) 0-4 O(CH2) 0-1Py, -CH CHPh, nitro, cyano, azido, -(CH2) 0-4 N(R A-1-1-1 )2, -(CH2) 0-4 N(R A-1-1-1 )C(=O)R A-1-1-1 , -N(R A-1-1-1 )C(=S)R A-1-1-1 , -(CH2) 0-4 N(R A-1-1- 1 )C(=O)N(R A-1-1-1 )2, -N(R A-1-1-1 )C(=S)N(R A-1-1-1 )2, -(CH2) 0-4 N(R A-1-1-1 )C(=O)OR A-1-1-1 , -N(R A-1-1-1 )N(R A-1-1-1 )C(=O)R A-1-1-1 , -N(R A-1-1-1 )N(R A-1-1-1 )C(=O)N(R A-1-1-1 )2, -N(R A-1-1-1 )N(R A-1-1-1 )C(=O)OR A-1-1-1 , -(CH2) 0-4 C(=O)R A-1-1-1 , -C(=S)R A-1-1-1 , -(CH2) 0- 4-C(=O)OR A-1-1-1 , -(CH2) 0-4 -C(=O)SR A-1-1-1 , -(CH2) 0-4 -C(=O)OSi(R A-1-1-1 )3, -(CH2) 0-4 OC(=O)R A-1-1-1 , -OC(=O)(CH2) 0-4 SR A-1- 1-1 , -(CH2) 0-4 SC(=O)R A-1-1-1 , -(CH2) 0-4 C(=O)N(R A-1-1-1 )2, -C(=S)N(R A-1-1-1 )2, -C(=S)SR A-1-1-1 , -SC(=S)SR A-1-1-1 , -(CH2) 0- 4OC(=O)N(R A-1-1-1 )2, -C(=O)N(OR A-1-1-1)R A-1-1-1 , -C(=O)C(=O)R A-1-1-1 , -C(=O)CH2C(=O)R A-1-1-1 , -C(=NOR A-1-1-1 )R A-1-1-1 , -(CH2) 0-4 SSR A-1-1-1 , -(CH2) 0-4 S(=O)2R A-1-1-1 , -(CH2) 0-4 S(=O)2OR A-1-1-1 , -(CH2) 0-4 OS(=O)2OR A-1-1-1 , -S(=O)2N(R A-1-1-1 )2, -(CH2) 0- 4S(=O)R A-1-1-1 , -N(R A-1-1-1 )S(=O)2N(R A-1-1-1 )2, -N(R A-1-1-1 )S(=O)2R A-1-1-1 , -N(OR A-1-1-1 )R A-1-1-1 , -C(=NH)N(R A-1-1-1 )2, -(CH2) 0- 4P(=O)(R A-1-1-1 )2, -(CH2) 0-4 OP(=O)(R A-1-1-1 )2, -(CH2) 0-4 OP(=O)(OR A-1-1-1 )2, -Si(R A-1-1-1 )3, -(CH=CH) 0-4 O-N(R A-1-1-1 )2, -(CH CH) 0-4 C(=O)O-N(R A-1-1-1 )2, =O, =S, =NR A-1-1-1 , =NN(R A-1-1-1 )2, =NNHC(=O)R A-1-1-1 , =NNHC(=O)OR A-1-1-1 , =NNHS(=O)2R A-1-1-1 , =NR A-1-1-1 or =NOR A-1-1-1 ;

[0079] R A-1-1-1 independently represents -(CH2) 0-2 R A-1-1-1-1 , -(CH2) 0-2 OH, -(CH2) 0-2 OR A-1-1-1-1-(CH2) 0-2 CH(OR A-1-1-1-1 2. Cyano, azide, nitro, -(CH2) 0-2 C(=O)R A-1-1-1-1 -(CH2) 0-2 C(=O)OH, -(CH2) 0-2 C(=O)OR A-1-1-1-1 -(CH2) 0-2 SR A-1-1-1-1 -(CH2) 0-2 SH, -(CH2) 0-2 NH2、-(CH2) 0- 2NHR A-1-1-1-1 -(CH2) 0-2 N(R A-1-1-1-1 )2、-Si(R A-1-1-1-1 3. -C(=O)SR A-1-1-1-1 -(CH CH) 0-4 C(=O)OR A-1-1-1-1 or -SSR A-1-1-1-1 ;

[0080] R A-1-1-1-1 Independently, it can be a hydrogen atom, halogen, benzyl, C1-C4 alkyl, or -O(CH2). 0-2 Ph, C5-C6 cycloalkyl or 5-6 membered heterocyclic alkyl;

[0081] Cy B1 and Cy B2 Each independently constitutes C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene or 5-14 quinone heteroarylene; wherein the C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene or 5-14 heteroarylene, optionally enclosed by one or more R A-1-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 member heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0082] Ring A is a saturated or partially unsaturated C3-C ring. 14 Carbon rings, saturated or partially unsaturated 3-14 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaromatic rings; in the 3-14 membered heterocycles, the heteroatom is selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5; in the 5-14 membered heteroaromatic rings, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3, 4 or 5; the C6-C 14 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; in the 3-12 membered heterocycle, 0, 1, or more -CH2- groups on the ring are independently replaced by the following groups: -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A-1 )-、-Si(=NR A-1 )-、 -P(=O)R A-1 -、 -NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -、-NR A-1 OC(=O)-, -CHF-, -CF2-, -S(=O)(=NR A-1 )-or

[0083] m can be 0, 1, 2, 3, 4, or 5;

[0084] Y is hydrogen, halogen, or...

[0085] q can be 0, 1, 2, 3, 4, or 5;

[0086] Ring Z is independently saturated or partially unsaturated C3-C 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 14Aromatic rings or 5-14 membered heteroaromatic rings; in the 3-12 membered heterocycles, the heteroatom is selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5; in the 5-14 membered heteroaromatic rings, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3, 4 or 5; the C6-C 14 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; in the 3-12 membered heterocycle, 0, 1, or more -CH2- groups on the ring are independently replaced by the following groups: -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A-1 )-、-Si(=NR A- 1 )-、 -P(=O)R A-1 -、 -NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -、-NR A-1 OC(=O)-, -CHF-, -CF2-, -S(=O)(=NR A-1 )-or

[0087] R A and R Z Each independently as R A-2 R A-1 Oxygenation (=O), =NR A-1 =S, hydrogen, halogen, cyano, nitro, -OR A-1 -SR A-1 -N(R) A-1 )2、-Si(R A-1 3. -S(=O)R A-1 -S(=O)2R A-1 -S(=O)(=NR) A-1 )R A-1 -S(=O)2N(R) A-1 )2、-C(=O)R A-1 -C(=O)OR A-1 -C(=O)N(R) A-1 )2、-C(=O)N(RA-1 OR A-1 -OC(=O)R A-1 -OC(=O)N(R) A-1 )2、-P(=O)(R A-1 )2、-P(=O)(OR A-1 )2、-OP(=O)(R A-1 )2、-OP(=O)(OR A-1 )2、-NR A-1 C(=O)OR A-1 -NR A-1 C(=O)R A-1 -NR A-1 C(=O)N(R A-1 )2 or -NR A-1 S(=O)2R A-1 ;

[0088] L A It is a C1-C5 alkylene group, wherein 0, 1, or more methylene groups are independently replaced by the following groups: -Cy X -, -O-, -C(=O)-, -C(=S)-, -C(=NR A- 1 -, -CF2-, -CR A-1 F-、-CR A-1 R A-1 -、-CR A-1 (OR A-1 )-、-NR A-1 -, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR A-1 )-、-CR A-1 =CR A-1 -or

[0089] Cy X Independently for C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene or 5-14 quinone heteroarylene; wherein the C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene, 5-14 arylene heteroarylene, optionally enclosed by one or more R ZThe substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 member heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0090] L a For C1-C 15 Alkylene, wherein 0, 1, or more methylene groups are independently replaced with -NR B -、-O-、-S-、 -CR B =CR B -、 Saturated or partially unsaturated C3-C 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings; wherein the C1-C 15 Alkylene, C3-C 12 Carbon rings, 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings are optionally surrounded by one or more R B The substituted 3-12 membered heterocycles have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5. The 5-14 membered heteroaromatic rings have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5. The C6-C 14 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0091] L b For covalent bonds, -O-, -S-, or -NL 11 -;

[0092] L 11 H or C1-C6 alkyl, C3-C 16 Cycloalkyl, 3-16 membered heterocycloalkyl, C3-C 16Cycloalkenyl, 3-16 membered heterocyclic alkenyl, phenyl or 6 membered heteroaryl, wherein the C1-C6 alkyl, C3-C 16 Cycloalkyl, 3-16 membered heterocycloalkyl, C3-C 16 Cycloalkenyl, 3-16-membered heterocyclic alkenyl, phenyl or 6-membered heteroaryl, optionally separated by one or more R A-1 The substituted 3-16-membered heterocyclic alkyl or 3-16-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5; the 6-membered heteroaryl group has heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3.

[0093] L X Covalent bond or C1-C 20 Alkylene, the C1-C 20 In the alkylene group, 0, 1, or more methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -NR. A-1 -、-C(R A-1 )2-、-CR A-1 CR A-1 -、 -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A-1 )-、-Si(=NR A-1 )-、 -P(=O)R A-1 -、 -NR A-1 C(=O)-、-C(=O)NR A- 1 -、-OC(=O)NR A-1 -、-NR A-1 OC(=O)-, -CHF-, -CF2-, -S(=O)(=NR A-1 )-、

[0094] With L X Connect any point on the [structure / structure];

[0095] L X When it is a covalent bond, -L a -L b - Connect to any point on ring X;

[0096] M can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 independently;

[0097] Or L X Independently for -L X1 -L X2 -L X3 -L X4 -;

[0098] L X1 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 -、 -NR A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -or-NR A-1 OC(=O)-;

[0099] L X2 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 -、 -NR A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -or-NR A-1 OC(=O)-;

[0100] L X3 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1)2-、-CR A-1 =CR A-1 -、 -NR A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -or-NR A-1 OC(=O)-;

[0101] L X4 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 -、 -NR A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -or-NR A-1 OC(=O)-;

[0102] Cy is independently saturated or partially unsaturated C3-C 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings; wherein the C3-C 12 Carbon rings, 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings are optionally surrounded by one or more R Z The substituted 3-12 membered heterocycles are selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14 membered heteroaromatic rings are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; the C6-C 14The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0103] for

[0104] X 2 It can be CH or N.

[0105] In one aspect of the present invention, ring B is a 5-14 membered heteroaromatic ring, for example, a 9-10 membered heteroaromatic ring with N heteroatom and one or two heteroatoms, wherein at least one ring of the 9-10 membered heteroaromatic ring is aromatic or each ring is aromatic.

[0106] In one aspect of the present invention, for Ring B1 is a 5-membered heteroaromatic ring or 5-membered heterocyclic alkene with N as the heteroatom and either one or two heteroatoms. For example, ring B1 is a 5-membered heteroaromatic ring with N as the heteroatom and either one heteroatom. The end marked with "#" is connected to ring A, and the end marked with "#1" is connected to ring L. X Connected.

[0107] In one aspect of the present invention, for The end marked with "#" is connected to ring A, and the end marked with "#1" is connected to L. X Connected.

[0108] In one embodiment of the present invention, n is 0, 1, or 2; for example, it is 1 or 2.

[0109] In one aspect of the present invention, R B Independently halogenated or -C(=O)N(R) A-1 )2, R A-1 It is hydrogen or C1-C6 alkyl.

[0110] In one aspect of the present invention, R B It can be F or -C(=O)N(CH3)2 independently.

[0111] In one aspect of the present invention, for The end marked with "#" is connected to ring A, and the end marked with "#1" is connected to L. X Connected.

[0112] In one aspect of the present invention, for The end marked with "#" is connected to ring A, and the end marked with "#1" is connected to L. X Connected.

[0113] In one embodiment of the present invention, ring A is a saturated or partially unsaturated 3-10 membered heterocycle, for example, a saturated or partially unsaturated 5-6 membered heterocycle with N heteroatoms and one or two heteroatoms.

[0114] In one aspect of the present invention, for In this ring, ring A is a 5-6 membered heterocycle with N heteroatoms, consisting of one or two N heteroatoms, and is either saturated or partially unsaturated. The end marked "#2" is connected to the L ring. A Connected, the end marked "#3" is connected to L a Connected, the end marked "#4" is connected to ring B.

[0115] In one aspect of the present invention, for For example, Among them, the end marked "#2" is connected to L. A Connected, the end marked "#3" is connected to L a Connected, the end marked "#4" is connected to ring B, and the carbon atom marked "*" has an R configuration, S configuration, or a mixture thereof. For example, For example, For example, For example, For example, For example, For example, For example,

[0116] In one aspect of the present invention, for Among them, the end marked "#2" is connected to L. A Connected, the end marked "#3" is connected to L aConnected, the end marked "#4" is connected to ring B, and the carbon atom marked "*" has an R configuration, S configuration, or a mixture thereof. For example, For example,

[0117] In one aspect of the present invention, for Among them, the end marked "#2" is connected to L. A Connected, the end marked "#3" is connected to L a Connected, the end marked "#4" is connected to ring B, and the carbon atom marked "*" has an R configuration, an S configuration, or a mixture thereof; For example,

[0118] In one aspect of the present invention, R A It is hydrogen.

[0119] In one embodiment of the present invention, m is 0 or 1.

[0120] In one aspect of the present invention, L A It is a C1-C6 alkylene (e.g., a C1-C6 straight-chain alkylene), wherein 0, 1 or more methylene groups are independently replaced by -C(=O)-.

[0121] In one aspect of the present invention, L A for Among them, L A-1 For connecting bonds or C1-C5 alkylene groups (e.g., C1-C5 straight-chain alkylene groups), the end marked "#5" is connected to ring A.

[0122] In one aspect of the present invention, L A for For example, The end marked "#5" is connected to ring A.

[0123] In one embodiment of the present invention, Y is hydrogen or... For example,

[0124] In one aspect of the present invention, ring Z is a 5-14 membered heteroaromatic ring, for example, a 5-6 membered monocyclic heteroaromatic ring with N heteroatom and 1, 2 or 3 heteroatoms.

[0125] In one aspect of the present invention, for

[0126] In one aspect of the present invention, RZ It is hydrogen.

[0127] In one embodiment of the present invention, q is 0 or 1.

[0128] In one aspect of the present invention, L a For C1-C 10 Alkylene (e.g., C1-C) 10 (linear alkylene), wherein 0, 1, 2 or 3 methylene groups are independently replaced by NR. B -、-O-、-S-、-CR B =CR B -or

[0129] In one aspect of the present invention, L a It is a C3-C6 alkylene (e.g., a C3-C6 straight-chain alkylene), wherein 0 or 1 methylene groups are replaced by -CR B =CR B -; Preferably, R B For H.

[0130] In one aspect of the present invention, L a It is a C4-C6 alkylene (e.g., a C4-C6 straight-chain alkylene), wherein one methylene group is replaced by -CR. B =CR B -; Preferably, R B For H.

[0131] In one aspect of the present invention, L a for Among them, the end marked "#6" is connected to L. b Connected, It is a double bond, which is either Z-configuration or E-configuration, such as E-configuration.

[0132] In one aspect of the present invention, L a for Among them, the end marked "#6" is connected to L. b Connected, It is a double bond, which is either Z-configuration or E-configuration, such as E-configuration.

[0133] In one aspect of the present invention, L a for Among them, the end marked "#6" is connected to L. b Connected, It is a double bond, which is either Z-configuration or E-configuration, such as E-configuration.

[0134] In one aspect of the present invention, L a for Among them, the end marked "#6" is connected to L. b Connected, It is a double bond, which has a Z configuration or an E configuration.

[0135] In one aspect of the present invention, L b It is O.

[0136] In one aspect of the present invention, B -L X - X For C1-C 20 Alkylene (e.g., C1-C) 20 (linear alkylene), the C1-C 20 In the alkylene group, 0, 1, 2, 3, 4, 5, 6, 7, or 8 methylene groups are independently replaced by the following groups: -Cy-, C(=O)-, -C(=S)-, -CR A-1 2-, -CF2-, -NR A-1 -、-O-、-S- or -S(=O)2-, the end marked "B" is connected to ring B, and the end marked "X" is connected to ring X.

[0137] In one aspect of the present invention, B -L X - X for The end marked "B" is connected to ring B; the end marked "X" is connected to ring X. With L X The ring C is connected in the middle, and the compound shown in formula (I) is the same as the compound shown in formula (I-1):

[0138] in,

[0139] Ring C is C6-C 10 An aromatic ring or a 5-10 membered heteroaromatic ring, wherein the heteroatom in the 5-10 membered heteroaromatic ring is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 10 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-10 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0140] R C It is H or halogen;

[0141] p is 0, 1, 2, 3, 4 or 5;

[0142] LX5 Covalent bond or C1-C 15 Alkylene, the C1-C 15 In the alkylene group, 0, 1, or more methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -NR A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A-1 )-、-Si(=NR A-1 )-、-P(=O)OR A-1 -、-P(=O)R A-1 -、-P(=O)N(R A-1 )2-、-NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A- 1 -、-NR A-1 OC(=O)-, -CHF-, -CF2-, -S(=O)(=NR A-1 )-、

[0143] M is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0144] Cy is independently saturated or partially unsaturated C3-C 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 10 Aromatic rings or 5-10 quinone heteroaryl rings; wherein the C3-C 12 Carbon rings, 3-12 membered heterocycles, C6-C 10 Aromatic rings or 5-10-membered heteroaryl rings are optionally surrounded by one or more R Z The substituted 3-12 membered heterocycles have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-10 membered heteroaromatic rings have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 10 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-10 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0145] Ring D is a saturated or partially unsaturated C3-C ring. 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 10 Aromatic rings or 5-10 quinone heteroaryl rings, wherein the C3-C 12 Carbon rings, 3-12 membered heterocycles, C6-C 10 Aromatic rings or 5-10-membered heteroaryl rings are optionally surrounded by one or more R Z The substituted 3-12 membered heterocycles have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-10 membered heteroaromatic rings have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 10 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-10 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic.

[0146] L D It is a covalently bonded or C1-C3 alkylene group, wherein in the C1-C3 alkylene group, 0, 1, 2, or 3 methylene groups are independently replaced by the following groups: -C(=O)-, -C(=S)-, -CR2-, -CF2-, -NR. A-1 -、-O-、-S- or -S(=O)2-;

[0147] The definitions of the remaining variables are as described in any embodiment of this invention.

[0148] In one aspect of the present invention, L X5 Covalent bond or C1-C 15 Alkylene, the C1-C 15 In the alkylene group, 0, 1, or more methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -NR. A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A- 1 -、-C(=S)-、-C(=NR A-1 )-、-Si(=NR A-1 )-、-P(=O)OR A-1 -、-P(=O)R A-1 -、-P(=O)N(R A-1 )2-、-NR A-1 C(=O)-、-C(=O)NR A-1-、-OC(=O)NR A-1 -、-NR A-1 OC(=O)-, -CHF-, -CF2-, -S(=O)(=NR A-1 )-、

[0149] In one embodiment of the present invention, ring C is C6-C. 10 Aromatic rings, such as benzene rings.

[0150] In one aspect of the present invention, for The end marked "#8" is connected to ring B; the end marked "#9" is connected to L. b Connected; the end marked "#10" is connected to L. X5 Connected.

[0151] In one aspect of the present invention, R C It can be hydrogen or F.

[0152] In one embodiment of the present invention, p is 0 or 1.

[0153] In one aspect of the present invention, L X5 Independently C1-C6 alkylene (e.g., C1-C6 straight-chain alkylene), wherein one, two, or three methylene groups in the C1-C6 alkylene are independently prefixed with -Cy-, -C(=O)-, or Alternatively, Cy is a saturated 4-9 membered heterocycle, wherein the heteroatom is N, and the number of heteroatoms is 1 or 2.

[0154] In one aspect of the present invention, L X5 Independently C1-C6 alkylene (e.g., C1-C6 straight-chain alkylene), wherein one, two, or three methylene groups in the C1-C6 alkylene are independently replaced by -Cy- or C (=O), Cy is a saturated 5-6 membered heterocycle, wherein the heteroatom in the 5-6 membered heterocycle is N, and the number of heteroatoms is one or two.

[0155] In one aspect of the present invention, L X5 Independently C1-C6 alkylene (e.g., C1-C6 straight-chain alkylene), wherein one or two methylene groups in the C1-C6 alkylene are independently replaced by -Cy- or C (=O), Cy is a saturated 5-6 membered heterocycle, wherein the heteroatom in the 5-6 membered heterocycle is N, and the number of heteroatoms is one or two.

[0156] In one aspect of the present invention, L X5Independently C1-C6 alkylene (e.g., C1-C6 straight-chain alkylene), wherein one methylene group in the C1-C6 alkylene is independently replaced by -Cy-, where Cy is a saturated 5-6 membered heterocycle, and the heteroatom in the 5-6 membered heterocycle is N, and the number of heteroatoms is one or two.

[0157] In one aspect of the present invention, L X5 Independently C1-C4 alkylene (e.g., C1-C4 straight-chain alkylene), wherein one, two, or three methylene groups in the C1-C4 alkylene are independently replaced by -Cy- or C (=O), Cy is a saturated 4-6 member monocyclic heterocycle or a saturated 9 member spirocyclic heterocycle, wherein the heteroatom in the 4-6 member monocyclic heterocycle or the 9 member spirocyclic heterocycle is N, and the number of heteroatoms is one or two.

[0158] In one aspect of the present invention, L X5 for Among them, Cy1 is a saturated 5-6 membered heterocycle, L XA and L XB Independently covalently bonded or C1-C5 alkylene (e.g., C1-C5 straight-chain alkylene), wherein 0, 1, or 2 methylene groups in the C1-C5 alkylene are independently bounded by -Cy-, -C(=O)-, or The alternative is that Cy is a saturated 4-6 membered heterocycle, in which the heteroatom is N, and the number of heteroatoms is 1 or 2; the end marked "#11" is connected to ring D.

[0159] In one aspect of the present invention, L X5 for Among them, Cy1 is a saturated 4-6 member monocyclic heterocyclic ring or a saturated 9 member spirocyclic heterocyclic ring, L XA and L XB Independently covalently bonded or C1-C5 alkylene (e.g., C1-C5 straight-chain alkylene, further for example -CH2-, -CH2CH2- or -CH2CH2CH2-), wherein 0, 1 or 2 methylene groups in the C1-C5 alkylene are independently replaced by -Cy- or -C(=O)-, where Cy is a saturated 4-6 membered monocyclic heterocycle, wherein the heteroatom is N, and the number of heteroatoms is 1 or 2; the end marked "#11" is connected to ring D.

[0160] In one aspect of the present invention, L X5 for Among them, Cy1 is a saturated 5-6 membered heterocycle, L XAIt is a covalent bond or a C1-C5 alkylene (e.g., a C1-C5 straight-chain alkylene), wherein 0, 1, or 2 methylene groups in the C1-C5 alkylene are independently replaced by -Cy- or -C(=O)-, Cy is a saturated 4-6 membered heterocycle, wherein the heteroatom in the 4-6 membered heterocycle is N, and the number of heteroatoms is 1 or 2; the end marked "#11" is connected to ring D.

[0161] In one aspect of the present invention, L X5 for The end marked "#11" is connected to ring D.

[0162] In one aspect of the present invention, L X5 for The end marked "#11" is connected to ring D.

[0163] In one aspect of the present invention, L X5 for The end marked "#11" is connected to ring D.

[0164] In one embodiment of the present invention, ring D is C6-C. 10 Aromatic rings or 5-10 quinone heteroaryl rings, the C6-C 10 Aromatic rings or 5-10-membered heteroaryl rings are optionally surrounded by one or more R Z Replaced by, R Z It is oxo (=O), halogen, C1-C6 alkyl, or C1-C6 alkoxy; preferably, R Z It is an oxo (=O), halogen, or C1-C6 alkyl group.

[0165] In one aspect of the present invention, It is any of the following:

[0166] (1) Where R Z It is a C1-C6 alkyl group; r is 0, 1, or 2, and the ring E1 is a 5-6 membered heterocyclic alkene with N heteroatom and 1 or 2 heteroatoms; preferably, R Z It is a C1-C6 alkyl group, r is 1, and the ring E1 is a 5-6 membered heterocyclic alkene with N heteroatom and 2 heteroatoms;

[0167] (2) Where r is 0, 1, or 2, R Z It is a halogen, a C1-C6 alkyl or a C1-C6 alkoxy, preferably a halogen or a C1-C6 alkyl;

[0168] (3) Where R Z It is a C1-C6 alkyl group; r is 0, 1 or 2, and ring E2 is a 5-6 membered heteroaromatic ring with N heteroatom and 1 or 2 heteroatoms, wherein the 5-6 membered heteroaromatic ring is aromatic;

[0169] (4) Where R Z It is a C1-C6 alkyl group; r is 0, 1, or 2; and the ring E1 is a 5-6 membered heterocyclic alkene with N heteroatom and 1 or 2 heteroatoms; or

[0170] (5) Where R Z It is a C1-C6 alkyl group; r is 0, 1 or 2, and ring E2 is a 5-6 membered heteroaromatic ring with N heteroatom and 1 or 2 heteroatoms, wherein the 5-6 membered heteroaromatic ring is aromatic;

[0171] (6) Where r is 0, 1, or 2, R Z It is a halogen, a C1-C6 alkyl or a C1-C6 alkoxy;

[0172] Among them, the end marked "#12" is connected to L. D Connected.

[0173] In one aspect of the present invention, When it is case (1), case (3), case (4) or case (5), L D It is a covalent bond.

[0174] In one aspect of the present invention, When it is case (2) or case (6), L D It is a covalent bond or -NH-.

[0175] In one aspect of the present invention, for Among them, the end marked "#12" is connected to L. D Connected.

[0176] In one aspect of the present invention, for Among them, the end marked "#12" is connected to L. D Connected.

[0177] In one aspect of the present invention, for For example, Among them, the end marked "#12" is connected to L.D Connected.

[0178] In one aspect of the present invention, L D It is a covalent bond, -C(=O)-, -NH- or -C(=O)NH-; for example, it is a covalent bond or -NH-.

[0179] In one aspect of the present invention, for Among them, the end marked "#12" is connected to L. D Connected, L D It is a covalent bond.

[0180] In one aspect of the present invention, for Among them, the end marked "#12" is connected to L. D Connected, L D It is a covalent bond or -NH-.

[0181] In one aspect of the present invention, for For example,

[0182] In one aspect of the present invention, the compound represented by formula (I) is selected from any one of the following compounds:

[0183] In this case, the chiral carbon atoms marked "#1" and "2" are independently of the R configuration, S configuration, or a mixture of both; for example,

[0184] Among them, including In the structure, It is a carbon-carbon double bond, which is either Z-configuration or E-configuration, preferably E-configuration.

[0185] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0186] The present invention also provides the use of a compound of formula (I) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a STAT6 inhibitor or degrader.

[0187] The present invention also provides the use of a compound of formula (I) as described in any of the above embodiments, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of STAT6-mediated diseases, preferably, the STAT6-mediated diseases being cancer, inflammatory diseases, esophageal diseases, chronic obstructive pulmonary disease, Alzheimer's disease, or peripheral nervous system diseases; the inflammatory diseases may be atopic dermatitis, sinusitis, or asthma.

[0188] The present invention also provides the use of any of the above-described compounds as shown in formula (I), pharmaceutically acceptable salts thereof, solvates thereof, solvates of pharmaceutically acceptable salts thereof, or the above-described pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of cancer, inflammatory diseases, esophageal diseases, chronic obstructive pulmonary disease, Alzheimer's disease, or peripheral nervous system diseases; wherein the inflammatory disease may be atopic dermatitis, sinusitis, or asthma.

[0189] Terminology Explanation

[0190] In this invention, "partially unsaturated carbon ring" refers to a ring with a specified number of ring atoms (e.g., C3-C). 12 Or C3-C 10 The ring atom has only a ring structure composed of carbon atoms, which contains at least one double or triple bond, but is not completely unsaturated (i.e. does not satisfy the aromaticity condition).

[0191] In this invention, a "partially unsaturated heterocycle" refers to a cyclic group having a specified number of ring atoms (e.g., 3-12 or 3-10), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified type of heteroatom (1, 2, or 3 of N, O, S, P, and Si), containing at least one double or triple bond, but not completely unsaturated (i.e., not satisfying the aromaticity condition). In the partially unsaturated heterocycle, the number of heteroatoms depends on the number of ring atoms, and the number of heteroatoms is less than the number of ring atoms. For example, when the number of ring atoms in the heterocycle is 3, the number of heteroatoms is at most two. "Partially unsaturated heterocycles" include, but are not limited to: For example, wait.

[0192] In this invention, "saturated carbon ring" refers to a ring with a specified number of ring atoms (e.g., C3-C). 12 Or C3-C 10Ring atoms are composed only of carbon atoms in a ring structure. The carbon atoms are connected to each other by single bonds. There are no double bonds, triple bonds or other unsaturated bonds in the ring. Each carbon atom in the ring is connected to four atoms, which reaches the maximum number of bonds and has saturation.

[0193] In this invention, a "saturated heterocycle" refers to a cyclic group having a specified number of ring atoms (e.g., 3-12 or 3-10), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified type of heteroatom (1, 2, or 3 of N, O, S, P, and Si). All atoms within the ring are connected by single bonds, and there are no double or triple bonds or other unsaturated bonds, thus exhibiting saturation. In the saturated heterocycle, the number of heteroatoms depends on the number of ring atoms, and the number of heteroatoms must be less than the number of ring atoms. For example, when the number of ring atoms in the heterocycle is 3, the number of heteroatoms is at most two. "Saturated heterocycles" include, but are not limited to: etc.; for example, as For example, wait.

[0194] In this invention, In the case of Cy1 rings, when one end of the ring is connected to other parts of the molecule, unless its structure clearly indicates that one end is connected to other parts of the molecule via a nitrogen atom, and the other end is not specified via which atom, it means that it can be connected to other parts of the molecule via a carbon atom or other heteroatoms (such as nitrogen atoms). The same applies to other cases similar to Cy1.

[0195] In this invention, "aromatic ring" refers to a ring having a specified number of carbon atoms (e.g., C6-C). 10 An aromatic ring is an unsaturated ring, which is monocyclic or polycyclic (e.g., one or two). When polycyclic, the monocyclic rings share two atoms and one bond. In the "aromatic ring", at least one ring or each ring is aromatic. The aromatic ring is connected to the rest of the molecule through an aromatic or non-aromatic ring and satisfies any of the following conditions: (1) it is connected to the rest of the molecule through two or more single bonds; (2) it shares two atoms and one bond with the rest of the molecule. An "aromatic ring" includes, but is not limited to: wait.

[0196] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which fall within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0197] In this invention, a "heteroaromatic ring" refers to an unsaturated cyclic group having a specified number of ring atoms (e.g., 5-14, 5-10, or 5-6), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, with the monocyclic rings sharing two atoms and one bond. In the "heteroaromatic ring," at least one ring or each ring is aromatic. The heteroaromatic ring is connected to the rest of the molecule via carbon atoms or heteroatoms; the heteroaromatic ring is connected to the rest of the molecule via a ring with or without heteroatoms; the heteroaromatic ring is connected to the rest of the molecule via an aromatic ring or a non-aromatic ring, and it satisfies any of the following conditions: (1) it is connected to the rest of the molecule via two or more single bonds; (2) it shares two atoms and one bond with the rest of the molecule. In the heteroaromatic ring, the number of heteroatoms depends on the number of ring atoms, and the number of heteroatoms is less than the number of ring atoms. "Heteroaromatic rings" include, but are not limited to: wait.

[0198] In this invention, "halogen" refers to F, Cl, Br or I.

[0199] In this invention, "alkyl" refers to a straight-chain or branched chain composed of a specified carbon atom (e.g., C1-C1). 12 () forms a monovalent saturated hydrocarbon group. For example, C1-C 12 Includes C 1-10 C 1- 9. C 1-8 C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C 10C8, C7, C6, and C5 alkyl groups, etc. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, and t-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), hexyl, heptyl, octyl, etc.

[0200] In this invention, "cycloalkyl" refers to a ring with a specified number of carbon atoms (e.g., C3-C4). 12 ), saturated monovalent monocyclic, bridged, fused, or spirocyclic groups whose ring atoms consist only of carbon atoms.

[0201] In this invention, "cycloalkenyl" refers to a group having a specified number of carbon atoms (e.g., C3-C4). 12 Unsaturated monovalent monocyclic, bridged, fused, or spirocyclic cyclic groups consisting only of carbon atoms, having one or more (e.g., 1, 2, or 3) carbon-carbon sp atoms. 2 It has a double bond and is not aromatic.

[0202] In this invention, "heterocyclic alkyl" refers to a saturated monovalent monocyclic, bridged, fused, or spirocyclic group having a specified number of ring atoms (e.g., 3-12), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified type of heteroatom (1, 2, or 3 of N, O, S, P, and Si). In the heterocyclic alkyl group, the number of heteroatoms depends on the number of ring atoms, and the number of heteroatoms is less than the number of ring atoms. "Heterocyclic alkyl" includes, but is not limited to, […]. wait.

[0203] In this invention, "heterocyclic alkenyl" refers to a cyclic, unsaturated monovalent monocyclic, bridged, fused, or spirocyclic group having a specified number of ring atoms (e.g., 3-12), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified heteroatom type (one or more of N, O, S, P, and Si), and having one or more (e.g., 1, 2, or 3) carbon-carbon sp... 2 The double bond is non-aromatic. In the heterocyclic alkenyl group, the number of heteroatoms depends on the number of ring atoms, and the number of heteroatoms is less than the number of ring atoms.

[0204] In this invention, "alkylene" refers to a divalent group formed by removing two hydrogen atoms from an alkane molecule. The "alkylene" in this invention can be straight-chain or branched, but is preferably straight-chain. "alkylene" includes, but is not limited to: For example, wait.

[0205] In this invention, "cycloalkylene" refers to a saturated divalent monocyclic, fused, bridged, or spirocyclic group having a specified number of ring atoms and consisting only of carbon atoms.

[0206] In this invention, "cycloene group" refers to a group having a specified number of carbon atoms (e.g., C3-C4). 12 An unsaturated divalent monocyclic, bridged, fused, or spirocyclic cyclic group consisting only of carbon atoms, having one or more (e.g., 1, 2, or 3) carbon-carbon sp atoms. 2 It has a double bond and is not aromatic.

[0207] In this invention, "heterocyclic alkyl group" refers to a saturated divalent monocyclic, bridged, fused, or spirocyclic group having a specified number of ring atoms (e.g., 3-12), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified type of heteroatom (1, 2, or 3 of N, O, S, P, and Si). In the heterocyclic alkyl group, the number of heteroatoms depends on the number of ring atoms, and the number of heteroatoms is less than the number of ring atoms.

[0208] In this invention, "heterocyclic alkenyl" refers to a cyclic, unsaturated divalent monocyclic, bridged, fused, or spirocyclic group having a specified number of ring atoms (e.g., 3-12), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified heteroatom type (one or more of N, O, S, P, and Si), and having one or more (e.g., 1, 2, or 3) carbon-carbon sp... 2 The double bond is non-aromatic. In the described heterocyclic alkenyl group, the number of heteroatoms depends on the number of ring atoms, and the number of heteroatoms is lower than the number of ring atoms.

[0209] In this invention, "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6-C). 14 Furthermore, for example, C6-C 10 An aryl group is a cyclic, unsaturated monovalent hydrocarbon group, which may be monocyclic or polycyclic (e.g., two or three). When polycyclic, the monocyclic rings share two atoms and one bond. In this aryl group, at least one ring or each ring is aromatic. The aryl group is attached to the rest of the molecule through an aromatic or non-aromatic ring.

[0210] In this invention, "aneryl" refers to a divalent aryl group.

[0211] In this invention, "heteroaryl" refers to a cyclic, unsaturated monovalent group having a specified number of ring atoms (e.g., 5-14, more specifically 5-10, and even more specifically 5-6), a specified number of heteroatoms (e.g., 1, 2, 3, 4, or 5), and a specified type of heteroatom (one or more of N, O, and S). It can be monocyclic or polycyclic, with the monocyclic rings sharing two atoms and one bond. In the heteroaryl group, at least one ring or each ring is aromatic. The number of heteroatoms in the heteroaryl group depends on the number of ring atoms, and the number of heteroatoms is less than the number of ring atoms.

[0212] In this invention, "hybrid aryl" refers to a divalent heteroaryl group.

[0213] In this invention, "alkenyl" refers to a straight-chain or branched divalent hydrocarbon group having a specified number of carbon atoms and at least one carbon-carbon double bond, wherein the carbon-carbon double bond can be located at any position within the alkenyl group. "Alkenyl" includes, but is not limited to: wait.

[0214] In this invention, "alkoxy" refers to the group R X -O-,R X The definition is the same as the term "alkyl".

[0215] In this invention, a "covalent bond" refers to a structure on both sides of a covalent bond that is directly connected by a single bond, such as -ABC-. ​​When B is a covalent bond, -ABC- is equivalent to -AC-.

[0216] In this invention, "optional" or "optionally" means that the event or condition described below may occur but is not required, and the description includes both cases where said event or condition occurs and cases where said event or condition does not occur. For example, the term "optionally replaced" means that it may or may not be replaced.

[0217] Those skilled in the art will understand that, according to conventions used in the art, the structural formulas of the groups described in this invention are... This refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site.

[0218] In this invention, a single dash "-" can be added before the substituent used to indicate that the named substituent is connected to the parent part by a single bond.

[0219] In this invention, an "=" can be added before the substituent to indicate that the named substituent is connected to the parent part by a double bond.

[0220] In this invention, when a variable is defined as an alkylene group substituted by one or more R groups, the R group can be a substituent at any site in the alkylene group. If the methylene group in the alkylene group can be replaced by other groups, the R group can also be a substituent on the replaced group.

[0221] In this invention, "multiple" can be 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0222] In this invention, "pharmaceutically acceptable salt" refers to the salt of the compounds of this invention, prepared by reacting a compound with a specific substituent discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of this invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.

[0223] In this invention, "solvate" refers to a substance formed by combining the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement.

[0224] In this invention, "pharmaceutical-acceptable salt" and "solvent" in "pharmaceutical-acceptable salt solvate" refer to substances formed by combining the compound of this invention with 1, a substance prepared with a relatively non-toxic, pharmaceutically acceptable acid or base, or a stoichiometric or non-stoichiometric solvent, as described above.

[0225] In this invention, "pharmaceuticalally acceptable excipients" refers to excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions; these are all substances included in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 Edition), Part IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0226] In this invention, “treatment” refers to a therapeutic therapy. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition, (2) interfering with (a) one or more points in a biological cascade that causes or induces the condition or (b) one or more biological manifestations of the condition, (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment, or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0227] In this invention, "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0228] In this invention, "STAT6-mediated diseases" refer to diseases directly or indirectly caused by abnormal activation or dysfunction of signal transduction and transcription activator 6 (STAT6).

[0229] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0230] The reagents and raw materials used in this invention are all commercially available.

[0231] The significant advantages of this invention are that the cyclic compounds exhibit good inhibitory or degradative activity against STAT6. Specifically, the compounds of this invention demonstrate excellent degradative activity against STAT6 protein, and further, possess favorable pharmacokinetic properties, such as excellent area under the plasma concentration-time curve in ICR mice, a long half-life, and good oral bioavailability. Attached Figure Description

[0232] Figure 1 shows the A549 cell degradation selectivity of compound 4B. Detailed Implementation

[0233] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the concept and scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product specification.

[0234] The preparation of the compounds of this invention can be referred to WO2025049820A1, wherein the -L in the compound structure a -L b -L c - Some of them can be synthesized using conventional synthesis methods in this field.

[0235] Example 1: (E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-3 4 -(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propylpiperazin-1-yl)-N,N-dimethyl-1 1 1 2 1 3 16 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclononane-7-ene-2-carboxamide compound 1

[0236] Step 1: 5-(pyrrolidone-1-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester 1b

[0237] Compound 1a (15 g, 64.30 mmol, 1.0 eq) of 3-oxopiperidin-1-carboxylic acid benzyl ester was dissolved in ultradry toluene (350 mL), and pyrrolidine (5.48 g, 77.167 mmol, 1.2 eq) was added at 15–25 °C. The prepared compound was stirred at 110 °C for 12 h using a Dean-Stark separator. Confirmation by silica gel thin-layer chromatography (petroleum ether / ethyl acetate = 2 / 1, RT = 0.56) showed that compound 1a was completely consumed and new spots were formed. The reaction solution was concentrated under vacuum to give compound 1b (15 g, yield: 81%) of 5-(pyrrolidine-1-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester as a black oil. The obtained compound was used directly in the next step without purification.

[0238] LCMS: m / z = 3032[M+17] + .

[0239] Step 2: Benzyl 2-allyl-3-oxopiperidine-1-carboxylate 1c

[0240] At room temperature, 15 g (52.4 mmol, 1 eq) of 5-(pyrrolidone-1-yl)-3,4-dihydropyridine-1(2H)-carboxylic acid benzyl ester 1b was added to an acetonitrile solution (150 mL). 3-bromoprop-1-ene (6.34 g, 52.44 mmol, 1 eq) was slowly added dropwise to the reaction solution at 40–45 °C. The reaction mixture was stirred at 40 °C for 12 hours. 50 mL of 0.5 N HCl was added, followed by dilution with 200 mL of ethyl acetate. The organic phase was then washed three times with 300 mL of water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%–15%) to give a yellow oily product, 10.3 g (yield: 72%) of 2-allyl-3-oxopiperidin-1-carboxylic acid benzyl ester 1c.

[0241] LCMS: m / z = 274.2[M+1] + .

[0242] Step 3: 6-Allyl-5-((fluoro-12-azacyclooxy)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester 1d

[0243] At room temperature, 10.0 g (36.6 mmol, 1 eq) of 1-allyl-3-oxopiperidin-1-carboxylic acid benzyl ester 1c was dissolved in tetrahydrofuran (100 mL), cooled to 0 °C, and 33.18 g (109.8 mmol, 3 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene (33.18 g, 109.8 mmol, 3 eq) was added. The reaction mixture was stirred at 0 °C for 5 minutes, and perfluorobutylsulfonyl fluoride (16.7 g, 109.8 mmol, 3 eq) was slowly added dropwise, followed by stirring at 25 °C for 4 hours. Water (150 mL) was added to the reaction mixture, and the mixture was extracted three times with dichloromethane (200 mL). The organic phase was washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-8%) to give 1d (15g, yield: 73.0%) of 6-allyl-5-((fluoro-12-azacyclooxy)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester, a white oil.

[0244] LCMS: m / z = 556.1 [M+1] + .

[0245] 1 H NMR (500MHz, DMSO-d6) δ7.42-7.28 (m, 5H), 6.16 (s, 1H), 5.70 (s, 1H), 5.22-4.91 (m, 4H), 4.69 (d, J=33.0Hz, 1H) , 4.03 (dd, J=14.2, 7.0Hz, 1H), 3.13-2.89 (m, 1H), 2.46 (s, 2H), 2.35 (dd, J=12.0, 5.9Hz, 1H), 2.27-2.17 (m, 1H).

[0246] Step 4: 6-Allyl-5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester 1e

[0247] At room temperature, pinacol diboronate (4.57 g, 18 mmol, 1 eq), potassium acetate (5.2 g, 54 mmol, 3 eq), and 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride (1 g, 1.80 mmol, 0.1 eq) were sequentially added to a solution of 6-allyl-5-((fluoro-12-azacyclooxy)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester 1d (10 g, 18 mmol, 1 eq) in dioxane (100 mL). The reaction mixture was then reacted at 100 °C for 4 hours. The reaction solution was cooled to room temperature, and water (150 mL) was added. The mixture was extracted three times with dichloromethane (200 mL), the organic phase was washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-20%) to give a yellow oily substance 6-allyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester 1e (6 g, yield: 86%).

[0248] LCMS: m / z = 384.3 [M+1] + .

[0249] Step 5: 1g of 4-(4-(6-(2-allyl-1-(benzyloxy)carbonyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-1H-indol-4-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester

[0250] At room temperature, tert-butyl 4-(4-(6-chloro-2-(dimethylcarbamoyl(-1H-indol-4-yl)-3-methoxyphenyl)piperazine-1-carboxylate 1f (intermediate 1f can be prepared by the method reported in patent WO2025049820A1) (1 g, 1.95 mmol, 1 eq), 6-allyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid benzyl ester 1e (822 mg, 2.14 mmol, 1.1 eq), potassium phosphate (1.24 g, 5.86 mmol, 3 eq) and methanesulfonic acid (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (10 0 mg) was added sequentially to 1,4-dioxane (20 mL) and water (5 mL). Nitrogen exchange was performed three times, and the mixture was stirred at 100 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, water (100 mL) was added, and the mixture was extracted three times with dichloromethane (100 mL). The organic phase was washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-72%) to obtain 1 g (0.62 g, yield 43.0%) of tert-butyl piperazine-1-carboxylate, a yellow solid.

[0251] LCMS: m / z = 734.4 [M+1] + .

[0252] Step 6: 4-(4-(6-(2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-1H-indol-4-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester 1h

[0253] At room temperature, 1 g (0.62 g, 0.84 mmol, 1 eq) of 4-(4-(6-(2-allyl-1-(benzyloxy)carbonyl)-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)1H-indol-4-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester and sodium methanethiol (0.236 g, 3.38 mmol, 4 eq) were sequentially added to an ultradry N,N-dimethylformamide (15 mL) solution. The reaction mixture was stirred at 70 °C for 12 hours. Water (80 mL) was added, and the mixture was extracted three times with dichloromethane (100 mL). The organic phase was washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-15%) to give a yellow solid product 4-(4-(6-(2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-1H-indol-4-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester 1h (0.40 g, yield: 78%).

[0254] LCMS: m / z = 600.3[M+1] + .

[0255] Step 7: 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-1H-indol-4-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester 1j

[0256] At room temperature, 4-(4-(6-(2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-1H-indol-4-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid tert-butyl ester 1h (0.40 g, 0.66 mmol, 1 eq), 3-(1H-1,2,3-triazol-1-yl)propionic acid 1i (intermediate 1i can be prepared by the method reported in patent WO2025049820A1) (0.376 g, 3.67 mmol, 4 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.384 g, 2.00 mmol, 3 eq) were sequentially added to a pyridine (20 mL) solution, and the reaction mixture was stirred at room temperature for 12 hours. Add water (80 mL), extract three times with dichloromethane (100 mL), wash the organic phase once with saturated brine (100 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-15%) to obtain a yellow solid product tert-butyl 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-1H-indol-4-yl)-3-methoxyphenyl)piperazine-1-carboxylic acid 1j (0.20 g, yield: 41%).

[0257] LCMS: m / z = 723.4 [M+1] + .

[0258] Step 8: 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-hydroxy-4-(piperazin-1-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 1k

[0259] At room temperature, 0.20 g (0.27 mmol, 1 eq) of tert-butyl piperazine-1-carboxylate 1 J was dissolved in dichloromethane (20 mL), and then cooled to 0 °C. A solution of boron tribromide in dichloromethane (17% wt, 2.77 mL, 2.77 mmol, 10 eq) was added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 1 hour, and then stirred at room temperature for 16 hours. The reaction solution was quenched with water (70 mL), adjusted to alkali with saturated sodium bicarbonate aqueous solution, and then extracted three times with dichloromethane (100 mL). The organic phase was washed once with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-15%) to obtain the yellow solid product 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-hydroxy-4-(piperazin-1-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 1k (0.07 g, yield: 41%).

[0260] LCMS: m / z = 609.2[M+1] + .

[0261] Step 9: 1 liter of 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-1H-indol-4-yl)-3-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester

[0262] At room temperature, 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-(2-hydroxy-4-(piperazin-1-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 1k (0.07 g, 0.11 mmol, 1 eq), triethylamine (34 mg, 0.34 mmol, 3 eq), and di-tert-butyl dicarbonate (25 mg, 0.11 mmol, 1 eq) were sequentially added to tetrahydrofuran (8 mL). The reaction mixture was stirred at room temperature for 12 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with dichloromethane (10 mL). The organic phase was washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-15%) to give 11 (0.07 g, yield: 85%) of 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-1H-indol-4-yl)-3-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester, a white solid.

[0263] LCMS: m / z = 709.3 [M+1] + .

[0264] Step 10: 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-1H-indol-4-yl)-3-(but-3-en-1-yloxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester 1m

[0265] At room temperature, 1 mL (0.07 g, 0.09 mmol, 1 eq) of 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-1H-indol-4-yl)-3-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester, potassium carbonate (34 mg, 0.24 mmol, 2.5 eq), and 4-bromobut-1-ene (13 mg, 0.09 mmol, 1 eq) were sequentially added to N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 80 °C for 16 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted three times with dichloromethane (10 mL). The organic phase was washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-15%) to obtain 1 m (0.04 g, yield: 53%) of tert-butyl piperazine-1-carboxylate, a white solid.

[0266] LCMS: m / z = 763.3 [M+1] + .

[0267] Step 11: (E)-4-(1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-2 2 -(dimethylcarbamoyl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3-(1,2)-benzocyclononane-7-ene-3 4 1n-(2-yl)piperazine-1-carboxylic acid tert-butyl ester

[0268] At room temperature, 1 mg (0.04 g, 0.05 mmol, 1 eq) of 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-1H-indol-4-yl)-3-(but-3-en-1-yloxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester and Grubbs II (5 mg) were added sequentially to dichloromethane (20 mL). The mixture was exchanged with nitrogen three times and stirred at 50 °C for 1 hour under nitrogen protection. The reaction solution was cooled to room temperature, 10 mL of water was added, and the mixture was extracted three times with dichloromethane (10 mL). The organic phase was washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-15%) to obtain (E)-4-(1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-2 2 -(dimethylcarbamoyl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3-(1,2)-benzocyclononane-7-ene-3 4 1n (18 mg, yield 46%) of piperazine-1-carboxylic acid tert-butyl ester is a white solid.

[0269] LCMS: m / z = 735.3 [M+1] + .

[0270] Step 12: (E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-N,N-dimethyl-3 4 -(piperazine-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridineα-3(1,2)-benzocyclononane-7-ene-2-carboxamide 1o

[0271] At room temperature, (E)-4-(1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-2 2 -(dimethylcarbamoyl)-1 1 1 2 1 3 16 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3-(1,2)-benzocyclononane-7-ene-3 4 1n (0.018 g, 0.02 mmol) of tert-butyl piperazine-1-carboxylate was dissolved in dichloromethane (3 mL), followed by the addition of trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The solvent was concentrated to obtain the crude product (E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-N,N-dimethyl-3,4-(piperazin-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indol-1(5,6)-pyridine α-3(1,2)-benzocyclononane-7-ene-2-carboxamide 1o (0.017 g, 0.02 mmol), 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1-hydro-benzo[d]imidazol-4-yl)propionaldehyde 1o (17 mg, 100% yield), are pale yellow solids.

[0272] LCMS: m / z = 635.4 [M+1] + .

[0273] Step 13: (E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-3 4 -(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propylpiperazin-1-yl)-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclononane-7-ene-2-carboxamide compound 1

[0274] At room temperature, (E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-N,N-dimethyl-3,4-(piperazin-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1H-4-oxa-2(6,4)-indol-1(5,6)-pyridine α-3(1,2)-benzocyclononane-7-en-2-carboxamide 1o (0.017 g, 0.02 mmol), 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1-hydro-benzo[d]imidazol-4-yl)propionaldehyde 1p (intermediate 1p can be prepared by the method reported in patent WO2025049820A1) (8 mg, 0.02 mmol) were added sequentially to dimethyl sulfoxide (1.5 mL) and tetrahydrofuran (1.5 mL), followed by sodium triacetylborohydride (0.017 g, 0.08 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (20 mL), then extracted twice with dichloromethane (40 mL). The combined dichloromethane phases were washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography to obtain product (E)-1. 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-3 4 -(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propylpiperazin-1-yl)-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridinea-3(1,2)-benzocyclononane-7-ene-2-carboxamide compound 1 (2 mg, yield 7.9%) is a white solid.

[0275] LCMS: m / z = 934.5 [M+1] + .

[0276] 1H NMR (500MHz, DMSO-d6): 11.55 (d, J=7.0Hz, 1H), 11.10 (s, 1H), 8.11 (d, J=8.0Hz, 1H), 7.70-7.64 (m, 1H), 7.53 -7.26(m, 3H), 7.08-6.91(m, 4H), 6.69-6.57(m, 3H), 5.58-5.35(m, 3H), 5.09-4.59(m, 3H), 3.94-3.88(m, 1H) , 3.77-3.70(m, 1H), 3.59(s, 3H), 3.26-3.17(m, 6H), 2.98-2.95(m, 2H), 2.92-2.85(m, 1H), 2.76-2.68(m, 1H) , 2.56-2.52(m, 5H), 2.50-2.40(m, 5H), 2.30-2.16(m, 3H), 2.11-1.95(m, 3H), 1.85-1.77(m, 2H), 1.23(s, 6H).

[0277] Preparative high performance liquid chromatography method: Column: Ultimate Prep C18 10μm 21.2×250mm; Mobile phase: A: water (10mM NH4HCO3) B: acetonitrile; Gradient: 36-66% B in 8min, stop at 16min; Flow rate: 30ml / min; Retention time (min): 11.8min.

[0278] Example 2: (E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodecane-8-ene-2-carboxamide compound 2

[0279] Following the same steps as in Example 1, 5-bromopent-1-ene was used instead of 4-bromobut-1-ene, and 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1-hydro-benzo[d]imidazol-4-yl)acetaldehyde was used instead of 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1-hydro-benzo[d]imidazol-4-yl)propionaldehyde was used to prepare the target product compound 2 (1.71 mg), which was a white solid.

[0280] LCMS: m / z = 935.3 [M+1] + 467.8 [M / 2+1] + .

[0281] 1H NMR (400MHz, DMSO-d6): 11.68(s, 1H), 11.13(s, 1H), 9.83-9.79(m, 1H), 8.09-8.04(m 1H), 7.70-7.67(m, 1H), 7.49-7.37(m, 2H), 7.31-7.29(m, 1H), 7.08-7.01(m, 2H), 6.99-6.97(m, 1H), 6.79-6.76(s, 1H), 6.72-6.62(m, 2H), 6.01-6.91(m, 1H), 5.76-5.25(m, 4H), 4.89-4.52(m, 3H), 4.26-4.06(m, 3H), 3.93-3.76(m, 4H), 3.66(s, 3H), 3.55-3.42(m, 2H), 3.21-3.03(m, 12H), 2.78-2.62(m, 2H), 2.42-2.38(m, 2H), 2.25-2.09(m, 3H), 2.06-1.99(m, 4H), 1.81-1.64(m, 2H).

[0282] Example 3: (E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -[4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl]-2 7 3 3 -Difluoro-N,N-dimethyl-1 1 1 2 1 3 1 4 -Tetrahydro-21H-4-oxa-2(6,4)-indolo-1(5,6)-pyrido-3(1,2)-benzocyclononen-8-ene-2 2 -Formamide compound 3A; (E)-1 1-[3-(1H-pyrazole-1-yl)propionyl]-3 4 -[4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl]-2 7 3 3 -Difluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indolo-1(5,6)-pyrido-3(1,2)-benzocyclodecene-8-ene-2 2 -Formamide compound 3B

[0283] Step 1: 1-Bromo-3-fluoro-4-iodo-2-(pent-4-en-1-oxy)benzene 3b

[0284] At room temperature, 6-bromo-2-fluoro-3-iodophenol (5.00 g, 15.82 mmol) was dissolved in N,N-dimethylformamide (40 mL), followed by the addition of 5-bromo-1-pentene (7.02 g, 47.46 mmol), cesium carbonate (15.40 g, 47.46 mmol), and potassium iodide (263 mg, 1.58 mmol). The reaction mixture was exchanged with nitrogen three times and reacted at 80 °C for 3 hours under nitrogen protection. The reaction was monitored by TCL until completion. The reaction mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted three times with ethyl acetate (100 mL), and the organic phase was washed three times with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the product 1-bromo-3-fluoro-4-iodo-2-(pent-4-en-1-oxy)benzene 3b (6.00 g, yield: 99%), which was a yellow oil.

[0285] 1 H NMR (400MHz, DMSO-d6): 7.52-7.48(m, 1H), 7.29-7.26(m, 1H), 5.91-5.81(m, 1H), 5.09- 4.98 (m, 2H), 4.05 (t, J=6.4Hz, 2H), 2.23 (dd, J=14.4Hz, 7.2Hz, 2H), 1.84-1.78 (m, 2H).

[0286] Step 2: Tert-butyl 4-(4-bromo-2-fluoro-3-(pent-4-en-1-oxy)phenyl)piperazine-1-carboxylic acid ester 3c

[0287] At room temperature, 1-bromo-3-fluoro-4-iodo-2-(pent-4-ene-1-hydroxy)benzene 3b (88 mg, 0.23 mmol) was dissolved in anhydrous 1,4-dioxane (6 mL), followed by the addition of tert-butylpiperazine-1-carboxylate (47 mg, 0.25 mmol), tris(dibenzylacetone)dipalladium (21 mg, 0.02 mmol), 9-dimethyloxanthracene (13 mg, 0.02 mmol), and cesium carbonate (112 mg, 0.34 mmol). The reaction mixture was subjected to three nitrogen exchanges and reacted at 80°C for 6 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-7%) to obtain crude tert-butyl 4-(4-bromo-2-fluoro-3-(pent-4-en-1-oxy)phenyl)piperazine-1-carboxylic acid ester 3c (56 mg, purity: 82%, yield 44.5%), which was a yellow solid.

[0288] LCMS: m / z: 4432 [M+H] + .

[0289] Step 3: 1-(4-bromo-2-fluoro-3-(pent-4-en-1-yloxy)phenyl)piperazine 3d

[0290] At room temperature, 2 mL of trifluoroacetic acid was added to a solution of tert-butyl 4-(4-bromo-2-fluoro-3-(pent-4-en-1-oxy)phenyl)piperazine-1-carboxylic acid ester 3c (56 mg, 0.13 mmol) in dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated directly to dryness under reduced pressure to give crude product 1-(4-bromo-2-fluoro-3-(pent-4-en-1-yloxy)phenyl)piperazine 3d (95 mg), a light brown oil. The crude product was not further purified and was used directly in the next step.

[0291] LCMS: m / z: 343.2 [M+H] + .

[0292] Step 4: 1-(4-bromo-2-fluoro-3-(penta-4-en-1-yloxy)phenyl)-4-(2-fluoro-5-methoxy-4-nitrophenyl)piperazine 3e

[0293] At room temperature, N,N-diisopropylethylamine (128 mg, 0.99 mmol) and 1,2-difluoro-4-methoxy-5-nitrobenzene (26 mg, 0.14 mmol) were added to a solution of crude product 1-(4-bromo-2-fluoro-3-(pent-4-en-1-yloxy)phenyl)piperazine 3d (95 mg, 0.28 mmol) in N,N-dimethylformamide (4 mL). The reaction solution was reacted at 80 °C for 5 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (15 mL). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-11%) to give 1-(4-bromo-2-fluoro-3-(penta-4-en-1-yloxy)phenyl)-4-(2-fluoro-5-methoxy-4-nitrophenyl)piperazine 3e (40 mg, two-step yield: 57%), as an orange-red solid.

[0294] LCMS: m / z: 511.8 [M+H] + .

[0295] 1 H NMR (400MHz, DMSO-d6): 7.88 (d, J=13.2Hz, 1H), 7.35 (d, J=8.8Hz, 1H), 6.82 (t, J=8.8Hz, 1H), 6.75 (d, J=7.6Hz, 1H), 5.92-5.81 (m, 1H), 5.07 ( d, J=16.8Hz, 1H), 5.00 (d, J=10.0Hz, 1H), 4.04 (t, J=6.4Hz, 2H), 3.96( s, 3H), 3.46 (s, 4H), 3.18 (s, 4H), 2.27-2.21 (m, 2H), 1.85-1.78 (m, 2H).

[0296] Step 5: 4-(4-(4-bromo-2-fluoro-3-(pent-4-en-1-oxy)phenyl)piperazin-1-yl)-5-fluoro-2-methoxyaniline 3f

[0297] At room temperature, 1-(4-bromo-2-fluoro-3-(penta-4-en-1-yloxy)phenyl)-4-(2-fluoro-5-methoxy-4-nitrophenyl)piperazine 3e (75 mg, 0.15 mmol), iron powder (82 mg, 1.47 mmol), and ammonium chloride (79 mg, 1.47 mmol) were added sequentially to ethanol (10 mL) and water (4 mL). The reaction mixture was subjected to three argon gas exchanges and reacted at 80 °C for 1 hour under argon protection. The reaction mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted twice with ethyl acetate (15 mL), washed once with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-30%) to give 4-(4-(4-bromo-2-fluoro-3-(pent-4-en-1-oxy)phenyl)piperazin-1-yl)-5-fluoro-2-methoxyaniline 3f (65 mg, yield: 92%), which was a brown liquid.

[0298] LCMS: m / z: 481.9 [M+H] + .

[0299] 1 H NMR (400MHz, DMSO-d6): 7.33 (dd, J=8.8Hz, 1.2Hz, 1H), 6.80 (t, J=8.8Hz, 1H), 6.61 (d, J=8.0Hz, 1H), 6.44 (d, J=13.2Hz, 1H), 5.92-5.81 (m, 1H), 5.07 ( dd, J=16.8Hz, 1.2Hz, 1H), 5.00 (d, J=10.0Hz, 1H), 4.03 (t, J=6.0Hz, 2H), 3. 75(s, 3H), 3.12(s, 4H), 3.03(s, 4H), 2.26-2.21(m, 2H), 1.85-1.80(m, 2H).

[0300] Step 6: 3g of 3-((4-(4-(4-(4-bromo-2-fluoro-3-(pent-4-en-1-yloxy)phenyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione

[0301] At room temperature, 4-(4-(4-bromo-2-fluoro-3-(pent-4-en-1-oxy)phenyl)piperazin-1-yl)-5-fluoro-2-methoxyaniline 3f (54 mg, 0.11 mmol), sodium bicarbonate (94 mg, 1.12 mmol), and 3-bromopiperidine-2,6-dione (32 mg, 0.17 mmol) were added sequentially to DMF (4 mL). The reaction mixture was subjected to three argon gas exchanges, and the reaction was carried out at 80 °C for 12 hours under argon protection. 3-bromopiperidine-2,6-dione (86 mg, 0.45 mmol) was added continuously in three portions. After the reaction was complete, the reaction mixture was cooled to room temperature. DMF was removed by vacuum distillation, and the remaining mixture was purified by silica gel column chromatography (eluent: methanol: dichloromethane = 0%-5%) to give 3 g (22 mg, yield: 36%) of 3-((4-(4-(4-bromo-2-fluoro-3-(pent-4-en-1-yloxy)phenyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidine-2,6-dione as a yellow solid.

[0302] LCMS: m / z: 592.8 [M+H] + .

[0303] Step 7: 2-Allyl-3-(((perfluorobutyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 3i

[0304] At room temperature, 1-tert-butoxycarbonyl-2-allyl-3-oxoperpiperidine 3h (29.0 g, 121.3 mmol) (3h can be prepared by the method reported in patent CN 118401509 A) was dissolved in tetrahydrofuran (300 mL), cooled to 0 °C, and 1,8-diazabicyclo[5.4.0]undec-7-ene (55.4 g, 364.0 mmol) was added. The reaction mixture was stirred at 0 °C for 5 minutes, and perfluorobutylsulfonyl fluoride (73.3 g, 242.6 mmol) was slowly added dropwise. The reaction mixture was then stirred at 25 °C for 4 hours. Ice water (300 mL) was slowly added dropwise to the reaction mixture under ice bath conditions. The mixture was extracted three times with ethyl acetate (300 mL), washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-6%) to obtain 3i of 2-allyl-3-(((perfluorobutyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (45 mg, yield: 71.0%), which was a colorless oil.

[0305] 1H NMR (400MHz, DMSO-d6): 6.13 (d, J=4.4Hz, 1H), 5.76-5.68 (m, 1H), 5.13-5.05 (m, 2H), 4.66-4.53 ( m, 1H), 4.01-3.82 (m, 1H), 3.01-2.82 (s, 1H), 2.44-2.36 (m, 2H), 2.35-2.16 (m, 2H), 1.39 (s, 9H).

[0306] Step 8: 2-Allyl-3-(4,4,5,5-Tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydropyridine-1(2H)-tert-butyl carboxylate 3j

[0307] At room temperature, pinacol diboronate (22.0 g, 86.4 mmol), potassium acetate (35.8 g, 259.2 mmol), and 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride (4.5 g) were sequentially added to a solution of 2-allyl-3-(((perfluorobutyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 3i (45.0 g, 86.4 mmol) in 1,4-dioxane (450 mL). The reaction mixture was purged with nitrogen three times and reacted at 100 °C for 4 hours under nitrogen protection. The reaction mixture was cooled to room temperature, and water (300 mL) was added. The mixture was extracted three times with dichloromethane (300 mL), washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-5%) to give a yellow oily substance, 2-allyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 3j (27.0 g, yield: 89%).

[0308] LCMS: m / z: 294.0 [M-56+H] + .

[0309] 1 H NMR (400MHz, DMSO-d6): 6.52 (s, 1H), 5.76-5.69 (m, 1H), 5.45-5.29 (m, 1H), 5.01-4.42 (m, 2H), 3.98-3.7 9 (m, 1H), 2.94-2.67 (m, 1H), 2.41-2.05 (m, 3H), 1.63 (d, J=6.0Hz, 1H), 1.39 (s, 9H), 1.22-1.67 (m, 12H).

[0310] Step 9: 6-Allyl-5-(4,4,5,5-Tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)-1,2,3,6-Tetrahydropyridine 3k

[0311] At room temperature, 2-allyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 3j (5.0 g, 14.3 mmol) was dissolved in dichloromethane (30 mL), followed by the addition of a 4M solution of 1,4-dioxane in hydrogen chloride (25 mL). The reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure to give 6-allyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)-1,2,3,6-tetrahydropyridine 3k (4.0 g, 100% yield) as a yellow oil. The obtained compound was used directly in the next step without purification.

[0312] LCMS: m / z: 250.4 [M+H] + .

[0313] Step 10: 1-(2-allyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydropyridin-1(2H)-yl)-3-(1H-pyrazol-1-yl)propane-1-one 3l

[0314] At room temperature, 6-allyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1,2,3,6-tetrahydropyridine 3k (4.0 g, 16.1 mmol), 3-(1H-pyrazol-1-yl)propionic acid (2.3 g, 16.1 mmol, 1 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.6 g, 24.2 mmol) were sequentially added to a pyridine (40 mL) solution, and the reaction mixture was stirred at room temperature for 2 hours. Water (100 mL) was added, and the mixture was extracted three times with dichloromethane (100 mL). The organic phase was washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-5%) to give 31 (3.3 g, yield: 55%) of the yellow solid product 1-(2-allyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydropyridin-1(2H)-yl)-3-(1H-pyrazol-1-yl)propane-1-one.

[0315] LCMS: m / z: 372.4 [M+H] + .

[0316] 1 H NMR (400MHz, DMSO-d6): 7.69-7.65 (m, 1H), 7.40 (s, 1H), 6.53-6.49 (m, 1H), 6.19-6.17 (m, 1H), 5.68-4.88 (m, 3H), 4. 60-4.20 (m, 3H), 3.75-3.65 (m, 1H), 3.16-2.67 (m, 3H), 2.40-2.01 (m, 3H), 1.61 (d, J=6.0Hz, 1H), 1.24-1.17 (m, 12H).

[0317] Step 11: 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 3m

[0318] At room temperature, 1-(2-propenyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-5,6-dihydropyridin-1(2H)-yl)-3-(1H-pyrazol-1-yl)acetone-1 3L (200 mg, 0.54 mmol) was dissolved in 1,4-dioxane / water (15 mL / 1.5 mL), followed by the addition of 6-bromo-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (171 mg, 0.54 mmol) (this intermediate can be prepared by the method reported in patent WO2025049820A1), potassium carbonate (224 mg, 1.62 mmol), and 1,1′-bis(diphenylphosphine)ferrocene palladium(II) chloride (39 mg, 0.05 mmol). The reaction mixture was exchanged with nitrogen three times and reacted at 80°C for 3 hours under nitrogen protection. The reaction was monitored by LCMS until completion. The reaction mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted three times with 100 mL of ethyl acetate. The organic phase was washed three times with 100 mL of saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-5%) to obtain 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 3m (220 mg, yield 85%), a yellow solid.

[0319] LCMS: m / z: 483.8 [M+1] + .

[0320] Step 12: 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-propenyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-indole-2-carboxamide 3n

[0321] At room temperature, 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 3m (200 mg, 0.41 mmol), pinacol diboronate (310 mg, 1.24 mmol), potassium acetate (120 mg, 1.23 mmol), and XPos-Pd-G3 (40 mg) were sequentially added to dimethyl sulfoxide (8 mL). The mixture was purged three times with nitrogen, and the reaction solution was microwaved at 110 °C for 1.5 hours. The reaction was detected as complete by LCMS. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phase was washed three times with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-5%) to obtain 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-propenyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-indole-2-carboxamide 3n (70 mg, yield 29%), which was a yellow oil.

[0322] LCMS: m / z = 576.4 [M+1] + .

[0323] Step 13: 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-(4-(((2,6-dioxopiridine-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)-3-fluoro-2-(penta-4-en-1-yloxy)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 3o

[0324] At room temperature, 3 g (30 mg, 0.05 mmol) of 3-((4-(4-(4-bromo-2-fluoro-3-(pent-4-en-1-yloxy)phenyl)piperazin-1-yl)-5-fluoro-2-methoxyphenyl)amino)piperidin-2,6-dione, 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7 -Fluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1H-indole-2-carboxamide 3n (35 mg, 0.06 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (20 mg, 0.02 mmol) and fluorinated Cesium (28 mg, 0.18 mmol) was added sequentially to a mixed solvent of dioxane (3 mL) and water (0.6 mL). The mixture was exchanged three times with argon gas, and the reaction solution was reacted at 80 °C for 2 hours under argon protection. The reaction solution was then cooled to room temperature, and dioxane and water were removed under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-10%) to obtain 6-(1-(3-(1H-pyrazol-1-yl)propionyl) 2-Allyl-1,2,5,6-Tetrahydropyridin-3-yl)-4-(4-(4-(4-(((2,6-dioxypiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)-3-fluoro-2-(penta-4-en-1-yloxy)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 3o (9 mg, yield: 18%), is a white solid.

[0325] LCMS: m / z = 962.7 [M+H] + .

[0326] Step Fourteen: (E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -[4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl]-2 7 3 3 -Difluoro-N,N-dimethyl-1 1 1 2 1 3 1 4 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indolo-1(5,6)-pyrido-3(1,2)-benzocyclononen-8-ene-2 2 -Formamide compound 3A; (E)-1 1 -[3-(1H-pyrazole-1-yl)propionyl]-34 -[4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl]-2 7 3 3 -Difluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indolo-1(5,6)-pyrido-3(1,2)-benzocyclodecene-8-ene-2 2 -Formamide compound 3B

[0327] At room temperature, 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-(4-(4-(4-(((2,6-dioxadiazin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl)-3-fluoro-2-(penta-4-en-1-yloxy)phenyl)-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 3o (9 mg, 0.01 mmol) and 1,3-bis(2,4,6-trimethylphenyl)-2-(imidazolidinediyl)(dichlorobenzylmethyl)(tricyclohexylphosphine)ruthenium (8 mg, 0.01 mmol) were added sequentially to dichloromethane (10 mL). The mixture was exchanged three times with argon gas, and the reaction solution was refluxed for 1 hour under argon protection. The reaction mixture was cooled to room temperature, and dichloromethane was removed by vacuum distillation. The remaining mixture was purified by high-performance liquid chromatography to give (E)-1. 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -[4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl]-2 7 3 3 -Difluoro-N,N-dimethyl-1 1 1 2 1 3 1 4 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indolo-1(5,6)-pyrido-3(1,2)-benzocyclononen-8-ene-2 2 -Formamide compound 3A (0.81 g, yield: 9%), is a white solid and (E)-1 1 -[3-(1H-pyrazole-1-yl)propionyl]-3 4 -[4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluoro-5-methoxyphenyl)piperazin-1-yl]-2 7 33 -Difluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indolo-1(5,6)-pyrido-3(1,2)-benzocyclodecene-8-ene-2 2 3B formamide compound (0.67 g, yield: 8%) is a white solid.

[0328] Compound 3A: LCMS: m / z: 919.7 [M+H] + .

[0329] Compound 3B: LCMS: m / z: 933.7 [M+H] + .

[0330] 1 H NMR (400MHz, DMSO-d6): 12.10-12.04 (m, 1H), 10.85 (s, 1H), 7.74-7.73 (m, 1H) ,7.43-7.23(m,1H),7.22-6.70(m,4H),6.60-6.36(m,2H),6.22-6.18(m,1H), 6.15-6.12(m, 1H), 5.57-5.13(m, 2H), 5.12-4.54(m, 2H), 4.41-4.38(m, 2H), 4 .32-4.28(m, 1H), 3.82-3.64(m, 5H), 3.22-2.57(m, 18H), 2.33-1.24(m, 12H).

[0331] Example 4: (E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 4 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-2 2 -Formamide compound 4

[0332] Step 1: tert-butyl 4-[4-bromo-3-(methoxymethoxy)phenyl]-1-piperazine carboxylate 4b

[0333] At room temperature, 1-bromo-4-iodo-2-(methoxymethoxy)benzene 4a (18.4 g, 53.64 mmol), tert-butylpiperazine-1-carboxylic acid ester (12.0 g, 64.37 mmol), potassium tert-butoxide (7.2 g, 64.37 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (3.10 g, 5.36 mmol), and tris(dibenzylideneacetone)dipalladium (4.9 g, 5.36 mmol) were sequentially added to 1,4-dioxane (400 mL). The mixture was exchanged with nitrogen three times and stirred at 80 °C for 16 hours under nitrogen protection. The reaction mixture was cooled to room temperature, and water (500 mL) was added. The mixture was extracted three times with ethyl acetate (600 mL), the organic phase was washed once with saturated brine (600 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-8%) to give tert-butyl 4-[4-bromo-3-(methoxymethoxy)phenyl]-1-piperazine carboxylate 4b (16.1 g, yield: 75%), as a yellow oily solid.

[0334] LCMS: m / z = 401.3[M+1] + .

[0335] 1 H NMR (400MHz, DMSO-d6): 7.36 (d, J=8.8Hz, 1H), 6.76 (d, J=2.4Hz, 1H), 6.55 (dd, J=8.4Hz, 2.4 Hz, 1H), 5.26 (s, 2H), 3.44 (t, J=5.2Hz, 4H), 3.41 (s, 3H), 3.10 (t, J=5.2Hz, 4H), 1.42 (s, 9H).

[0336] Step 2: Tert-butyl 4-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]-1-piperazincarboxylate 4c

[0337] At room temperature, tert-butyl 4-[4-bromo-3-(methoxymethoxy)phenyl]-1-piperazinic acid ester 4b (5.0 g, 12.50 mmol) was added to tetrahydrofuran (40 mL) in a three-necked flask. The mixture was exchanged with nitrogen three times. The reaction flask was placed in a dry ice-ethanol bath, and the temperature was controlled to -70°C. A 2.5 M n-butyllithium solution in n-hexane (10 mL, 25 mmol) was slowly added dropwise to the reaction solution. The reaction was stirred at -70°C for 1 hour. A solution of isobutylborate pinacol ester (7.0 g, 37.50 mmol) dissolved in tetrahydrofuran (20 mL) was slowly added dropwise to the above reaction solution. The reaction was considered complete when the addition was finished. The reaction solution was slowly poured into a saturated ammonium chloride solution (100 mL), extracted three times with ethyl acetate (100 mL), and the organic phase was washed once with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-15%) to give 4-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl]-1-piperazincarboxylate 4c (3.8 g, yield 68%), which was a pale yellow oil.

[0338] LCMS: m / z = 449.4 [M+1] + .

[0339] 1 H NMR (400MHz, DMSO-d6): 7.42 (d, J=8.4Hz, 1H), 6.58-6.54 (m, 2H), 5.13 (s, 2H), 3.45-3.41 (m, 7H), 3.19-3.17 (m, 4H), 1.42 (s, 9H), 1.24 (s, 12H).

[0340] Step 3: 2-Allyl-1,2,5,6-Tetrahydropyridin-3-yl1,1,2,2,3,3,4,4,4-Nonfluorobutane-1-sulfonate 4e

[0341] At room temperature, tert-butyl-2-allyl-3-(((perfluorobutyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid ester 3i (4.5 g, 6.71 mmol) was dissolved in dichloromethane (30 mL), followed by the addition of a 4M solution of 1,4-dioxane in hydrogen chloride (25 mL). The reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated to dryness under reduced pressure to give 2-allyl-1,2,5,6-tetrahydropyridine-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate ester 4e (3.6 g, 100% yield) as a yellow oil. The obtained compound was used directly in the next step without further purification.

[0342] LCMS: m / z = 422.4 [M+H] + .

[0343] Step 4: 1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate 4f

[0344] At room temperature, 2-allyl-1,2,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate 4e (3.6 g, 8.55 mmol, 1 eq), 3-(1H-pyrazol-1-yl)propionic acid (1.2 g, 8.55 mmol, 1 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.5 g, 12.8 mmol, 1.5 eq) were sequentially added to pyridine (36 mL), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (100 mL), extracted three times with dichloromethane (100 mL), washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-5%) to obtain 1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate 4f (2.8 g, yield: 60%), as a yellow solid.

[0345] LCMS: m / z = 544.2 [M+H] + .

[0346] 1 H NMR (400MHz, DMSO-d6): 7.69-7.66 (m, 1H), 7.40-7.39 (m, 1H), 6.19-6.18 (m, 1H), 6.11-6.10 (m, 1H), 5.80-5 .60 (m, 1H), 5.12-4.98 (m, 3H), 4.52-4.30 (m, 2H), 3.85-3.80 (m, 1H), 3.25-2.83 (m, 3H), 2.44-2.16 (m, 4H).

[0347] Step 5: 1-Piperazine carboxylate tert-butyl ester-4-(4-(6-chloro-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)-3-(methoxymethoxy)phenyl)4h

[0348] At room temperature, 4 g of methyl 4-bromo-6-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (this intermediate can be prepared by the method reported in patent WO2025049820A1) (400 mg, 1.26 mmol) was dissolved in 1,4-dioxane / water (15 mL / 3 mL), followed by the sequential addition of tert-butyl-4-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-1-piperazincarboxylate 4c (564 mg, 1.26 mmol), potassium carbonate (521 mg, 3.77 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (92 mg, 0.13 mmol). The reaction mixture was purged with nitrogen three times and reacted at 100 °C for 3 hours under nitrogen protection. The reaction was detected by LCMS. The crude product was concentrated under reduced pressure by solvent and purified by silica gel column chromatography (eluent: dichloromethane: ethyl acetate = 0%-40%) to obtain tert-butyl 1-piperazinate-4-(4-(6-chloro-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)-3-(methoxymethoxy)phenyl)4h (350 mg, yield: 50%), as a yellow solid.

[0349] LCMS: m / z = 560.9 [M+H] + .

[0350] Step 6: 1-Piperazine carboxylic acid tert-butyl ester-4-[4-(2-dimethylcarbamoyl)-7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indol-4-yl]-3-(methoxymethoxy)phenyl 4i

[0351] At room temperature, tert-butyl 1-piperazinate-4-(4-(6-chloro-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)-3-(methoxymethoxy)phenyl)4h (350 mg, 0.63 mmol) was dissolved in 1,4-dioxane (15 mL), followed by the addition of pinacol diboronate (238 mg, 0.94 mmol), potassium acetate (184 mg, 1.88 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (92 mg, 0.06 mmol). The reaction mixture was purged with nitrogen three times and reacted at 100 °C for 3 hours under nitrogen protection. The reaction was detected by LCMS. The crude product was concentrated under reduced pressure by solvent and purified by silica gel column chromatography (eluent: dichloromethane: ethyl acetate = 0%-40%) to obtain 1-piperazincarboxylic acid tert-butyl ester-4-[4-(2-dimethylcarbamoyl)-7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indol-4-yl]-3-(methoxymethoxy)phenyl 4i (300 mg, yield 74%), as a yellow solid.

[0352] LCMS: m / z = 652.9 [M+H] + .

[0353] Step 7: 1-Piperazincarboxylic acid tert-butyl ester-4-[4-(6-(1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-dimethylcarbamoyl-7-fluoro-1H-indol-4-yl)-3-(methoxymethoxy)phenyl]4j

[0354] At room temperature, 1-piperazinic acid tert-butyl ester-4-[4-(2-dimethylcarbamoyl)-7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indol-4-yl]-3-(methoxymethoxy)phenyl 4i (300 mg, 0.53 mmol) was dissolved in 1,4-dioxane / water (8 mL / 2 mL), and then 1-(3-(1H-pyrazol-1-yl)propionyl)-2- Allyl-1,2,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate 4f (290 mg, 0.53 mmol), potassium carbonate (190 mg, 1.38 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (45 mg, 0.05 mmol). The reaction mixture was purged with nitrogen three times and reacted at 80 °C for 3 hours under nitrogen protection. The reaction was detected by LCMS. The crude product was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-4%) to obtain 1-piperazincarboxylic acid tert-butyl ester-4-[4-(6-(1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-dimethylcarbamoyl-7-fluoro-1H-indol-4-yl)-3-(methoxymethoxy)phenyl]4j (330 mg, yield 93%), as a yellow solid.

[0355] LCMS: m / z = 769.9 [M+H] + .

[0356] Step 8: 6-(1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(2-hydroxy-4-(piperazin-1-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 4k

[0357] At room temperature, 100 mg (0.13 mmol) of 1-piperazincarboxylic acid tert-butyl ester-4-[4-(6-(1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-dimethylcarbamoyl-7-fluoro-1H-indol-4-yl)-3-(methoxymethoxy)phenyl]4j was dissolved in methanol (2 mL), and a 4M dioxane solution of hydrogen chloride (2 mL) was added dropwise. After the addition was complete, the reaction solution was stirred at room temperature for 2 hours and concentrated under reduced pressure to obtain the product 6-(1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(2-hydroxy-4-(piperazin-1-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 4k (86 mg, yield: 100.0%), a yellow solid.

[0358] LCMS: m / z = 626.0 [M+1] + .

[0359] Step 9: 1-Piperazincarboxylic acid tert-butyl ester-4-[4-(6-(1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-dimethylcarbamoyl-7-fluoro-1H-indole-4-yl)-3-hydroxyphenyl]4l

[0360] At room temperature, 6-(1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(2-hydroxy-4-(piperazin-1-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 4k (86 mg, 0.13 mmol), triethylamine (39 mg, 0.39 mmol), and di-tert-butyl dicarbonate (31 mg, 0.14 mmol) were added sequentially to dichloromethane (4 mL). The reaction solution... The mixture was stirred at room temperature for 2 hours. The crude product was concentrated under reduced pressure using a solvent. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-3%) to give 1-piperazinic acid tert-butyl ester-4-[4-(6-(1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-dimethylcarbamoyl-7-fluoro-1H-indol-4-yl)-3-hydroxyphenyl]4l (70 mg, yield: 74%) as a yellow solid.

[0361] LCMS: m / z = 726.0 [M+H] + .

[0362] Step 10: 1-Piperazincarboxylic acid tert-butyl ester-4-[4-(6-(1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-dimethylcarbamoyl-7-fluoro-1H-indol-4-yl)-3-(4-penten-1-yloxy)phenyl 4m

[0363] At room temperature, 1-piperazinic acid tert-butyl ester-4-[4-(6-(1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-dimethylcarbamoyl-7-fluoro-1H-indol-4-yl)-3-hydroxyphenyl]4l (140 mg, 0.19 mmol), potassium carbonate (80 mg, 0.58 mmol), and 5-bromo-1-pentene (35 mg, 0.23 mmol) were added sequentially to acetonitrile (5 mL). The reaction mixture was stirred overnight at 60 °C. The reaction mixture was cooled to room temperature, diluted with water (10 mL), extracted three times with ethyl acetate (10 mL), washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography and high performance liquid chromatography to obtain 1-piperazine carboxylic acid tert-butyl ester-4-[4-(6-(1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-dimethylcarbamoyl-7-fluoro-1H-indol-4-yl)-3-(4-penten-1-yloxy)phenyl 4m (90 mg, yield: 59%), as a white solid.

[0364] LCMS: m / z = 793.9 [M+H] + .

[0365] Step 11: (E)-1-piperazine carboxylic acid tert-butyl ester-4-[1] 1 -(3-(1H-pyrazole-1-yl)propionyl)-2 2 -Dimethylcarbamoyl-2 7 -Fluorine-1 1 1 2 1 3 1 6 -Tetrahydro-21H-4-oxa-2(6,4)-indolyl-1(5,6)-pyridyl-3(1,2)-phenylcyclodecane-8-ene-3 4 -base]4n

[0366] At room temperature, 90 mg (0.11 mmol) of 1-piperazinic acid tert-butyl ester-4-[4-(6-(1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-dimethylcarbamoyl-7-fluoro-1H-indol-4-yl)-3-(4-penten-1-yloxy)phenyl 4m and 25 mg of Grubbs II were added sequentially to dichloromethane (20 mL). The mixture was exchanged with nitrogen three times and stirred at room temperature for 3 hours under nitrogen protection. The mixture was diluted with water (10 mL), extracted three times with dichloromethane (10 mL), washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-8%) to obtain (E)-1-piperazine carboxylic acid tert-butyl ester-4-[1] 1 -(3-(1H-pyrazole-1-yl)propionyl)-2 2 -Dimethylcarbamoyl-2 7 -Fluorine-1 1 1 2 1 3 1 6 -Tetrahydro-21H-4-oxa-2(6,4)-indolyl-1(5,6)-pyridyl-3(1,2)-phenylcyclodecane-8-ene-3 4 -Base]4n (70 mg, yield 81%) is a white solid.

[0367] LCMS: m / z = 765.8 [M+H] + .

[0368] Step 12: (E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-2 7 -Fluoro-N,N-dimethyl-3,4-(piperazin-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodecane-8-ene-2 2 -formamide 4o

[0369] At room temperature, (E)-1-piperazine carboxylic acid tert-butyl ester-4-[1] 1 -(3-(1H-pyrazole-1-yl)propionyl)-2 2 -Dimethylcarbamoyl-2 7 -Fluorine-1 1 1 2 13 1 6 -Tetrahydro-21H-4-oxa-2(6,4)-indolyl-1(5,6)-pyridyl-3(1,2)-phenylcyclodecane-8-ene-3 4 [-base]4n (35 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (1.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The solution was concentrated to dryness under reduced pressure to give the crude product (E)-1. 1 -(3-(1H-pyrazole-1-yl)propionyl)-2 7 -Fluoro-N,N-dimethyl-3,4-(piperazin-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodecane-8-ene-2 2 -Formamide 4o (37mg, crude) is a pale yellow solid.

[0370] LCMS: m / z = 665.9 [M+H] + .

[0371] Step 13: (E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-27-fluoro-N,N-dimethyl-1 1 1 2 1 3 1 4 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-2 2 -Formamide compound 4

[0372] At room temperature, (E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-2 7 -Fluoro-N,N-dimethyl-3,4-(piperazin-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodecane-8-ene-22 -Formamide 4o (37 mg, crude), 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1-hydro-benzo[d]imidazol-4-yl)propionaldehyde (this intermediate can be prepared by the method reported in patent WO2025049820A1) (17 mg, 0.05 mmol) were added sequentially to dichloromethane (4 mL) and methanol (2 mL), followed by the addition of sodium triacetylborohydride (24 mg, 0.11 mmol). The reaction mixture was stirred at 40 °C for 6 hours. The reaction was quenched with water (5 mL), and then extracted twice with dichloromethane (20 mL). The combined dichloromethane phases were washed once with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by preparative high performance liquid chromatography to obtain product (E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-27-fluoro-N,N-dimethyl-1 1 1 2 1 3 1 4 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-2 2 -Formamide compound 4 (5.34 mg, two-step yield 12%) is a white solid.

[0373] LCMS: m / z = 476.3 [M / 2 + H] + .

[0374] 1 H NMR (400MHz, DMSO-d6): 12.02(s, 1H), 11.09(s, 1H), 7.70-7.64(m, 1H), 7.42-7.24( m, 3H), 7.00-6.93 (m, 3H), 6.68-6.61 (m, 3H), 6.20-6.16 (m, 1H), 6.04-5.95 (m, 1H), 5.62-5.26(m, 4H), 4.75-4.52(m, 1H), 4.39-4.30(m, 2H), 4.25-4.13(m, 1H), 3.89-3 .77(m, 2H), 3.62(s, 3H), 3.27-2.61(m, 24H), 2.39-1.95(m, 6H), 1.80-1.60(m, 2H).

[0375] Example 4A: (1 6 R / S,E)-11-(3-(1H-pyrazol-1-yl)propionyl)-2 7 -Fluoro-N,N-dimethyl-3 4 -(4-(2-(3-methyl-2-oxo-1-(2-oxopiridine-3-yl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecene-8-ene-2 2 -Formamide compound 4A; (1 6 S / R, E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-2 7 -Fluoro-N,N-dimethyl-3 4 -(4-(2-(3-methyl-2-oxo-1-(2-oxopiridine-3-yl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecene-8-ene-2 2 -Formamide compound 4B

[0376] The intermediate tert-butyl 4-[4-[6-[1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl]-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl]-3-(pent-4-en-1-yloxy)phenyl]piperazine-1-carboxylate 4m (240 mg, 0.13 mmol) was chirally resolved to give two isomers, 4m-P1 and 4m-P2.

[0377] Chiral resolution conditions: Instrument: SFC-80; chiral column: Daicel IB 25*250mm, 10um (Regis); column temperature: 35℃; mobile phase: CO2 / [MeOH / ACN]=50 / 50; flow rate: 45ml / min; column pressure: 2000psi; detection wavelength: 214nm; cycle time: 3.4min; sample volume: 240mg sample dissolved in 8mL methanol; injection volume: 1mL per injection.

[0378] 4m-P1: (R / S)-tert-butyl 4-[4-[6-[1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl]-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl]-3-(pent-4-en-1-yloxy)phenyl]piperazine-1-carboxylic acid ester (95 mg, yield: 40%), white solid.

[0379] Retention time of chiral column: RT = 1.836 min;

[0380] 4m-P2: (S / R)-tert-butyl4-[4-[6-[1-[3-(1H-pyrazol-1-yl)propionyl]-2-allyl-1,2,5,6-tetrahydropyridin-3-yl]-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl]-3-(pent-4-en-1-yloxy)phenyl]piperazine-1-carboxylic acid ester (90 mg, yield: 38%), white solid.

[0381] Retention time of chiral column: RT = 2.218 min.

[0382] Following the same synthesis conditions as in Example 4, using intermediate 4m-P1 as a starting material, (1) was prepared to obtain (1) 6 R / S,E)-11-(3-(1H-pyrazol-1-yl)propionyl)-2 7 -Fluoro-N,N-dimethyl-3 4 -(4-(2-(3-methyl-2-oxo-1-(2-oxopiridine-3-yl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecene-8-ene-2 2 -Formamide compound 4A (12 mg, two-step yield: 28%) is a white solid.

[0383] LCMS: m / z = 476.6M / 2 + H] + .

[0384] 1 H NMR (400MHz, DMSO-d6): 12.02(s, 1H), 11.09(s, 1H), 7.71-7.64(m, 1H), 7.42-7.23( m, 3H), 6.99-6.96 (m, 3H), 6.68-6.61 (m, 3H), 6.20-6.16 (m, 1H), 6.04-5.95 (m, 1H), 5.62-5.24(m, 4H), 4.74-4.52(m, 1H), 4.44-4.33(m, 2H), 4.24-4.14(m, 1H), 4.09-3 .73(m, 2H), 3.62(s, 3H), 3.27-2.59(m, 24H), 2.39-1.92(m, 6H), 1.75-1.63(m, 2H).

[0385] (1) was prepared using intermediate 4m-P2 as a raw material. 6 S / R, E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-2 7 -Fluoro-N,N-dimethyl-3 4 -(4-(2-(3-methyl-2-oxo-1-(2-oxopiridine-3-yl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecene-8-ene-2 2 -Formamide compound 4B (24 mg, two-step yield: 56%) is a white solid.

[0386] LCMS: m / z = 476.5 [M / 2 + H] + .

[0387] 1H NMR (400MHz, DMSO-d6): 12.02(s, 1H), 11.09(s, 1H), 7.71-7.65(m, 1H), 7.42-7.24( m, 3H), 7.00-6.94 (m, 3H), 6.68-6.61 (m, 3H), 6.20-6.16 (m, 1H), 6.04-5.96 (m, 1H), 5.62-5.23(m, 4H), 4.75-4.52(m, 1H), 4.42-4.32(m, 2H), 4.25-4.13(m, 1H), 3.90-3 .75(m, 2H), 3.62(s, 3H), 3.27-2.61(m, 24H), 2.42-1.91(m, 6H), 1.77-1.61(m, 2H).

[0388] Example 5: (E)-1 1 -[3-(1H-pyrazole-1-yl)propionyl]-3 4 -{4-[(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl]piperazin-1-yl}-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecene-8-ene-2 2 -Formamide compound 5

[0389] Following the same synthetic method as in Example 4, 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-carboxaldehyde (which can be prepared by the method reported in patent WO2024 / 263586) was used instead of 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetaldehyde to obtain (E)-1 1 -[3-(1H-pyrazole-1-yl)propionyl]-3 4 -{4-[(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl]piperazin-1-yl}-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 16 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecene-8-ene-2 2 5-Formamide compound (2.23 mg) is a white solid.

[0390] LCMS: m / z = 937.2 [M+H] + .

[0391] 1 H NMR (400MHz, DMSO-d6): 12.01 (s, 1H), 11.10 (s, 1H), 7.70-7.64 (m, 1H), 7.42-7.23 (m, 3H), 7.10 (d, J=7.6Hz, 1H), 7.02-6.94 (m, 2H), 6.67-6.59 (m, 3H), 6.20-6.15 (m, 1H), 6 .03-5.95(m,1H),5.61-5.25(m,4H),4.74-4.51(m,1H),4.41-4.31(m,2H),4.23-4.08 (m, 1H), 3.89-3.73 (m, 7H), 3.22-3.57 (m, 20H), 2.37-1.91 (m, 6H), 1.77-1.59 (m, 2H).

[0392] Example 6: (E)-1 1 -[3-(1H-pyrazole-1-yl)propionyl]-3 4 -[4-([1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]methyl)piperazin-1-yl]-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 ,2 1 -pentahydro-4-oxa-2(6,4)-indolo[1(5,6)]pyridine-3(1,2)-benzocyclodeceno-8-ene-2 2 -Formamide compound 6

[0393] Following the same synthetic method as in Example 4, the intermediate 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-carboxaldehyde (which can be prepared by the method reported in patent WO2024 / 263586) was used instead of 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetaldehyde to obtain (E)-1 1 -[3-(1H-pyrazole-1-yl)propionyl]-3 4 -[4-([1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]methyl)piperazin-1-yl]-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 ,2 1 -pentahydro-4-oxa-2(6,4)-indolo[1(5,6)]pyridine-3(1,2)-benzocyclodeceno-8-ene-2 2 6-Formamide compound (8.2 mg) is a white solid.

[0394] LCMS: m / z = 937.3 [M+H] + .

[0395] 1 H NMR (400MHz, DMSO-d6): 12.01 (s, 1H), 11.09 (s, 1H), 7.75-7.64 (m, 1H), 7.43-7.23 (m, 3H) ,7.17(s,1H),7.10-7.02(m,2H),6.67-6.59(m,3H),6.22-6.15(m,1H),6.05-5.95(m,1H), 5.61-5.24(m, 4H), 4.73-4.52(m, 1H), 4.41-4.33(m, 2H), 4.24-4.10(m, 1H), 3.90-3.75(m , 1H), 3.57(s, 2H), 3.35(s, 4H), 3.24-2.56(m, 20H), 2.36-1.97(m, 6H), 1.77-1.63(m, 2H).

[0396] Example 7: 2 7 -Fluorine-1 1 -[3-(1H-pyrazol-1-yl)propionyl]-N,N-dimethyl-3 4-[4-[2-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl]ethyl]piperazin-1-yl]-1 1 1 2 1 3 1 6 ,2 1 -pentahydro-4-oxa-2(6,4)-indolo[1(5,6)]pyridine-3(1,2)-benzocyclodecenophene-2 2 -Formamide compound 7

[0397] Step 1: (E)-tert-butyl-4-[1 1 -(3-(1H-pyrazole-1-yl)propionyl)-2 2 -(dimethylcarbamoyl)-2 7 -Fluorine-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indolo[1(5,6)]pyridine-3(1,2)-benzocyclodeceno-8-ene-3 4 [-yl]piperazine-1-carboxylate 7a

[0398] At room temperature, (E)-tert-butyl-4-[1 1 -(3-(1H-pyrazole-1-yl)propionyl)-2 2 -(dimethylcarbamoyl)-2 7 -Fluorine-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-3 4 (E)-tert-butyl-4-[1-yl]piperazine-1-carboxylate 4n (84 mg, 0.11 mmol) and Pd / C (50 mg) were added sequentially to ethyl acetate (20 mL). The mixture was purged with hydrogen three times and reacted at room temperature under hydrogen atmosphere for 2 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain (E)-tert-butyl-4-[1-yl]piperazine-1-carboxylate 4n (84 mg, 0.11 mmol) and Pd / C (50 mg) were added sequentially to ethyl acetate (20 mL). 1 -(3-(1H-pyrazole-1-yl)propionyl)-2 2 -(dimethylcarbamoyl)-2 7 -Fluorine-1 1 1 2 1 3 1 6-Tetrahydro-2 1 H-4-oxa-2(6,4)-indolo[1(5,6)]pyridine-3(1,2)-benzocyclodeceno-8-ene-3 4 [-yl]piperazine-1-carboxylate 7a (68 mg, yield 81%) is a white solid.

[0399] LCMS: m / z = 767.9 [M+H] + .

[0400] Step 2: 2 7 -Fluorine-1 1 -(3-(1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-3,4-(piperazin-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indolo[1(5,6)]pyridine-3(1,2)-benzocyclodecanophen-2 2 -Formamide 7b

[0401] At room temperature, (E)-tert-butyl-4-[1 1 -(3-(1H-pyrazole-1-yl)propionyl)-2 2 -(dimethylcarbamoyl)-2 7 -Fluorine-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indolo[1(5,6)]pyridine-3(1,2)-benzocyclodeceno-8-ene-3 4 [-yl]piperazine-1-carboxylate 7a (68 mg, 0.09 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was confirmed to be complete by LCMS, the crude product was concentrated under reduced pressure. The crude product was dissolved in saturated potassium carbonate aqueous solution (10 mL) and extracted three times with dichloromethane (30 mL). The collected organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2 7 -Fluorine-1 1 -(3-(1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-3,4-(piperazin-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1H-4-oxa-2(6,4)-indolo[1(5,6)]pyridine-3(1,2)-benzocyclodecanophen-2 2 -Formamide 7b (58 mg, 98% yield) is a yellowish-brown solid.

[0402] LCMS: m / z = 667.9 [M+H] + .

[0403] Step 3: 2 7 -Fluorine-1 1 -[3-(1H-pyrazol-1-yl)propionyl]-N,N-dimethyl-3 4 -[4-[2-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl]ethyl]piperazin-1-yl]-1 1 1 2 1 3 1 6 ,2 1 -pentahydro-4-oxa-2(6,4)-indolo[1(5,6)]pyridine-3(1,2)-benzocyclodecenophene-2 2 -Formamide compound 7

[0404] At room temperature, 2 7 -Fluorine-1 1 -(3-(1H-pyrazol-1-yl)propionyl)-N,N-dimethyl-3 4 -(piperazine-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indolo[1(5,6)]pyridine-3(1,2)-benzocyclodecanophen-2 2 -Formamide 7b (58 mg, 0.09 mmol) and 2-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl]acetaldehyde (26 mg, 0.09 mmol) were dissolved in dimethyl sulfoxide (1 mL) and tetrahydrofuran (4 mL). The reaction mixture was purged three times with nitrogen and reacted at room temperature for 1 h under nitrogen protection. Then, sodium triacetylborohydride (110 mg, 0.52 mmol) was added, and the reaction mixture was stirred overnight. After the reaction was confirmed to be complete by LCMS, the reaction was quenched with water (20 mL), extracted twice with dichloromethane (40 mL), and the collected organic phase was washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography to obtain 2... 7 -Fluorine-1 1-[3-(1H-pyrazol-1-yl)propionyl]-N,N-dimethyl-3 4 -[4-[2-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl]ethyl]piperazin-1-yl]-1 1 1 2 1 3 1 6 ,2 1 -pentahydro-4-oxa-2(6,4)-indolo[1(5,6)]pyridine-3(1,2)-benzocyclodecenophene-2 2 -Formamide compound 7 (14 mg, yield: 17%) is a white solid.

[0405] LCMS: m / z = 953.3 [M+H] + .

[0406] 1 H NMR (400MHz, DMSO-d6): 12.00(s, 1H), 11.09(s, 1H), 7.71-7.64(m, 1H), 7.42-7.31(m , 1H), 7.21 (d, J=8.8Hz, 1H), 6.99-6.90 (m, 4H), 6.71-6.48 (m, 3H), 6.19-6.13 (m, 1H) ,5.97-5.91(m,1H),5.51-5.35(m,2H),4.43-4.33(m,2H),4.12-3.82(m,3H),3.62(s , 3H), 3.26-2.61(m, 24H), 2.21-2.16(m, 1H), 2.03-1.99(m, 1H), 1.58-1.13(m, 11H).

[0407] Example 8: (E)-1 1 -[3-(1H-1,2,3-triazol-1-yl)propionyl]-3 4 -[4-[2-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl]ethyl]piperazin-1-yl]-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-2 2 -Formamide compound 8

[0408] Following the same synthetic method as in Example 4, 3-(1H-1,2,3-triazol-1-yl)propionic acid was used instead of 3-(1H-pyrazol-1-yl)propionic acid to obtain (E)-1 1 -[3-(1H-1,2,3-triazol-1-yl)propionyl]-3 4 -[4-[2-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl]ethyl]piperazin-1-yl]-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-2 2 -Formamide compound 8 (17 mg) is a white solid.

[0409] LCMS: m / z = 953.4 [M+H] + .

[0410] 1 H NMR (400MHz, DMSO-d6): 12.02 (m, 1H), 11.09 (s, 1H), 8.08-8.04 (m, 1H), 7.70-7.68 (m, 1H) , 7.40-7.24(m, 2H), 7.00-6.93(m, 3H), 6.69-6.60(m, 3H), 6.06-5.97(m, 1H), 5.62-5.12(m , 4H), 4.74-4.52(m, 3H), 4.26-4.10(m, 1H), 3.92-3.78(m, 2H), 3.62-3.58(m, 3H), 3.41-3 .36 (m, 1H), 3.27-2.85 (m, 15H), 2.63-2.60 (m, 8H), 2.28-1.909 (m, 6H), 1.77-1.46 (m, 2H).

[0411] Example 9: (E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-2 7 3 3 -Difluoro-N,N-dimethyl-1 1 12 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecene-8-ene-2 2 -Formamide compound 9

[0412] Following the same synthetic method as in Example 4, tert-butyl 4-[2-fluoro3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-1-piperazincarboxylate was used instead of tert-butyl 4-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-1-piperazincarboxylate 4c to obtain (E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-2 7 3 3 -Difluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecene-8-ene-2 2 16 mg of formamide compound 9 is a white solid.

[0413] LCMS: m / z = 969.4 [M+H] + .

[0414] 1H NMR (400MHz, DMSO-d6): 12.11-12.06 (m, 1H), 11.11 (s, 1H), 7.74-7.69 (m, 1H), 7.43- 7.37(m, 1H), 7.20-6.83(m, 7H), 6.60-6.35(m, 1H), 6.22-6.18(m, 1H), 5.97-5.87(m, 1H), 5.57-5.36(m, 2H), 5.18-4.54(m, 3H), 4.41-4.36(m, 2H), 3.87-3.68(m, 2H), 3.6 2(s, 3H), 321-2.85(m, 17H), 2.70-2.61(m, 7H), 2.33-1.99(m, 6H), 1.75-1.46(m, 2H).

[0415] Example 10: (E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-3 4 -(4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azacyclobutane-3-yl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecane-8-ene-2 2 -Formamide compound 10

[0416] Step 1: 3-[4-(3-hydroxyazacyclobutane-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl]piperidine-2,6-dione 10b

[0417] At room temperature, 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 10a (1.0 g, 2.97 mmol), cesium carbonate (2.92 g, 8.91 mmol), 3-hydroxyazacyclobutane hydrochloride (323.4 mg, 3.94 mmol), and (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylyl]dichloro(3-chloropyridine-KN)palladium were sequentially added to 1,4-dioxane (20 mL). The reaction mixture was reacted in a microwave environment at 100 °C for 3 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), extracted three times with ethyl acetate (100 mL), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: methanol: dichloromethane = 0%-5%) to give 3-[4-(3-hydroxyazacyclobutane-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl]piperidine-2,6-dione 10b (300 mg, yield: 31%), as a yellow oil.

[0418] LCMS: m / z = 331.0 [M+H] + .

[0419] Step 2: 3-(3-methyl-2-oxo-4-(3-oxozyracyclobutan-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 10c

[0420] At room temperature, 3-[4-(3-hydroxyazacyclobutan-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl]piperidine-2,6-dione 10b (300 mg, 0.91 mmol) and 2-iodobenzoic acid (510 mg, 1.82 mmol) were added sequentially to dimethyl sulfoxide (10 mL), and the reaction mixture was reacted at room temperature for 16 hours. The mixture was diluted with water (30 mL), extracted three times with ethyl acetate (100 mL), washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: methanol: dichloromethane = 0%-5%) to give 3-(3-methyl-2-oxo-4-(3-oxozyracyclobutane-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 10c (160 mg, yield: 54%), which was a yellow oil.

[0421] Step 3: (E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-3 4 -(4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azacyclobutane-3-yl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecane-8-ene-2 2 -Formamide compound 10

[0422] At room temperature, 7-[(dimethylamino)formyl]-5-fluoro-12-{4-[2-(1,2,4-triazol-1-yl)acetamyl]piperidin-1-yl}-1,2,3,4-tetrahydrobenzo[5,6]cycloheptane[1,2-b]pyridin-8-carboxylic acid piperazine amide 10d (using the same synthesis method as in Example 4, but replacing 3-(1H-1,2,3-triazol-1-yl)propionic acid with 3-(1H-pyrazol-1-yl)propionic acid) was synthesized. The following were prepared by adding 3-(3-methyl-2-oxo-4-(3-oxozyracyclobutane-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 10c (49.2 mg, 0.15 mmol) and acetic acid (2 drops) to dichloromethane (2 mL) and methanol (2 mL) respectively. The reaction mixture was stirred at 70 °C for 16 hours. After cooling to room temperature, sodium cyanoborohydride (30.0 mg, 4.73 mmol) was added to the reaction mixture, and the mixture was reacted at room temperature for 16 hours. The reaction mixture was diluted with water (30 mL), extracted three times with dichloromethane (50 mL), washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography to obtain (E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-3 4 -(4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azacyclobutane-3-yl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 16 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecane-8-ene-2 2 -Formamide compound 10 (5.2 mg, yield: 4%) is a white solid.

[0423] LCMS: m / z = 979.5 [M+H] + .

[0424] 1 H NMR (400MHz, DMSO-d6): 12.02 (s, 1H), 11.08 (s, 1H), 8.08-8.03 (m, 1H), 7.69-7.67 (m, 1H) ), 7.40-7.24(m, 2H), 6.97(d, J=8.0Hz, 1H), 6.76-6.60(m, 5H), 6.06-5.97(m, 1H), 5.62-5 .23(m, 4H), 4.74-4.53(m, 3H), 4.25-4.16(m, 1H), 3.97-3.72(m, 6H), 3.60(s, 3H), 3.47-3 .39 (m, 1H), 3.26-2.85 (m, 15H), 2.71-2.60 (m, 4H), 2.37-1.96 (m, 6H), 1.75-1.60 (m, 2H).

[0425] Example 11: (Z)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indolo-1(5,6)-pyrido-3(1,2)-benzocyclononen-7-ene-2 2 -Formamide compound 11A; (E)-11-(3-(1H-pyrazol-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 12 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indolo-1(5,6)-pyrido-3(1,2)-benzocyclononen-7-ene-2 2 -Formamide compound 11B

[0426] Following the same synthesis method as in Example 4, 4-bromo-1-butene was used instead of 5-bromo-1-pentene, and the final sample was purified and separated by high performance liquid chromatography to obtain (Z)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indolo-1(5,6)-pyrido-3(1,2)-benzocyclononen-7-ene-2 2 -Formamide compound 11A (8.35 mg) is a white solid.

[0427] LCMS: m / z = 469.4 [M / 2 + H] + .

[0428] 1 H NMR (400MHz, DMSO-d6): 11.95 (s, 1H), 11.09 (s, 1H), 7.72 (s, 1H), 7.42-7.39 (m, 1H) , 7.28 (d, J = 8.0Hz, 1H), 6.99-6.94 (m, 3H), 6.84 (d, J = 6.0Hz, 1H), 6.65-6.56 (m, 3H) , 6.61-6.18(m, 1H), 6.01-5.93(m, 1H), 5.40-5.34(m, 3H), 5.15-5.08(m, 1H), 4.72- 4.36 (m, 3H), 3.88-3.74 (m, 3H), 3.62 (s, 3H), 3.24-2.67 (m, 24H), 2.41-1.99 (m, 6H).

[0429] and (E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indolo-1(5,6)-pyrido-3(1,2)-benzocyclononen-7-ene-2 2 -Formamide compound 11B (8.40 mg) is a white solid.

[0430] LCMS: m / z = 469.4 [M / 2 + H] + .

[0431] 1 H NMR (400MHz, DMSO-d6): 11.98 (s, 1H), 11.09 (s, 1H), 7.72 (s, 1H), 7.42-7.40 (m, 2H), 7.16 (d, J=6.8Hz, 1H), 6.99-6.93 (m, 3H), 6.65-6.63 (m, 3H) ), 6.46(s, 3H), 6.20-6.12(m, 1H), 5.46-5.35(m, 4H), 4.53-5.28(m, 3H) , 4.13-3.78(m, 3H), 3.62(s, 3H), 3.27-2.61(m, 24H), 2.41-1.99(m, 6H).

[0432] Example 12: (E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetyl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-2 2 -Formamide compound 12

[0433] Step 1: 3-(4-allyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 12c

[0434] At room temperature, 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 12a (500 mg, 1.48 mmol) was dissolved in 1,4-dioxane / water (20 mL / 0.5 mL), followed by the sequential addition of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane 12b (750 mg, 4.45 mmol), cesium carbonate (328 mg, 4.45 mmol), and dichloro[1,1′-bis(diphenylphosphine)ferrocene]palladium(II) (110 mg, 0.15 mmol). The reaction mixture was purged with nitrogen three times and reacted at 80 °C for 1 hour under nitrogen protection. The reaction was detected by LCMS. The crude product was concentrated under reduced pressure by solvent and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-50%) to obtain 3-(4-allyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 12c (500 mg, crude product), which is a brown solid.

[0435] LCMS: RT=1.32mm, m / z=300.2[M+H] + .

[0436] Step 2: 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetic acid 12d

[0437] At room temperature, 200 mg (0.67 mmol) of 3-(4-allyl-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione 12c was added to carbon tetrachloride (4 mL) and acetonitrile (4 mL), followed by the addition of sodium periodate (429 mg, 2.01 mmol) and ruthenium trichloride (15 mg, 0.07 mmol) in water (4 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was filtered, and the mother liquor was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase column chromatography (eluent: water: acetonitrile = 0%-5%) to give 12d (100 mg, two-step yield: 47%) of 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetic acid, as a brown solid.

[0438] LCMS: RT=0.952min, m / z=318.2[M+H]+ .

[0439] Step 3: (E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetyl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-2 2 -Formamide compound 12

[0440] At room temperature, 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetic acid 12d (40 mg, 0.11 mmol), intermediate 4n (50 mg, 0.08 mmol), and N,N-methylformamide (5 mL) were added sequentially, followed by 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate (60 mg, 0.15 mmol) and N,N-diisopropylethylamine (30 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched with water (5 mL), then extracted twice with dichloromethane (20 mL). The combined dichloromethane phases were washed once with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography to obtain (E)-1. 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetyl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-2 2 -Formamide compound 12 (22.16 mg, yield 31%) is a white solid.

[0441] LCMS: m / z = 483.3 [M / 2 + H] + .

[0442] 1 H NMR (400MHz, DMSO-d6): 12.04(s, 1H), 11.09(s, 1H), 7.75-7.65(m, 1H), 7.43-7.25(m , 3H), 7.04-6.95 (m, 2H), 6.84-6.83 (m, 1H), 6.71-6.60 (m, 3H), 6.20-6.16 (m, 1H), 6. 04-5.96(m, 1H), 5.62-5.24(m, 4H), 4.75-4.24(m, 4H), 4.17(s, 2H), 3.91-3.79(m, 4H ), 3.69 (s, 2H), 3.48 (s, 3H) 3.26-2.61 (m, 16H), 2.50-1.97 (m, 6H), 1.79-1.62 (m, 2H).

[0443] Example 13: (E)-1 1 -[3-(1H-pyrazole-1-yl)propionyl]-3 4 -{4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]piperazin-1-yl}-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclononfen-7-ene-2 2 -Formamide compound 13

[0444] At room temperature, intermediate 4n (30 mg, 0.05 mmol) was dissolved in 1,4-dioxane (4 mL), followed by the sequential addition of 3-(4-bromo-3-fluorophenyl)piperidine-2,6-dione (this intermediate can be prepared by the method reported in patent WO2025049820A1) (26 mg, 0.09 mmol), cesium carbonate (45 mg, 0.14 mmol), and methanesulfonic acid (2-dicyclohexylphosphine). The reaction mixture consisted of 2′,6′-diisopropoxy-1,1′-biphenyl)(2-amino-1,1′-biphenyl-2-yl)palladium(II) (8 mg, 0.01 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylylene]dichloro(3-chloropyridine-KN)palladium (10 mg, 0.01 mmol). Nitrogen exchange was performed three times, and the reaction mixture was reacted at 90 °C for 3 hours under nitrogen protection. The reaction was completed by LCMS. The solvent was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-10%) and high-performance liquid chromatography to obtain (E)-1 1 -[3-(1H-pyrazole-1-yl)propionyl]-3 4 -{4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]piperazin-1-yl}-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclononfen-7-ene-2 2 -Formamide compound 13 (1.10 mg, yield 3%) is a purple solid.

[0445] LCMS: m / z = 857.3 [M+H] + .

[0446] 1 H NMR (400MHz, CD3CN): 9.96-9.94 (m, 1H), 8.71 (s, 1H), 7.56-7.22 (m, 4H), 7.09-6.79 (m, 4H), 6.69-6.46 (m, 3H), 6. 20-6.11 (m, 1H), 5.50-5.12 (m, 3H), 4.77-4.38 (m, 3H), 4.12-3.73 (m, 4H), 3.40-2.91 (m, 19H), 2.70-2.01 (m, 7H).

[0447] Example 14: (16 R / S,E)-11-(3-(1H-pyrazol-1-yl)propionyl)-3 4 -(4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azacyclobutane-3-yl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-11,12,13,16-tetrahydro-21H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-22-carboxamide compound 14A; (1 6 S / R,E)-11-(3-(1H-pyrazol-1-yl)propionyl)-3 4 -(4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azacyclobutane-3-yl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-11,12,13,16-tetrahydro-21H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodecenophen-8-ene-22-carboxamide compound 14B

[0448] Following the same synthesis conditions as in Example 10, using intermediate 4n as a raw material, the following was prepared: (1) 6 R / S,E)-11-(3-(1H-pyrazol-1-yl)propionyl)-3 4 -(4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azacyclobutane-3-yl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-11,12,13,16-tetrahydro-21H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-22-carboxamide compound 14A: (8.30 mg, yield: 16%) is a white solid.

[0449] LCMS: m / z = 490.0 [M / 2 + H] + .

[0450] 1H NMR (400MHz, DMSO-d6): 12.02 (s, 1H), 11.08 (s, 1H), 7.74-7.64 (m, 1H), 7.44-7.24 (m, 3H), 7. 03-6.95(m, 1H), 6.76-6.60(m, 5H), 6.22-6.19(m, 1H), 6.04-5.95(m, 1H), 5.62-5.24(m, 4H), 4.74-4.52(m, 1H), 4.42-4.30(m, 2H), 4.25-4.12(m, 1H), 3.97-3.72(m, 6H), 3.60(s, 3H), 3.4 2-3.36 (m, 1H), 3.26-3.85 (m, 16H), 2.73-2.60 (m, 4H), 2.39-1.98 (m, 6H), 1.75-1.65 (m, 2H).

[0451] The sample was prepared using intermediate 4m-P1 as a starting material under the same synthesis conditions as in Example 10. (1) 6 S / R,E)-11-(3-(1H-pyrazol-1-yl)propionyl)-3 4 -(4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azacyclobutane-3-yl)piperazin-1-yl)-2 7 14B (14.41 mg, yield: 19%) of fluoro-N,N-dimethyl-11,12,13,16-tetrahydro-21H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-22-carboxamide is a white solid.

[0452] LCMS: m / z = 489.9 [M / 2 + H] + .

[0453] 1H NMR (400MHz, DMSO-d6): 12.04 (s, 1H), 11.08 (s, 1H), 7.75-7.64 (m, 1H), 7.44-7.24 (m, 3H), 7. 03-6.95(m, 1H), 6.77-6.60(m, 5H), 6.22-6.15(m, 1H), 6.04-5.96(m, 1H), 5.62-5.24(m, 4H), 4.74-4.52(m, 1H), 4.42-4.30(m, 2H), 4.25-4.13(m, 1H), 3.96-3.77(m, 6H), 3.60(s, 3H), 3.4 2-3.37 (m, 1H), 3.26-2.85 (m, 16H), 2.74-2.59 (m, 4H), 2.33-1.98 (m, 6H), 1.75-1.61 (m, 2H).

[0454] Example 15: (E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -(4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-21H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-2 2 -Formamide compound 15

[0455] Following the same synthetic conditions as in Example 10, using intermediate 4n as the starting material, and replacing 2,6-dione with 3-(3-methyl-2-oxo-4-(4-oxopiperidin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine as the intermediate, we obtained (E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -(4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 12 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-2 2 -Formamide compound 15 (8.70 mg, yield: 16%) is a white solid.

[0456] LCMS: m / z = 503.8 [M / 2 + H] + .

[0457] 1 H NMR (400MHz, DMSO-d6): 12.02 (s, 1H), 11.09 (s, 1H), 7.74-7.64 (m, 1H), 7.44-7.25 (m, 3H ), 7.04-6.87(m, 3H), 6.69-6.61(m, 3H), 6.22-6.16(m, 1H), 6.03-5.96(m, 1H), 5.62-5.2 4(m, 4H), 4.74-4.52(m, 1H), 4.42-4.32(m, 2H), 4.25-4.13(m, 1H), 3.98-3.72(m, 2H), 3. 65(s, 3H), 3.25-2.60(m, 25H), 2.43-2.14(m, 4H), 2.10-1.89(m, 4H), 1.80-1.66(m, 4H).

[0458] Example 16: 1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclononaphthalene-2 2 -Formamide compound 16

[0459] Using the same experimental procedures as in Example 7, a mixture of synthetic intermediates 16a and 16b was prepared by replacing 5-bromo-1-pentene with 4-bromo-1-butene, and then 1 was prepared using the synthetic route of Example 7. 1-(3-(1H-pyrazole-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclononaphthalene-2 2 -Formamide compound 16 (34.89 mg, yield: 53%) is a white solid.

[0460] LCMS: m / z = 470.5M / 2 + H + .

[0461] 1 H NMR (400MHz, DMSO-d6): 11.98 (s, 1H), 11.09 (s, 1H), 7.71-7.62 (m, 1H), 7.42-7.18 (m, 3H), 7 .00-6.93(m, 3H), 6.64-6.59(m, 3H), 6.31-6.28(m, 1H), 6.19-6.12(m, 1H), 5.67(d, J=8.8Hz, 1H), 5.38 (dd, J=12.4Hz, 5.2Hz, 1H), 4.48-4.30 (m, 2H), 3.97-3.79 (m, 3H), 3.62 (s, 3H), 3.2 6-2.87(m, 16H), 2.72-2.61(m, 8H), 2.37-2.21(m, 2H), 2.02-1.99(m, 1H), 1.74-1.05(m, 8H).

[0462] Example 17: (1) 6 S,E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -((4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperazin-1-yl)methyl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecene-8-ene-2 2 -formamide or (1 6 R,E)-11-(3-(1H-pyrazole-1-yl)propionyl)-3 4 -((4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperazin-1-yl)methyl)-2 7 -Fluoro-N,N-dimethyl-11,12,13,16-tetrahydro-21H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecene-8-ene-2 2 -Formamide compound 17

[0463] Step 1: 4-[(4-bromo-3-hydroxyphenyl)methyl]-1-tert-butoxycarbonylpiperazine 17a

[0464] To a solution of 4-bromo-3-hydroxybenzaldehyde (350 mg, 1.75 mmol) in dichloromethane (20 mL), 1-tert-butyloxycarbonylpiperazine (326 mg, 1.75 mmol) was added. After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (742 mg, 3.5 mmol) was added. The reaction mixture was stirred for another 2 hours. After the reaction was complete, the mixture was poured into water (30 mL) and extracted with dichloromethane (20 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate) to give 4-[(4-bromo-3-hydroxyphenyl)methyl]-1-tert-butyloxycarbonylpiperazine 17a (520 mg, yield: 80%) as a colorless oil.

[0465] LCMS: m / z = 370.9 [M+H] + .

[0466] Step 2: 4-[(4-bromo-3-(methoxymethoxy)phenyl)methyl]-1-tert-butoxycarbonylpiperazine 17b

[0467] Sodium hydride (60% dispersed in mineral oil) (97 mg, 2.43 mmol) was added to a tetrahydrofuran (10 mL) solution of compound 4-[(4-bromo-3-hydroxyphenyl)methyl]-1-tert-butyloxycarbonylpiperazine 17a (450 mg, 0.14 mmol) at room temperature. The mixture was stirred for 30 minutes, and then chloromethyl ether (195 mg, 2.43 mmol) was added. After the addition was complete, the mixture was stirred for another 2 hours. Water (30 mL) was then added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (silica gel, petroleum ether / ethyl acetate = 0% to 80% gradient elution) to give 4-[(4-bromo-3-(methoxymethoxy)phenyl)methyl]-1-tert-butoxycarbonylpiperazine 17b (410 mg, yield: 81%), as a yellow oil.

[0468] LCMS: m / z = 414.9 [M+H] + .

[0469] Step 3: 4-{[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]methyl}-1-tert-butoxycarbonylpiperazine 17c

[0470] Under nitrogen protection, at 25 °C, [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (18 mg, 0.02 mmol) was added to a toluene (4 mL) suspension of 4-[(4-bromo-3-(methoxymethoxy)phenyl)methyl]-1-tert-butoxycarbonylpiperazine 17b (50 mg, 0.12 mmol), pinacol diborate (92 mg, 0.36 mmol), and potassium acetate (59 mg, 0.60 mmol). The mixture was refluxed and stirred for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude residue. This residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 0% to 80% gradient elution) to give compound 4-{[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl]methyl}-1-tert-butoxycarbonylpiperazine 17c (35 mg, yield: 63%), which was a yellow oil.

[0471] LCMS: m / z = 463.0 [M+H] + .

[0472] Step 4: Tert-butyl 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indole-4-yl)-3-(methoxymethoxy)benzyl)piperazine-1-carboxylic acid ester 17d

[0473] Under argon protection, 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (250 mg, 0.52 mmol), potassium carbonate (214 mg, 1.55 mmol), and 4-{[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-yl)-carboxamide (250 mg, 0.52 mmol), potassium carbonate (214 mg, 1.55 mmol), and 4-{[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-yl)-2-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (250 mg, 0.52 mmol), potassium carbonate (214 mg, 1.5 ... [-Dioxoboronyl-2-yl)phenyl]methyl}-1-tert-butoxycarbonylpiperazine 17c (239 mg, 0.52 mmol) was added to a mixture of dioxane (10 mL) and water (2 mL) at 25 °C. Methanesulfonic acid (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (44 mg, 0.05 mmol) was then added. The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was completed, the mixture was concentrated under vacuum to obtain a crude residue, which was purified by column chromatography (silica gel, dichloromethane / methanol = 0% to 10% gradient elution) to give tert-butyl 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)-3-(methoxymethoxy)benzyl)piperazine-1-carboxylic acid ester 17d (320 mg, yield: 79%) as a yellow solid.

[0474] LCMS: m / z = 463.0 [M+H] + .

[0475] Step 5: 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(2-hydroxy-4-(piperazin-1-ylmethyl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 17e

[0476] A methanol solution of 4 mol / L dioxane hydrochloric acid (4 mL) was added to a methanol solution of tert-butyl 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)-3-(methoxymethoxy)benzyl)piperazine-1-carboxylic acid 17d (400 mg, 0.51 mmol). The reaction mixture was allowed to react at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(2-hydroxy-4-(piperazin-1-ylmethyl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 17e (360 mg, crude product), which is a yellow solid.

[0477] LCMS: m / z = 640.0 [M+H] + .

[0478] Step 6: 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indole-4-yl)-3-hydroxybenzyl)piperazine-1-carboxylic acid tert-butyl ester 17f

[0479] To a solution of 6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(2-hydroxy-4-(piperazin-1-ylmethyl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 17e (360 mg, crude) and triethylamine (155 mg, 1.53 mmol) in dichloromethane (15 mL), di-tert-butyl dicarbonate (123 mg, 0.56 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with dichloromethane (20 mL) and water (40 mL) was added. The organic phase was collected by separation, and the aqueous phase was extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (silica gel, dichloromethane / methanol gradient 0–10%) to give compound 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)-3-hydroxybenzyl)piperazine-1-carboxylic acid tert-butyl ester 17f (300 mg, yield: 80%) as a yellow solid.

[0480] LCMS: m / z = 739.9 [M+H] + .

[0481] Step 7: (R / S)-4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)-3-(pent-4-en-1-oxy)benzyl)piperazine-1-carboxylic acid tert-butyl ester 17g (R / S)

[0482] Potassium carbonate (112 mg, 0.81 mmol) was added to an acetonitrile (8 mL) solution of 4-(4-(6-(1-(3-(1H-pyrazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)-3-hydroxybenzyl)piperazine-1-carboxylate 17f (200 mg, 0.27 mmol), 5-bromo-1-pentene (44 mg, 0.30 mmol), and potassium iodide (20 mg). The mixture was stirred overnight at 60 °C. After the reaction was complete, the reaction solution was diluted with ethyl acetate (EtOAc, 20 mL) and poured into water (30 mL). The organic phase was collected by separation, and the aqueous phase was extracted with ethyl acetate (15 mL × 2). The combined organic phases were washed with brine (25 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. This crude product was purified by column chromatography (silica gel, dichloromethane / methanol gradient 0% to 10%), followed by chiral separation (instrument: SFC-80; chiral column: Daicel IB 25*250 mm, 10 μm (Regis); column temperature: 35℃; mobile phase: CO2 / [MeOH / ACN] = 65 / 35; flow rate: 45 mL / min; column pressure: 2000 psi; detection wavelength: 214 nm; cycle time: 4.8 min; sample volume: 200 mg sample dissolved in 7.5 mL methanol; injection volume: 0.5 mL per injection). This yielded 17 g (R / S) (80 mg, yield: 40%) as a yellow solid.

[0483] LCMS: m / z = 808.0 [M+H] + .

[0484] Retention time of chiral column: RT = 2.390 mm.

[0485] Step 8: ((R / S, E)-4-((1) 1 -(3-(1H-pyrazole-1-yl)propionyl)-2 2 -(dimethylcarbamoyl)-2 7 -Fluorine-1 1 1 2 1 31 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecano-8-ene-3 4 17h (R / S) tert-butyl piperazine-1-carboxylate (-methyl)piperazine-1-carboxylate

[0486] To a solution of 17 g (R / S) (40 mg, 0.05 mmol) of tert-butyl piperazine-1-carboxylate in 10 mL of dichloromethane, 25 mg of benzyl-1,3-bis(2,4,6-trimethylmethyl)-2-(imidazoline carbene)(tricyclohexylphosphine) ruthenium dichloride was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction solution was poured into 20 mL of water, and the organic phase was collected by separation. The aqueous phase was extracted with dichloromethane (15 mL × 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification was performed by column chromatography (silica gel, dichloromethane / methanol gradient 0–10%) to give 17h(R / S) (35 mg, yield: 91%), as a brown solid.

[0487] LCMS: m / z = 780.0 [M+H] + .

[0488] Step 9: (R / S, E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-2 7 -Fluoro-N,N-dimethyl-3 4 -(piperazine-1-ylmethyl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecyl-8-ene-2 2 -Formamide 17i(R / S)

[0489] Trifluoroacetic acid (2 mL) was added to a 17h(R / S) (35 mg, 0.04 mmol) solution of dichloromethane (2 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (15 mL) and neutralized with aqueous potassium carbonate solution to pH > 9. The organic phase was collected by separation, and the aqueous phase was extracted with dichloromethane (15 mL × 2). The organic phases were combined and concentrated to give 17i(R / S) (30 mg, yield: 98%) as a brown solid.

[0490] LCMS: m / z = 679.9 [M+H] + .

[0491] Step 10: (1) 6 S,E)-1 1 -(3-(1H-pyrazole-1-yl)propionyl)-3 4 -((4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperazin-1-yl)methyl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecene-8-ene-2 2 -formamide or (1 6 R,E)-11-(3-(1H-pyrazole-1-yl)propionyl)-3 4 -((4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperazin-1-yl)methyl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-21H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecene-8-ene-2 2 -Formamide compound 17

[0492] To a solution of 17i(R / S) (18 mg, 0.03 mmol) and 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-4-carboxaldehyde 17j (15 mg, 0.05 mmol) in N,N-dimethylformamide / tetrahydrofuran (1 mL / 1 mL), sodium triacetoxyborohydride (11 mg, 0.05 mmol) was added, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was purified by preparative high-performance liquid chromatography to give compound 17 (6.5 mg, yield: 26%) as a white solid.

[0493] LCMS: m / z = 952[M+H] + ;

[0494] 1 H NMR (400MHz, DMSO-d6): 12.10 (s, 1H), 11.10 (s, 1H), 7.71-7.64 (m, 1H), 7.49-7.30 (m, 3H), 7.08-6.89(m, 5H), 6.67-6.58(m, 1H), 6.20-6.13(m, 1H), 6.05-5.96(m, 1H), 5.62-5.22(m, 4 H), 4.77-4.52(s, 1H), 4.42-4.30(s, 2H), 4.22-4.07(s, 1H), 3.90-3.79(s, 2H), 3.68(s, 5H) , 3.50 (s, 2H), 3.46-3.32 (s, 1H), 3.16-2.60 (m, 19H), 2.38-1.93 (m, 6H), 1.78-1.63 (m, 2H).

[0495] Example 18: (1) 6 E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-3 4 -(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-2 7 3 5 -Difluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecyl-8-ene-2 2 -Formamide compound 18

[0496] Step 1: 1-Bromo-4-chloro-2-fluoro-5-(methoxymethoxy)benzene 18b

[0497] 5-Bromo-2-chloro-4-fluorophenol 18a (1.0 g, 4.47 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, cooled to 0 °C, and sodium hydride (357 mg, 8.93 mmol) was added. The reaction mixture was stirred at 0 °C for 1 hour, and chloromethyl methyl ether (723 mg, 8.93 mmol) was slowly added dropwise, followed by stirring at 25 °C for 2 hours. Ice water (500 mL) was slowly added dropwise to the reaction mixture, and the mixture was extracted three times with ethyl acetate (100 mL). The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%–5%) to give 1-bromo-4-chloro-2-fluoro-5-(methoxymethoxy)benzene 18b (1.1 g, yield: 92.0%) as a colorless oil.

[0498] 1 H NMR (400MHz, DMSO-d6): 7.68 (d, J=8.4Hz, 1H), 7.581 (d, J=6.4Hz, 1H), 5.31 (s, 2H), 3.41 (s, 3H).

[0499] Step 2: Tert-butyl 4-(4-chloro-2-fluoro-5-(methoxymethoxy)phenyl)piperazine-1-carboxylate 18c

[0500] At room temperature, tert-butyl piperazine-1-carboxylate (1.14 g, 6.15 mmol), sodium tert-butoxide (1.18 g, 12.3 mmol), tris(dibenzyl indeneacetone)dipalladium(0) (110 mg), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (361 mg, 0.62 mmol) were sequentially added to a toluene (450 mL) solution of 1-bromo-4-chloro-2-fluoro-5-(methoxymethoxy)benzene 18b (1.1 g, 4.10 mmol). The reaction mixture was purged with nitrogen three times, and the reaction mixture was reacted at 120 °C for 1 hour under nitrogen protection. The reaction solution was cooled to room temperature, and water (50 mL) was added. The mixture was extracted three times with ethyl acetate (100 mL), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-5%) to give tert-butyl 4-(4-chloro-2-fluoro-5-(methoxymethoxy)phenyl)piperazine-1-carboxylate 18c (1.5 g, yield: 98%), which is a yellow oil.

[0501] LCMS: m / z = 319.0 [M-56+H] + .

[0502] Step 3: 4-(2-fluoro-5-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 18d

[0503] At room temperature, methyl tert-butyl 4-(4-chloro-2-fluoro-5-(methoxymethoxy)phenyl)piperazine-1-carboxylate 18c (1.50 g, 4.01 mmol) was dissolved in NN-methylacetamide (25 mL), followed by the addition of pinacol diboronate (3.06 g, 12.03 mmol), potassium acetate (1.18 g, 12.03 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (0.68 g, 0.80 mmol). The reaction mixture was purged with nitrogen three times and reacted at 110 °C for 3 hours under nitrogen protection. The reaction was confirmed by LCMS. Water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-15%) to give 18d (1.65 g, yield: 88%) of 4-(2-fluoro-5-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester, a yellow oil.

[0504] LCMS: m / z = 466.9 [M+H] + .

[0505] Step 4: tert-butyl 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indole-4-yl)-2-fluoro-5-(methoxymethoxy)phenyl)piperazine-1-carboxylic acid ester 18f

[0506] At room temperature, 18d (100 mg, 0.21 mmol) of methyl 4-(2-fluoro-5-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in 1,4-dioxane / water (10 / 1, 5 mL), followed by the addition of 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2-dioxane. 5,6-Tetrahydropyridin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide (104 mg, 0.21 mmol), potassium phosphate (134 mg, 0.63 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (34 mg, 0.04 mmol). The reaction mixture was refluxed under nitrogen protection for 2 hours after three nitrogen exchanges. The reaction was detected by LCMS. The solvent was concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in ethyl acetate (50 mL), washed twice with saturated brine (30 mL), dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-7%) to obtain 18f (150 mg, yield 92%), which was a colorless solid.

[0507] LCMS: m / z = 789.2 [M+H] + .

[0508] Step 5: 18g of 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(5-fluoro-2-hydroxy-4-(piperazin-1-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide

[0509] At room temperature, a solution of 1,4-dioxane in hydrogen chloride (6 mL) was added to a solution of tert-butyl 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)-2-fluoro-5-(methoxymethoxy)phenyl)piperazine-1-carboxylate 18f (140 mg, 0.18 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reactants had reacted completely (as monitored by LCMS), the solvent was removed by concentration under reduced pressure to obtain 18 g (100 mg, crude product) of 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(5-fluoro-2-hydroxy-4-(piperazin-1-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide, which was a colorless solid.

[0510] LCMS: m / z = 645.1 [M+H] + .

[0511] Step 6: Tert-butyl 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indole-4-yl)-2-fluoro-5-hydroxyphenyl)piperazine-1-carboxylic acid ester 18h

[0512] At room temperature, 18 g (100 mg, 0.16 mmol) of 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(5-fluoro-2-hydroxy-4-(piperazin-1-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide, 46 mg (0.46 mmol), and 51 mg (0.23 mmol) of ditert-butyl dicarbonate were sequentially added to 10 mL of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted three times with 30 mL of dichloromethane. The organic phase was washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-15%) to give tert-butyl 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)-2-fluoro-5-hydroxyphenyl)piperazine-1-carboxylic acid ester for 18 h (120 mg, yield: 74%), as a white solid.

[0513] LCMS: m / z = 745.2 [M+H] + .

[0514] Step 7: tert-butyl 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indole-4-yl)-2-fluoro-5-(pent-4-en-1-yloxy)phenyl)piperazine-1-carboxylate 18i

[0515] Potassium carbonate (66 mg, 0.48 mmol) was added to a 10 mL solution of tert-butyl 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)-2-fluoro-5-hydroxyphenyl)piperazine-1-carboxylic acid ester (18 h, 120 mg, 0.16 mmol) and 5-bromopent-1-ene (30 mg, 0.19 mmol). The mixture was stirred at 60 °C for 16 h. After the reaction was complete (monitored by LCMS), the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-10%) to give tert-butyl 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)-2-fluoro-5-(pent-4-en-1-yloxy)phenyl)piperazine-1-carboxylic acid ester 18i (100 mg, yield: 76%), as a white solid.

[0516] LCMS: m / z = 813.3 [M+H] + .

[0517] Step 8: tert-butyl(E)-4-(1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-2 2 -(dimethylcarbamoyl)-2 7 3 5 -Difluoro-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecane-8-en-3,4-yl)piperazine-1-carboxylate 18j

[0518] At room temperature, tert-butyl 4-(4-(6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(dimethylcarbamoyl)-7-fluoro-1H-indol-4-yl)-2-fluoro-5-(pent-4-en-1-yloxy)phenyl)piperazine-1-carboxylic acid ester 18i (100 mg, 0.12 mmol) and Grubbs II (50 mg) were added sequentially to dichloromethane (30 mL). The mixture was exchanged with nitrogen three times and stirred at 35 °C for 1 hour under nitrogen protection. The reaction solution was cooled to room temperature, water (20 mL) was added, and the mixture was extracted three times with dichloromethane (20 mL). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-10%) to obtain 18j (80mg, yield 93%), which was a yellow solid.

[0519] LCMS: m / z = 785.3 [M+H] + .

[0520] Step 9: (E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-2 7 3 5 -Difluoro-N,N-dimethyl-3 4 -(piperazine-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodeceno-8-ene-2 2 -Formamide 18k

[0521] At room temperature, a solution of 1,4-dioxane (5 mL) of hydrogen chloride was added to a 10 mL solution of 18kJ (80 mg, 0.10 mmol) of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. After the reaction proceeded completely (monitored by LCMS), the mixture was concentrated to dryness under reduced pressure to give 18kJ (60 mg, crude product) as a colorless solid.

[0522] LCMS: m / z = 685.3 [M+H] + .

[0523] Step 10: (1) 6 E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-3 4-(4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethyl)piperazin-1-yl)-2 7 3 5 -Difluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-21H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecyl-8-ene-22-carboxamide compound 18

[0524] At room temperature, sodium triacetoxyborohydride (92 mg, 0.44 mmol) was added to a solution of 18 kJ (60 mg, 0.09 mmol) and 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetaldehyde (40 mg, 0.13 mmol) in dichloroethane (5 mL), and the mixture was stirred at 70 °C for 4 hours. After the starting materials had reacted completely (monitored by LCMS), the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 0%-10%), and then further purified by preparative high performance liquid chromatography to obtain compound 18 (6.68 mg, yield 8%), which was a white solid.

[0525] LCMS: m / z = 971.1 [M+H] + .

[0526] 1 H NMR (400MHz, DMSO-d6): 12.13 (s, 1H), 11.10 (s, 1H), 8.09-8.04 (m, 1H), 7.70-7 .68(m, 1H), 7.36-7.22(m, 2H), 6.99-6.95(m, 3H), 6.72-6.62(m, 2H), 6.06-5.9 7(m, 1H), 5.61-5.26(m, 4H), 4.75-4.62(m, 3H), 4.24-4.11(m, 1H), 3.91-3.82( m, 2H), 3.62 (s, 3H), 3.25-2.67 (m, 24H), 2.33-1.92 (m, 6H), 1.76-1.58 (m, 2H).

[0527] Example 19:

[0528] (16 R, E)-1 1 -[3-(1H-1,2,3-triazol-1-yl)propionyl]-3 4 -[2-({1-(2,6-dioxopiridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl}methyl)-2,7-diazaspiro[3.5]non-7-yl]-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodecene-8-ene-2 2 -formamide or (1 6 S,E)-1 1 -[3-(1H-1,2,3-triazol-1-yl)propionyl]-3 4 -[2-({1-(2,6-dioxopiridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl}methyl)-2,7-diazaspiro[3.5]non-7-yl]-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodecene-8-ene-2 2 -Formamide compound 19

[0529] Following the same synthetic method as in Example 4, intermediate 19m was synthesized using tert-butyl 7-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-2,7-diazaspiro[3,5]nonane-2-carboxylate instead of 4-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-1-piperazine carboxylate 4c. The chiral isomers 19m-P1 (the first of the two stereoisomers of 19m) and 19m-P2 (the second of the two stereoisomers of 19m) were separated using the same chiral resolution method as in Example 4A. Following the same synthetic method as in Example 4, 19m-P1 was used, and the intermediate 1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-carboxaldehyde (which can be prepared by the method reported in patent WO2024 / 263586) was used instead of 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetaldehyde to obtain compound 19 (2.39 mg), which was a white solid.

[0530] LCMS: m / z = 978.9 [M+1] + ;

[0531] 1 H NMR (400MHz, DMSO-d6): 12.01 (m, 1H), 11.09 (s, 1H), 8.06-8.09 (m, 1H), 7.67-7. 65(m, 1H), 7.34-7.21(m, 2H), 7.03-6.91(m, 3H), 6.64-6.53(m, 3H), 6.02-5.92( m, 1H), 5.58-5.20 (m, 4H), 4.71-4.50 (m, 3H), 4.20-4.06 (m, 1H), 3.96-3.75 (m, 6 H), 3.21-2.87(m, 18H), 2.70-2.58(m, 3H), 2.30-2.17(m, 6H), 1.78-1.52(m, 6H).

[0532] Example 20: (1) 6 R, E)-1 1 -[3-(1H-1,2,3-triazol-1-yl)propionyl]-3 4 -[1-(2-{1-[(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl]ethyl}piperidin-4-yl]-2 7-Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodecene-8-2 2 -formamide or (1 6 S,E)-1 1 -[3-(1H-1,2,3-triazol-1-yl)propionyl]-3 4 -[1-(2-{1-[(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl]ethyl}piperidin-4-yl]-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclodecene-8-2 2 -Formamide compound 20

[0533] Following the same synthetic method as in Example 4, tert-butyl 4-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]piperidine-1-carboxylate was used instead of 4-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-1-piperazincarboxylate 4c to prepare intermediate 20m. Following the same chiral resolution method as in Example 4A, chiral isomers 20m-P1 (the first of the two stereoisomers of 20m to elute) and 20m-P2 (the second of the two stereoisomers of 20m to elute) were obtained. Then, following the same synthetic method as in Example 4, using 20m-P1 as the starting material, compound 20 (104 mg, yield: 33%) was prepared as a white solid.

[0534] LCMS: m / z = 951.3 [M+H] + ;

[0535] 1H NMR (400MHz, DMSO-d6): 12.10 (s, 1H), 11.10 (s, 1H), 8.06 (d, J=21.6Hz, 1H), 7.69 (d, J=6. 8Hz, 1H), 7.48-7.28(m, 2H), 7.03-6.93(m, 5H), 6.67-6.57(m, 1H), 6.07-5.98(m, 1H), 5.62 -5.24(m, 3H), 4.76-4.52(m, 3H), 4.28-4.12(m, 1H), 3.93-3.79(m, 2H), 3.62(s, 3H), 3.46- 3.38 (m, 1H), 3.12-2.99 (m, 11H), 2.90-2.58 (m, 7H), 2.40-2.16 (m, 7H), 2.08-1.64 (m, 8H).

[0536] Example 21: (1) 6 R, E)-1 1 -[3-(1H-1,2,3-triazol-1-yl)propionyl]-3 4 -[1-(2-{1-[(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl]ethyl}piperidin-4-yl]-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclononene-7-2 2 -formamide or (1 6 S,E)-11-[3-(1H-1,2,3-triazol-1-yl)propionyl]-3 4 -[1-(2-{1-[(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl]ethyl}piperidin-4-yl]-2 7 -Fluoro-N,N-dimethyl-11,12,13,16-tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclononene-7-2 2 -Formamide compound 21

[0537] Following the same synthetic method as in Example 4, tert-butyl piperidine-1-carboxylate was used instead of 4-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl]-1-piperazine carboxylate 4c, and 5-bromo-1-butene was used instead of 4-bromobut-1-ene to prepare intermediate 21m. Following the same chiral resolution method as in Example 4A, chiral isomers 21m-P1 (the first of the two stereoisomers of 21m) and 21m-P2 (the second of the two stereoisomers of 21m) were obtained. Following the same synthesis method as in Example 4, using 21m-P1 as a starting material, compound 21 (92 mg, yield: 37%) was prepared as a white solid.

[0538] LCMS: RT 1.948min, m / z=937.4[M+H] + ;

[0539] 1 H NMR (400MHz, DMSO-d6): 12.06 (d, J=15.6Hz, 1H), 11.11 (s, 1H), 8.12 (d, J=2. 8Hz, 1H), 7.69 (s, 1H), 7.49-7.18 (m, 1H), 6.99-6.86 (m, 5H), 6.66-6.49 (m, 1 H), 6.02-5.93(m, 1H), 5.40-5.07(m, 4H), 4.67-4.62(m, 2H), 4.15-3.87(m, 3 H), 3.61 (s, 3H), 3.42-3.39 (m, 1H), 3.21-2.56 (m, 19H), 2.33-1.74 (m, 13H).

[0540] Example 22: (1) 6 R, E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-3 4 -(4-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperazin-1-yl)piperidin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecano-8-ene-2 2 -formamide or (16 S,E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-3 4 -(4-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperazin-1-yl)piperidin-1-yl)-2 7 -Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecano-8-ene-2 2 -Formamide compound 22

[0541] Step 1: 2-Allyl-3-(((perfluorobutyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 22b

[0542] At room temperature, 54.0 g (225.80 mmol) of 1-tert-butoxycarbonyl-2-allyl-3-oxoperpiperidine 22a (22a can be prepared by the method reported in patent CN 118401509A) was dissolved in tetrahydrofuran (540 mL), cooled to 0 °C, and 41.3 g (270.96 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene was added. The reaction mixture was stirred at 0 °C for 5 minutes, and perfluorobutylsulfonyl fluoride (81.8 g (270.96 mmol) was slowly added dropwise. The reaction mixture was then stirred at 25 °C for 4 hours. Ice water (450 mL) was slowly added dropwise to the reaction mixture under ice bath conditions. The mixture was extracted three times with ethyl acetate (500 mL), washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 0%-6%) to give 2-allyl-3-(((perfluorobutyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 22b (97g, yield: 82.9%), as a colorless oil.

[0543] 1H NMR (400MHz, DMSO-d6): 6.13 (d, J=4.4Hz, 1H), 5.76-5.68 (m, 1H), 5.13-5.05 (m, 2H), 4.66-4.53 ( m, 1H), 4.01-3.82 (m, 1H), 3.01-2.82 (s, 1H), 2.44-2.36 (m, 2H), 2.35-2.16 (m, 2H), 1.39 (s, 9H).

[0544] Step 2: 2-Allyl-1,2,5,6-Tetrahydropyridin-3-yl1,1,2,2,3,3,4,4,4-Nonfluorobutane-1-sulfonate 22c

[0545] At room temperature, 2-allyl-3-(((perfluorobutyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 22b (97 g, 186.15 mmol) was dissolved in dichloromethane (400 mL), followed by the addition of a 4M solution of 1,4-dioxane in hydrogen chloride (485 mL). The reaction mixture was stirred at room temperature for 1–2 hours. The solution was concentrated to dryness under reduced pressure to give product 2-allyl-1,2,5,6-tetrahydropyridine-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate ester 22c (77.6 g, yield: 100%) as a yellow oil. The obtained compound was used directly in the next step without further purification.

[0546] LCMS: m / z = 422.4 [M+H] + .

[0547] Step 3: 1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate 22e

[0548] At room temperature, 2-allyl-1,2,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate 22c (27.0 g, 64.1 mmol), 3-(1H-1,2,3-triazol-1-yl)propionic acid 22d (10.9 g, 76.9 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18.4 g, 96.2 mmol) were sequentially added to pyridine (100 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, diluted with water (150 mL), extracted twice with ethyl acetate (100 mL), washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-100%) to give 1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate 22e (30.0 g, yield: 86.0%), as a yellow solid.

[0549] LCMS: m / z = 545.2 [M+H] + .

[0550] Step 4: 22g of 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide

[0551] At room temperature, 1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate 22e (36.6 g, 67.2 mmol) was dissolved in 1,4-dioxane / water (370 mL / 92 mL), followed by the addition of 4-chloro-7-fluoro-N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-indole-2-carboxamide 22f (30.0 g, 80.6 mmol), potassium carbonate (28.0 g, 201.5 mmol), and 1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (983.0 mg, 1.3 mmol). The reaction mixture was exchanged with nitrogen three times and reacted at 80°C for 2 hours under nitrogen protection. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth to remove the catalyst. The mixture was concentrated under reduced pressure to remove 1,4-dioxane. It was diluted with water (150 mL), extracted twice with ethyl acetate (500 mL), washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate: dichloromethane = 0%-100%) to give 22 g (28.0 g, yield: 85.9%) of 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide, as a yellow solid.

[0552] LCMS: m / z = 485.3 [M+H] + .

[0553] Step 5: (R / S)-6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 22h-1; (S / R)-6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 22h-2

[0554] 22 g (6.0 g) of racemic 6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide was chirally separated under the following conditions to obtain (R / S)-6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide. (Pinidin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 22h-1 (2.4 g, yield: 40%) and (S / R)-6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 22h-2 (2.8 g, yield: 46%).

[0555] Chiral column conditions: Equipment: SFC-150 (Waters); chiral column; AD25*250mm, 10um (Daicel); mobile phase: CO2 / [MEOH(0.2% NH3 (7M in MeOH):ACN=1:1]=40 / 60; flow rate: 120mL / min; outlet pressure: 100bar; wavelength: 214nM; injection volume: 4.8mL; sample preparation: 6000mg mixture dissolved in 100mL dichloromethane / methanol (1:2).

[0556] Intermediate 22h-1:

[0557] Chiral column retention time: 2.06 min;

[0558] LCMS: m / z = 485.3 [M+H] + ;

[0559] 1 H NMR (400MHz, DMSO-d6) 12.48 (d, J=12.3Hz, 1H), 8.11 (dd, J=7.0, 1.0Hz, 1H), 7.71 (d, J=1.1Hz, 1H), 7.06 (dd, J=84.5, 5.2Hz, 1H), 6.84 (d, J=3.1Hz , 1H), 5.95 (d, J=5.6Hz, 1H), 5.73-5.46 (m, 2H), 4.99-4.78 (m, 2H), 4.65 ( q, J=7.3Hz, 2H), 4.51-3.83 (m, 1H), 3.32-2.90 (m, 9H), 2.44-2.10 (m, 4H).

[0560] Intermediate 22h-2:

[0561] Chiral column retention time: 3.92 min;

[0562] LCMS: m / z = 485.2 [M+H] + ;

[0563] 1 H NMR (400MHz, DMSO-d6) 12.48 (d, J=12.3Hz, 1H), 8.11 (dd, J=7.0, 1.0Hz, 1H), 7.71 (d, J=1.1Hz, 1H), 7.06 (dd, J=84.5, 5.2Hz, 1H), 6.84 (d, J=3.1Hz , 1H), 5.95 (d, J=5.6Hz, 1H), 5.73-5.46 (m, 2H), 4.99-4.78 (m, 2H), 4.65 ( q, J=7.3Hz, 2H), 4.51-3.83 (m, 1H), 3.32-2.90 (m, 9H), 2.44-2.10 (m, 4H).

[0564] Step 6: Benzyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate 22j

[0565] At room temperature, benzylpiperazine-1-carboxylate (1.4 g, 6.40 mmol), tris(dibenzylacetone)dipalladium (489 mg, 0.53 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (308 mg, 0.53 mmol), and sodium tert-butoxide (1.5 g, 15.99 mmol) were added sequentially to a toluene solution (34 mL) of 4-bromo-2-fluoro-1-iodobenzene (1.6 g, 5.33 mmol). The reaction mixture was purged with nitrogen three times and stirred in an oil bath at 120 °C for 1 h. After the reaction was confirmed to be complete by LCMS, the reaction mixture was evaporated to dryness to obtain a crude product. The crude product was further purified by silica gel column chromatography (petroleum ether / ethyl acetate = 14%) to obtain benzyl 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate 22j (1.2 g, yield: 57%), which was a yellow liquid.

[0566] LCMS: RT=1.108min, m / z=394.9[M+H] + .

[0567] Step 7: 4-[4-[2,6-bis(benzyloxy)pyridin-3-yl]-2-fluorophenyl]piperazine-1-methyl ester 22k

[0568] At room temperature, a mixture of 4-(4-bromo-2-fluorophenyl)piperazine-1-carboxylate 22j (700 mg, 1.78 mmol) in 1,4-dioxane (45 mL) and water (9 mL) was successively added with 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)pyridine (1.1 g, 2.67 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (129 mg, 0.18 mmol), and potassium acetate (492 mg, 5.36 mmol). The reaction mixture was purged three times with nitrogen and stirred overnight in an oil bath at 100 °C. After the reaction of the raw materials was confirmed to be complete by LCMS, the reaction solution was evaporated to dryness to obtain the crude product. The crude product was further purified by silica gel column chromatography (petroleum ether / ethyl acetate = 24%) to obtain the crude product benzoic acid 4-[4-[2,6-bis(benzyloxy)pyridin-3-yl]-2-fluorophenyl]piperazine-1-methyl ester 22k (900mg, yield: 84%), which was a yellow solid.

[0569] LCMS: RT=1.279min, m / z=603.8[M+H] + .

[0570] Step 8: 3-(3-fluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione 221

[0571] At room temperature, Pd / C (50 mg) and Pd(OH)₂ (150 mg) were added sequentially to a solution of benzoic acid 4-[4-[2,6-bis(benzyloxy)pyridin-3-yl]-2-fluorophenyl]piperazine-1-methyl ester 22k (900 mg, 1.49 mmol) in trifluoroethanol (20 mL). The reaction solution was purged with hydrogen three times and stirred in an oil bath at 45 °C for 14 h. After the reaction was confirmed to be complete by LCMS, the reaction solution was filtered to remove the solid, and the filtrate was evaporated to dryness to obtain the crude product 3-(3-fluoro-4-(piperazine-1-yl)phenyl)piperidine-2,6-dione 221 (400 mg, yield: 92%) as a black solid. The crude product did not require further purification and was used directly in the next step.

[0572] LCMS: RT=0.634min, m / z=292.1[M+H] + .

[0573] Step 9: 8-(4-bromo-3-(methoxymethoxy)phenyl)-1,4-dioxa-8-azaspiro[4.5]decane 22n

[0574] At room temperature, 1,4-dioxa-8-azaspiro[4.5]decane (2.0 g, 13.99 mmol), tris(dibenzylacetone)dipalladium (1.1 g, 1.17 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (674 mg, 1.17 mmol), and potassium tert-butoxide (1.6 g, 13.99 mmol) were added sequentially to a toluene solution (320 mL) of 22 mL (4.0 g, 11.66 mmol) of 1-bromo-4-iodo-2-(methoxymethoxy)benzene. The reaction mixture was purged with nitrogen three times and stirred in an oil bath at 110 °C for 4 h. After the reaction of the raw materials was detected by LCMS to be complete, the reaction solution was evaporated to dryness to obtain the crude product. The crude product was further purified by silica gel column chromatography (petroleum ether / ethyl acetate = 17%) to obtain the product 8-(4-bromo-3-(methoxymethoxy)phenyl)-1,4-dioxa-8-azaspiro[4.5]decane 22n (3.1 g, yield: 75%), which was a brown liquid.

[0575] LCMS: RT=1.985mm, m / z=358.0[M+H] + .

[0576] Step 10: 8-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1,4-dioxa-8-azaspiro[4.5]decane 22o

[0577] At room temperature, a solution of 22n (2.8 g, 7.84 mmol) of 8-(4-bromo-3-(methoxymethoxy)phenyl)-1,4-dioxa-8-azaspiro[4.5]decane 22n in dimethyl sulfoxide (20 mL) was added sequentially with pinacol diborate (19.8 g, 78.43 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (568 mg, 0.78 mmol), and potassium acetate (3.8 g, 39.21 mmol). The reaction solution was purged with nitrogen three times and stirred in an oil bath at 110 °C for 3 h. After the reaction was confirmed to be complete by LCMS, the reaction solution was diluted with water (50 mL) and extracted three times with ethyl acetate (50 mL). The collected organic phase was washed once more with saturated brine (50 mL), then dried with anhydrous sodium sulfate, filtered, and the crude product was further purified by silica gel column chromatography (petroleum ether / ethyl acetate = 16%) to obtain the crude product 8-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentan-2-yl)phenyl)-1,4-dioxa-8-azaspiro[4.5]decane 220 (2.8 g, yield: 89%), which was a yellow liquid.

[0578] LCMS: RT=0.986min, m / z=406.0[M+H]+ .

[0579] Step 11: (R / S)-6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(2-(methoxymethoxy)-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 22p(R / S)

[0580] At room temperature, a mixture of 1,4-dioxane (80 mL) and water (20 mL) of the crude product 8-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)-1,4-dioxa-8-azaspiro[4.5]decane 220 (2.8 g, 6.91 mmol) was added sequentially to (R / S)-6-(1-(3-( The reaction mixture consisted of 1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-4-chloro-7-fluoro-N,N-dimethyl-1H-indole-2-carboxamide 22h-1(R / S) (1.7 g, 3.46 mmol), Xphos-Pd-G3 (583 mg, 0.69 mmol), and potassium carbonate (2.9 g, 20.74 mmol). The reaction solution was purged three times with nitrogen and stirred in an oil bath at 80 °C for 2 h. After the reaction was confirmed to be complete by LCMS, the reaction solution was evaporated to dryness to obtain the crude product. The crude product was further purified by silica gel column chromatography (dichloromethane / methanol = 2%) to give crude product 22p(R / S) (2.0 g, yield: 78%), as a white solid.

[0581] LCMS: RT=1.813min, m / z=728.3[M+H] + .

[0582] Step 12: (R / S)-6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(2-hydroxy-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 22q(R / S)

[0583] At room temperature, a methanol (10 mL) solution of the crude product (R / S)-6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(2-(methoxymethoxy)-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 22p(R / S) (2.0 g, 2.75 mmol) was slowly added to a 4N hydrochloric acid solution (10 mL) of 1,4-dioxane. The reaction mixture was stirred at room temperature for 2 h. After the reaction was confirmed to be complete by LCMS, the reaction mixture was evaporated to dryness to obtain the crude product. The crude product was diluted with saturated K2CO3 solution (20 mL) and extracted three times with dichloromethane (30 mL). The collected organic phase was washed once more with saturated brine (20 mL), then dried with anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was further purified by silica gel column chromatography (dichloromethane / methanol = 5%) to obtain the crude product (R / S)-6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(2-hydroxy-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 22q(R / S) (705 mg, yield: 34%), as a white solid.

[0584] LCMS: RT=0.758min, m / z=684.0[M+H] + .

[0585] Step 13: (R / S)-6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(2-(pent-4-en-1-yloxy)-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)-1H-indole-2-carboxamide 22r(R / S)

[0586] At room temperature, 5-bromopent-1-ene (169 mg, 1.13 mmol), potassium carbonate (426 mg, 3.09 mmol), and potassium iodide (170 mg, 1.03 mmol) were added sequentially to a 20 mL solution of crude product (R / S)-6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-4-(2-hydroxy-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)-N,N-dimethyl-1H-indole-2-carboxamide 22q(R / S) (705 mg, 1.03 mmol) in acetonitrile (20 mL). The reaction mixture was stirred in an oil bath at 65 °C for 3 days. After the reaction of the raw materials was confirmed to be complete by LCMS, the reaction solution was evaporated to dryness to obtain the crude product. The crude product was diluted with water (20 mL) and extracted three times with dichloromethane (30 mL). The collected organic phase was washed once with saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was further purified by preparative high performance liquid chromatography to obtain product (R / S)-6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(2-(pent-4-en-1-yloxy)-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)-1H-indole-2-carboxamide 22r(R / S) (260 mg, yield: 27%), which is a white solid.

[0587] LCMS: RT=1.940min, m / z=752.5[M+H] + .

[0588] Step 14: (R / S,E)-11-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2 7 -Fluoro-N,N-dimethyl-3 4 -(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecano-8-ene-2 2 -Formamide 22s(R / S)

[0589] At room temperature, a Grubbs second-generation catalyst (100 mg) was added to a solution of product (R / S)-6-(1-(3-(1H-1,2,3-triazol-1-yl)propionyl)-2-allyl-1,2,5,6-tetrahydropyridin-3-yl)-7-fluoro-N,N-dimethyl-4-(2-(pent-4-en-1-yloxy)-4-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)phenyl)-1H-indole-2-carboxamide 22r (260 mg, 0.35 mmol) in dichloromethane (80 mL). The reaction solution was purged with nitrogen three times at -78 °C and stirred in an oil bath at 30 °C for 2 h. After the reaction was confirmed to be complete by LCMS, the reaction solution was diluted with water (20 mL) and extracted three times with dichloromethane (30 mL). The collected organic phase was washed once more with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was further purified by silica gel column chromatography (dichloromethane / methanol = 5%) to give crude product (R / S,E)-1. 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-2 7 -Fluoro-N,N-dimethyl-3 4 -(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecano-8-ene-2 2 -Formamide 22s(R / S) (176 mg, yield: 70%) is a dark brown solid.

[0590] LCMS: RT=1.818min, m / z=724.3[M+H] + .

[0591] Step 15: (R / S, E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-2 7 -Fluoro-N,N-dimethyl-3 4 -(4-oxopiperidin-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecano-8-ene-2 2 -Formamide 22t(R / S)

[0592] At room temperature, to crude product (R / S, E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-2 7 -Fluoro-N,N-dimethyl-3 4 -(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecano-8-ene-2 2 1,4-dioxane in 4N HCl solution (2 mL) was slowly added to a formic acid solution (5 mL) containing 176 mg (0.24 mmol) of formamide 22s. The reaction mixture was stirred in an oil bath at 60 °C for 0.5 h. After the reaction was confirmed to be complete by LCMS, the reaction mixture was evaporated to dryness to obtain the crude product. The crude product was diluted with saturated K2CO3 solution (20 mL) and extracted three times with dichloromethane (30 mL). The collected organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was further purified by silica gel column chromatography (dichloromethane / methanol = 4%) to obtain the crude product (R / S, E)-1. 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-2 7 -Fluoro-N,N-dimethyl-3 4 -(4-oxopiperidin-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecano-8-ene-2 2 -Formamide 22t(R / S) (100 mg, yield: 64%) is a grayish-white solid.

[0593] LCMS: RT=0.769min, m / z=679.9[M+H] + .

[0594] Step 16: (1) 6 R, E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-3 4 -(4-(4-(4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl)piperazin-1-yl)piperidin-1-yl)-2 7-Fluoro-N,N-dimethyl-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecano-8-ene-2 2 -Formamide compound 22

[0595] At room temperature, to crude product (R / S, E)-1 1 -(3-(1H-1,2,3-triazol-1-yl)propionyl)-2 7 -Fluoro-N,N-dimethyl-3 4 -(4-oxopiperidin-1-yl)-1 1 1 2 1 3 1 6 -Tetrahydro-2 1 H-4-oxa-2(6,4)-indole-1(5,6)-pyridine-3(1,2)-benzocyclododecano-8-ene-2 2 To a mixture of 4 mL of dimethyl sulfoxide and 4 mL of tetrahydrofuran, 93 mg (93 mg, 0.14 mmol) of formamide 22t(R / S) was added, along with 80 mg (0.27 mmol) of 3-(3-fluoro-4-(piperazin-1-yl)phenyl)piperidine-2,6-dione and 2 drops of acetic acid. The reaction mixture was purged three times with nitrogen and stirred at room temperature for 1 h. Then, sodium triacetoxyborohydride (116 mg, 0.55 mmol) was added. After the addition was complete, the reaction mixture was stirred at room temperature overnight. After the reaction was confirmed to be complete by LCMS, the reaction mixture was diluted with 20 mL of water and extracted three times with dichloromethane (30 mL). The collected organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was further purified by preparative high performance liquid chromatography to give compound 22 (11.39 mg, yield: 8%) as a white solid.

[0596] LCMS: RT=1.751min, m / z=956.2[M+H] + ;

[0597] 1H NMR (400MHz, DMSO-d6): 12.04(s, 1H), 10.83(s.1H), 8.09-8.04(m, 1H), 7.70-7.68(m , 1H), 7.39-7.25(m, 2H), 7.05-7.00(m, 3H), 6.69-6.60(m, 3H), 6.06-5.97(m, 1H), 5.6 2-5.22(m, 3H), 4.74-4.53(m, 3H), 4.25-4.11(m, 1H), 3.88-3.78(m, 5H), 3.23-2.93( m, 14H), 2.78-2.61 (m, 8H), 2.42-2.15 (m, 5H), 12.05-1.91 (m, 4H), 1.75-1.59 (m, 4H).

[0598] Example of effect:

[0599] Cell culture: MV411, Jurkat, and A549 were purchased from Beyotime Biotechnology Co., Ltd., and hPBMCs were purchased from Rubai Biotechnology Co., Ltd. Cells were cultured in RPMI-1640 (Gibco, 22400089) medium containing 10% FBS (Gibco, 10091-148) at 37°C in a 5% CO2 incubator.

[0600] Example 1: Western blot (WB) detection of protein degradation

[0601] Western blotting was used to quantify the degradation of STAT6 protein and to detect the selectivity of STAT1, 2, 3, 4, and 5 proteins. 400,000 cells were seeded into 24-well plates and cultured overnight. A compound concentration gradient was prepared, starting at 10 μM and diluted 1:3. The serially diluted compounds were added to the cell wells and incubated at 37°C in a 5% CO2 incubator for 24 h. Cells were centrifuged and washed once with PBS. RIPA lysis buffer (ThermoFisher, 89900) containing 1% protease inhibitor & phosphatase inhibitor (ThermoFisher, 78442) was added to the cell pellet, and the mixture was placed on ice for 10 min. The lysis buffer was transferred to 1.5 mL centrifuge tubes by pipetting several times, centrifuged at 12,000 rpm for 10 min, and the supernatant was transferred to a new 1.5 mL centrifuge tube and stored at -80°C. Total protein was quantified using a BCA protein assay kit (Beyotime, P0012). Combine 4X LDS Sample Buffer (ThermoFisher, 84788), 10X NuPAGE TMAfter mixing the reducing agent (ThermoFisher, NP009) with the protein sample, incubate at 95°C for 5 minutes in a thermostatic mixer to denature the protein. Load 20-40 μg of protein onto a NuPAGE plate. TM 4-12% Bis-Tris Gel (Invitrogen) TM NuPAGE (NP0336BOX) was added to the electrophoresis tank. TM MOPS SDS electrophoresis buffer (Novex, NP001) was used for electrophoresis at a constant voltage of 100V. After protein separation, iBlot was used. TM 2. Transfer apparatus (Invitrogen) TM (IB21001) using the iBlot2 dry blotting system (Invitrogen) TM The membrane was transferred using IB23001. After transfer, it was blocked at room temperature for 1 hour with Quick Block blocking buffer (Beyotime, P0231). Primary antibody was added, and the membrane was incubated overnight at 4°C with gentle shaking. The membrane was washed three times for 5 minutes each with Western blotting buffer (Beyotime, P0023C-1L). The corresponding secondary antibody was added, and the membrane was incubated at room temperature for 1 hour with gentle shaking. The membrane was washed five times for 5 minutes each with Western blotting buffer. The SuperSignal... TM West Pico PLUS (ThermoFisher, 34577) chemiluminescent substrates were applied to the membrane. Chemiluminescence imaging was performed using a chemiluminescence imaging system (ChemiScope 6100). Antibodies used in the experiment: Stat1 (Cell Signaling Technologies, (D1K9Y) Rabbit mAb, #14994S), Stat2 (Cell Signaling Technologies, (D9J7L) Rabbit mAb, #72604S), Stat3 (Cell Signaling Technologies, (D3Z2G) Rabbit mAb, #12640S), Stat4 (Cell Signaling Technologies, (C46B10) Rabbit mAb, #2653S), Stat5 (Cell Signaling Technologies, (D2O6Y) Rabbit mAb, #94205S), phospho-Stat5 (Cell Signaling Technologies, (Tyr694, D47E7) Rabbit mAb, #4322S), Stat6 (Cell Signaling Technologies, (D3H4) Rabbit mAb, #5397S), phospho-Stat6 (Cell Signaling Technologies, (Tyr641)Rabbit mAb, #9361S), Vinculin (Cell Signaling Technologies, (E1E9V) Rabbit mAb (#13901S), Anti-rabbit IgG HRP-linked Antibody (Cell Signaling Technologies, 7074S). Test results are shown in Table 1.

[0602] Table 1: Results of protein degradation detection experiments using Western blotting (WB) of the patented compounds

[0603] Western blot (WB) results showed that the compound of the present invention specifically degraded Stat6 protein, but did not degrade STAT1, 2, 3, 4, and 5 proteins, as shown in Figure 1.

[0604] Example 2: Degradation experiment of STAT6-HiBiT A549

[0605] A HiBiT tag was knocked into the C-terminus of the A549 STAT6 gene using CRISPR / Cas9 technology (refer to WO2025049820A1). The degradation of endogenous STAT6 in STAT6-HiBiT A549 cells was quantified using the Nano-Glo HiBiT Lytic Detection System (Promega, 3040). A549 (STAT6-HiBiT) cells were seeded at a density of 1250 cells (20 μL) per well in 384-well plates. The compound was added to the detection plates at a working concentration of 10 μM, with 4-fold serial dilutions for a total of 10 dose gradients. The plates were then incubated at 37°C and 5% CO2 for 24 hours. At the endpoint, 20 μL of Nano-Glo HiBiT lysis reagent was added to each well, and the plates were shaken at 300 rpm for 10 minutes at room temperature. The luminescence values ​​were read using a Tecan microplate reader. Data were analyzed using GraphPad Prism software, and a four-parameter inhibitor-response nonlinear regression model was used to fit the dose-dependent STAT6 degradation. The test results are shown in Table 2.

[0606] Table 2: Degradation Experiment Results of the Patented Compound STAT6-HiBiT A549

[0607] The STAT6-HiBiT A549 degradation experiment showed that the specific compound disclosed in this paper has good STAT6 degradation activity.

[0608] Example 3: Pharmacokinetic Test in Mice

[0609] 1. Drug preparation

[0610] Weigh a certain amount of the drug and prepare the preparation for gavage and intravenous injection (0.2 mg / ml solution for IV and 0.3 mg / ml solution for PO). The solvent for both the gavage and intravenous injection preparations is 10% DMA + 10% Solutol HS15 + 80% Saline.

[0611] 2. Administration

[0612] ICR mice were fasted for 12 hours before administration, but had free access to water. The intravenous dose was 1 mg / kg, and the oral dose was 2 mg / kg or 5 mg / kg. Mice were allowed to resume eating 4 hours after administration.

[0613] 3. Sampling

[0614] At 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h after intravenous administration, and at 0.25, 0.5, 1, 2, 4, 8 and 24 h after gavage administration, 30 μL of whole blood was collected from the submandibular vein of mice and placed in anticoagulant centrifuge tubes containing EDTA-K2. The centrifuge tubes were centrifuged at 5000 rpm and 4℃ for 5 min, and the separated plasma was stored at -80℃ for analysis.

[0615] 4. Measurement

[0616] Take 10 μL of plasma sample and add 200 μL of MeOH / Acetonitrile (1:1, v / v) containing internal standards (50 nM terfenadine and 500 nM tolbutamide) for protein precipitation (vortex for 10 min, then centrifuge at 4000 rpm for 10 min). Transfer 100 μL of the supernatant to a 96-well plate and perform LC-MS / MS analysis.

[0617] 5. Pharmacokinetic Parameter Results

[0618] The pharmacokinetic parameters of some of the compounds disclosed herein are shown in Table 3 below.

[0619] Table 3: Pharmacokinetic parameters of some compounds in this invention

[0620] The pharmacokinetic tests conducted in mice revealed that the specific compound disclosed herein exhibits a high area under the curve, a long half-life, and good oral bioavailability, demonstrating favorable pharmacokinetic characteristics.

Claims

A compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: in, Indicates a single bond or a double bond; Ring B is a saturated or partially unsaturated C3-C ring. 18 Carbon rings, saturated or partially unsaturated 3-18 membered heterocycles, C6-C 18 Aromatic rings or 5-18 membered heteroaromatic rings; in the 3-18 membered heterocycles, the heteroatom is selected from one or more of N, O, S, Si, and P, and the number of heteroatoms is 1, 2, 3, 4, or 5; in the 5-18 membered heteroaromatic rings, the heteroatom is selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 18 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-18 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. n is 0, 1, 2, 3, 4 or 5; R B independently R A-2 , R B-1 , hydrogen, halogen, cyano, nitro, oxo (=O), =NR A-1 , =S, -OR A-1 , -SR A-1 , -N(R A-1 )2, -Si(R A-1 )3, -S(=O)R A-1 , -S(=O)2R A-1 , -S(=O)(=NR A-1 )R A-1 , -S(=NR A-1 )2R A-1 , -S(=O)2N(R A-1 )2, -C(=O)R A-1 , -C(=O)OR A-1 , -C(=O)N(R A- 1 )2, -C(=O)N(R A-1 )OR A-1 , -OC(=O)R A-1 , -OC(=O)N(R A-1 )2, -P(=O)(R A-1 )2, -P(=O)(OR A-1 )2, -OP(=O)(R A-1 )2, -OP(=O)(OR A- 1 )2, -NR A-1 C(=O)OR A-1 , -NR A-1 C(=NR A-1 )OR A-1 , -NR A-1 C(=O)R A-1 , -NR A-1 C(=NR A-1 )R A-1 , -NR A-1 C(=O)N(R A-1 )2, -NR A- 1 C(=NR A-1 )N(R A-1 )2, -NR A-1 C(=NOR A-1 )N(R A-1 )2, -NR A-1 C(=NR A-1 )NH(OR A-1 ) or -NR A-1 S(=O)2R A-1 ; R A-2 Independently for C1-C 12 Alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C1-C 12 Alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 aryl or 5-14 heteroaryl groups are optionally surrounded by one or more R groups. A-2-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. R B-1 -L B -H, -L B -Cy B1’ or -L B -Cy B11 -Cy B2’ ; L B Independently C1-C4 alkylene groups, wherein 0, 1, 2, 3, or 4 methylene groups are independently replaced by the following groups: -O-, -C(=O)-, -C(=S)-, -C(=NR)-. A-1 )′-CF2-、-CR A-1 F-、-CR A-1 R A-1 -、-CR A-1 (OR A-1 )-、-NR A-1 -, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR A- 1 )-、-CR A-1 =CR A-1 -or Cy B11 Independently for C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene or 5-14 quinone heteroarylene; wherein the C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene or 5-14 heteroarylene, optionally enclosed by one or more R A-1-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 member heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. Cy B1’ and Cy B2’ Each independently constitutes C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 aryl or 5-14 heteroaryl groups are optionally surrounded by one or more R groups. A-1-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. R A-1 Independently hydrogen, C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 aryl or 5-14 heteroaryl groups are optionally surrounded by one or more R groups. A-1-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. Alternatively, two R atoms on the same atom or two adjacent atoms A-1 Together with the atoms bonded to them, they form saturated or partially unsaturated C3-C atoms. 12 Carbon rings, or saturated or partially unsaturated 3-12 membered heterocycles; wherein the C3-C 12 The carbon ring or 3-12 membered heterocycle is optionally separated by one or more R A-1-1 The substituted 3-12 membered heterocycles are selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5. R A-1-1 and R A-2-1 Each independently for Cy X1 Halogen, -(CH2) 0-4 R A-1-1-1 -(CH2) 0-4 OR A-1-1-1 -O(CH2) 0-4 R A-1-1-1 -O(CH2) 0-4 -C(=O)OR A- 1-1-1 -(CH2) 0-4 CH(OR A-1-1-1 2、-(CH2) 0-4 SR A-1-1-1 -(CH2) 0-4 Ph、-(CH2) 0-4 O(CH2) 0-1 Ph、-(CH2) 0-4 Py, -(CH2) 0-4 O(CH2) 0-1 Py, -CH=CHPh, nitro, cyano, azide, -(CH2) 0-4 N(R A-1-1-1 2、-(CH2) 0-4 N(R A-1-1-1 )C(=O)R A-1-1-1 -N(R) A-1-1-1 )C(=S)R A-1-1-1 -(CH2) 0- 4N(R A-1-1-1 )C(=O)N(R A-1-1-1 )2、-N(R A-1-1-1 )C(=S)N(R A-1-1-1 2、-(CH2) 0-4 N(R A-1-1-1 )C(=O)OR A-1-1-1 -N(R) A-1-1-1 )N(R A-1-1- 1 )C(=O)R A-1-1-1 -N(R) A-1-1-1 )N(R A-1-1-1 )C(=O)N(R A-1-1 - 1 )2、-N(R A-1-1-1 )N(R A-1-1-1 )C(=O)OR A-1-1-1 -(CH2) 0-4 C(=O)R A-1-1-1 -C(=S)R A-1-1-1 -(CH2) 0-4 -C(=O)OR A-1-1-1 、-(CH2) 0-4 -C(=O)SR A-1-1-1 、-(CH2) 0-4 -C(=O)OSi(R A-1-1-1 )3、-(CH2) 0-4 OC(=O)R A-1-1-1 、-OC(=O)(CH2) 0-4 SR A-1-1-1 、-(CH2) 0-4 SC(=O)R A-1-1-1 、-(CH2) 0-4 C(=O)N(R A-1-1-1 )2、-C(=S)N(R A-1-1-1 )2、-C(=S)SR A-1-1-1 、-SC(=S)SR A-1-1-1 、-(CH2) 0-4 OC(=O)N(R A-1-1-1 )2、-C(=O)N(OR A-1-1-1 )R A-1-1-1 、-C(=O)C(=O)R A-1-1-1 、-C(=O)CH2C(=O)R A-1-1-1 、-C(=NOR A-1-1-1 )R A-1-1-1 、-(CH2) 0-4 SSR A-1-1-1 、-(CH2) 0-4 S(=O)2R A-1-1-1 、-(CH2) 0-4 S(=O)2OR A-1-1-1 、-(CH2) 0-4 OS(=O)2OR A-1-1-1 、-S(=O)2N(R A-1-1-1 )2、-(CH2) 0-4 S(=O)R A-1-1-1 、-N(R A-1-1-1 )S(=O)2N(R A-1-1-1 )2、-N(R A-1-1-1 )S(=O)2R A-1-1-1 、-N(OR A-1-1-1 )R A-1-1-1 、-C(=NH)N(R A-1-1-1 )2、-(CH2) 0-4 P(=O)(R A-1-1-1 )2、-(CH2) 0-4 OP(=O)(R A-1-1-1 )2、-(CH2) 0-4 OP(=O)(OR A-1-1-1 )2, -Si(R A-1-1-1 )3, -(CH=CH) 0-4 O-N(R A-1-1-1 )2, -(CH=CH) 0-4 C(=O)O-N(R A-1-1-1 )2, =O, =S, =NR A-1-1-1 , =NN(R A-1-1-1 )2, =NNHC(=O)R A-1-1-1 , =NNHC(=O)OR A-1-1-1 , =NNHS(=O)2R A-1-1-1 , =NR A-1-1-1 or =NOR A-1-1-1 ; Cy X1 Independently for C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl, 5-14 heteroaryl, optionally bounded by one or more R Z1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. R Z1 independently R Z1-1 , oxo (=O), =NR Z1-1 , =S, hydrogen, halogen, cyano, nitro, -OR Z1-1 , -SR Z1-1 , -N(R Z1-1 )2, -Si(R Z1-1 )3, -S(=O)R Z1-1 , -S(=O)2R Z1-1 , -S(=O)(=NR Z1-1 )R Z1-1 , -S(=O)2N(R Z1-1 )2, -S(=NR Z1-1 )2R Z1-1 , -C(=O)R Z1-1 , -C(=O)OR Z1-1 , -C(=O)N(R Z1-1 )2, -C(=O)N(R Z1-1 )OR Z1-1 , -OC(=O)R Z1-1 , -OC(=O)N(R Z1-1 )2, -P(=O)(R Z1-1 )2, -P(=O)(OR Z1-1 )2, -OP(=O)(R Z1- 1 )2, -OP(=O)(OR Z1-1 )2, -NR Z1-1 C(=O)OR Z1-1 , -NR Z1-1 C(=O)R Z1-1 , -NR Z1-1 C(=NR Z1-1 )OR Z1-1 , -NR Z1-1 C(=NR Z1-1 )R Z1-1 , -NR Z1- 1 C(=NR Z1-1 )N(R Z1-1 )2, -NR Z1-1 C(=NOR Z1-1 )N(R Z1-1 )2, -NR Z1-1 C(=NR Z1-1 )NH(OR Z1-1 ), -NR Z1-1 C(=O)N(R Z1-1 )2 or -NR Z1- 1 S(=O)2R Z1-1 ; R Z1-1 Independently hydrogen, C1-C 12 Alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C1-C 12 Alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 aryl or 5-14 heteroaryl groups are optionally surrounded by one or more R groups. Z1-1-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. Alternatively, two R atoms on the same atom or two adjacent atoms Z1-1 Together with the atoms bonded to them, they form saturated or partially unsaturated C3-C atoms. 12 Carbon rings, or saturated or partially unsaturated 3-12 membered heterocycles; wherein the C3-C 12 The carbon ring or 3-12 membered heterocycle is optionally separated by one or more R Z1-1-1 The substituted 3-12 membered heterocycles are selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5. R Z1-1-1 Independently halogenated, -(CH2) 0-4 R Z1-1-1-1 -(CH2) 0-4 OR Z1-1-1-1 -O(CH2) 0-4 R Z1-1-1-1 -O(CH2) 0-4 -C(=O)OR Z1-1-1-1 -(CH2) 0- 4CH(OR Z1-1-1-1 2、-(CH2) 0-4 SR Z1-1-1-1 -(CH2) 0-4 Ph、-(CH2) 0-4 O(CH2) 0-1 Ph、-(CH2) 0-4 Py, -(CH2) 0-4 O(CH2) 0-1 Py, -CH=CHPh, nitro, cyano, azide, -(CH2) 0-4 N(R Z1-1-1-1 2、-(CH2) 0-4 N(R Z1-1-1-1 )C(=O)R Z1-1-1-1 -N(R) Z1-1-1-1 )C(=S)R Z1-1-1-1 -(CH2) 0-4 N(R Z1- 1-1-1 )C(=O)N(R Z1-1-1-1 )2、-N(R Z1-1-1-1 )C(=S)N(R Z1-1-1-1 2、-(CH2) 0-4 N(R Z1-1-1-1 )C(=O)OR Z1-1-1-1 -N(R) Z1-1-1-1 )N(R Z1-1-1-1 )C(=O)R Z1- 1-1-1 -N(R) Z1-1-1-1 )N(R Z1-1-1-1 )C(=O)N(R Z1-1-1-1 )2、-N(R Z1-1-1-1 )N(R Z1-1-1-1 )C(=O)OR Z1-1-1-1 -(CH2) 0-4 C(=O)R Z1-1-1-1 -C(=S)R Z1- 1-1-1 -(CH2) 0-4 -C(=O)OR Z1-1-1-1 -(CH2) 0-4 -C(=O)SR Z1-1-1-1 、-(CH2) 0-4 -C(=O)OSi(R Z1-1-1-1 )3、-(CH2) 0-4 OC(=O)R Z1-1-1-1 、-OC(=O)(CH2) 0-4 SR Z1-1-1-1 、-(CH2) 0-4 SC(=O)R Z1-1-1-1 、-(CH2) 0-4 C(=O)N(R Z1-1-1-1 )2、-C(=S)N(R Z1-1-1-1 )2、-C(=S)SR Z1-1-1-1 、-SC(=S)SR Z1-1-1-1 、-(CH2) 0-4 OC(=O)N(R Z1-1-1-1 )2、-C(=O)N(OR Z1-1-1-1 )R Z1-1-1-1 、-C(=O)C(=O)R Z1-1-1-1 、-C(=O)CH2C(=O)R Z1- 1-1-1 、-C(=NOR Z1-1-1-1 )R Z1-1-1-1 、-(CH2) 0-4 SSR Z1-1-1-1 、-(CH2) 0-4 S(=O)2R Z1-1-1-1 、-(CH2) 0-4 S(=O)2OR Z1-1-1-1 、-(CH2) 0-4 OS(=O)2OR Z1- 1-1-1 、-S(=O)2N(R Z1-1-1-1 )2、-(CH2) 0-4 S(=O)R Z1-1-1-1 、-N(R Z1-1-1-1 )S(=O)2N(R Z1-1-1-1 )2、-N(R Z1-1-1-1 )S(=O)2R Z1-1-1-1 、-N(OR Z1-1- 1-1 )R Z1-1-1-1 、-C(=NH)N(R Z1-1-1-1 )2、-(CH2) 0-4 P(=O)(R Z1-1-1-1 )2、-(CH2) 0-4 OP(=O)(R Z1-1-1-1 )2、-(CH2) 0-4 OP(=O)(OR Z1-1-1-1 )₂, -Si(R Z1-1-1-1 )₃, -(CH=CH) 0-4 O-N(R Z1-1-1-1 )₂, -(CH=CH) 0-4 C(=O)O-N(R Z1-1-1-1 )₂, =O, =S, =NR Z1-1-1-1 , =NN(R Z1-1-1-1 )₂, =NNHC(=O)R Z1-1-1-1 , =NNHC(=O)OR Z1-1-1-1 , =NNHS(=O)₂R Z1-1-1-1 , =NR Z1-1-1-1 or =NOR Z1-1-1-1 ; R Z1-1-1-1 Independently -(CH2) 0-2 R Z1-1-1-1-1 -(CH2) 0-2 OH, -(CH2) 0-2 OR Z1-1-1-1-1 -(CH2) 0-2 CH(OR Z1-1-1-1-1 2. Cyano, azide, nitro, -(CH2) 0-2 C(=O)R Z1-1-1-1-1 -(CH2) 0-2 C(=O)OH, -(CH2) 0-2 C(=O)OR Z1-1-1-1-1 -(CH2) 0-2 SR Z1-1-1-1-1 -(CH2) 0-2 SH, -(CH2) 0- 2NH2、-(CH2) 0-2 NHR Z1-1-1-1-1 -(CH2) 0-2 N(R Z1-1-1-1-1 )2、-Si(R Z1-1-1-1-1 3. -C(=O)SR Z1-1-1-1-1 -(CH=CH) 0-4 C(=O)OR Z1-1-1-1-1 or -SSR Z1-1-1-1-1 ; R Z1-1-1-1-1 Independently hydrogen, halogen, benzyl, C1-C6 alkyl, -O(CH2) 0-2 Ph, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl; wherein the heteroatom in the 3-6 membered heterocyclic alkyl is selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2 or 3; R A-1-1-1 Independently -(CH2) 0-2 R A-1-1-1-1 -(CH2) 0-2 OH, -(CH2) 0-2 OR A-1-1-1-1 -(CH2) 0-2 CH(OR A-1-1-1-1 2. Cyano, azide, nitro, -(CH2) 0-2 C(=O)R A-1-1-1-1 -(CH2) 0-2 C(=O)OH, -(CH2) 0-2 C(=O)OR A-1-1-1-1 -(CH2) 0-2 SR A-1-1-1-1 -(CH2) 0-2 SH, -(CH2) 0-2 NH2、-(CH2) 0-2 NHR A-1-1-1-1 -(CH2) 0-2 N(R A-1-1-1-1 )2、-Si(R A-1-1-1-1 3. -C(=O)SR A-1-1-1-1 -(CH=CH) 0-4 C(=O)OR A-1-1-1-1 or -SSR A-1-1-1- 1 ; R A-1-1-1-1 Independently hydrogen, halogen, benzyl, C1-C6 alkyl, -O(CH2) 0-2 Ph, C3-C6 cycloalkyl or 3-6 membered heterocyclic alkyl; wherein the heteroatom in the 3-6 membered heterocyclic alkyl is selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2 or 3; Ring A is a saturated or partially unsaturated C3-C ring. 20 Carbon rings, saturated or partially unsaturated 3-20 membered heterocycles, C6-C 20 Aromatic rings or 5-20 membered heteroaromatic rings; in the 3-20 membered heterocycles, the heteroatom is selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5; in the 5-20 membered heteroaromatic rings, the heteroatom is selected from one or more of N, O, S and Se, and the number of heteroatoms is 1, 2, 3, 4 or 5; the C6-C 20 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-20 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; in the 3-20 membered heterocycle, 0, 1, or more -CH2- groups on the ring are independently replaced by the following groups: -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A- 1 )-、-Si(=NR A-1 )-、 -P(=O)R A-1 -、 -NR- A-1 C(=O)-, -C(=O)NR- A-1 -, -OC(=O)NR- A-1 -, -NR- A- 1 OC(=O)-, -CHF-, -CF2-, -S(=O)(=NR- A-1 )- or m can be 0, 1, 2, 3, 4, or 5; Y is hydrogen, halogen, or... q can be 0, 1, 2, 3, 4, or 5; Ring Z is independently saturated or partially unsaturated C3-C 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaromatic rings; in the 3-12 membered heterocycles, the heteroatom is selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5; in the 5-14 membered heteroaromatic rings, the heteroatom is selected from one or more of N, O, S and Se, and the number of heteroatoms is 1, 2, 3, 4 or 5; the C6-C 14 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; in the 3-12 membered heterocycle, 0, 1, or more -CH2- groups on the ring are independently replaced by the following groups: -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A- 1 )-、-Si(=NR A-1 )-、 -P(=O)R A-1 -、 -NR A-1 C(=O)-, -C(=O)NR A-1 -, -OC(=O)NR A-1 -, -NR A- 1 OC(=O)-, -CHF-, -CF2-, -S(=O)(=NR A-1 )- or R A and R Z Each independently as R A-2 R A-1 Oxygenation (=O), =NR A-1 =S, hydrogen, halogen, cyano, nitro, -OR A-1 -SR A-1 -N(R) A-1 )2、-Si(R A-1 3. -S(=O)R A-1 -S(=O)2R A-1 -S(=O)(=NR) A-1 )R A-1 -S(=NR) A-1 )2R A-1 -S(=O)2N(R) A-1 )2、-C(=O)R A-1 -C(=O)OR A- 1 -C(=O)N(R) A-1 )2、-C(=O)N(R A-1 OR A-1 -OC(=O)R A-1 -OC(=O)N(R) A-1 )2、-P(=O)(R A-1 )2、-P(=O)(OR A-1 )2、-OP(=O)(R A- 1 )2、-OP(=O)(OR A-1 )2、-NR A-1 C(=NR A-1 OR A-1 -NR A-1 C(=NR A-1 )R A-1 -NR A-1 C(=NR A-1 )N(R A-1 )2、-NR A-1 C(=NOR A-1 )N(R A- 1 )2、-NR A-1 C(=NR A-1 )NH(OR A-1 -NR A-1 C(=O)OR A-1 -NR A-1 C(=O)R A-1 -NR A-1 C(=O)N(R A-1 )2 or -NR A-1 S(=O)2R A-1 ; L A It is a C1-C5 alkylene group, wherein 0, 1, or more methylene groups are independently replaced by the following groups: -Cy X -, -O-, -C(=O)-, -C(=S)-, -C(=NR A-1 -, -CF2-, -CR A-1 F-、-CR A-1 R A-1 -、-CR A-1 (OR A-1 )-、-NR A-1 -, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR A-1 )-、-CR A- 1 =CR A-1 -or Cy X Independently for C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene or 5-14 quinone heteroarylene; wherein the C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene, 5-14 arylene heteroarylene, optionally enclosed by one or more R Z The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 member heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. L a For C1-C 15 Alkylene, wherein 0, 1, or more methylene groups are independently replaced with -NR B -、-O-、-S-、 -CR B =CR B -、 Saturated or partially unsaturated C3-C 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings; wherein the C1-C 15 Alkylene, C3-C 12 Carbon rings, 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings are optionally surrounded by one or more R B The substituted 3-12 membered heterocycles have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5. The 5-14 membered heteroaromatic rings have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5. The C6-C 14 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. L b For covalent bonds, -O-, -S-, or -NL 11 -; L 11 H, C1-C6 alkyl, C3-C 16 Cycloalkyl, 3-16 membered heterocycloalkyl, C3-C 16 Cycloalkenyl, 3-16 membered heterocyclic alkenyl, phenyl or 6 membered heteroaryl, wherein the C1-C6 alkyl, C3-C 16 Cycloalkyl, 3-16 membered heterocycloalkyl, C3-C 16 Cycloalkenyl, 3-16-membered heterocyclic alkenyl, phenyl or 6-membered heteroaryl, optionally separated by one or more R A-1 The substituted 3-16-membered heterocyclic alkyl or 3-16-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5; the 6-membered heteroaryl group has heteroatoms selected from one or more of N, O, S and Se, and the number of heteroatoms is 1, 2 or 3. L X Covalent bond or C1-C 20 Alkylene, the C1-C 20 In the alkylene group, 0, 1, or more methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -NR. A-1 -、-C(R A-1 )2-、-CR A-1 =CR A-1 -、 -C(=O)-、-OC(=O)-、-C(=O)O′-S(=O)-、-S(=O)2-、-NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A-1 )-、-Si(=NR A-1 )-、 -P(=O)R A-1 -、 -NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -、-NR A-1 OC(=O)-、-CHF-、-CF2-、-S(=O)(=NR A-1 )-、 M can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 independently; With L X Connect any point on the [structure / structure]; L X When it is a covalent bond, -L a -L b - Connect to any point on ring X; Or L X Independently for -L X1 -L X2 -L X3 -L X4 -; L X1 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 -、 -NR A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-, -S(=O)2NR A-1 -, -NR A-1 C(=O)-, -C(=O)NR A-1 -, -OC(=O)NR A-1 - or -NR A-1 OC(=O)-; L X2 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 -、 -NR A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-, -S(=O)2NR A-1 -, -NR A-1 C(=O)-, -C(=O)NR A-1 -, -OC(=O)NR A-1 - or -NR A-1 OC(=O)-; L X3 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 -、 -NR A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-, -S(=O)2NR A-1 -, -NR A-1 C(=O)-, -C(=O)NR A-1 -, -OC(=O)NR A-1 - or -NR A-1 OC(=O)-; L X4 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 -、 -NR- A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-, -S(=O)2NR A-1 -, -NR A-1 C(=O)-, -C(=O)NR A-1 -, -OC(=O)NR A-1 - or -NR A-1 OC(=O)-; Cy is independently saturated or partially unsaturated C3-C 14 Carbon rings, saturated or partially unsaturated 3-14 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings; wherein the C3-C 14 Carbon rings, 3-14 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings are optionally surrounded by one or more R Z The substituted 3-14 membered heterocycles are selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14 membered heteroaromatic rings are selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, or 3; the C6-C 14 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. for X 5 and X 6 Independently covalent bond, -C(R) A-3 )2-, -SO2-, -S(=O)-, -P(=O)R A-3 -、-P(=O)OR A-3 -、-P(=O)N(R A-3 -, -C(=O)- or -C(=S)-; X 2 For N, CR 2-1 Si-R 2-1 Or P = O; It can be a single bond or a double bond; when When it is a single bond, X 3 and X 4 Independently covalent bond, -C(R) A-3 -2-, -CF2-, -O-, or -S-; X 3 When it is a covalent bond, X 2 and X 4 Directly connected; X 4 When it is a covalent bond, X 3 and X 5 Directly connected; X 3 and X 4 When all are covalent bonds, X 2 and X 5 Directly connected; when When it is a double bond, is -CR A-3 CR A-3 -; R A-3 Independently hydrogen, C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 aryl or 5-14 heteroaryl groups are optionally surrounded by one or more R groups. A-1-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, S, and Se, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. Alternatively, two R atoms on the same atom or two adjacent atoms A-3 Together with the atoms bonded to them, they form saturated or partially unsaturated C3-C atoms. 12 Carbon rings, or saturated or partially unsaturated 3-12 membered heterocycles; wherein the C3-C 12 The carbon ring or 3-12 membered heterocycle is optionally separated by one or more R A-1-1 The substituted 3-12 membered heterocycles are selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5. R2-1 is independently hydrogen, -OR A-1 -SR A-1 -S(=O)R A-1 -SO2R A-1 -N(R) A-1 2. Or optionally by one or more R A-1-1 Replacement C1-C 12 alkyl; Or R 2-1 and R A-3 Together with the atoms bonded to them, they form saturated or partially unsaturated C3-C atoms. 12 Carbon rings, or saturated or partially unsaturated 3-12 membered heterocycles; wherein the C3-C 12 The carbon ring or 3-12 membered heterocycle is optionally separated by one or more R A-1-1 The substituted 3-12 membered heterocycles are selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5. Ring E3 is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the heteroatom in the 5-6 membered heteroaromatic ring is selected from one or more of N, O, S and Se, and the number of heteroatoms is 1, 2 or 3; Cycle E4 is a C4-C7 cycloene or a 4-7 membered heterocyclic alkene, wherein the heteroatom in the 4-7 membered heterocyclic alkene is selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3 or 4. n1 is 1, 2, 3, or 4; R 3 Substituents on ring E3 or ring E4; R 3 It can be hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, C1-C6 alkyl substituted with one or more halogens, or C1-C6 alkoxy substituted with one or more halogens. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, is characterized in that, Indicates a single bond or a double bond; Ring B is a saturated or partially unsaturated C3-C ring. 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaromatic rings; in the 3-12 membered heterocycles, the heteroatom is selected from one or more of N, O, S, Si, and P, and the number of heteroatoms is 1, 2, 3, 4, or 5; in the 5-14 membered heteroaromatic rings, the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. n is 0, 1, 2, 3, 4 or 5; R B Independently for R A-2 R B-1 Hydrogen, halogen, cyano, nitro, oxo (=O), =NR A-1 =S, -OR A-1 -SR A-1 -N(R) A-1 )2、-Si(R A-1 3. -S(=O)R A-1 -S(=O)2R A-1 -S(=O)(=NR) A-1 )R A-1 -S(=O)2N(R) A-1 )2、-C(=O)R A-1 -C(=O)OR A-1 -C(=O)N(R) A-1 )2、-C(=O)N(R A- 1 OR A-1 -OC(=O)R A-1 -OC(=O)N(R) A-1 )2、-P(=O)(R A-1 )2、-P(=O)(OR A-1 )2、-OP(=O)(R A-1 )2、-OP(=O)(OR A-1 )2、-NR A- 1 C(=O)OR A-1 -NR A-1 C(=O)R A-1 -NR A-1 C(=O)N(R A-1 )2 or -NR A-1 S(=O)2R A-1 ; R A-2 Independently for C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 aryl or 5-14 heteroaryl groups are optionally surrounded by one or more R groups. A-2-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. R B-1 is -L B -Cy B1 -H or -L B -Cy B1 -Cy B2 -H; L B Independently C1-C3 alkylene groups, wherein 0, 1, 2 or 3 methylene groups are independently replaced by the following groups: -O-, -C(=O)-, -C(=S)-, -C(=NR)-. A-1 -, -CF2-, -CR A-1 F-、-CR A-1 R A-1 -、-CR A-1 (OR A-1 )-、-NR A-1 -, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR A-1 )-、-CR A- 1 =CR A-1 -or R A-1 Independently hydrogen, C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 Aryl or 5-14 heteroaryl; wherein the C1-C 12 Alkyl, C3-C 12 cycloalkyl, C3-C 12 Cycloalkenyl, 3-12 membered heterocyclic alkyl, 3-12 membered heterocyclic alkenyl, C6-C 14 aryl or 5-14 heteroaryl groups are optionally surrounded by one or more R groups. A-1-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. Alternatively, two R atoms on the same atom or two adjacent atoms A-1 Together with the atoms bonded to them, they form saturated or partially unsaturated C3-C atoms. 12 Carbon rings, or saturated or partially unsaturated 3-12 membered heterocycles; wherein the C3-C 12 The carbon ring or 3-12 membered heterocycle is optionally separated by one or more R A-1-1 The substituted 3-12 membered heterocycles are selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5. R A-1-1 and R A-2-1 Each is independently a halogen, -(CH2) 0-4 R A-1-1-1 -(CH2) 0-4 OR A-1-1-1 -O(CH2) 0-4 R A-1-1-1 -O(CH2) 0-4 -C(=O)OR A-1-1- 1 -(CH2) 0-4 CH(OR A-1-1-1 2、-(CH2) 0-4 SR A-1-1-1 -(CH2) 0-4 Ph、-(CH2) 0-4 O(CH2) 0-1 Ph、-(CH2) 0-4 Py, -(CH2) 0-4 O(CH2) 0-1 Py, -CH=CHPh, nitro, cyano, azide, -(CH2) 0-4 N(R A-1-1-1 2、-(CH2) 0-4 N(R A-1-1-1 )C(=O)R A-1-1-1 -N(R) A-1-1-1 )C(=S)R A-1-1-1 -(CH2) 0- 4N(R A-1-1-1 )C(=O)N(R A-1-1-1 )2、-N(R A-1-1-1 )C(=S)N(R A-1-1-1 2、-(CH2) 0-4 N(R A-1-1-1 )C(=O)OR A-1-1-1 -N(R) A-1-1-1 )N(R A-1-1- 1 )C(=O)R A-1-1-1 -N(R) A-1-1-1 )N(R A-1-1-1 )C(=O)N(R A-1-1-1 )2、-N(R A-1-1-1 )N(R A-1-1-1 )C(=O)OR A-1-1-1 -(CH2) 0-4 C(=O)R A-1-1-1 -C(=S)R A-1-1-1 -(CH2) 0-4 -C(=O)OR A-1-1-1 -(CH2) 0-4 -C(=O)SR A-1-1-1 、-(CH2) 0-4 -C(=O)OSi(R A-1-1-1 )3、-(CH2) 0-4 OC(=O)R A-1-1-1 、-OC(=O)(CH2) 0-4 SR A-1-1-1 、-(CH2) 0-4 SC(=O)R A-1-1-1 、-(CH2) 0-4 C(=O)N(R A-1-1-1 )2、-C(=S)N(R A-1-1-1 )2、-C(=S)SR A-1-1-1 、-SC(=S)SR A-1-1-1 、-(CH2) 0-4 OC(=O)N(R A-1-1-1 )2、-C(=O)N(OR A-1-1-1 )R A-1-1-1 、-C(=O)C(=O)R A-1-1-1 、-C(=O)CH2C(=O)R A-1-1-1 、-C(=NOR A-1-1-1 )R A-1-1-1 、-(CH2) 0-4 SSR A-1-1-1 、-(CH2) 0-4 S(=O)2R A-1-1-1 、-(CH2) 0-4 S(=O)2OR A-1-1-1 、-(CH2) 0-4 OS(=O)2OR A-1-1-1 、-S(=O)2N(R A-1-1-1 )2、-(CH2) 0-4 S(=O)R A-1-1-1 、-N(R A-1-1-1 )S(=O)2N(R A-1-1-1 )2、-N(R A-1-1-1 )S(=O)2R A-1-1-1 、-N(OR A-1-1-1 )R A-1-1-1 、-C(=NH)N(R A-1-1-1 )2、-(CH2) 0-4 P(=O)(R A-1-1-1 )2、-(CH2) 0-4 OP(=O)(R A-1-1-1 )2、-(CH2) 0-4 OP(=O)(OR A-1-1-1 )2、-Si(R A-1-1-1 )3, -(CH=CH) 0-4 O-N(R A-1-1-1 )2, -(CH=CH) 0-4 C(=O)O-N(R A-1-1-1 )2, =O, =S, =NR A-1-1-1 , =NN(R A-1-1-1 )2, =NNHC(=O)R A-1-1-1 , =NNHC(=O)OR A-1-1-1 , =NNHS(=O)2R A-1-1-1 , =NR A-1-1-1 or =NOR A-1-1-1 ; R A-1-1-1 Independently -(CH2) 0-2 R A-1-1-1-1 -(CH2) 0-2 OH, -(CH2) 0-2 OR A-1-1-1-1 -(CH2) 0-2 CH(OR A-1-1-1-1 2. Cyano, azide, nitro, -(CH2) 0-2 C(=O)R A-1-1-1-1 -(CH2) 0-2 C(=O)OH, -(CH2) 0-2 C(=O)OR A-1-1-1-1 -(CH2) 0-2 SR A-1-1-1-1 -(CH2) 0-2 SH, -(CH2) 0-2 NH2、-(CH2) 0-2 NHR A-1-1-1-1 -(CH2) 0-2 N(R A-1-1-1-1 )2、-Si(R A-1-1-1-1 3. -C(=O)SR A-1-1-1-1 -(CH=CH) 0-4 C(=O)OR A-1-1-1-1 or -SSR A-1-1-1- 1 ; R A-1-1-1-1 Independently, it can be a hydrogen atom, halogen, benzyl, C1-C4 alkyl, or -O(CH2). 0-2 Ph, C5-C6 cycloalkyl or 5-6 membered heterocyclic alkyl; Cy B1 and Cy B2 Each independently constitutes C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene or 5-14 quinone heteroarylene; wherein the C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene or 5-14 heteroarylene, optionally enclosed by one or more R A-1-1 The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 member heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. Ring A is a saturated or partially unsaturated C3-C ring. 14 Carbon rings, saturated or partially unsaturated 3-14 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaromatic rings; in the 3-14 membered heterocycles, the heteroatom is selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5; in the 5-14 membered heteroaromatic rings, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3, 4 or 5; the C6-C 14 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; in the 3-12 membered heterocycle, 0, 1, or more -CH2- groups on the ring are independently replaced by the following groups: -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A-1 )-、-Si(=NR A-1 )-、 -P(=O)R A-1 -、 -NR A-1 C(=O)-, -C(=O)NR A-1 -, -OC(=O)NR A-1 -, -NR A-1 OC(=O)-, -CHF-, -CF2-, -S(=O)(=NR A-1 )- or m can be 0, 1, 2, 3, 4, or 5; Y is hydrogen, halogen, or... q can be 0, 1, 2, 3, 4, or 5; Ring Z is independently saturated or partially unsaturated C3-C 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaromatic rings; in the 3-12 membered heterocycles, the heteroatom is selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5; in the 5-14 membered heteroaromatic rings, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3, 4 or 5; the C6-C 14 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; in the 3-12 membered heterocycle, 0, 1, or more -CH2- groups on the ring are independently replaced by the following groups: -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A- 1 )-、-Si(=NR A-1 )-、 -P(=O)R A-1 -、 -NR- A-1 C(=O)-, -C(=O)NR- A-1 -, -OC(=O)NR- A-1 -, -NR- A- 1 OC(=O)-, -CHF-, -CF2-, -S(=O)(=NR- A-1 )- or R A and R Z Each independently as R A-2 R A-1 Oxygenation (=O), =NR A-1 =S, hydrogen, halogen, cyano, nitro, -OR A-1 -SR A-1 -N(R) A-1 )2、-Si(R A-1 3. -S(=O)R A-1 -S(=O)2R A-1 -S(=O)(=NR) A-1 )R A-1 -S(=O)2N(R) A-1 )2、-C(=O)R A-1 -C(=O)OR A-1 -C(=O)N(R) A-1 )2、-C(=O)N(R A-1 OR A-1 -OC(=O)R A-1 -OC(=O)N(R) A-1 )2、-P(=O)(R A-1 )2、-P(=O)(OR A-1 )2、-OP(=O)(R A-1 )2、-OP(=O)(OR A- 1 )2、-NR A-1 C(=O)OR A-1 -NR A-1 C(=O)R A-1 -NR A-1 C(=O)N(R A-1 )2 or -NR A-1 S(=O)2R A-1 ; L A It is a C1-C5 alkylene group, wherein 0, 1, or more methylene groups are independently replaced by the following groups: -Cy X -, -O-, -C(=O)-, -C(=S)-, -C(=NR A-1 -, -CF2-, -CR A-1 F-、-CR A-1 R A-1 -、-CR A-1 (OR A-1 )-、-NR A-1 -, -S-, -S(=O)-, -S(=O)2-, -S(=O)(=NR A-1 )-、-CR A- 1 =CR A-1 -or Cy X Independently for C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene or 5-14 quinone heteroarylene; wherein the C3-C 12 Cycloalkylene, C3-C 12 Cycloalkenyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, C6-C 14 arylene, 5-14 arylene heteroarylene, optionally enclosed by one or more R Z The substituted 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14-membered heteroaryl groups have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 14 The aryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 member heteroaryl group is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. L a For C1-C 15 Alkylene, wherein 0, 1, or more methylene groups are independently replaced with -NR B -、-O-、-S-、 -CR B =CR B -、 Saturated or partially unsaturated C3-C 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings; wherein the C1-C 15 Alkylene, C3-C 12 Carbon rings, 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings are optionally surrounded by one or more R B The substituted 3-12 membered heterocycles have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5. The 5-14 membered heteroaromatic rings have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5. The C6-C 14 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. L b For covalent bonds, -O-, -S-, or -NL 11 -; L 11 H or C1-C6 alkyl, C3-C 16 Cycloalkyl, 3-16 membered heterocycloalkyl, C3-C 16 Cycloalkenyl, 3-16 membered heterocyclic alkenyl, phenyl or 6 membered heteroaryl, wherein the C1-C6 alkyl, C3-C 16 Cycloalkyl, 3-16 membered heterocycloalkyl, C3-C 16 Cycloalkenyl, 3-16-membered heterocyclic alkenyl, phenyl or 6-membered heteroaryl, optionally separated by one or more R A-1 The substituted 3-16-membered heterocyclic alkyl or 3-16-membered heterocyclic alkenyl groups have heteroatoms selected from one or more of N, O, S, P and Si, and the number of heteroatoms is 1, 2, 3, 4 or 5; the 6-membered heteroaryl group has heteroatoms selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3. L X Covalent bond or C1-C 20 Alkylene, the C1-C 20 In the alkylene group, 0, 1, or more methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -NR. A-1 -、-C(R A-1 )2-、-CR A-1 =CR A-1 -、 -C(=O)-、-OC(=O)-、-C(=O)O-、-S(=O)-、-S(=O)2-、-NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A-1 )-、-Si(=NR A-1 )-、 -P(=O)R A-1 -、 -NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -、-NR A-1 OC(=O)-、-CHF-、-CF2-、-S(=O)(=NR A-1 )-、 With L X Connect any point on the [structure / structure]; L X When it is a covalent bond, -L a -L b - Connect to any point on ring X; M can be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 independently; Or L X Independently for -L X1 -L X2 -L X3 -L X4 -; L X1 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 -、 -NR- A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-, -S(=O)2NR A-1 -, -NR A-1 C(=O)-, -C(=O)NR A-1 -, -OC(=O)NR A-1 - or -NR A - 1 OC(=O)-; L X2 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 one, -NR- A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-, -S(=O)2NR A-1 -, -NR A-1 C(=O)-, -C(=O)NR A-1 -, -OC(=O)NR A-1 - or -NR A-1 OC(=O)-; L X3 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 -、 -NR A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-, -S(=O)2NR A-1 -, -NR A-1 C(=O)-, -C(=O)NR A-1 -, -OC(=O)NR A-1 - or -NR A-1 OC(=O)-; L X4 It is a covalent bond or a C1-C6 alkylene group, wherein in the C1-C6 alkylene group, 0, 1, or 2 methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -C(R A-1 )2-、-CR A-1 =CR A-1 -、 -NR- A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-, -S(=O)2NR A-1 -, -NR A-1 C(=O)-, -C(=O)NR A-1 -, -OC(=O)NR A-1 - or -NR A-1 OC(=O)-; Cy is independently saturated or partially unsaturated C3-C 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings; wherein the C3-C 12 Carbon rings, 3-12 membered heterocycles, C6-C 14 Aromatic rings or 5-14 membered heteroaryl rings are optionally surrounded by one or more R Z The substituted 3-12 membered heterocycles are selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-14 membered heteroaromatic rings are selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3; the C6-C 14 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-14 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. for X 2 It can be CH or N. The compound of formula (I) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, is characterized in that, It meets one or more of the following conditions: (1) Ring B is a 5-14 membered heteroaromatic ring, for example, a 9-10 membered heteroaromatic ring with N heteroatom and 1 or 2 heteroatoms, wherein at least one ring of the 9-10 membered heteroaromatic ring is aromatic or each ring is aromatic. Better place, for Ring B1 is a 5-membered heteroaromatic ring or 5-membered heterocyclic alkene with N as the heteroatom and either one or two heteroatoms. For example, ring B1 is a 5-membered heteroaromatic ring with N as the heteroatom and either one heteroatom. The end marked with "#" is connected to ring A, and the end marked with "#1" is connected to ring L. X Connected; (2) n is 0, 1, or 2; for example, it is 1 or 2. (3)R B Independently halogenated or -C(=O)N(R) A-1 )2, R A-1 It is hydrogen or C1-C6 alkyl; (4) Ring A is a saturated or partially unsaturated 3-10 membered heterocycle, for example, a saturated or partially unsaturated 5-6 membered heterocycle with N heteroatom and 1 or 2 heteroatoms. (5)R A It is hydrogen; (6) m is 0 or 1; (7)L A For any of the following schemes: Option 1: C1-C6 alkylene groups, wherein 0, 1 or more methylene groups are independently replaced by -C(=O)-; Option 2: Among them, L A-1 For connecting bonds or C1-C5 alkylene groups, the end marked "#5" is connected to ring A; (8) Y is hydrogen or For example, (9) Ring Z is a 5-14 membered heteroaromatic ring, such as a 5-6 membered monocyclic heteroaromatic ring with N heteroatom and 1, 2 or 3 heteroatoms; (10)R Z It is hydrogen; (11) q is 0 or 1; (12)L a For C1-C 10 Alkylene, wherein 0, 1, 2 or 3 methylene groups are independently replaced by NR. B -、-O-、-S-、-CR B =CR B -or Ideally, L a It is a C3-C6 alkylene (e.g., a C3-C6 straight-chain alkylene), wherein 0 or 1 methylene groups are replaced by -CR B =CR B -(R B For example, H); Better yet, L a It is a C4-C6 alkylene group, wherein one methylene group is replaced by a -CR group. B =CR B -(R B For example, H); (13)L b It is O; (14) B -L X - X For C1-C 20 Alkylene, the C1-C 20 In the alkylene group, 0, 1, 2, 3, 4, 5, 6, 7, or 8 methylene groups are independently replaced by the following groups: -Cy-, C(=O)-, -C(=S)-, -CR A-1 2-, -CF2-, -NR A-1 -、-O-、-S- or -S(=O)2-, the end marked "B" is connected to ring B, and the end marked "X" is connected to ring X; (15) for The compound of formula (I) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, is characterized in that, It meets one or more of the following conditions: (1) for The end marked "#" is connected to ring A, and the end marked "#1" is connected to L. X Connected; (2)R B Independently, it is either F or -C(=O)N(CH3)2; (3) for In this ring, ring A is a 5-6 membered heterocycle with N as the heteroatom and one or two heteroatoms, which is either saturated or partially unsaturated. The end marked "#2" is connected to L. A Connected, the end marked "#3" is connected to L a Connected, the end marked "#4" is connected to ring B; (3)L A for For example, The end marked "#5" is connected to ring A; (4) for (5)L a For any of the following schemes: Option 1: Among them, the end marked "#6" is connected to L. b Connected, It is a double bond, and it has either a Z configuration or an E configuration; Option 2: For example, Among them, the end marked "#6" is connected to L. b Connected, It is a double bond, which is either Z-configuration or E-configuration, such as E-configuration; Option 3: Among them, the end marked "#6" is connected to L. b Connected, It is a double bond, which is either Z-configuration or E-configuration, such as E-configuration. The compound of formula (I) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, is characterized in that, It meets one or more of the following conditions: (1) for The end marked "#" is connected to ring A, and the end marked "#1" is connected to L. X Connected; (2) for For example, Among them, the end marked "#2" is connected to L. A Connected, the end marked "#3" is connected to L a Connected, the end marked "#4" is connected to ring B, and the carbon atom marked "*" has an R configuration, S configuration, or a mixture thereof. For example, For example, For example, For example, For example, For example, For example, For example, Better place, for Among them, the end marked "#2" is connected to L. A Connected, the end marked "#3" is connected to L a Connected, the end marked "#4" is connected to ring B, and the carbon atom marked "*" has an R configuration, an S configuration, or a mixture thereof; For example, The compound of formula (I) as claimed in at least one of claims 1-5, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, is characterized in that, B -L X - X for The end marked "B" is connected to ring B; the end marked "X" is connected to ring X. With L X The ring C is connected in the middle, and the compound shown in formula (I) is the same as the compound shown in formula (I-1): in, Ring C is C6-C 10 An aromatic ring or a 5-10 membered heteroaromatic ring, wherein the heteroatom in the 5-10 membered heteroaromatic ring is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 10 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-10 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. R C It is H or halogen; p is 0, 1, 2, 3, 4 or 5; L X5 Covalent bond or C1-C 15 Alkylene, the C1-C 15 In the alkylene group, 0, 1, or more methylene groups are independently replaced by the following groups: -Cy-, -O-、-S-、-NR A-1 -、-C(=O)-、-OC(=O)-、-C(=O)O-、-S(=O)-、-S(=O)2-、-NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A-1 )-、-Si(=NR A-1 )-、-P(=O)OR A-1 -、-P(=O)R A-1 -、-P(=O)N(R A-1 )2-、-NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -、-NR A-1 OC(=O)-、-CHF-、-CF2-、-S(=O)(=NR A-1 )-、 M is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Cy is independently saturated or partially unsaturated C3-C 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 10 Aromatic rings or 5-10 quinone heteroaryl rings; wherein the C3-C 12 Carbon rings, 3-12 membered heterocycles, C6-C 10 Aromatic rings or 5-10-membered heteroaryl rings are optionally surrounded by one or more R Z The substituted 3-12 membered heterocycles have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-10 membered heteroaromatic rings have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 10 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-10 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. Ring D is a saturated or partially unsaturated C3-C ring. 12 Carbon rings, saturated or partially unsaturated 3-12 membered heterocycles, C6-C 10 Aromatic rings or 5-10 quinone heteroaryl rings, wherein the C3-C 12 Carbon rings, 3-12 membered heterocycles, C6-C 10 Aromatic rings or 5-10-membered heteroaryl rings are optionally surrounded by one or more R Z The substituted 3-12 membered heterocycles have heteroatoms selected from one or more of N, O, S, P, and Si, and the number of heteroatoms is 1, 2, 3, 4, or 5; the 5-10 membered heteroaromatic rings have heteroatoms selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, 3, 4, or 5; the C6-C 10 The aromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic; the 5-10 membered heteroaromatic ring is monocyclic or polycyclic, and at least one ring is aromatic or each ring is aromatic. L D It is a covalently bonded or C1-C3 alkylene group, wherein in the C1-C3 alkylene group, 0, 1, 2, or 3 methylene groups are independently replaced by the following groups: -C(=O)-, -C(=S)-, -CR2-, -CF2-, -NR. A-1 -、-O-、-S- or -S(=O)2-; The definitions of the remaining variables are as described in at least one of claims 1-5. The compound of formula (I) as claimed in claim 6, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, satisfies one or more of the following conditions: (1) Ring C is C6-C 10 Aromatic rings, such as benzene rings; (2)R C It is hydrogen or F; (3) p is 0 or 1; (4)L X5 Covalent bond or C1-C 15 Alkylene, the C1-C 15 In the alkylene group, 0, 1, or more methylene groups are independently replaced by the following groups: -Cy-, -O-, -S-, -NR. A-1 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NR A-1 S(=O)2-、-S(=O)2NR A-1 -、-C(=S)-、-C(=NR A- 1 )-、-Si(=NR A-1 )-、-P(=O)OR A-1 -、-P(=O)R A-1 -、-P(=O)N(R A-1 )2-、-NR A-1 C(=O)-、-C(=O)NR A-1 -、-OC(=O)NR A-1 -、-NR A- 1 OC(=O)-, -CHF-, -CF2-, -S(=O)(=NR A-1 )-、 Ideally, L X5 Independently C1-C6 alkylene groups, wherein one, two, or three methylene groups in the C1-C6 alkylene groups are independently prefixed with -Cy-, -C(=O)-, or... Alternatively, Cy can be a saturated 4-9 membered heterocycle, wherein the heteroatom is N, and the number of heteroatoms is 1 or 2; for example, a C1-C6 alkylene ring, wherein one or two methylene groups in the C1-C6 alkylene ring are independently replaced by -Cy- or C (=O); Cy can also be a saturated 5-6 membered heterocycle, wherein the heteroatom is N, and the number of heteroatoms is 1 or 2. Better yet, L X5 Independently C1-C6 alkylene, wherein one, two, or three methylene groups in the C1-C6 alkylene are independently replaced by -Cy- or C (=O), Cy is a saturated 5-6 membered heterocycle, wherein the heteroatom in the 5-6 membered heterocycle is N, and the number of heteroatoms is one or two; for example, C1-C6 alkylene, wherein one methylene group in the C1-C6 alkylene is independently replaced by -Cy-, Cy is a saturated 5-6 membered heterocycle, wherein the heteroatom in the 5-6 membered heterocycle is N, and the number of heteroatoms is one or two; For example, L X5 Independently C1-C4 alkylene (e.g., C1-C4 straight-chain alkylene), wherein one, two, or three methylene groups in the C1-C4 alkylene are independently replaced by -Cy- or C (=O), where Cy is a saturated 4-6 member monocyclic heterocycle or a saturated 9 member spirocyclic heterocycle, wherein the heteroatom in the 4-6 member monocyclic heterocycle or the 9 member spirocyclic heterocycle is N, and the number of heteroatoms is one or two; (5) Ring D is C6-C 10 Aromatic rings or 5-10 quinone heteroaryl rings, the C6-C 10 Aromatic rings or 5-10-membered heteroaryl rings are optionally surrounded by one or more R Z Replaced by, R Z It is oxo (=O), halogen, C1-C6 alkyl, or C1-C6 alkoxy; preferably, R Z It is an oxo (=O), halogen, or C1-C6 alkyl group; (6)L D It is a covalent bond, -C(=O)-, -NH- or -C(=O)NH-; for example, it is a covalent bond or -NH-. The compound of formula (I) as claimed in claim 6, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, satisfies one or more of the following conditions: (1) for The end marked "#8" is connected to ring B; the end marked "#9" is connected to L. b Connected; the end marked "#10" is connected to L. X5 Connected; (2)L X5 For any of the following groups: Group (1): L X5 for in, Cy1 and L XA The definition satisfies any of the following schemes: Option 1: Cy1 is a saturated 5-6 membered heterocyclic ring. L XA It is a covalent bond or a C1-C5 alkylene bond, for example, a C1-C5 alkylene bond, with the end marked "#11" connected to ring D; Option 2: Cy1 is a saturated 5-6 membered heterocyclic ring. L XA It is a covalent bond or a C1-C5 alkylene group, wherein 0, 1, or 2 methylene groups in the C1-C5 alkylene group are independently replaced by -Cy- or -C(=O)-, Cy is a saturated 4-6 membered heterocycle, wherein the heteroatom in the 4-6 membered heterocycle is N, and the number of heteroatoms is 1 or 2; the end marked "#11" is connected to ring D; Group (2): L X5 for Among them, Cy1 is a saturated 5-6 membered heterocycle, L XA and L XB Independently covalently bonded or C1-C5 alkylene, wherein 0, 1, or 2 methylene groups in the C1-C5 alkylene are independently bounded by -Cy-, =C(=O)=, or The alternative is that Cy is a saturated 4-6 membered heterocycle, wherein the heteroatom is N, and the number of heteroatoms is 1 or 2; the end marked "#11" is connected to ring D; Or, L X5 for Among them, Cy1 is a saturated 4-6 member monocyclic heterocyclic ring or a saturated 9 member spirocyclic heterocyclic ring, L XA and L XB Independently covalently bonded or C1-C5 alkylene (e.g., C1-C5 straight-chain alkylene, further for example -CH2-, -CH2CH2- or -CH2CH2CH2-), wherein 0, 1 or 2 methylene groups in the C1-C5 alkylene are independently replaced by -Cy- or -C(=O)-, where Cy is a saturated 4-6 membered monocyclic heterocycle, wherein the heteroatom is N, and the number of heteroatoms is 1 or 2; the end marked "#11" is connected to ring D; (3) For any of the following groups: Group (1): Where R Z It is a C1-C6 alkyl group; r is 0, 1, or 2, and the ring E1 is a 5-6 membered heterocyclic alkene with N heteroatoms and 1 or 2 heteroatoms; preferably, R Z It is a C1-C6 alkyl group, r is 1, and the ring E1 is a 5-6 membered heterocyclic alkene with N heteroatom and 2 heteroatoms; Group (2): Where r is 0, 1, or 2, R Z It is a halogen, a C1-C6 alkyl or a C1-C6 alkoxy, preferably a halogen or a C1-C6 alkyl; Group (3): Where R Z It is a C1-C6 alkyl group; r is 0, 1 or 2, and ring E2 is a 5-6 membered heteroaromatic ring with N heteroatom and 1 or 2 heteroatoms, wherein the 5-6 membered heteroaromatic ring is aromatic; Group (4): Where R Z It is a C1-C6 alkyl group; r is 0, 1 or 2, and the ring E1 is a 5-6 membered heterocyclic alkene with N heteroatom and 1 or 2 heteroatoms; Group (5): Where R Z It is a C1-C6 alkyl group; r is 0, 1 or 2, and ring E2 is a 5-6 membered heteroaromatic ring with N heteroatom and 1 or 2 heteroatoms, wherein the 5-6 membered heteroaromatic ring is aromatic; Group (6): Where r is 0, 1, or 2, R Z It is a halogen, a C1-C6 alkyl or a C1-C6 alkoxy; Among them, the end marked "#12" is connected to L. D Connected; Better place, When L is group (1), group (3), group (4) or group (5), D It is a covalent bond; When it is group (2) or group (6), L D It is a covalent bond or -NH-. The compound of formula (I) as claimed in claim 6, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, satisfies one or more of the following conditions: (1)L X5 For any of the following schemes: Option 1: The end marked "#11" is connected to ring D; Option 2: For example, The end marked "#11" is connected to ring D; Option 3: The end marked "#11" is connected to ring D; (2) for For example, For example, in, The end marked "#12" is connected to L D Connected; (3) for The compound of formula (I) as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, is characterized in that, The compound represented by formula (I) is selected from any of the following compounds: In this case, the chiral carbon atoms marked "#1" and "2" are independently of the R configuration, S configuration, or a mixture of both; for example, Among them, including In the structure, It is a carbon-carbon double bond, which is either Z-configuration or E-configuration, preferably E-configuration. A pharmaceutical composition comprising a compound of formula (I) as described in at least one of claims 1-10, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The use of a compound of formula (I) as described in at least one of claims 1-10, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 11 in the preparation of a STAT6 inhibitor or degrader. The use of a compound of formula (I) as described in at least one of claims 1-10, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 11 in the preparation of a medicament for the prevention and / or treatment of STAT6-mediated diseases, preferably, wherein the STAT6-mediated diseases are cancer, inflammatory diseases, esophageal diseases, chronic obstructive pulmonary disease, Alzheimer's disease, or peripheral nervous system diseases; wherein the inflammatory diseases may be atopic dermatitis, sinusitis, or asthma. The use of a compound of formula (I) as described in at least one of claims 1-10, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 11 in the preparation of a medicament for the prevention and / or treatment of cancer, inflammatory diseases, esophageal diseases, chronic obstructive pulmonary disease, Alzheimer's disease, or peripheral nervous system diseases; wherein the inflammatory disease may be atopic dermatitis, sinusitis, or asthma.

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