Novel prmt5 inhibitor and use thereof

Abstract

The present disclosure describes novel molecules with protein arginine methyltransferase 5 inhibitory activity, and methods for synthesis and use of the compound. Specifically, the present disclosure describes the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and methods for synthesis and use of the compound.

Description

Novel PRMT5 inhibitors and their applications Technical Field

[0001] The present disclosure belongs to the field of drug synthesis, and specifically relates to a PRMT5 inhibitor and applications thereof. Background Art

[0002] Epigenetic alterations are key mediators driving and maintaining the malignant phenotype of tumors. Changes in DNA methylation, histone acetylation and methylation, noncoding RNAs, and post-translational modifications are all epigenetic drivers of cancer development, independent of DNA sequence changes. Arginine methylation is an important post-translational modification that influences cell growth and proliferation, apoptosis, angiogenesis, and metastasis by regulating transcription and post-transcriptional RNA processing. Three types of methylarginine exist: ω-NG, N'G-asymmetric dimethylarginine (ADMA) and ω-NG, N'G-symmetric dimethylarginine (SDMA). This modification is catalyzed by the protein arginine methyltransferase (PRMT) family, transferring a methyl group from S-adenosylmethionine (AdoMet) to arginine side chains on histones and non-histone proteins. Nine PRMT genes have been annotated in the human genome and are categorized as type I (PRMT1, 2, 3, 4, 6, and 8), type II (PRMT5 and PRMT9), and type III enzymes (PRMT7) based on the type of methylarginine produced. PRMT5 is primarily a type II enzyme that catalyzes the symmetric dimethylation of arginine. PRMT5 was first discovered in a two-hybrid assay to detect proteins that interact with Janus tyrosine kinase (Jak2).

[0003] PRMT5 is a universal transcriptional repressor that forms a complex with other transcription factors, including BRG1 and Hbrm, Blimp1, and Snail. PRMT5 participates in diverse cellular processes by methylating a variety of cytoplasmic and nuclear substrates, including histone H4 residue Arg3 (H4R3) and H3 residue Arg8 (H3R8). H4R3 methylation is associated with transcriptional repression, while H3R8 methylation is considered to be involved in both transcriptional activation and repression. In addition to directly inducing repressive histone marks, PRMT5's role in gene silencing is mediated by the formation of a multi-repressor protein complex, including NuRD components, HDACs, MDB proteins, and DNA methyltransferases. PRMT5 influences its substrate specificity through interactions with several binding proteins. A core component of this protein complex is MEP50, which is essential for the enzymatic activity of PRMT5. Studies have found that PRMT5 can methylate proteins involved in RNA splicing, such as SmD3, which can be used to track the chemical activity of PRMT5 in cell biology.

[0004] PRMT5 plays a crucial role in tumorigenesis. Studies have found that PRMT5 expression is upregulated in a variety of tumors, including lymphoma, lung cancer, breast cancer, and colorectal cancer. Furthermore, PRMT5 expression is elevated in samples from patients with mantle cell lymphoma (MCL), and PRMT5 knockout inhibits MCL cell proliferation, suggesting a key role for PRMT5 in MCL. PRMT5 overexpression promotes cell proliferation, while PRMT5 knockout inhibits cell proliferation in melanoma, breast cancer, and lung cancer cell lines. Therefore, PRMT5 is a potential target for cancer therapy.

[0005] Loss of methylthioadenosine phosphorylase (MTAP) confers a selective reliance on PRMT5 and its binding protein, WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene CDKN2A. Cells harboring MTAP deletion have increased levels of intracellular methylthioadenosine (MTA), a metabolite cleaved by MTAP. MTA shares a similar structure to S-adenosylmethionine (SAM). As concentrations increase, MTA acts as an intrinsic, selective inhibitor, inhibiting the binding of SAM to PRMT5 and, consequently, the methyltransferase activity of PRMT5.

[0006] The most significant structural difference between MTAP-deficient and MTAP-wild-type cancer cells lies in the accumulation of MTA in MTAP-deficient cancer cells, which results in the formation of a PRMT5-MTA complex. Inhibitors developed against the PRMT5-MTA complex can selectively target MTAP-deficient cancer cells while minimizing the effect on normal cells, significantly improving the therapeutic index.

[0007] Therefore, identifying and developing small molecules that inhibit PRMT5 activity will be useful as therapeutic approaches for treating various PRMT5-associated diseases or disorders, such as cancer. Summary of the Invention

[0008] To solve the technical problem of the present disclosure, the present disclosure provides a class of compounds with novel structures that have excellent inhibitory activity against PRMT5.

[0009] Specifically, the present disclosure provides a compound represented by formula (I), and its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives,

[0010] Wherein, Cy represents the following structure: or

[0011] Wherein, the dotted line represents a single bond or a double bond;

[0012] Wherein, Y1 independently represents O, S, Se, N or CRY1 ;

[0013] Wherein, Y2 independently represents O, S, Se, N or CR Y2 ;

[0014] Wherein, Y3 independently represents O, S, Se, N or CR Y3 ;

[0015] Wherein, Y4 independently represents O, S, Se, N or CR Y4 ;

[0016] Where X1 represents N or CR X1 ;

[0017] Where X2 represents N or CR X2 ;

[0018] Where X3 represents N or CR X3 ;

[0019] Among them, X4 represents N or CR X4 ;

[0020] Among them, X5 represents N or CR X5 ;

[0021] Among them, X6 represents N or CR X6 ;

[0022] Among them, R X1 、R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b 、-SF5、-C(O)OR a 、-CO2NR a R b ;

[0023] Among them, R X3 、R X5 、R X6Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, -C(O)OR a 、-CO2NR a R b or be selected from 0-4 of the following substituents: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), -NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0024] Among them, R X4 Indicates -LR X4-1 ;

[0025] Among them, L means non-existent or CR a R b 、SiR a R b 、O、S、Se、NR a ;

[0026] Among them, R X4-1represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b 、-C(O)OR a 、-OC(O)R a 、-OCONR a R b 、-NR a COR b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0027] Among them, R Y1 、R Y2 、R Y3 、R Y4 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b 、-SF5、-C(O)OR a 、-CO2NR a R b ;

[0028] Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X3 and X4, and the ring may contain 0-3 heteroatoms selected from O, N, and S; wherein, the ring may be optionally substituted with 0, 1, 2, or 3 heteroatoms selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b substituted by a substituent;

[0029] Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X4 and X5, and the ring may contain 0-3 heteroatoms selected from O, N, and S; wherein, the ring may be optionally substituted with 0, 1, 2, or 3 heteroatoms selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b substituted by a substituent;

[0030] Among them, R 1 represents hydrogen or substituted by 0-3 groups selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic monoheterocyclic group, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0031] Preferably, R 1 Indicates -CHR s R t or -CDR s R t ;

[0032] Among them, R s 、R t Each independently represents hydrogen, deuterium, -OR a , halogen, -CN, C1-C6 alkyl, , C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, -C3-C 10 Cycloalkyl or 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b substituted 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0033] Among them, R 2 、R 3Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxy, carboxyl, halogenated C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl);

[0034] Among them, M1 represents CR a R b 、-SiR a R b NR a , O, S or Se;

[0035] Wherein, M2 represents C or Si;

[0036] Among them, R L 、R L’ Each independently represents a C1-C6 alkyl group, or R L , RL' together with the atoms connected thereto form a 3-10 membered saturated or unsaturated ring, and the ring may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, S, and Se; further, the ring may also be arbitrarily replaced by 0, 1, or 2 heteroatoms selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-C(O)OR a 、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , substituted by a substituent of -SF5;

[0037] Among them, R T 、R T’ Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxyl, carboxyl, halogenated C1-C6 alkyl, hydroxyl (C1-C6 alkyl), mercapto (C1-C6 alkyl) together with the atoms connected thereto to form a 3-10 membered saturated or unsaturated ring, and the ring may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, S, and Se; further, the ring may also be arbitrarily replaced by 0, 1, or 2 heteroatoms selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a、-S(O)2R a 、-S(O)R a 、-CN、-C(O)OR a 、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , substituted by a substituent of -SF5;

[0038] Where o represents 0, 1 or 2;

[0039] Among them, R a 、R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a 、R b Together with the atoms to which they are connected, they form a 3-14 membered saturated or unsaturated monocyclic ring, a 3-14 membered saturated or unsaturated spirocyclic ring, or a 3-14 membered saturated or unsaturated fused ring, each of which may arbitrarily contain 0-2 heteroatoms selected from O, S, Se, N, and Si.

[0040] In addition, the present disclosure provides a compound represented by formula (I-1), and its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives,

[0041] Wherein, Cy represents the following structure: or

[0042] Wherein, the dotted line represents a single bond or a double bond;

[0043] Wherein, Y1 independently represents O, S, Se, N or CR Y1 ;

[0044] Wherein, Y2 independently represents O, S, Se, N or CR Y2 ;

[0045] Wherein, Y3 independently represents O, S, Se, N or CR Y3 ;

[0046] Wherein, Y4 independently represents O, S, Se, N or CR Y4 ;

[0047] Where X1 represents N or CR X1 ;

[0048] Where X2 represents N or CR X2;

[0049] Where X3 represents N or CR X3 ;

[0050] Among them, X4 represents N or CR X4 ;

[0051] Among them, X5 represents N or CR X5 ;

[0052] Among them, X6 represents N or CR X6 ;

[0053] Among them, R X1 、R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b 、-SF5、-C(O)OR a 、-CO2NR a R b ;

[0054] Among them, R X3 、R X5 、R X6 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, -C(O)OR a 、-CO2NR a R bor be selected from 0-4 of the following substituents: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), -NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0055] Among them, R X4 Indicates -LR X4-1 ;

[0056] Among them, L means non-existent or CR a R b 、SiR a R b 、O、S、Se、NR a ;

[0057] Among them, R X4-1 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b 、-C(O)OR a 、-OC(O)R a 、-OCONR a R b 、-NR a COR b, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0058] Among them, R Y1 、R Y2 、R Y3 、R Y4 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b 、-SF5、-C(O)OR a 、-CO2NR a R b ;

[0059] Among them, R 1represents hydrogen or substituted by 0-3 groups selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic monoheterocyclic group, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0060] Preferably, R 1 Indicates -CHR s R t or -CDR s R t ;

[0061] Among them, R s 、R t Each independently represents hydrogen, deuterium, -OR a , halogen, -CN, C1-C6 alkyl, , C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, -C3-C 10 Cycloalkyl or 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b substituted 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0062] Among them, R 2 、R 3 Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxy, carboxyl, halogenated C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl);

[0063] Among them, M1 represents CR a R b 、-SiR a R b NR a , O, S or Se;

[0064] Wherein, M2 represents C or Si;

[0065] Among them, R L 、R L’ Each independently represents a C1-C6 alkyl group, or R L 、R L’ Together with the atoms connected to it, they form a 3-10 membered saturated or unsaturated ring, and the ring may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, S, and Se; further, the ring may also be arbitrarily replaced by 0, 1, or 2 heteroatoms selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-C(O)OR a 、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , substituted by a substituent of -SF5;

[0066] Among them, R T 、RT’ Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxyl, carboxyl, halogenated C1-C6 alkyl, hydroxyl (C1-C6 alkyl), mercapto (C1-C6 alkyl) together with the atoms connected thereto to form a 3-10 membered saturated or unsaturated ring, and the ring may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, S, and Se; further, the ring may also be arbitrarily replaced by 0, 1, or 2 heteroatoms selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-C(O)OR a 、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , substituted by a substituent of -SF5;

[0067] Where o represents 0, 1 or 2;

[0068] Among them, R a 、R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a 、R b Together with the atoms to which they are connected, they form a 3-14 membered saturated or unsaturated monocyclic ring, a 3-14 membered saturated or unsaturated spirocyclic ring, or a 3-14 membered saturated or unsaturated fused ring, each of which may arbitrarily contain 0-2 heteroatoms selected from O, S, and N.

[0069] In the preferred technical solution of formula (I) or formula (I-1), Cy represents the following structure:

[0070] In the preferred technical solution of formula (I) or formula (I-1), wherein X1 represents CR X1 or N, where R X1 represents hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, or halogenated C1-C6 alkyl.

[0071] In the preferred technical solution of formula (I) or formula (I-1), X1 represents CH, CF or N.

[0072] In the preferred technical solution of formula (I) or formula (I-1), X2 represents CH or CD.

[0073] In the preferred technical solution of formula (I) or formula (I-1), X2 is represented by CH.

[0074] In the preferred technical solution of formula (I) or formula (I-1), X3 represents CH, CD or N.

[0075] In the preferred technical solution of formula (I) or formula (I-1), X3 represents CH.

[0076] In the preferred technical solution of formula (I) or formula (I-1), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10Aryl, 5-10 membered heteroaryl.

[0077] In the preferred technical solution of formula (I) or formula (I-1), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 It represents hydrogen, deuterium, C1-C6 alkyl, halogen, halogenated C1-C6 alkyl, -CN, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -SF5, -P(O)(CH3)2.

[0078] In the preferred technical solution of formula (I) or formula (I-1), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 It represents hydrogen, halogen (preferably F), -CF3, -NH2, -NHCH3, -N(CH3)2, -OCH3, -OCF3, -SF5, -P(O)(CH3)2.

[0079] In the preferred technical solution of formula (I) or formula (I-1), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 represents 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C6-C 10 aryl or 5-10 membered heteroaryl.

[0080] In the preferred technical solution of formula (I) or formula (I-1), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups:

[0081] Furthermore, R X4 It may be arbitrarily substituted with 0, 1, or 2 groups selected from halogen, hydroxy, C1-C6 alkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy.

[0082] In the preferred technical solution of formula (I) or formula (I-1), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 represents 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic ring.

[0083] In the preferred technical solution of formula (I) or formula (I-1), wherein X 4 Represents CLR X4-1 , wherein L represents O, S or NH, N(CH3), R X4-1 Represents the following groups:

[0084] Furthermore, R X4-1 It may be arbitrarily substituted with 0, 1, or 2 groups selected from halogen, hydroxy, -CN, C1-C6 alkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy.

[0085] In the preferred technical solution of formula (I) or formula (I-1), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups:

[0086] Among them, W1 represents CR C R D NR C 、O、S、SiR C R D ;

[0087] Wherein, W2 represents -(CR M R N ) i -;

[0088] wherein R1′, R2′, R3′, R4′, R5′, R6′, R7′, and R8′ each independently represent hydrogen, deuterium, halogen, C1-C6 alkyl, or hydroxyl; or, individually, a pair of R1′ and R2′; a pair of R3′ and R4′; a pair of R5′ and R6′; and a pair of R7′ and R8′ together with the atoms to which they are attached form a 3-6 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, S, and N; further, the ring may be arbitrarily substituted with 0, 1, or 2 substituents selected from deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, and hydroxyl;

[0089] Among them, R C 、R D Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, hydroxyl; or R S 、R T Together with the atoms to which it is attached, it forms a 3-6 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, S, and N; further, the ring may optionally be substituted with 0, 1, or 2 substituents selected from deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, and hydroxyl;

[0090] Among them, R M 、R N Each independently represents hydrogen or C1-C6 alkyl;

[0091] Here, i represents an integer of 1 or 2.

[0092] Furthermore, R X4-1 It may be arbitrarily substituted with 0, 1, or 2 groups selected from halogen, hydroxy, -CN, C1-C6 alkyl, halogenated C1-C6 alkyl, and halogenated C1-C6 alkoxy.

[0093] In the preferred technical solution of formula (I) or formula (I-1), wherein X 4 Represents CLR X4-1 , where L means non-existent, RX4-1 Represents the following groups:

[0094] Among them, the R X4-1 It may be arbitrarily substituted with 0, 1, or 2 substituents selected from halogen, hydroxy, cyano, C1-C6 alkyl, and halo-substituted C1-C6 alkyl.

[0095] In the preferred technical solution of formula (I) or formula (I-1), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups:

[0096] In the preferred technical solution of formula (I) or formula (I-1), wherein X4 represents CR X4 ; Among them, R X4 It represents a C1-C6 alkoxy group, a C1-C6 alkylthio group, a halogenated C1-C6 alkoxy group, a halogenated C1-C6 alkylthio group, a halogenated C1-C6 alkyl group, or -SF5.

[0097] In the preferred technical solution of formula (I) or formula (I-1), wherein X4 represents CR X4 ; Among them, R X4 It represents a halogenated C1-C6 alkoxy group, a halogenated C1-C6 alkylthio group, a halogenated C1-C6 alkyl group, or -SF5.

[0098] In the preferred technical solution of formula (I) or formula (I-1), wherein X5 represents CR X5 or N, where R X5 represents hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5 or cyano.

[0099] In the preferred technical solution of formula (I) or formula (I-1), X5 represents CH.

[0100] In the preferred technical solution of formula (I) or formula (I-1), X6 represents CH, CD or N.

[0101] In the preferred technical solution of formula (I) or formula (I-1), X6 represents CH.

[0102] In the preferred technical solution of formula (I) or formula (I-1), wherein R 1 Indicates -CHR 2 R 3 or -CDR 2 R 3 , where R 2 、R3 Each independently represents hydrogen, deuterium, C1-C6 alkyl, or 0-3 selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

[0103] In the preferred technical solution of formula (I) or formula (I-1), wherein R 1 Indicates -CHR 2 R 3 or -CDR 2 R 3 , where R 2 represents hydrogen, deuterium, C1-C6 alkyl; R 3 represents hydrogen, deuterium, C1-C6 alkyl, or 0-3 selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR bor -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

[0104] In the preferred technical solution of formula (I) or formula (I-1), wherein R 1 represents 0-3 selected from deuterated, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-CN、NR a R b , C3-C substituted by halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy 10 Cycloalkyl.

[0105] In the preferred technical solution of formula (I) or formula (I-1), wherein R 1 represents a C1-C6 alkyl group (preferably a methyl group or an ethyl group) or a deuterated C1-C6 alkyl group (preferably a deuterated methyl group or a deuterated ethyl group) or a C3-C6 cycloalkyl group (preferably a cyclopropyl group).

[0106] In the preferred technical solution of formula (I) or formula (I-1), M1 is O or S.

[0107] In the preferred technical solution of formula (I) or formula (I-1), o is 1 or 2.

[0108] In the preferred technical solution of formula (I) or formula (I-1), o is 1.

[0109] In the preferred technical solution of formula (I) or formula (I-1), wherein R L 、R L’ Each independently represents a C1-C6 alkyl group.

[0110] In the preferred technical solution of formula (I) or formula (I-1), wherein R L 、R L’ Together with the atoms to which they are attached, they form a 3-6 membered ring.

[0111] In the preferred technical solution of formula (I) or formula (I-1), wherein R L 、R L’ Together with the atoms to which they are attached, they form a 3-membered or 4-membered ring.

[0112] In the preferred technical solution of formula (I) or formula (I-1), wherein R L 、R L’ Together with the atoms to which they are attached, they form a ring with the following structure:

[0113] Among them, * represents R L 、R L’ Commonly connected atomic sites, further, the above-mentioned ring structure can be arbitrarily replaced by 0, 1, or 2 selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-C(O)OR a 、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5 substituents.

[0114] In the preferred technical solution of formula (I) or formula (I-1), wherein R T 、R T’ Together with the atoms to which they are attached, they form a ring with the following structure:

[0115] Among them, * represents R T 、R T’ Commonly connected atomic sites, further, the above-mentioned ring structure can be arbitrarily replaced by 0, 1, or 2 selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-C(O)OR a 、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5 substituents.

[0116] In addition, the present disclosure provides a compound represented by formula (I-2), and its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives,

[0117] Where X3 represents N or CR X3 ; X4 represents N or CR X4 ; X5 represents N or CR X5 ; X6 represents N or CR X6 ;

[0118] Among them, when X3 represents CR X3 When R X3 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0119] Among them, when X4 represents CR X4 When R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2Ra 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0120] Among them, when X5 represents CR X5 When R X5 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SRa 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0121] Among them, when X6 represents CR X6 When R X6 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0122] Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X3 and X4, and the ring may contain 0-3 heteroatoms selected from O, N, and S;

[0123] Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X4 and X5, and the ring may contain 0-3 heteroatoms selected from O, N, and S;

[0124] Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X5 and X6, and the ring may contain 0-3 heteroatoms selected from O, N, and S;

[0125] Wherein, the ring A can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b substituted by a substituent;

[0126] Wherein, R' represents 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic monoheterocyclic group, -OR a, oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0127] Preferably, R 1 Indicates -CHR 2 R 3 or -CDR 2 R 3 ;

[0128] Among them, R 2 、R 3 Each independently represents hydrogen, deuterium, -OR a , halogen, -CN, -C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, -C3-C 10 Cycloalkyl or 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a CORb or -CONR a R b substituted 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0129] Among them, M 1 Indicates CR a R b NR a , O, S or Se;

[0130] Among them, R L 、R L’ Each independently represents a C1-C6 alkyl group, or R L 、R L’ Together with the atoms to which they are attached, they form a 3-6 membered ring;

[0131] Where o represents 0, 1 or 2;

[0132] Wherein, m represents an integer from 0 to 10;

[0133] Among them, ring B represents a 3-10 membered carbocyclic ring, a 6-10 membered unsaturated carbocyclic ring, a 4-10 membered heterocyclic ring, a 6-10 membered unsaturated heterocyclic ring, a C6-C 10 Aromatic ring, 5-10 membered aromatic heterocycle, the 4-10 membered heterocycle, 6-10 membered unsaturated heterocycle, 5-10 membered aromatic heterocycle may contain 0-3 O, S, N atoms.

[0134] Wherein, the ring B can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)ORa 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b substituted by a substituent;

[0135] Where X1 represents N or CR X1 ;

[0136] Where X2 represents N or CR X2 ;

[0137] Among them, R X1 、R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5;

[0138] in, Indicates a single bond or a double bond;

[0139] In addition, the present disclosure provides a compound represented by formula (I-3), and its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives,

[0140] Where X3 represents N or CR X3 ; X4 represents N or CR X4 ; X5 represents N or CR X5 ; X6 represents N or CR X6 ;

[0141] Among them, when X3 represents CR X3 When R X3 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0142] Among them, when X4 represents CR X4 When R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3Ra 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0143] Among them, when X5 represents CR X5 When R X5 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C10 Aryl, 5-10 membered heteroaryl;

[0144] Among them, when X6 represents CR X6 When R X6 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0145] Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X3 and X4, and the ring may contain 0-3 heteroatoms selected from O, N, and S;

[0146] Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X4 and X5, and the ring may contain 0-3 heteroatoms selected from O, N, and S;

[0147] Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X5 and X6, and the ring may contain 0-3 heteroatoms selected from O, N, and S;

[0148] Wherein, the ring A can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b substituted by a substituent;

[0149] Among them, R 1 represents 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic monoheterocyclic group, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0150] Preferably, R 1 Indicates -CHR 2 R 3 or -CDR 2 R 3 ;

[0151] Among them, R 2 、R 3 Each independently represents hydrogen, deuterium, -OR a , halogen, -CN, -C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, -C3-C 10 Cycloalkyl or 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b substituted 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0152] Among them, M 1 Indicates CR a R b NR a , O, S or Se;

[0153] Among them, R L 、R L’ Each independently represents a C1-C6 alkyl group, or R L 、R L’ Together with the atoms to which they are attached, they form a 3-6 membered ring;

[0154] Where o represents 0, 1 or 2;

[0155] Wherein, m represents an integer from 0 to 10;

[0156] Among them, ring B represents a 3-10 membered carbocyclic ring, a 6-10 membered unsaturated carbocyclic ring, a 4-10 membered heterocyclic ring, a 6-10 membered unsaturated heterocyclic ring, a C6-C 10 Aromatic ring, 5-10 membered aromatic heterocycle, the 4-10 membered heterocycle, 6-10 membered unsaturated heterocycle, 5-10 membered aromatic heterocycle may contain 0-3 O, S, N atoms.

[0157] Wherein, the ring B can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b substituted by a substituent;

[0158] Where X1 represents N or CR X1 ;

[0159] Where X2 represents N or CR X2 ;

[0160] Among them, R X1 、R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5;

[0161] in, Indicates a single bond or a double bond.

[0162] In the preferred technical solution of formula (I-2) or formula (I-3), wherein ring B represents the following structure:

[0163] Among them, Y1 represents CR Y1 R Y1’ NR Y1 ,O,S;

[0164] Among them, Y2 represents CR Y2 R Y2’ NR Y2 ,O,S;

[0165] Among them, Y3 represents CR Y3 R Y3’ NR Y3 ,O,S;

[0166] Among them, R Y1 、R Y1’ 、R Y2 、R Y2’ 、R Y3 、R Y3’ Each independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5;

[0167] Among them, R a 、R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a 、R b Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

[0168] In the preferred technical solution of formula (I-2) or formula (I-3), wherein ring B represents the following structure:

[0169] Among them, Y3 represents CR Y3 R Y3’ , R Y3 、R Y3’ Each independently represents hydrogen, deuterium, or a C1-C6 alkyl group.

[0170] In the preferred technical solution of formula (I-2) or formula (I-3), wherein ring B represents the following structure:

[0171] R Y1 represents hydrogen, deuterium, C1-C6 alkyl;

[0172] In the preferred technical solution of formula (I-2) or formula (I-3), wherein ring B represents the following structure:

[0173] R Y3 represents hydrogen, deuterium, or a C1-C6 alkyl group.

[0174] In the preferred technical solution of formula (I-2) or formula (I-3), wherein ring B represents the following structure:

[0175] R Y3 represents hydrogen, deuterium, or a C1-C6 alkyl group.

[0176] In the preferred technical solution of formula (I-2) or formula (I-3), wherein ring B represents the following structure:

[0177] RY1 represents hydrogen, deuterium, or a C1-C6 alkyl group.

[0178] In the preferred technical solution of formula (I-2) or formula (I-3), wherein ring B represents the following structure:

[0179] R Y3 represents hydrogen, deuterium, or a C1-C6 alkyl group.

[0180] In the preferred technical solution of formula (I-2) or formula (I-3), wherein ring B represents the following structure:

[0181] R Y1 represents hydrogen, deuterium, or a C1-C6 alkyl group.

[0182] In the preferred technical solution of formula (I-2) or formula (I-3), wherein ring B represents the following structure:

[0183] Among them, Y4 represents CR Y4 R Y4’ NR Y4 ,O,S;

[0184] Among them, R Y4 、R Y4’ Each independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5; among which, R a 、R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a 、R b Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

[0185] In the preferred technical solution of formula (I-2) or formula (I-3), wherein ring B represents the following structure:

[0186] Among them, Y5 represents CR Y5 R Y5’ NR Y5 ,O,S;

[0187] Among them, R Y5 、R Y5’ Each independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5; among which, R a 、R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a 、R b Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

[0188] In the preferred technical solution of formula (I-2) or formula (I-3), Indicates a double bond.

[0189] In the preferred technical solution of formula (I-2) or formula (I-3), wherein X1 represents CR X1 or N, where R X1 represents hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, or halogenated C1-C6 alkyl.

[0190] In the preferred technical solution of formula (I-2) or formula (I-3), X1 represents CH, CF or N.

[0191] In the preferred technical solution of formula (I-2) or formula (I-3), X2 represents CH or CD.

[0192] In the preferred technical solution of formula (I-2) or formula (I-3), X2 is represented by CH.

[0193] In the preferred technical solution of formula (I-2) or formula (I-3), X3 represents CH, CD or N.

[0194] In the preferred technical solution of formula (I-2) or formula (I-3), X3 represents CH.

[0195] In the preferred technical solution of formula (I-2) or formula (I-3), wherein X4 represents CR X4 ; Among them, R X4 It represents a C1-C6 alkoxy group, a C1-C6 alkylthio group, a halogenated C1-C6 alkoxy group, a halogenated C1-C6 alkylthio group, a halogenated C1-C6 alkyl group, or -SF5.

[0196] In the preferred technical solution of formula (I-2) or formula (I-3), wherein X4 represents CR X4 ; Among them, R X4 It represents a halogenated C1-C6 alkoxy group, a halogenated C1-C6 alkylthio group, a halogenated C1-C6 alkyl group, or -SF5.

[0197] In the preferred technical solution of formula (I-2) or formula (I-3), wherein X5 represents CR X5 or N, where R X5 represents hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5 or cyano.

[0198] In the preferred technical solution of formula (I-2) or formula (I-3), X5 represents CH.

[0199] In the preferred technical solution of formula (I-2) or formula (I-3), X6 represents CH, CD or N.

[0200] In the preferred technical solution of formula (I-2) or formula (I-3), X6 represents CH.

[0201] In the preferred technical solution of formula (I-2) or formula (I-3), wherein R 1 Indicates -CHR 2 R 3 or -CDR 2 R 3 , where R 2 、R 3 Each independently represents hydrogen, deuterium, C1-C6 alkyl, or 0-3 selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a, oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

[0202] In the preferred technical solution of formula (I-2) or formula (I-3), wherein R 1 Indicates -CHR 2 R 3 or -CDR 2 R 3 , where R 2 represents hydrogen, deuterium, C1-C6 alkyl; R 3 represents hydrogen, deuterium, C1-C6 alkyl, or 0-3 selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10Aryl, 5-10 membered heteroaryl.

[0203] In the preferred technical solution of formula (I-2) or formula (I-3), wherein R 1 represents 0-3 selected from deuterated, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-CN、NR a R b , C3-C substituted by halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy 10 Cycloalkyl.

[0204] In the preferred technical solution of formula (I-2) or formula (I-3), wherein R 1 represents a C1-C6 alkyl group (preferably a methyl group or an ethyl group) or a deuterated C1-C6 alkyl group (preferably a deuterated methyl group or a deuterated ethyl group) or a C3-C6 cycloalkyl group (preferably a cyclopropyl group).

[0205] In the preferred technical solution of formula (I-2) or formula (I-3), M1 is O or S.

[0206] In the preferred technical solution of formula (I-2) or formula (I-3), o is 1 or 2.

[0207] In the preferred technical solution of formula (I-2) or formula (I-3), o is 1.

[0208] In the preferred technical solution of formula (I-2) or formula (I-3), wherein R L 、R L’ Each independently represents a C1-C6 alkyl group.

[0209] In the preferred technical solution of formula (I-2) or formula (I-3), wherein R L 、R L’ Together with the atoms to which they are attached, they form a 3-6 membered ring.

[0210] In the preferred technical solution of formula (I-2) or formula (I-3), wherein R L 、R L’ Together with the atoms to which they are attached, they form a 3-membered or 4-membered ring.

[0211] Specifically, the present disclosure provides the following compounds:

[0212] Unless otherwise indicated, the compounds of the present disclosure may be interpreted to include, in addition to the specific structures of the compounds, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotopomers (e.g., deuterated compounds), solvates, hydrates, prodrugs, and metabolites. In other words, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotopomers, solvates, hydrates, prodrugs, and metabolites also fall within the scope of protection of the compounds.

[0213] Preferably, the pharmaceutical composition disclosed above may further include a second active substance, wherein the second active substance is an anti-tumor drug, and the anti-tumor drug includes one or more of a chemotherapy drug, a targeted tumor treatment drug or a tumor treatment antibody drug.

[0214] In addition, the present disclosure also provides a compound of the present disclosure, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotope derivative thereof, for treating a disease by inhibiting the action of PRMT5, preferably the disease is a tumor.

[0215] definition:

[0216] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent refers to a straight chain (i.e., unbranched) or branched chain, or cyclic hydrocarbon radical, or combinations thereof, which may be saturated, mono- or polyunsaturated, and may include divalent or polyvalent groups, having the specified number of carbon atoms (i.e., C1-C 10 Refers to one to ten carbon atoms). Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclohexylmethyl, cyclopropylmethyl, and homologs and isomers such as n-pentyl, n-hexyl, n-heptyl, and n-octyl. Unsaturated alkyl groups are alkyl groups having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkyl groups that are limited to hydrocarbon groups are referred to as "homoalkyl". The alkyl group is optionally substituted with one or more halogen atoms.

[0217] The term "haloalkyl" refers to an alkyl group as defined above wherein one or more hydrogen atoms are replaced by a halogen atom.

[0218] The term "alkylene" by itself or as part of another substituent refers to a divalent radical derived from an alkyl group, for example, but not limited to, -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2C≡CCH2-, -CH2CH2CH(CH2CH2CH3)CH2-. Alkyl (or alkylene) groups typically have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in this disclosure. "Lower alkyl" or "lower alkylene" refers to shorter chain alkyl or alkylene groups, typically having eight or fewer carbon atoms. The alkylene group is optionally substituted with one or more halogen atoms.

[0219] The term "alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, which may be linear or branched, or a combination thereof. Examples of alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like. The alkynyl group may be optionally substituted with one or more halogen atoms.

[0220] The term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbocyclic ring, each having 3 to 10 carbon atoms. A "fused analog" of a cycloalkyl refers to a monocyclic ring fused to an aryl or heteroaryl group, wherein the point of attachment is on the non-aromatic portion. Examples of cycloalkyls and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, decahydronaphthyl, dihydroindanyl, and the like. The cycloalkyl group is optionally substituted with one or more halogen atoms. Furthermore, the term "cycloalkyl" in this disclosure includes bridged ring systems and spirocyclic ring systems.

[0221] The term "alkoxy" refers to a straight or branched chain alkoxy group having the indicated number of carbon atoms. 1-6 The alkoxy group includes, for example, methoxy, ethoxy, propoxy, isopropoxy and the like.

[0222] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched chain, or cyclic hydrocarbon radical consisting of at least one carbon atom and at least one heteroatom selected from O, N, P, Si, S, or combinations thereof, wherein the nitrogen, phosphorus, or sulfur atom may be optionally oxidized and the nitrogen atom may be optionally quaternized. The heteroatoms O, N, P, S, and Si may be placed at any position within the heteroalkyl radical or at the position at which the alkyl radical is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive. For example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene," by itself or in combination with other terms, refers to a divalent radical derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene, the heteroatom can be at either or both ends of the chain (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Additionally, for alkylene and heteroalkylene linking groups, the direction in which the linking group formula is written does not indicate the orientation of the linking group. For example, the formula -C(O)OR'- refers to both -C(O)OR'- and -R'OC(O)-. As described above, heteroalkyl groups as used herein include those groups that are attached to the rest of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -S02R'. Where "heteroalkyl" is mentioned followed by a specific heteroalkyl group such as -NR'R", it is understood that the terms heteroalkyl and -NR'R" are not redundant and are not mutually exclusive. Rather, these specific heteroalkyl groups are cited for clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups such as -NR'R".

[0223] The term "cycloalkoxy" refers to a cycloalkyl group as defined above bound to an oxygen atom, such as cyclopropyloxy.

[0224] The term "haloalkoxy" refers to an alkoxy group as defined above in which one or more hydrogen atoms are replaced by a halo.

[0225] The term "aryl" refers to a monocyclic or bicyclic aromatic group containing only carbon atoms. A "fused analog" of an aryl group refers to an aryl group fused to a monocyclic cycloalkyl group or a monocyclic heterocyclic group, wherein the point of attachment is on the aryl portion. Examples of aryl groups and fused ring analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrochromenyl, 1,4-benzodioxanyl, and the like.

[0226] The term "heteroaryl" refers to a monocyclic or bicyclic aromatic group containing at least one heteroatom selected from N, O, and S. A "fused analog" of a heteroaryl group refers to a heteroaryl group fused to a monocyclic cycloalkyl group or a monocyclic heterocyclyl group, wherein the point of attachment is located on the aromatic portion. Examples of heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothienyl, furo(2,3-b)pyridinyl, quinolinyl, indolyl, isoquinolinyl, and the like.

[0227] "Substituted or unsubstituted": the alkyl, aryl and heteroaryl groups are defined as being unsubstituted or substituted with at least one substituent selected from the group consisting of halogen atoms, alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, haloalkyl groups having 1 to 6 carbon atoms, haloalkoxy groups having 1 to 6 carbon atoms, -CN, alkynyl groups having 2 to 6 carbon atoms, alkanoyl groups having 1 to 6 carbon atoms, cycloalkyl groups having 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkyloxy groups having 7-10 carbon atoms, arylcarbonyl groups, aminocarbonyl groups, alkyl groups having 2 to 6 carbon atoms, alkynyl groups having 1 to 6 carbon atoms, alkanoyl groups having 1 to 6 carbon atoms, cycloalkyl groups having 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkyloxy groups having 7-10 carbon atoms, arylcarbonyl groups, aminocarbonyl groups, alkyl groups having 2 to 6 carbon atoms, alkyl groups having 1 to 6 carbon atoms, alkyl groups having 1 to 6 carbon atoms, alkyl groups having 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkyloxy groups having 7-10 carbon atoms, arylcarbonyl groups, aralkyloxy groups having 7-10 carbon atoms, aralkyl groups having 1 to ... an alkenyl group having 1 to 5 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an aminosulfinyl group, an aminosulfonyl group, a hydroxyl group, -SF5, a hydroxyalkyl group having 1 to 4 carbon atoms, a nitro group, an amino group, a carboxyl group, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxyalkyl group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1-4 carbon atoms, an alkanoylamino group having 1 to 4 carbon atoms, an alkanoyl(alkyl)amino group having 1 to 6 carbon atoms, an alkanoylaminoalkyl group having 1 to 6 carbon atoms in both the alkanoyl and alkyl moieties, an alkanoyl(alkyl)aminoalkyl group having 1 to 6 carbon atoms in both the alkanoyl and alkyl moieties, an alkylsulfonylamino group having 1 to 4 carbon atoms, a monoalkylaminocarbonyl group or a dialkylaminocarbonyl group having 1 to 6 carbon atoms, a monoalkylaminosulfinyl group or a dialkylaminosulfinyl group having 1 to 6 carbon atoms, a monoalkylaminosulfonyl group or a dialkylaminosulfonyl group having 1 to 6 carbon atoms dialkylaminosulfonyl, aminoalkyl having 1 to 4 carbon atoms, mono- or dialkylamino having 1 to 6 carbon atoms, mono- or dialkylaminoalkyl having 1 to 6 carbon atoms in each alkyl moiety, aralkyl having 7 to 10 carbon atoms, heteroaralkyl having 1 to 4 carbon atoms in the alkyl moiety, heteroarylalkoxy having from 1 to 4 carbon atoms in the alkoxy moiety, and alkylsulfonamide having 1 to 4 carbon atoms.

[0228] As used herein, the term "heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated, partially saturated or unsaturated group (but not aromatic) having a single ring or a fused ring (including bridged ring systems and spiro ring systems) with 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in the ring. In a fused ring system, one or more rings can be cycloalkyl, aryl or heteroaryl, as long as the point of attachment is through the non-aromatic ring. In one embodiment, the nitrogen atom and / or sulfur atom of the heterocyclic group is optionally oxidized. , to provide N-oxide, sulfinyl and sulfonyl moieties. Examples of "heterocyclyl" and its fused analogs include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuryl (2,3-b) pyridinyl, benzoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolinyl, etc. The term also includes non-aromatic partially unsaturated monocyclic rings, such as 2- or 4-pyridones or N-substituted-(1H,3H)-pyrimidine-2,4-diones (N-substituted uracils) attached through a nitrogen atom.

[0229] As used herein, the term "substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclic group substituted with 1 to 5 (e.g., 1 to 3) substituents, the substituents being the same as those defined for substituted cycloalkyl.

[0230] Unless otherwise indicated, the term "halogenated" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine, or iodine atom. Additionally, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C6)alkyl" includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0231] "Prodrug" refers to a substance that is converted into the parent drug in vivo. In some cases, prodrugs are often used because they are easier to administer than the parent drug. For example, a prodrug may be bioavailable orally while the parent drug cannot. In a pharmaceutical composition, a prodrug may also have a higher solubility than the parent drug. Examples of prodrugs, but not limited to, may be any of the compounds of Formula I administered in the form of an ester (prodrug) to facilitate transcellular transport, where water solubility in the cell membrane is detrimental to migration, and once in the cell where water solubility is beneficial, the ester is subsequently metabolically hydrolyzed to the active substance, carboxylic acid. Another example of a prodrug may be a short peptide (polyamino acid) bonded to an acid group, wherein the peptide is metabolized to release the active portion.

[0232] Optical isomers - diastereomers - geometric isomers - tautomers:

[0233] The compounds of formula (I) contain one or more asymmetric centers and can occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present disclosure is intended to encompass all such isomeric forms of the compounds of formula (I).

[0234] Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are intended to include both E and Z geometric isomers.

[0235] Some of the compounds of the present disclosure may contain one or more than one ring system and thus may exist as cis- and trans-isomers. The present disclosure is intended to encompass all such cis- and trans-isomers.

[0236] Some compounds described herein may have different sites of attachment to hydrogen atoms, known as tautomers. Examples of such tautomers include a ketone and its enol form, known as keto-enol tautomers. Individual tautomers as well as mixtures thereof are encompassed by the compounds of the present disclosure.

[0237] The compounds of the present disclosure can be separated into diastereomeric pairs of enantiomers, for example, by fractional crystallization from a suitable solvent, such as methanol or ethyl acetate or a mixture thereof. A pair of enantiomers thus obtained can be separated into individual stereoisomers by conventional methods, for example, using an optically active amine or acid as a resolving agent or in a chiral HPLC column.

[0238] Alternatively, any enantiomer of a compound of the present disclosure may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

[0239] Stable Isotope-Labeled Analogs: One or more protons in the compounds of the present disclosure may be replaced with deuterium atoms to provide deuterated analogs with improved pharmacological activity.

[0240] Salt and dosage form

[0241] It should be understood that, as used herein, references to the compounds of the present disclosure also include the pharmaceutically acceptable salts.

[0242] application

[0243] The compounds disclosed herein can be used to treat PRMT5-related diseases.

[0244] The compounds of the present disclosure can be prepared by the following reaction formula:

[0245] Method A:

[0246] Method A-SFC

[0247] Among them, R L 、R L’ 、R ’ , A ring, B ring, o, M1, X1, X2, X3, X4, X5, X6, As defined in claim 1.

[0248] Method A: Compound AP can be prepared by the amino acid condensation reaction of carboxylic acid A-1 and amine A-2. The condensing agent can be HATU or PyBrOP, the base can be DIPEA or TEA, and the solvent can be DMF or DMAc. If the amine used is a racemic form, chiral SFC will be used for resolution, and the stereochemistry of the resulting isomers will be randomly assigned to R or S.

[0249] Analytical HPLC

[0250] Equipment: Agilent 1260; Column dimensions: Agilent Poroshell HPH-C18 (3.0 × 50 mm, 2.7 μm); Binary solvent system: Mobile phase A: Water (0.1% v / v ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 1 mL / min; Gradient: 10% B to 90% B; Duration: 12 min; Detector: DAD; Wavelength: 254 / 220 nm; Preparative HPLC-MS

[0251] HPLC equipment: Waters 2489; Column specifications: Ultimate μXB-C18 (130A, 5 μm, 30 mm × 150 mm); Binary solvent system: Mobile phase A: Water (0.1% v / v ammonium bicarbonate), Mobile phase B: Acetonitrile; Flow rate: 60–100 mL / min; Gradient: 10% B to 90% B; Detector: DAD; Wavelength: 254 / 220 nm;

[0252] Mass spectrometer: Agilent G6125B.

[0253] The compounds of the present disclosure can be prepared by chemical synthesis, examples of which are shown below. It should be understood that the order of the steps in the process can be changed, those specifically mentioned reagents, solvents and reaction conditions can be replaced, and if necessary, reactive sites can be protected and deprotected.

[0254] The following abbreviations have the following meanings: ACN means acetonitrile; EA means ethyl acetate; CDI means N,N'-carbonyldiimidazole; DBU means 1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL-H means diisobutylaluminum hydride; DIEA means diisopropylethylamine; DMAP means N,N-dimethylaminopyridine; DME means 1,2-dimethoxyethane; DMF means N,N-dimethylformamide; DMA and DMAc mean N,N-dimethylformamide; DMPE means 1,2-bis(dimethylformamide) phosphino)ethane; DMSO denotes dimethyl sulfoxide; DPPB refers to 1,4-bis(diphenylphosphino)butane; dppe denotes 1,2-bis(diphenylphosphino)ethane; dppf denotes 1,1'-bis(diphenylphosphino)ferrocene; dppm denotes 1,1'-bis(diphenylphosphino)methane; DIAD denotes diisopropyl azodicarboxylate; EDCI denotes 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; HATU denotes 2-(7-aza-1H-benzotriazol-1-yl)-1,1, 3,3-Tetramethyluronium hexafluorophosphate; HMPA is hexamethylphosphoramide; IPA is isopropyl alcohol; LDA is lithium diisopropylamide; LHMDS is lithium bis(trimethylsilyl)amide; LAH is lithium aluminum hydride; NCS is N-chlorosuccinimide; NaHMDS is sodium bis(trimethylsilyl)amide; PyBOP is benzotriazol-1-yl-oxytripyrrolidinylphosphonium benzotriazole hexafluorophosphate; PyBrOP is tripyrrolidinylphosphonium bromide hexafluorophosphate; TDA-I is tris(trimethylsilyl)phosphonium benzotriazole hexafluorophosphate. (2-(2-methoxyethoxy)ethyl)amine; DCM refers to dichloromethane; TEA refers to triethylamine, TFA refers to trifluoroacetic acid; THF refers to tetrahydrofuran; NCS refers to N-chlorosuccinimide; NMM refers to N-methylmorpholine; NMP refers to N-methylpyrrolidone; PPh3 refers to triphenylphosphine, rt refers to room temperature; PMB refers to p-methoxybenzyl; Tosmic refers to p-toluenesulfonylmethyl isocyanide; (Boc)2O refers to di-tert-butyl dicarbonate; PE refers to petroleum ether; o / n refers to overnight reaction.

[0255] The following preparations and examples illustrate the present disclosure but do not limit it in any way.

[0256] The features and advantages of the disclosed subject matter will become more apparent from the detailed description of selected embodiments. As will be appreciated, the disclosed and claimed subject matter is capable of modification in various respects, all of which remain within the scope of the claims. Therefore, the description should be considered illustrative in nature, not restrictive. The full scope of the disclosed subject matter is set forth in the claims.

[0257] The present disclosure can be more easily understood by referring to the following examples, which are intended only to illustrate the present disclosure rather than to limit the scope of the present disclosure.

[0258] The following intermediates were prepared with reference to Amgen patents WO2022 / 115377A1, WO2022 / 132914A1, WO2022 / 169948A1 and WO2023 / 034786A1

[0259] The present disclosure can be more easily understood by referring to the following examples, which are intended only to illustrate the present disclosure rather than to limit the scope of the present disclosure.

[0260] The following intermediates were prepared with reference to Amgen patents WO2022 / 115377A1, WO2022 / 132914A1, WO2022 / 169948A1 and WO2023 / 034786A1

[0261] Synthesis of Intermediate 47 N,1,1-trimethyl-7-trifluoromethylisochromen-4-amine

[0262] Step 1: To a solution of 1-acetyl-2-bromo-5-(trifluoromethyl)benzene (5.00 g, 18.72 mmol) in tetrahydrofuran (10.00 mL) was added methylmagnesium bromide (9.36 mL, 28.09 mmol) at 0°C. The mixture was warmed to 25°C and stirred under a nitrogen atmosphere for 16 hours. After completion of the reaction, the mixture was poured into water (150 mL), extracted with ethyl acetate (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to yield 2-(2-bromo-5-(trifluoromethyl)phenyl)propan-2-ol (3.1 g, 46.7% yield).

[0263] LCMS (ESI): 283.1 [M+H] +

[0264] Step 2: 2-(2-Bromo-5-(trifluoromethyl)phenyl)propan-2-ol (3.00 g, 10.60 mmol) was dissolved in tetrahydrofuran (30.00 mL). 3-Propylene bromide (2.62 g, 21.20 mmol) and tetrabutylammonium hydrogen sulfate (0.55 g, 1.59 mmol) were added, followed by potassium hydroxide (1.20 g, 21.20 mmol). The mixture was allowed to react at room temperature overnight. After completion, the reaction mixture was poured into water (50 mL), extracted with ethyl acetate (30 mL x 3), washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to obtain 2-(2-(allyloxy)propan-2-yl)-1-bromo-4-(trifluoromethyl)benzene (2.40 g, 70% yield).

[0265] LCMS (ESI): 323.1 [M+H] +

[0266] Step 3: Under an N2 atmosphere, palladium acetate (1.39 g, 6.19 mmol) was added to a solution of 2-(2-(allyloxy)propan-2-yl)-1-bromo-4-(trifluoromethyl)benzene (20.00 g, 61.89 mmol), triphenylphosphine (8.11 g, 30.95 mmol), and cesium carbonate (24.14 g, 74.27 mmol) in dimethylformamide (200 ml). The reaction was stirred at 100°C for 2 hours. The mixture was poured into water (100 ml), and the aqueous layer was extracted with ethyl acetate (2 x 100 ml). The organic layers were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1) to give 1,1-dimethyl-4-methylene-7-(trifluoromethyl)isochroman (10.00 g, yield: 53%).

[0267] LCMS (ESI): 243.2 [M+H] +

[0268] Step 4: A mixture of 1,1-dimethyl-4-methylene-7-(trifluoromethyl)isochroman (10.00 g, 41.28 mmol), potassium osmate (1.21 g, 4.13 mmol), and N-methylmorpholine (16.90 g, 144.48 mmol) in tetrahydrofuran (100.00 ml) was stirred at room temperature overnight. After the reaction was complete, the mixture was poured into water (100 ml), and the aqueous layer was extracted with ethyl acetate (2×100 ml). The organic layers were combined and washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and concentrated to give crude 4-(hydroxymethyl)-1,1-dimethyl-7-(trifluoromethyl)isochroman-4-ol (6.00 g, yield: 42%).

[0269] LCMS (ESI): 277.2 [M+H] +

[0270] Step 5: A mixture of 4-(hydroxymethyl)-1,1-dimethyl-7-(trifluoromethyl)isochroman-4-ol (6.00 g, 21.72 mmol), sodium periodate (14.07 g, 65.16 mmol) in tetrahydrofuran (50.00 mL) and water (10.00 mL) was stirred at room temperature for 2 hours. The mixture was poured into water (100 mL) and diluted, and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to afford 1,1-dimethyl-7-(trifluoromethyl)isochroman-4-one (5.00 g, 75% yield).

[0271] LCMS (ESI): 245.2 [M+H] +

[0272] Step 6: A mixture of 1,1-dimethyl-7-(trifluoromethyl)isochroman-4-one (5.00 g, 20.47 mmol), methylamine (1.91 g, 61.42 mmol), and molecular sieves (17.81 g, 61.42 mmol) in methanol (50.00 ml) was stirred at room temperature overnight. The mixture was poured into water (100 ml), and the aqueous layer was extracted with ethyl acetate (2 x 100 ml). The organic layers were combined and washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give N,1,1-trimethyl-7-(trifluoromethyl)isochroman-4-imine (3.00 g, 57%).

[0273] LCMS(ESI):257[M+H] +

[0274] Step 7: Sodium borohydride (294 mg, 7.78 mmol) was added to a mixed solution of N,1,1-trimethyl-7-(trifluoromethyl)isochroman-4-amine (1.00 g, 3.89 mmol) in methanol (10.00 ml) and stirred at room temperature for 1 hour. The mixture was poured into water (10 ml), and the aqueous layer was extracted with ethyl acetate (2×10 ml). The organic layers were combined and washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1.5) to give N,1,1-trimethyl-7-(trifluoromethyl)isochroman-4-amine (0.60 g, yield 60%).

[0275] The following intermediates were prepared by using the preparation method and steps of intermediate 47, replacing only the corresponding raw material intermediates:

[0276] Intermediate 49 Synthesis of N,1,1-trimethyl-7-(1-methyl-1H-pyrazol-4-yl)isochroman-4-amine

[0277] Step 1: Under N2 atmosphere, 7-bromo-1,1-dimethyl-4-methyleneisocyanate (500 mg, 1.976 mmol) was dissolved in 1,4-dioxane and water (4:1, 10 ml), and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (455 mg, 2.173 mmol), potassium carbonate (819 mg, 5.928 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (148 mg, 0.20 mmol) were added. The reaction was carried out at 100°C for 16 hours. The mixture was poured into water (30 ml) and extracted with ethyl acetate (40 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give 4-(1,1-dimethyl-4-methyleneisothiazolin-7-yl)-1-methylpyrazole (360 mg, 71.7% yield) as a brown solid.

[0278] LCMS (ESI) m / z: 255.2 [M+H] +

[0279] Step 2: 4-(1,1-Dimethyl-4-methyleneisocyanate-7-yl)-1-methylpyrazole (360 mg, 1.417 mmol) was dissolved in a mixed solvent of acetone (5 mL) and water (1 mL) at room temperature, and N-methylmorpholine-N-oxide (613 mg, 4.534 mmol) and potassium osmate (44 mg, 0.142 mmol) were added. Under N2 atmosphere, the reaction was stirred at 25°C for 16 hours. After completion of the reaction, solid sodium sulfite (350 mg) was added to the reaction solution, stirred for ten minutes, concentrated under reduced pressure to remove a certain amount of acetone, poured into water (20 ml), extracted with ethyl acetate (20 ml × 3), combined the organic phases, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product of 4-(hydroxymethyl)-1,1-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)isochroman-4-ol (310 mg, crude).

[0280] LCMS (ESI) m / z: 289.1 [M+H] +

[0281] Step 3: 4-(Hydroxymethyl)-1,1-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)isochroman-4-ol (310 mg, 1.076 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 ml) and water (0.3 ml) at room temperature, and sodium periodate (698 mg, 3.228 mmol) was added. The mixture was stirred at 25°C under a N2 atmosphere for 4 hours. After the reaction was completed, the reaction solution was diluted with ethyl acetate, filtered, washed, and the filtrate was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 1,1-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)isochroman-4-one (200 mg, 72.5% yield).

[0282] LCMS (ESI) m / z: 257.1 [M+H] +

[0283] Step 4: Compound 1,1-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)isochroman-4-one (200 mg, 0.781 mmol) was dissolved in 1.2-dichloroethane (5 ml) at room temperature, and tetraethoxytitanium (446 mg, 1.952 mmol) and methylamine tetrahydrofuran solution (1 ml, 30%) were added. The reaction was stirred at room temperature for 16 hours, and then sodium borohydride (46 mg, 1.171 mmol) was added. The mixture was stirred at room temperature for another 8 hours. When LCMS showed that the reaction was complete, water (10 mL) was added and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (50-100% ethyl acetate / petroleum ether) to give N,1,1-trimethyl-7-(1-methyl-1H-pyrazol-4-yl)isochroman-4-amine (130 mg, yield: 61.4%).

[0284] LCMS (ESI) m / z: 272.1 [M+H] +

[0285] The following intermediates were prepared by using the preparation method and steps of intermediate 49, with only the corresponding raw material intermediates being replaced:

[0286] Intermediate 51 Synthesis of N-methyl-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanhydro]-4'-amine

[0287] Step 1: Synthesis of 1-(2-bromo-5-(trifluoromethyl)phenyl)cyclobutane-1-ol

[0288] At room temperature, 2-bromo-5-trifluoromethylbenzaldehyde (10 g, 39.52 mmol) was dissolved in tetrahydrofuran (100 ml). At 0°C, 3M methylmagnesium chloride tetrahydrofuran solution (20 ml, 59.28 mmol) was slowly added dropwise to the system. The reaction was stirred at 0°C for 2 hrs. After completion of the reaction, the reaction solution was quenched with ammonium chloride solution, poured into water (200 ml), and extracted with ethyl acetate (100 ml * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product 1-(2-bromo-5-(trifluoromethyl)phenyl)cyclobutane-1-ol (10 g, crude), which was used directly in the next step without purification.

[0289] LCMS (ESI) m / z: 295.1 [M-OH] +

[0290] Step 2: Synthesis of 2-[1-(allyloxy)cyclobutyl]-1-bromo-4-(trifluoromethyl)benzene

[0291] 1-(2-Bromo-5-(trifluoromethyl)phenyl)cyclobutan-1-ol (7 g, 23.80 mmol) was dissolved in tetrahydrofuran (100 ml) at room temperature, and potassium hydroxide (2.69 g, 47.60 mmol), tetrabutylammonium hydrogen sulfate (1.67 g, 4.760 mmol), and 3-bromopropene (4.3 g, 35.70 mmol) were added. The reaction was allowed to proceed at 25°C for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and poured into water (100 ml), and extracted with ethyl acetate (100 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product. Column chromatography (petroleum ether:ethyl acetate = 10:1) gave 2-[1-(allyloxy)cyclobutyl]-1-bromo-4-(trifluoromethyl)benzene (4.8 g, 60.3% yield).

[0292] LCMS (ESI) m / z: 335.1 [M+H] +

[0293] Step 3: Synthesis of 4'-methylene-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromatic hexacyclic]

[0294] To a solution of 2-[1-(allyloxy)cyclobutyl]-1-bromo-4-(trifluoromethyl)benzene (4.8 g, 14.37 mmol) in DMF (100 mL) at room temperature were added DIEA (5.57 g, 43.11 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (1.67 g, 2.874 mmol) and palladium acetate (0.325 g, 1.437 mmol). Under N2 atmosphere, the mixture was stirred at 100°C for 16 hours. The reaction solution was poured into 400 ml of water and extracted with ethyl acetate (100 ml × 3). The organic phases were combined and dried over anhydrous Na2SO4. The crude product was obtained by concentration under reduced pressure. 4'-methylene-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromatic hexacyclic] (2.7 g, 73.9% yield) was obtained by column chromatography (petroleum ether: ethyl acetate = 10:1).

[0295] LCMS (ESI) m / z: 255.1 [M+H] +

[0296] Step 4: Synthesis of 4'-(hydroxymethyl)-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-ol

[0297] 4'-Methylene-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromatic hexacyclo] (2.7 g, 10.62 mmol) was dissolved in a mixed solvent of acetone (60 ml) and water (20 ml) at room temperature, and N-methylmorpholine-N-oxide (3.9 g, 31.86 mmol) and potassium osmate (0.41 g, 1.062 mmol) were added. Under N2 atmosphere, the reaction was stirred at 25°C for 16 hours. After completion of the reaction, solid sodium sulfite (5 g) was added to the reaction solution, stirred for ten minutes, and concentrated under reduced pressure to remove a certain amount of acetone. The solution was poured into water (200 ml) and extracted with ethyl acetate (100 ml x 3). The organic phases were combined and dried over anhydrous Na2SO4. The organic phases were concentrated under reduced pressure to give crude 4'-(hydroxymethyl)-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromatic hydropyran]-4'-ol (2.1 g, 68.67% yield).

[0298] LCMS (ESI) m / z: 289.0 [M+H]+

[0299] Step 5: Synthesis of 7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-one

[0300] 4'-(Hydroxymethyl)-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-ol (2.1 g, 7.29 mmol) was dissolved in a mixed solvent of tetrahydrofuran (50 mL) and water (2 mL) at room temperature. Sodium periodate (6.37 g, 29.16 mmol) was added, and the mixture was stirred at 25°C under a nitrogen atmosphere for 4 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, filtered, washed, and the filtrates were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. 7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-one (0.9 g, 48.23% yield) was obtained by column chromatography (petroleum ether:ethyl acetate = 5:1).

[0301] LCMS (ESI) m / z: 257.1 [M+H] +

[0302] Step 6: Preparation of N-methyl-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-amine

[0303] Compound 7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanane]-4'-one (500 mg, 1.953 mmol) was dissolved in 1.2-dichloroethane (5 ml) at room temperature, and tetraethoxytitanium (1115 mg, 4.88 mmol) and methylamine tetrahydrofuran solution (2 ml, 30%) were added. The reaction was stirred at room temperature for 16 hours, then sodium borohydride (115 mg, 2.928 mmol) was added, and the mixture was stirred at room temperature for another 8 hours. When LCMS showed that the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (50-100% ethyl acetate / petroleum ether) to give N-methyl-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-amine (150 mg, yield: 28.33%).

[0304] LCMS (ESI) m / z: 272.1 [M+H] +

[0305] The following intermediates were prepared by using the preparation method and steps of intermediate 51, with only the corresponding raw material intermediates being replaced:

[0306] Synthesis of Intermediate 55 (S)-N-methyl-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanhydro]-4'-amine

[0307] Step 1: Synthesis of (R)-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-ol

[0308] At room temperature, 7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-one (2.5 g, 9.76 mmol) was dissolved in dichloromethane (30 ml), (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) chloride (605 mg, 1.17 mmol) and formic acid (1.34 g, 29.28 mmol) were added, and triethylamine (2.54 g, 25.0 9 mmol), the mixture was reacted at 25°C for 4 hours. After the reaction was completed, the reaction solution was poured into 50 ml of water and extracted with ethyl acetate (50 ml × 3). The organic phases were combined and dried over anhydrous Na2SO4. The organic phases were concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain (R)-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromatic hydropyran]-4'-ol (1.8 g, 71.4% yield).

[0309] LCMS (ESI) m / z: 259.2 [M+H] +

[0310] Step 2: Synthesis of tert-butyl (S)-(tert-butyloxycarbonyl)(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-yl)carbamate

[0311] At room temperature, (R)-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-ol (1.8 g, 6.97 mmol) was dissolved in tetrahydrofuran (20 ml), triphenylphosphine (2.2 g, 8.37 mmol) and bis(tert-butyloxycarbonyl)amine (1.81 g, 8.37 mmol) were added, and the mixture was reacted at 0°C under N2 atmosphere for 10 minutes. Diisopropyl azodicarboxylate (1.69 g, 8.37 mmol) was slowly added dropwise to the reaction system, and the mixture was heated at 2°C. The reaction was carried out at 5°C for 16 hours. After completion of the reaction, the reaction solution was poured into water (40 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give tert-butyl (S)-(tert-butoxycarbonyl)(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-yl)carbamate (1.3 g, yield: 40.7%) as a yellow solid.

[0312] LCMS (ESI) m / z: 458.1 [M+H] +

[0313] Step 3: Synthesis of tert-butyl (S)-(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-yl)carbamate

[0314] Tert-butyl (S)-(tert-butoxycarbonyl)(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-yl)carbamate (1.3 g, 2.84 mmol) was dissolved in acetonitrile (20 mL) at room temperature, and lithium bromide (1.23 g, 14.22 mmol) was added. The reaction mixture was allowed to react at 60°C for 16 hours. Upon completion, the reaction solution was concentrated under reduced pressure, poured into water (50 mL), and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield crude tert-butyl (S)-(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-yl)carbamate (0.7 g, 89.7% yield).

[0315] LCMS (ESI) m / z: 358.1 [M+H] +

[0316] Step 4: Synthesis of tert-butyl (S)-methyl (7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-yl)carbamate

[0317] Tert-butyl (S)-(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-yl)carbamate (0.7 g, 1.96 mmol) was dissolved in DMF (20 mL) at room temperature. 60% sodium hydroxide (158 mg, 3.92 mmol) was added at 0°C. After stirring for 30 minutes, iodomethane (418 mg, 2.94 mmol) was added. The reaction mixture was incubated at 25°C for 4 hours. After completion of the reaction, the reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude tert-butyl (S)-methyl(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-yl)carbamate (0.6 g, yield: 82.5%).

[0318] LCMS (ESI) m / z: 372.1 [M+H] +

[0319] Step 5: Synthesis of (S)-N-methyl-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-amine hydrochloride

[0320] Tert-butyl (S)-methyl(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-yl)carbamate (0.6 g, 1.61 mmol) was dissolved in 4 M ethyl acetate (4 mL, 12.93 mmol) at room temperature. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure to afford the crude product (S)-N-methyl-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-amine hydrochloride (430 mg, 98.1% yield).

[0321] LCMS (ESI) m / z: 272.1 [M+H]+

[0322] Intermediate 56 Synthesis of N,1,1-trimethyl-7-(4-(trifluoromethyl)-1H-pyrazol-1-yl)isochroman-4-amine

[0323] Step 1: Synthesis of tert-butyl (1,1-dimethyl-7-(4-(trifluoromethyl)-1H-pyrazol-1-yl)isochroman-4-yl)(methyl)carbamate

[0324] Under N2 atmosphere, tert-butyl (7-bromo-1,1-dimethylisochroman-4-yl)(methyl)carbamate (150 mg, 0.405 mmol) was dissolved in DMF (2 ml), and 4-trifluoromethyl-1H-pyrazole (66 mg, 0.486 mmol), potassium phosphate (343 mg, 1.62 mmol), trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (116 mg, 0.810 mmol) and cuprous oxide (78.0 mg, 0.405 mmol) were added. The reaction was carried out at 100°C for 16 hours. The system was poured into water (20 ml) and extracted with ethyl acetate (10 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give tert-butyl(1,1-dimethyl-7-(4-(trifluoromethyl)-1H-pyrazol-1-yl)isochroman-4-yl)(methyl)carbamate (90 mg, 0.212 mmol, 52.3% yield) as a brown oil.

[0325] LCMS (ESI) m / z: 426.1 [M+H] +

[0326] Step 2: Synthesis of N,1,1-trimethyl-7-(4-(trifluoromethyl)-1H-pyrazol-1-yl)isochroman-4-amine

[0327] Tert-butyl (1,1-dimethyl-7-(4-(trifluoromethyl)-1H-pyrazol-1-yl)isochroman-4-yl)(methyl)carbamate (90 mg, 0.308 mmol) was dissolved in 4 M hydrochloric acid and ethyl acetate (2 mL, 2.46 mmol) at room temperature. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure to give the crude product, N,1,1-trimethyl-7-(4-(trifluoromethyl)-1H-pyrazol-1-yl)isochroman-4-amine hydrochloride (90 mg, crude), which was used directly in the next step without purification.

[0328] LCMS (ESI) m / z: 326.2 [M+H] +

[0329] Intermediate 57 Synthesis of N-methyl-7'-morpholino-3',4'-dihydrospiro[cyclobutane-1,1'-pyranone[4,3-c]pyridine]4'-amine

[0330] Step 1: Synthesis of 1-(5-bromo-2-chloropyridin-4-yl)cyclobutane-1-ol

[0331] At room temperature, 5-bromo-2-chloro-4-iodopyridine (25 g, 78.6 mmol) was dissolved in tetrahydrofuran (250 ml), and the atmosphere was replaced with nitrogen three times. At -78 ° C, isopropylmagnesium chloride lithium chloride (60.4 ml, 1.3 M, 78.5 mmol) was slowly added dropwise to the system, and the reaction was stirred at -78 ° C for 2 hours. Then, a solution of cyclobutanone (5.5 g, 78.5 mmol) in tetrahydrofuran (30 ml) was added to the above reaction solution, and the reaction was slowly heated to room temperature. The reaction was carried out at room temperature for 16 hours. After completion of the reaction, the reaction solution was quenched with ammonium chloride solution (150 ml), poured into water (200 ml), and extracted with ethyl acetate (200 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-10:1) to give 1-(5-bromo-2-chloropyridin-4-yl)cyclobutane-1-ol (10.9 g, yield: 53%) as a light yellow oil.

[0332] 1 H NMR (400MHz, DMSO-d6) δ8.53(s,1H),7.49(s,1H),5.78(s,1H),2.65–2.56(m,2H),2.36–2.27(m,2H),2.03–1.99(m,1H),1.63–1.55(m,1H).

[0333] Step 2: Synthesis of 2-[1-(allyloxy)cyclobutyl]-1-bromo-4-(trifluoromethyl)benzene

[0334] 1-(5-Bromo-2-chloropyridin-4-yl)cyclobutan-1-ol (10.9 g, 41.5 mmol) was dissolved in tetrahydrofuran (100 ml) at room temperature, and potassium hydroxide (4.28 g, 83.0 mmol), tetrabutylammonium hydrogen sulfate (2.59 g, 8.3 mmol), and 3-bromopropene (4.6 g, 41.5 mmol) were added. The mixture was reacted at 25°C for 16 hours. After completion of the reaction, the reaction solution was poured into water (200 ml) and extracted with ethyl acetate (200 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. Column chromatography (petroleum ether:ethyl acetate = 10:1) gave 2-[1-(allyloxy)cyclobutyl]-1-bromo-4-(trifluoromethyl)benzene (6.6 g, yield: 57.4%) as a light yellow oil.

[0335] LCMS(ESI):[M+H] + 301.9 / 303.9.

[0336] Step 3: Synthesis of 4-(4-(1-(allyloxy)cyclobutyl]-5-bromopyridin-2-yl)morpholine

[0337] 2-[1-(Allyloxy)cyclobutyl]-1-bromo-4-(trifluoromethyl)benzene (6.6 g, 21.9 mmol) was dissolved in morpholine (10 ml) at room temperature and reacted at 100°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give a crude product. Column chromatography (petroleum ether:ethyl acetate = 5:1) gave 4-(4-(1-(allyloxy)cyclobutyl]-5-bromopyridin-2-yl)morpholine (4.5 g, yield: 58.4%) as a pale yellow oil.

[0338] LCMS(ESI):[M+H] + 353.1 / 355.1.

[0339] Step 4: Synthesis of 4'-methylene-7'-morpholine-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]

[0340] 4-(4-(1-(allyloxy)cyclobutyl)-5-bromopyridin-2-yl)morpholine (1.0 g, 2.8 mmol) was dissolved in DMF (20 ml) at room temperature, and potassium carbonate (1.2 g, 8.5 mmol) and 1,1-bis(diphenylphosphine)diphenylferric palladium dichloride (0.2 g, 0.28 mmol) were added. Under N2 atmosphere, the mixture was stirred at 70°C for 16 hours. The reaction solution was poured into 200 ml of water and extracted with ethyl acetate (80 ml × 3). The organic phases were combined and dried over anhydrous Na2SO4. The organic phases were concentrated under reduced pressure to obtain a crude product. Column chromatography (petroleum ether: ethyl acetate = 10:1) gave a colorless oily product 4'-methylene-7'-morpholine-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine] (0.2 g pure product, yield: 25.94%).

[0341] 1 H NMR(400MHz,DMSO-d6)δ8.53(s,1H),6.79(s,1H),5.54(s,1H),4.85(s,1H),4.25(s,2H),3. 73–3.70(m,4H),3.53–3.51(m,4H),2.45–2.37(m,2H),2.33–2.26(m,2H),2.05–1.97(m,2H).

[0342] Step 5: Synthesis of 4'-(hydroxymethyl)-7'-morpholino-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-ol

[0343] 4'-Methylene-7'-morpholine-3'-,4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine] (0.8 g, 2.9 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 ml) and water (10 ml) at room temperature, and N-methylmorpholine-N-oxide (1.0 g, 8.8 mmol) and potassium osmate (0.09 g, 0.3 mmol) were added. Under N2, the reaction was stirred at 25°C for 16 hours. After completion of the reaction, solid sodium sulfite (1.5 g) was added to the reaction solution, stirred for ten minutes, concentrated under reduced pressure to remove a certain amount of acetone, poured into water (60 ml), extracted with ethyl acetate (80 ml × 4), combined the organic phases, and dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product 4'-(hydroxymethyl)-7'-morpholine-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-ol (0.55 g, crude product).

[0344] LCMS(ESI):[M+H] + 307.2.

[0345] Step 6: Synthesis of 7'-morpholinospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'(3'H)-one

[0346] 4'-(Hydroxymethyl)-7'-morpholino-3'-,4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-ol (0.55 g, 1.8 mmol) was dissolved in a mixture of tetrahydrofuran (20 ml) and water (0.8 ml) at room temperature. Sodium periodate (1.2 g, 5.6 mmol) was added, and the mixture was stirred at 25°C under N2 for 4 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, filtered, washed, and the filtrates were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. Column chromatography (petroleum ether:ethyl acetate = 2:1) gave 7'-morpholinospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'(3'H)-one (0.3 g, yield: 39% (2 steps)) as a white solid.

[0347] LCMS(ESI):[M+H] + 275.2.

[0348] 1 H NMR (400MHz, DMSO-d6) δ8.59(s,1H),6.79(s,1H),4.23(s,2H),3.75–3.69(m,8H),2.44–2.40(m,4H),2.03–1.96(m,2H).

[0349] Step 7: Synthesis of N-methyl-7'-morpholino-3',4'-dihydrospiro[cyclobutane-1,1'-pyranone[4,3-c]pyridine]4'-amine

[0350] At room temperature, compound 7'-morpholinospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridin]-4'(3'H)-one (300 mg, 1.09 mmol) was dissolved in 1.2-dichloroethane (5 ml), and tetraethoxytitanium (750 mg, 3.27 mmol) and methylamine tetrahydrofuran solution (2 ml, 30%) were added. The reaction was stirred at room temperature for 16 hours, then sodium borohydride (62 mg, 1.64 mmol) was added, and the mixture was stirred at room temperature for another 8 hours. When LCMS showed that the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (50-100% ethyl acetate / petroleum ether) to give N-methyl-7'-morpholino-3',4'-dihydrospiro[cyclobutane-1,1'-pyrone[4,3-c]pyridine]4'-amine (100 mg, yield: 32%).

[0351] LCMS(ESI):[M+H] + 290.2

[0352] The following intermediates were prepared by using the preparation method and steps of intermediate 57, replacing only the corresponding raw material intermediates:

[0353] Intermediate 59 Synthesis of N,1,1-trimethyl-7-morpholino-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-amine

[0354] Step 1: Synthesis of 2-(5-bromo-2-chloropyridin-4-yl)propan-2-ol

[0355] Under nitrogen protection, methyl magnesium chloride solution (19.96 ml, 59.89 mmol) was slowly added to a solution of methyl 2-bromo-5-chloropyridine-4-carboxylate (10.00 g, 39.92 mmol) in THF (50.00 ml) at -65 ° C, and then the mixture was slowly returned to room temperature and stirred overnight. TLC (petroleum ether: ethyl acetate = 10: 1) monitored the reaction, and a small amount of raw material remained, mainly the product with increased polarity. The reaction mixture was poured into water and added 1N NaOH aqueous solution until no precipitate formed, then filtered and the filtrate was extracted with ethyl acetate. The organic layers were combined and dried and concentrated. The residue was purified by silica gel column chromatography, eluting with 0% to 10% petroleum ether / ethyl acetate (about 20 minutes) to obtain 2-(5-bromo-2-chloropyridin-4-yl) propan-2-ol (5.00 g, 50% yield) as a light yellow oil.

[0356] 1 H NMR (400MHz, CDCl3) δ8.44(s,1H),7.74(s,1H),1.74(s,6H).

[0357] Step 2: Synthesis of 4-(2-(allyloxy)prop-2-yl)-5-bromo-2-chloropyridine

[0358] To a solution of 2-(5-bromo-2-chloro-4-pyridyl)propan-2-ol (5.00 g, 19.96 mmol) in THF (20.00 ml) were added 3-bromoprop-1-ene (3.70 g, 29.94 mmol), potassium hydroxide (2.26 g, 39.92 mmol) and tetrabutylammonium hydrogen sulfate (1.37 g, 3.99 mmol), and the mixture was stirred at 70° C. for 4 hours. The mixture was filtered and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography using 0% to 10% petroleum ether ethyl acetate as the eluent (30 minutes) to give 4-(2-(allyloxy)propan-2-yl)-5-bromo-2-chloropyridine (4.12 g, 71% yield) as a pale yellow oil.

[0359] 1 H NMR (400MHz, CDCl3) δ8.48(s,1H),7.45(s,1H),6.02-5.92(m,1H),5.35-5.30(m,1H),5.21-5.18(m,1H),3.81-3.79(m,2H),1.69(s,6H).

[0360] Step 3: Synthesis of 4-(4-(2-(allyloxy)prop-2-yl)-5-bromopyridin-2-yl)morpholine

[0361] 4-(2-(Allyloxy)prop-2-yl)-5-bromo-2-chloropyridine (3.40 g, 11.70 mmol) was dissolved in morpholine (10.00 ml) and stirred at 100° C. overnight without solvent. The solvent was removed under oil pump vacuum, and then purified by silica gel column chromatography, eluting with 0% to 15% petroleum ether / ethyl acetate over 15-20 minutes to provide 4-(4-(2-(allyloxy)prop-2-yl)-5-bromopyridin-2-yl)morpholine (3.15 g, 79% yield) as a pale yellow oil.

[0362] LCMS(ESI):[M+H] + 341.2 / 343.2.

[0363] Step 4: Synthesis of 1,1-dimethyl-4-methyl-7-morpholino-3,4-dihydro-1H-pyrano[4,3-c]pyridine

[0364] To a solution of 1-[1-(5-bromo-2-morpholin-4-yl(4-pyridinyl))-isopropoxy]prop-2-ene (1.75 g, 5.13 mmol) in DMF (20.00 ml) were added tetrabutylammonium chloride (1.43 g, 5.13 mmol), palladium(II) acetate (0.23 g, 1.03 mmol), potassium carbonate (1.45 g, 10.26 mmol) and potassium acetate (1.02 g, 10.2 mmol) and the mixture was stirred at 80° C. under N2 for 1 h. After completion of the reaction, the mixture was diluted with water (100 ml), extracted with ethyl acetate (2×100 ml), the organic layers were combined and washed with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography, eluting with 0% to 20% petroleum ether ethyl acetate (30 minutes) to give a light yellow oil, which turned into a light yellow solid 1,1-dimethyl-4-methyl-7-morpholino-3,4-dihydro-1H-pyrano[4,3-c]pyridine (0.45 g, yield 34%) after standing.

[0365] LCMS(ESI):[M+H] + 261.01.

[0366] 1 H NMR (400MHz, CDCl3) δ8.51(s,1H),6.29(s,1H),5.47(s,1H),4.88(s,1H),4.37(s,2H),3.84–3.81(m,4H),3.53–3.49(m,4H),1.52(s,6H).

[0367] Step 5: Synthesis of 4-(hydroxymethyl)-1,1-dimethyl-7-morpholinyl-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol

[0368] 1,1-Dimethyl-4-methyl-7-morpholin-4-yl-3-hydro-1H-pyrano[4,3-c]pyridine (300.00 mg, 1.15 mmol) was dissolved in THF (3.00 mL) and H₂O (0.50 mL). Potassium osmate(VI) dihydrate (43.33 mg, 0.12 mmol) and sodium periodate (377.27 mg, 1.73 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL x 2), dried, and spin-dried to obtain crude 4-(hydroxymethyl)-1,1-dimethyl-7-morpholin-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol (400 mg, 94% yield), which was used directly in the next step without purification.

[0369] LCMS(ESI):[M+H]+ 295.28.

[0370] Step 6: Synthesis of 1,1-dimethyl-7-morpholino-1H-pyrano[4,3-c]pyridin-4(3H)-one

[0371] 4-(Hydroxymethyl)-1,1-dimethyl-7-morpholin-4-yl-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-ol (400.00 mg, 1.09 mmol) was dissolved in THF (4.00 ml) and H2O (2.00 ml), sodium periodate (711.82 mg, 3.26 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was poured into water (50 ml), extracted with ethyl acetate (50 ml × 2), dried and dried, and the residue was purified by silica gel column chromatography eluting with 0%-20% petroleum ether / ethyl acetate to obtain 1,1-dimethyl-7-morpholin-1H-pyrano[4,3-c]pyridin-4(3H)-one (230 mg, 81% yield) as a white solid.

[0372] LCMS(ESI):[M+H] + 263.2.

[0373] 1 H NMR (400MHz, DMSO-d6) δ8.60(s,1H),6.68(s,1H),4.26(s,2H),3.69(s,8H),1.54(s,6H).

[0374] Step 7: Synthesis of N,1,1-trimethyl-7-morpholino-3,4-dihydro-1H-pyrano[4,3-c]pyridin-4-amine

[0375] At room temperature, the compound 1,1-dimethyl-7-morpholino-1H-pyrano[4,3-c]pyridin-4(3H)-one (230 mg, 0.878 mmol) was dissolved in 1.2-dichloroethane (5 ml), and tetraethoxytitanium (600 mg, 2.63 mmol) and methylamine tetrahydrofuran solution (2 ml, 30%) were added. The reaction was stirred at room temperature for 16 hours, and then sodium borohydride (50 mg, 1.32 mmol) was added, and the mixture was stirred at room temperature for another 8 hours. When LCMS showed that the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by column chromatography (50-100% ethyl acetate / petroleum ether) to give N,1,1-trimethyl-7-morpholine-3,4-dihydro-1H-pyrano[4,3-c]pyridine-4-amine (78 mg, yield: 32%).

[0376] LCMS(ESI):[M+H] + 278.2

[0377] The following intermediates were prepared by using the preparation method and steps of intermediate 59, replacing only the corresponding raw material intermediates:

[0378] Synthesis of Intermediate 61(S)-N-1,1-Trimethyl-7-morpholinoisochroman-4-amine

[0379] Under N2 atmosphere, (S)-7-bromo-N,1,1-trimethylisochroman-4-amine (150 mg, 0.56 mmol) was dissolved in 1,4-dioxane (5 ml), and morpholine (97 mg, 1.11 mmol), cesium carbonate (725 mg, 2.23 mmol), and methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphinoxanthene)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (53 mg, 0.056 mmol) were added. The reaction solution was stirred at 100°C for 16 hours. The system was poured into water (20 ml) and extracted with ethyl acetate (10 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was dried to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give (S)-N-1,1-trimethyl-7-morpholinoisochran-4-amine (80 mg, 52% yield) as an oily liquid.

[0380] The following intermediates were prepared by using the preparation method and steps of intermediate 61, replacing only the corresponding raw material intermediates:

[0381] Synthesis of Intermediate 63 (S)-7-(3,6-dihydro-2H-pyran-4-yl) N,1,1-trimethylisochroman-4-amine

[0382] Under N2 atmosphere, (S)-7-bromo-N,1,1-trimethylisochroman-4-amine (150 mg, 0.56 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-boronate (175 mg, 0.84 mmol) were dissolved in 1,4-dioxane (5 ml) and water (1 ml). 1,1-Bis(diphenylphosphino)ferrocenepalladium dichloride (40 mg, 0.056 mmol) and potassium carbonate (230 mg, 1.68 mmol) were added to the reaction solution. The reaction solution was stirred at 80°C for 16 hours. The mixture was poured into water (15 ml) and extracted with ethyl acetate (15 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove anhydrous sodium sulfate, and the filtrate was dried to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give (S)-7-(3,6-dihydro-2H-pyran-4-yl)N,1,1-trimethylisochroman-4-amine (130 mg, 85% yield) as an oily liquid.

[0383] LCMS (ESI): m / z 274.2 [M+H] +

[0384] Intermediate 64: Synthesis of 4-amino-[1,2,5]thiadiazolo[3,4-c]quinoline-8-carboxylic acid

[0385] Step 1: Synthesis of methyl 4-oxo-4,5-dihydro-[1,2,5]thiadiazolo[3,4-C]quinoline-8-carboxylate

[0386] At room temperature, methyl 4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2 g, 7.217 mmol) and methyl 4-bromo-1,2,5-thiadiazole-3-carboxylate (1.9 g, 8.66 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (25 ml, 4:1), tetrakistriphenylphosphine palladium (851 mg, 0.722 mmol) and potassium carbonate (3 g, 21.6 mmol) were added, and N2 was replaced three times. The reaction solution was stirred at 100°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, poured into water, filtered, and the filter cake was washed with water and dried in vacuo to obtain a crude product (1.3 g, yield: 68%), which was directly used in the next step without purification.

[0387] LCMS (ESI) m / z: 262.1 [M+H] +

[0388] Step 2: Synthesis of methyl 4-chloro-[1,2,5]thiadiazolo[3,4-c]quinoline-8-carboxylate

[0389] At room temperature, 4-oxo-4,5-dihydro-[1,2,5]thiadiazolo[3,4-C]quinoline-8-carboxylic acid methyl ester (1.4 g, 5.359 mmol) was dissolved in phosphorus oxychloride (30 ml) and stirred at 100°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with a small amount of acetonitrile, poured into water (80 ml), filtered, and the filter cake was washed with water and dried in vacuo to obtain brown solid 4-chloro-[1,2,5]thiadiazolo[3,4-C]quinoline-8-carboxylic acid methyl ester (1.4 g, crude product).

[0390] LCMS (ESI) m / z: 280.1 [M+H] +

[0391] Step 3: Synthesis of methyl 4-((4-methoxybenzyl)amino)-[1,2,5]thiadiazo[3,4-c]quinoline-8-carboxylate

[0392] Methyl 4-chloro-[1,2,5]thiadiazolo[3,4-c]quinoline-8-carboxylate (1 g, 3.575 mmol) was dissolved in DMSO (30 mL) at room temperature, and 4-methoxybenzylamine (735 mg, 5.363 mmol) and N,N-diisopropylethylamine (943 mg, 7.15 mmol) were added. The mixture was reacted at 90°C for 3 hours. After completion of the reaction, the reaction solution was poured into water (200 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (PE:EA=1:1) to give methyl 4-((4-methoxybenzyl)amino)-[1,2,5]thiadiazolo[3,4-c]quinoline-8-carboxylate (1.25 g, 91% yield) as a yellow solid.

[0393] LCMS (ESI) m / z: 381 [M+H] +

[0394] Step 4: Synthesis of methyl 4-amino-[1,2,5]thiadiazolo[3,4-c]quinoline-8-carboxylate

[0395] Methyl 4-((4-methoxybenzyl)amino)-[1,2,5]thiadiazolo[3,4-c]quinoline-8-carboxylate (800 mg, 2.103 mmol) was dissolved in TFA (10 ml) at room temperature and the reactants were reacted at 80°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, poured into water (10 ml), filtered, and the filter cake was dried under vacuum to obtain a crude product (800 mg, crude product), which was used directly in the next step without purification.

[0396] LCMS (ESI) m / z: 261 [M+H] +

[0397] Step 5: Synthesis of 4-amino-[1,2,5]thiadiazolo[3,4-c]quinoline-8-carboxylic acid

[0398] 4-Amino-[1,2,5]thiadiazolo[3,4-C]quinoline-8-carboxylic acid methyl ester (600 mg, 2.305 mmol) was dissolved in THF / MeOH / H2O (25 ml, 2:2:1), lithium hydroxide (167 mg, 6.916 mmol) was added, and the mixture was reacted at 50°C for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give the crude product 4-amino-[1,2,5]thiadiazolo[3,4-C]quinoline-8-carboxylic acid (0.7 g, crude product), which was used directly in the next step without purification.

[0399] LCMS (ESI) m / z: 247 [M+H] + Example 1

[0400] Example 1 Synthesis of 4-amino-N-(1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0401] A mixture of [1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl]methanamine (60 mg, 0.23 mmol), 4-amino-1-methylpyrazolo[4,5-c]quinoline-8-carboxylic acid (56 mg, 0.23 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (194 mg, 0.69 mmol), N-methylimidazole (57 mg, 0.69 mmol), and N,N-dimethylacetamide (1.00 ml) was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was poured into water (10 ml), and the aqueous layer was extracted with ethyl acetate (2 x 10 ml). The organic layers were combined, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by high pressure preparative liquid chromatography (column: Sunfire C185 m, 30 mm × 150 mm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 60 ml / min ml / min; gradient: from 18% B to 35% B in 8 min; wavelength: 254 nm / 220 nm; RT1 (min): 7.35) to give 4-amino-N-(1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (9.18 mg, 8%) as a white solid.

[0402] LCMS (ESI): 484.05 [M+H] +

[0403] 1 H NMR(400MHz,DMSO-d6)δ8.36–8.31(m,2H),8.25(s,1H),7.71(m,1H),7.66-7.65(m,1H),7.62-7 .61(m,2H),7.15(s,2H),5.81-4.95(m,1H),4.39(s,3H),4.13(s,2H),2.79(s,3H),1.57(m,6H)

[0404] The following examples can be prepared by using the same synthetic steps as described in Example 1, replacing only the corresponding starting materials:

[0405] Example 7 Synthesis of 4-amino-N-(1,1-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0406] At room temperature, the compound 4-amino-1-methylpyrazolo[4,3-c]quinoline-8-carboxylic acid (140 mg, 0.575 mmol) was dissolved in DMF (3 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (110 mg, 0.575 mmol) and 1-hydroxybenzotriazole (79 mg, 0.575 mmol) were added, followed by the addition of DIEA (186 mg, 1.437 mmol), and the reaction was stirred at room temperature for 0.5 hour. N,1,1-trimethyl-7-(1-methyl-1H-pyrazol-4-yl)isochroman-4-amine (130 mg, 0.479 mmol) was then added, and the mixture was reacted at room temperature for 16 hours. When LCMS showed that the reaction was complete, water (20 ml) was poured into the mixture, and the mixture was extracted with ethyl acetate (30 ml). The organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by column chromatography (0-5% methanol / dichloromethane) to give 4-amino-N-(1,1-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (25 mg, yield: 8.78%) as a white solid.

[0407] LCMS (ESI) m / z: 496.2 [M+H] +

[0408] 1H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.27(s,1H),8.20(s,1H),7.93(s,1H),7.71–7.59(m,2H),7.48(s,2H),7.28(s,1H),7 .15(s,2H),5.29(d,J=286.9Hz,1H),4.41(s,3H),4.13(d,J=30.6Hz,2H),3.87(s,3H),2.81(s,3H),1.49(d,J=71.8Hz,6H).

[0409] The following examples can be prepared by using the same synthetic steps as described in Example 7, replacing only the corresponding starting materials:

[0410] Example 14 Synthesis of (4-amino-7-fluoro-1-methylpyrazolo[4,5-c]quinolin-8-yl)-N-[1,1-dimethyl-7-(1-methylpyrazol-5-yl)isothiophen-4-yl]-N-methylformamide

[0411] A mixture of (4-amino-7-fluoro-1-methylpyrazolo[4,5-c]quinolin-8-yl)-N-(7-bromo-1,1-dimethylisothiophen-4-yl)-N-methylformamide (70 mg, 0.14 mmol), (1-methyl-1H-pyrazol-5-yl)boronic acid (17.2 mg, 0.14 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (10 mg, 0.01 mmol), potassium carbonate (38 mg, 0.27 mmol) in dioxane / water (4 ml / 1 ml) was stirred at 80° C. for 2 h, the mixture was poured into water, extracted with ethyl acetate, and purified by preparative high performance liquid chromatography (chromatographic column specifications: Sunfire C185 m, 30 mm × 150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 11% B to 30% B in 8 minutes; wavelength: 254 nm / 220 nm; retention time (minutes): 7.33) to obtain (4-amino-7-fluoro-1-methylpyrazolo[4,5-c]quinolin-8-yl)-N-[1,1-dimethyl-7-(1-methylpyrazol-5-yl)isothiophen-4-yl]-N-methylformamide (7.90 mg, 11%)

[0412] LCMS (ESI): m / z 513.90 [M+H] +

[0413] 1 H NMR (400MHz, DMSO-d6) δ8.41–8.11(m,2H),7.56–7.18(m,7H),6.44(d,J=10.7Hz,1H),5.75-4.73(t,J=4.4Hz,1 H),4.40(d,J=5.8Hz,3H),4.15–3.98(m,2H),3.86(d,J=17.0Hz,3H),2.78(d,J=53.0Hz,3H),1.66–1.31(m,6H).

[0414] Example 49 Synthesis of (S)-4-amino-N-(1,1-dimethyl-7-(2-oxa-6-azaspiro[3.3]heptane-6-yl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0415] Step 1: Synthesis of (S)-4-amino-N-(7-bromo-1,1-dimethylisochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0416] At room temperature, the compound 4-amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (97.0 mg, 0.390 mmol) was dissolved in DMF (3 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (767 mg, 4.01 mmol) and 1-hydroxybenzotriazole (546 mg, 4.01 mmol) were added, followed by the addition of DIEA (1293 mg, 10.02 mmol), and the reaction was stirred at room temperature for 0.5 hour. (S)-7-Bromo-N,1,1-trimethylisochroman-4-amine hydrochloride (900.0 mg, 3.34 mmol) was then added, and the mixture was reacted at room temperature for 16 hours. When LCMS showed the reaction was complete, it was poured into water (100 mL) and extracted with ethyl acetate (50×3 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give (S)-4-amino-N-(7-bromo-1,1-dimethylisochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (700 mg, 42.5%).

[0417] LCMS (ESI) m / z: 494.1 [M+H] +

[0418] Step 2: Synthesis of (S)-4-amino-N-(1,1-dimethyl-7-(2-oxa-6-azaspiro[3.3]heptane-6-yl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0419] Under N2 atmosphere, (S)-4-amino-N-(7-bromo-1,1-dimethylisochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (110 mg, 0.223 mmol) was dissolved in 1,4-dioxane (2 ml), and 2-oxa-6-azaspiro[3.3]heptane (34 mg, 0.335 mmol), cesium carbonate (290 mg, 0.8 92 mmol), and methanesulfonic acid (9,9-dimethyl-4,5-bisdiphenylphosphinothrene)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (28.0 mg, 0.03 mmol), react at 100 ° C for 16 hours, pour into water (20 ml), extract with ethyl acetate (10 ml × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter to remove anhydrous sodium sulfate, and the filtrate is dried to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give (S)-4-amino-N-(1,1-dimethyl-7-(2-oxa-6-azaspiro[3.3]heptan-6-yl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (20 mg, 0.039 mmol, 17.5% yield) as a white solid.

[0420] LCMS (ESI) m / z: 513.1 [M+H] +

[0421] 1 H NMR (400MHz, DMSO-d6) δ8.28(d,J=4.0Hz,2H),7.62(s,2H),7.48–6.99(m,3H),6.38(s,1H),6.26(d,J=17.9H z,1H),4.80(s,1H),4.70(s,4H),4.38(s,3H),4.06(d,J=32.1Hz,2H),3.96(s,4H),2.74(s,3H),1.49(s,6H).

[0422] The following examples can be prepared by using the same synthetic steps as described in Example 49, replacing only the corresponding starting materials:

[0423] Example 58 (S)-4-amine-N-(1,1-dimethyl-7-(tetrahydro-2H-pyran-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoxaline-8-carboxamide

[0424] At room temperature, (S)-4-amino-N-(7-(3,6-dihydro-2H-pyran-4-yl)-1,1-dimethylisochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (50 mg, 0.100 mmol) was dissolved in methanol / THF (1:1, 2 ml), and Pd / C (212 mg, 0.200 mmol) was added. The reaction solution was replaced with a hydrogen balloon three times and stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was completed, water was poured into the mixture. (20 ml), extracted with ethyl acetate (20×3 ml), the organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give the product (S)-4-amino-N-(1,1-dimethyl-7-(tetrahydro-2H-pyran-4-yl)isochromatic-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (5 mg, 10.0% yield).

[0425] LCMS (ESI) m / z: 500.2 [M+H]+

[0426] 1 H NMR(400MHz, DMSO-d6)δ8.28(d,J=22.2Hz,2H),7.62(s,2H),7.44–7.02(m,5H),5.32(s,1H),4.54–4 .22(m,3H),4.10–3.91(m,3H),3.44(s,4H),2.82–2.72(m,3H),1.80–1.60(m,4H),1.59–1.31(m,6H).

[0427] Example 88 (S)-4-amino-N,1-dimethyl-N-(7'-(piperazin-1-yl)-3'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-yl)-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0428] Step 1: 4-Amino-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid (270 mg, 1.11 mmol) was dissolved in N,N-dimethylformamide (5.0 ml), and chloro-N,N,N',N'-tetramethylformamidoammonium hexafluorophosphate (435 mg, 1.52 mmol), N-methylimidazole (420 mg, 5.06 mmol) and N,N-diisopropylethylamine (400 mg, 3.04 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. Then, benzyl (S)-4-(4'-(tert-butoxycarbonyl)(methyl)amino)-3'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridin]-7'-yl)piperazine-1-carboxylate (428 mg, 1.01 mmol) was added, and the mixture was stirred at 60°C for 16 hours. After the reaction was completed, the reaction solution was poured into water (40 mL) and extracted with ethyl acetate (60 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase column chromatography (acetonitrile:water = 40:60) to obtain benzyl (S)-4-(4'-(4-amino-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamido)-3'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-7'-yl)piperazine-1-carboxylate (280 mg, yield: 42.7%).

[0429] LCMS (ESI) m / z: [M+H]+ = 647.38.

[0430] Step 2: Benzyl (S)-4-(4'-(4-amino-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamido)-3'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-7'-yl)piperazine-1-carboxylate (20 mg, 0.03 mmol) was dissolved in methanol (3.0 ml), palladium carbon (20 mg) was added, the reaction solution was replaced with hydrogen three times and stirred at room temperature for 1 hour. After completion of the reaction, palladium carbon was filtered off using celite and the solvent was removed in vacuo. The residue was purified by high performance liquid chromatography (HPLC) using a 10% to 90% acetonitrile and water system (containing 0.1% ammonium bicarbonate) as eluent and lyophilized to afford (S)-4-amino-N-methyl-N-(7'-(piperazin-1-yl)-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (5.52 mg, 34.57% yield) as a white solid.

[0431] LCMS (ESI) m / z: [M+H]+ = 513.4.

[0432] 1H NMR (400MHz, DMSO-d6) δ8.30(s,1H),8.25(s,1H),8.05(d,J=36.2Hz,1H),7.61(s,2H),7.12(s,2H),6.78(s,1H),5.74(s,1H) ,5.22(d,J=281Hz,1H),4.39(s,3H),4.01(s,2H),3.44(s,4H),2.76(d,J=20.6Hz,7H),2.36-2.25(m,3H),2.05-1.95(m,2H).

[0433] Examples 16 & 17

[0434] Example 16 (S) -4-amino-N-(1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide & Example 17 (R) -4-amino-N-(1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0435] Compound 4-amino-N-(1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (70 mg) was subjected to SFC (column: ChiralPak IBN, 250×40 mm ID, 10 μm) under the following conditions:

[0436] After purification with A for CO2 and B for MeOH (0.1% NH3·H2O), 40% / 40%, flow rate: 120 ml / min), (S)-4-amino-N-(1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (20 mg) and (R)-4-amino-N-(1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide (22 mg) were obtained.

[0437] Example 16 (S)-4-amino-N-(1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0438] LCMS (ESI) m / z: 484.2 [M+H] +

[0439] 1 H NMR(400MHz,DMSO-d6)δ8.34(d,J=1.8Hz,1H),8.27(s,1H),7.76–7.69(m,1H),7.69–7.56(m,4H) ,7.16(s,2H),5.38(d,J=286.9Hz,1H),4.40(s,3H),4.14(s,2H),2.80(s,3H),1.64–1.34(m,6H).

[0440] Example 17 (R)-4-amino-N-(1,1-dimethyl-7-(trifluoromethyl)isochroman-4-yl)-N,1-dimethyl-1H-pyrazolo[4,3-c]quinoline-8-carboxamide

[0441] LCMS (ESI) m / z: 484.2 [M+H]+

[0442] 1 H NMR (400MHz, DMSO-d6) δ8.34(d,J=1.9Hz,1H),8.27(s,1H),7.73(s,1H),7.69–7.55(m,4H),7. 16(s,2H),5.38(d,J=286.9Hz,1H),4.40(s,3H),4.14(s,2H),2.80(s,3H),1.64–1.35(m,6H).

[0443] Using the procedures described in Example 16 and Example 17 and the corresponding chiral SFC separation conditions, the compounds shown in the following table were obtained:

[0444] Biological activity evaluation

[0445] Experimental study on the inhibitory activity of compounds on tumor cell proliferation

[0446] Test Example 1: Inhibitory activity of compounds on proliferation of HCT-116MTAP(- / -) deficient cells

[0447] Materials and cells: HCT-116MTAP(- / -) deficient cells were purchased from Kangyuan Bochuang (China); RPMI-1640 medium and fetal bovine serum were purchased from Thermo Fisher Scientific (USA); 384-well plates were purchased from PerkinElmer (USA); and the Cell-Titer Glo kit was purchased from Promega (USA).

[0448] Cell culture: HCT116 MTAP(- / -)-deficient cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum at 37°C and 5% CO2. Cells in the logarithmic growth phase were used for experiments.

[0449] Cell proliferation inhibitory activity assay: The Cell-Titer Glo kit was used to detect the inhibitory activity of the compound against HCT-116MTAP(- / -) deficient cells. The cell concentration was adjusted, and 40 μL was inoculated into each well of a 384-well plate. The plate was incubated overnight at 37°C and 5% CO2. 80 nL of compound was added to each well to a final concentration of 0-1,000 nM (starting concentration 1,000 nM, 2.5-fold dilution, 10 points), with a DMSO content of 0.2%. The cell plate was incubated at 37°C and 5% CO2 for 6 days. 40 μL of Cell-Titer Glo reagent was added to detect cell viability. The test results are shown in Table 1.

[0450] Test Example 2: Experimental study on the inhibitory activity of compounds on HCT-116 wild-type cell proliferation

[0451] Materials and cells: HCT-116 wild-type cells were purchased from Kangyuan Bochuang (China); RPMI-1640 medium and fetal bovine serum were purchased from Thermo Fisher Scientific (USA); 384-well plates were purchased from PerkinElmer (USA); and the Cell-Titer Glo kit was purchased from Promega (USA).

[0452] Cell culture: HCT-116 wild-type cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum at 37°C and 5% CO2. Cells in the logarithmic growth phase were used in the experiments.

[0453] Cell proliferation activity assay: The Cell-Titer Glo kit was used to detect the inhibitory activity of the compound on HCT-116 wild-type cells. The cell concentration was adjusted, and 40 μL was inoculated into each well of a 384-well plate and cultured overnight at 37°C and 5% CO2. 80 nL of compound was added to each well to a final concentration of 0-10,000 nM (starting concentration 10,000 nM, 2.5-fold dilution, 10 points), with a DMSO content of 0.2%. The cell plate was incubated at 37°C and 5% CO2 for 6 days. 40 μL of Cell-Titer Glo reagent was added to detect cell activity. The test results are shown in Table 1.

[0454] Table 1 shows the inhibitory activity of the compounds in the examples on the proliferation of HCT116 MTAP(- / -) deficient cells and HCT116 wild-type cells.

[0455] It can be seen from Table 1 above that the compounds of the present disclosure have very good anti-proliferative activity against HCT116 MTAP (- / -) cells and exhibit very good selectivity relative to HCT MTAP WT cells.

[0456] Test Example 3: Inhibitory activity of compounds on LU99 MTAP(- / -) deficient cell proliferation

[0457] Materials and cells: LU99 MTAP(- / -)-deficient cell line was purchased from Kangyuan Bochuang (China); cell culture medium and fetal bovine serum were purchased from Thermo Fisher Scientific (USA); 384-well plates were purchased from PerkinElmer (USA); and Cell-Titer Glo kit was purchased from Promega (USA).

[0458] Cell culture: LU99 MTAP(- / -)-deficient cells were cultured in a medium containing 10% fetal bovine serum at 37°C and 5% CO2. Cells in the logarithmic growth phase were used for experiments.

[0459] Cell proliferation inhibitory activity assay: The Cell-Titer Glo assay was used to assess the inhibitory activity of compounds against LU99 MTAP(- / -)-deficient cells. The cell concentration was adjusted, and 40 μL of the compound was seeded into each well of a 384-well plate. The plate was incubated overnight at 37°C, 5% CO2. 40 nL of the compound was added to each well to a final concentration of 0-1,000 nM (starting at 1,000 nM, 2.5-fold dilution, 10 points) with 0.2% DMSO. The plate was incubated at 37°C, 5% CO2 for 6 days. Cell viability was assessed by adding 40 μL of Cell-Titer Glo reagent. The results are shown in Table 2.

[0460] Test Example 4: Inhibitory activity of compounds on the proliferation of LU99 MTAP-overexpressing cells

[0461] Materials and cells: LU99 MTAP-overexpressing cell line was purchased from Kangyuan Bochuang (China); cell culture medium and fetal bovine serum were purchased from Thermo Fisher Scientific (USA); 384-well plates were purchased from PerkinElmer (USA); and the Cell-Titer Glo kit was purchased from Promega (USA).

[0462] Cell culture: LU99 MTAP-overexpressing cells were cultured in a medium containing 10% fetal bovine serum at 37°C and 5% CO2. Cells in the logarithmic growth phase were used for experiments.

[0463] Cell proliferation inhibitory activity detection: The Cell-Titer Glo kit was used to detect the proliferation inhibitory activity of the compound on LU99 MTAP overexpressing cells. The cell concentration was adjusted, 40 μL per well was inoculated into a 384-well plate, and cultured overnight at 37°C and 5% CO2. 40 nL of compound was added to each well to a final concentration of 0-10,000 nM (starting concentration 10,000 nM, 2.5-fold dilution, 10 points), and the DMSO content was 0.2%. The cell plate was incubated at 37°C and 5% CO2 for 6 days. 40 μL of Cell-Titer Glo reagent was added to detect cell activity. The test results are shown in Table 2. Table 2

[0464] As can be seen from Table 2 above, the compounds of the present disclosure have very good anti-proliferative activity against LU99 MTAP(- / -) cells and exhibit very good selectivity relative to LU99 MTAP-overexpressing cells.

[0465] Although preferred embodiments have been described above, it will be apparent to those skilled in the art that modifications may be made without departing from the present disclosure. Such modifications are considered to be possible variations within the scope of the present disclosure.

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotope derivative thereof, in, Cy represents the following structure: or Wherein, the dotted line represents a single bond or a double bond; Wherein, Y1 independently represents O, S, Se, N or CR Y1 ; Wherein, Y2 independently represents O, S, Se, N or CR Y2 ; Wherein, Y3 independently represents O, S, Se, N or CR Y3 ; Wherein, Y4 independently represents O, S, Se, N or CR Y4 ; Where X1 represents N or CR X1 ; Where X2 represents N or CR X2 ; Where X3 represents N or CR X3 ; Among them, X4 represents N or CR X4 ; Among them, X5 represents N or CR X5 ; Among them, X6 represents N or CR X6 ; Among them, R X1 , R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b 、-SF5、-C(O)OR a 、-CO2NR a R b ; Among them, R X3 , R X5 , R X6 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, -C(O)OR a 、-CO2NR a R b or is selected from 0-4 of the following substituents: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy(C1-C6 alkyl), -NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, R X4 Indicates -LR X4-1 ; Among them, L means non-existent or CR a R b 、SiR a R b 、O、S、Se、NR a ; Among them, R X4-1 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b 、-C(O)OR a 、-OC(O)R a 、-OCONR a R b 、-NR a COR b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, R Y1 , R Y2 , R Y3 , R Y4 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b 、-SF5、-C(O)OR a 、-CO2NR a R b ; Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X3 and X4, and the ring may contain 0-3 heteroatoms selected from O, N, and S; wherein the ring may be optionally substituted with 0, 1, 2, or 3 heteroatoms selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b substituted by a substituent; Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X4 and X5, and the ring may contain 0-3 heteroatoms selected from O, N, and S; wherein the ring may be optionally substituted with 0, 1, 2, or 3 heteroatoms selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b substituted by a substituent; Among them, R 1 represents hydrogen or substituted by 0-3 groups selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic monoheterocyclic group, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Preferably, R 1 Indicates -CHR s R t or-CDR s R t ; Among them, R s , R t Each independently represents hydrogen, deuterium, -OR a , halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, -C3-C 10 Cycloalkyl or 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Substituted 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, M1 represents CR a R b 、-SiR a R b NR a , O, S or Se; Wherein, M2 represents C or Si; Among them, R L , R L’ Each independently represents a C1-C6 alkyl group, or R L , R L’ Together with the atoms connected to it, they form a 3-10 membered saturated or unsaturated ring, and the ring may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, S, and Se; further, the ring may also be arbitrarily replaced by 0, 1, or 2 heteroatoms selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-C(O)OR a 、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , substituted by a substituent of -SF5; Among them, R T , R T’ Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxyl, carboxyl, halogenated C1-C6 alkyl, hydroxyl (C1-C6 alkyl), thiol (C1-C6 alkyl) together with the atoms connected thereto to form a 3-10 membered saturated or unsaturated ring, and the ring may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, S, and Se; further, the ring may also be arbitrarily replaced by 0, 1, or 2 heteroatoms selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-C(O)OR a 、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , substituted by a substituent of -SF5; Where o represents 0, 1 or 2; Among them, R a , R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a , R b Together with the atoms connected to it, they form a 3-14-membered saturated or unsaturated monocyclic ring, a 3-14-membered saturated or unsaturated spirocyclic ring, or a 3-14-membered saturated or unsaturated condensed ring, each of which may arbitrarily contain 0-2 heteroatoms selected from O, S, Se, N, and Si.

2. A compound represented by formula (I-1), or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, in, Cy represents the following structure: or Wherein, the dotted line represents a single bond or a double bond; Wherein, Y1 independently represents O, S, Se, N or CR Y1 ; Wherein, Y2 independently represents O, S, Se, N or CR Y2 ; Wherein, Y3 independently represents O, S, Se, N or CR Y3 ; Wherein, Y4 independently represents O, S, Se, N or CR Y4 ; Where X1 represents N or CR X1 ; Where X2 represents N or CR X2 ; Where X3 represents N or CR X3 ; Among them, X4 represents N or CR X4 ; Among them, X5 represents N or CR X5 ; Among them, X6 represents N or CR X6 ; Among them, R X1 , R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b 、-SF5、-C(O)OR a 、-CO2NR a R b ; Among them, R X3 , R X5 , R X6 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, -C(O)OR a 、-CO2NR a R b or is selected from 0-4 of the following substituents: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy(C1-C6 alkyl), -NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, R X4 Indicates -LR X4-1 ; Among them, L means non-existent or CR a R b 、SiR a R b 、O、S、Se、NR a ; Among them, R X4-1 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b 、-C(O)OR a 、-OC(O)R a 、-OCONR a R b 、-NR a COR b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, R Y1 , R Y2 , R Y3 , R Y4 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b 、-SF5、-C(O)OR a 、-CO2NR a R b ; Among them, R 1 represents hydrogen or substituted by 0-3 groups selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic monoheterocyclic group, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Preferably, R 1 Indicates -CHR s R t or-CDR s R t ; Among them, R s , R t Each independently represents hydrogen, deuterium, -OR a , halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, -C3-C 10 Cycloalkyl or 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Substituted 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, M1 represents CR a R b 、-SiR a R b NR a , O, S or Se; Wherein, M2 represents C or Si; Among them, R L , R L’ Each independently represents a C1-C6 alkyl group, or R L , R L’ Together with the atoms connected to it, they form a 3-10 membered saturated or unsaturated ring, and the ring may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, S, and Se; further, the ring may also be arbitrarily replaced by 0, 1, or 2 heteroatoms selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-C(O)OR a 、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , substituted by a substituent of -SF5; Among them, R T , R T’ Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxyl, carboxyl, halogenated C1-C6 alkyl, hydroxyl (C1-C6 alkyl), thiol (C1-C6 alkyl) together with the atoms connected thereto to form a 3-10 membered saturated or unsaturated ring, and the ring may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, N, S, and Se; further, the ring may also be arbitrarily replaced by 0, 1, or 2 heteroatoms selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-C(O)OR a 、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , substituted by a substituent of -SF5; Where o represents 0, 1 or 2; Among them, R a , R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a , R b Together with the atoms connected to it, they form a 3-14-membered saturated or unsaturated monocyclic ring, a 3-14-membered saturated or unsaturated spirocyclic ring, or a 3-14-membered saturated or unsaturated condensed ring, each of which may arbitrarily contain 0-2 heteroatoms selected from O, S, and N.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Cy represents the following structure:

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotope derivative thereof, wherein: X1 means CR X1 or N, where R X1 It represents hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, and halogenated C1-C6 alkyl.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X1 represents CH, CF or N.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X2 represents CH or CD.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X2 is represented by CH.

8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X3 represents CH, CD or N.

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X3 represents CH.

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl.

11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 It represents hydrogen, deuterium, C1-C6 alkyl, halogen, halogenated C1-C6 alkyl, -CN, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -SF5, -P(O)(CH3)2.

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 It represents hydrogen, halogen (preferably F), -CF3, -NH2, -NHCH3, -N(CH3)2, -OCH3, -OCF3, -SF5, -P(O)(CH3)2.

13. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 represents 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C6-C 10 Aryl or 5-10 membered heteroaryl.

14. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups: Furthermore, R X4 It may be arbitrarily substituted with 0, 1 or 2 groups selected from halogen, hydroxy, -CN, C1-C6 alkyl, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy.

15. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 represents 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic ring.

16. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X 4 Represents CLR X4-1 , where L represents O, S or NH, N(CH3), R X4-1 Represents the following groups: Furthermore, R X4-1 It may be arbitrarily substituted with 0, 1 or 2 groups selected from halogen, hydroxy, -CN, C1-C6 alkyl, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy.

17. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups: Where W1 represents CR C R D NR C 、O、S、SiR C R D ; Where W2 represents -(CR M R N ) i -; Wherein, R1′, R2′, R3′, R4′, R5′, R6′, R7′, R8′ each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, hydroxyl; or, respectively, R1′, R2′ pair; R3′, R4′ pair; R5′, R6′ pair; R7′, R8′ pair together with the atoms connected thereto form a 3-6 membered saturated or unsaturated ring, and the ring may also arbitrarily contain 0, 1, 2 heteroatoms selected from O, S, N; further, the ring may also be arbitrarily substituted with 0, 1, 2 substituents selected from deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl; Among them, R C , R D Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, hydroxyl; or R C , R D Together with the atoms connected thereto, they form a 3-6 membered saturated or unsaturated ring, and the ring may also arbitrarily contain 0, 1, or 2 heteroatoms selected from O, S, and N; further, the ring may also be arbitrarily substituted with 0, 1, or 2 substituents selected from deuterium, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, and hydroxyl; Among them, R M , R N Each independently represents hydrogen or C1-C6 alkyl; Here, i represents an integer of 1 or 2. Furthermore, R X4-1 It may be arbitrarily substituted with 0, 1 or 2 groups selected from halogen, hydroxy, -CN, C1-C6 alkyl, halogenated C1-C6 alkyl and halogenated C1-C6 alkoxy.

18. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups: Among them, the R X4-1 It may be arbitrarily substituted with 0, 1 or 2 substituents selected from halogen, hydroxy, cyano, C1-C6 alkyl and halogenated C1-C6 alkyl.

19. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups:

20. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X4 means CR X4 ; Among them, R X4 It represents a C1-C6 alkoxy group, a C1-C6 alkylthio group, a halogenated C1-C6 alkoxy group, a halogenated C1-C6 alkylthio group, a halogenated C1-C6 alkyl group, or -SF5.

21. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X4 means CR X4 ; Among them, R X4 It represents a halogenated C1-C6 alkoxy group, a halogenated C1-C6 alkylthio group, a halogenated C1-C6 alkyl group, or -SF5.

22. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X5 means CR X5 or N, where R X5 It represents hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5 or cyano.

23. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X5 represents CH.

24. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X6 represents CH, CD or N.

25. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X6 represents CH.

26. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R 1 Indicates -CHR 2 R 3 or-CDR 2 R 3 , where R 2 , R 3 Each independently represents hydrogen, deuterium, C1-C6 alkyl, or 0-3 selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

27. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R 1 Indicates -CHR 2 R 3 or-CDR 2 R 3 , where R 2 represents hydrogen, deuterium, C1-C6 alkyl; R 3 represents hydrogen, deuterium, C1-C6 alkyl, or 0-3 selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

28. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R 1 represents 0-3 selected from deuterated, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-CN、NR a R b , C3-C6 substituted by halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy 10 Cycloalkyl.

29. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R 1 It represents a C1-C6 alkyl group (preferably a methyl group or an ethyl group) or a deuterated C1-C6 alkyl group (preferably a deuterated methyl group or a deuterated ethyl group) or a C3-C6 cycloalkyl group (preferably a cyclopropyl group).

30. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: M1 is O or S.

31. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: o is 1 or 2.

32. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: o is 1.

33. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R L , R L’ Each independently represents a C1-C6 alkyl group.

34. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R L , R L’ Together with the atoms to which they are attached, they form a 3-6 membered ring.

35. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R L , R L’ Together with the atoms to which they are attached, they form a 3-membered ring or a 4-membered ring.

36. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R L , R L’ Together with the atoms to which they are attached, they form a ring with the following structure: Among them, * represents R L , R L’ The atom sites connected together, further, the above-mentioned ring structure can be arbitrarily replaced by 0, 1, or 2 selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-C(O)OR a 、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5 substituent.

37. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R T , R T’ Together with the atoms to which they are attached, they form a ring with the following structure: Among them, * represents R T , R T’ The atom sites connected together, further, the above-mentioned ring structure can be arbitrarily replaced by 0, 1, or 2 selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-C(O)OR a 、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5 substituent.

38. A compound represented by formula (I-2), or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, in, X3 means N or CR X3 ; X4 means N or CR X4 ; X5 means N or CR X5 ; X6 means N or CR X6 ; Among them, when X3 represents CR X3 When R X3 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X4 represents CR X4 When R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X5 represents CR X5 When R X5 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X6 represents CR X6 When R X6 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Wherein, the ring A may also be arbitrarily fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X3 and X4, and the ring may contain 0-3 heteroatoms selected from O, N, and S; Wherein, the ring A may also be arbitrarily fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X4 and X5, and the ring may contain 0-3 heteroatoms selected from O, N, and S; Wherein, the ring A may also be arbitrarily fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X5 and X6, and the ring may contain 0-3 heteroatoms selected from O, N, and S; Wherein, the ring A can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b substituted by a substituent; Wherein, R1 represents 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic monoheterocyclic group, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Preferably, R 1 Indicates -CHR 2 R 3 or-CDR 2 R 3 ; Among them, R 2 , R 3 Each independently represents hydrogen, deuterium, -OR a , halogen, -CN, -C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, -C3-C 10 Cycloalkyl or 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Substituted 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, M 1 Represents CR a R b NR a , O, S or Se; Among them, R L , R L’ Each independently represents a C1-C6 alkyl group, or R L , R L’ Together with the atoms to which they are attached, they form a 3-6 membered ring; Where o represents 0, 1 or 2; Among them, ring B represents a 3-10 membered carbocyclic ring, a 6-10 membered unsaturated carbocyclic ring, a 4-10 membered heterocyclic ring, a 6-10 membered unsaturated heterocyclic ring, a C6-C 10 Aromatic ring, 5-10 membered aromatic heterocycle, the 4-10 membered heterocycle, 6-10 membered unsaturated heterocycle, 5-10 membered aromatic heterocycle may contain 0-3 O, S, N atoms. Wherein, the ring B can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b substituted by a substituent; Where X1 represents N or CR X1 ; Where X2 represents N or CR X2 ; Among them, R X1 , R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5; in, Indicates a single bond or a double bond; Among them, R a , R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a , R b Together with the atoms connected to it, they form a 3-14-membered saturated or unsaturated monocyclic ring, a 3-14-membered saturated or unsaturated spirocyclic ring, or a 3-14-membered saturated or unsaturated condensed ring, each of which may arbitrarily contain 0-2 heteroatoms selected from O, S, Se, N, and Si.

39. The compound according to claim 38, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, having the following formula (I-3): in, X3 means N or CR X3 ; X4 means N or CR X4 ; X5 means N or CR X5 ; X6 means N or CR X6 ; Among them, when X3 represents CR X3 When R X3 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X4 represents CR X4 When R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X5 represents CR X5 When R X5 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X6 represents CR X6 When R X6 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Wherein, the ring A may also be arbitrarily fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X3 and X4, and the ring may contain 0-3 heteroatoms selected from O, N, and S; Wherein, the ring A may also be arbitrarily fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X4 and X5, and the ring may contain 0-3 heteroatoms selected from O, N, and S; Wherein, the ring A may also be arbitrarily fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X5 and X6, and the ring may contain 0-3 heteroatoms selected from O, N, and S; Wherein, the ring A can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b substituted by a substituent; Among them, R 1 represents 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic monoheterocyclic group, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Preferably, R 1 Indicates -CHR 2 R 3 or-CDR 2 R 3 ; Among them, R 2 , R 3 Each independently represents hydrogen, deuterium, -OR a , halogen, -CN, -C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, -C3-C 10 Cycloalkyl or 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Substituted 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, M 1 Represents CR a R b NR a , O, S or Se; Among them, R L , R L’ Each independently represents a C1-C6 alkyl group, or R L , R L’ Together with the atoms to which they are attached, they form a 3-6 membered ring; Where o represents 0, 1 or 2; Among them, ring B represents a 3-10 membered carbocyclic ring, a 6-10 membered unsaturated carbocyclic ring, a 4-10 membered heterocyclic ring, a 6-10 membered unsaturated heterocyclic ring, a C6-C 10 Aromatic ring, 5-10 membered aromatic heterocycle, the 4-10 membered heterocycle, 6-10 membered unsaturated heterocycle, 5-10 membered aromatic heterocycle may contain 0-3 O, S, N atoms. Wherein, the ring B can be arbitrarily replaced by 0, 1, 2, or 3 groups selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b substituted by a substituent; Where X1 represents N or CR X1 ; Where X2 represents N or CR X2 ; Among them, R X1 , R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5; in, Indicates a single bond or a double bond; Among them, R a , R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a , R b Together with the atoms connected to it, they form a 3-14-membered saturated or unsaturated monocyclic ring, a 3-14-membered saturated or unsaturated spirocyclic ring, or a 3-14-membered saturated or unsaturated condensed ring, each of which may arbitrarily contain 0-2 heteroatoms selected from O, S, Se, N, and Si.

40. The compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Ring B represents the following structure: Among them, Y1 represents CR Y1 R Y1’ NR Y1 , O, S; Among them, Y2 represents CR Y2 R Y2’ NR Y2 , O, S; Among them, Y3 represents CR Y3 R Y3’ NR Y3 , O, S; Among them, R Y1 , R Y1’ , R Y2 , R Y2’ , R Y3 , R Y3’ Each independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5; Among them, R a , R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a , R b Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may arbitrarily contain 0-2 heteroatoms selected from O, S and N.

41. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Ring B represents the following structure: Among them, Y3 represents CR Y3 R Y3’ , R Y3 , R Y3’ Each independently represents hydrogen, deuterium, or a C1-C6 alkyl group.

42. [Corrected 21.01.2025 in accordance with Rule 26] A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Ring B represents the following structure: R Y1 It represents hydrogen, deuterium, or C1-C6 alkyl.

43. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Ring B represents the following structure: R Y3 It represents hydrogen, deuterium, or C1-C6 alkyl.

44. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Ring B represents the following structure: R Y3 It represents hydrogen, deuterium, or C1-C6 alkyl.

45. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Ring B represents the following structure: R Y1 It represents hydrogen, deuterium, or C1-C6 alkyl.

46. ​​A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Ring B represents the following structure: R Y3 It represents hydrogen, deuterium, or C1-C6 alkyl.

47. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Ring B represents the following structure: R Y1 It represents hydrogen, deuterium, or C1-C6 alkyl.

48. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Ring B represents the following structure: Among them, Y4 represents CR Y4 R Y4’ NR Y4 , O, S; Among them, R Y4 , R Y4’ Each independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5; where R a , R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a , R b Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may arbitrarily contain 0-2 heteroatoms selected from O, S and N.

49. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Ring B represents the following structure: Among them, Y5 represents CR Y5 R Y5’ NR Y5 , O, S; Among them, R Y5 , R Y5’ Each independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5; where R a , R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a , R b Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may arbitrarily contain 0-2 heteroatoms selected from O, S and N.

50. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Represents a double bond.

51. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X1 means CR X1 or N, where R X1 It represents hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, and halogenated C1-C6 alkyl.

52. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X1 represents CH, CF or N.

53. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X2 represents CH or CD.

54. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X2 is represented by CH.

55. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X3 represents CH, CD or N.

56. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X3 represents CH.

57. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X4 means CR X4 ; Among them, R X4 It represents a C1-C6 alkoxy group, a C1-C6 alkylthio group, a halogenated C1-C6 alkoxy group, a halogenated C1-C6 alkylthio group, a halogenated C1-C6 alkyl group, or -SF5.

58. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X4 means CR X4 ; Among them, R X4 It represents a halogenated C1-C6 alkoxy group, a halogenated C1-C6 alkylthio group, a halogenated C1-C6 alkyl group, or -SF5.

59. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X5 means CR X5 or N, where R X5 It represents hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5 or cyano.

60. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X5 represents CH.

61. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X6 represents CH, CD or N.

62. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X6 represents CH.

63. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R 1 Indicates -CHR 2 R 3 or-CDR 2 R 3 , where R 2 , R 3 Each independently represents hydrogen, deuterium, C1-C6 alkyl, or 0-3 selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

64. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R 1 Indicates -CHR 2 R 3 or-CDR 2 R 3 , where R 2 represents hydrogen, deuterium, C1-C6 alkyl; R 3 represents hydrogen, deuterium, C1-C6 alkyl, or 0-3 selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b Or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

65. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R 1 represents 0-3 selected from deuterated, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-CN、NR a R b , C3-C6 substituted by halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy 10 Cycloalkyl.

66. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R 1 It represents a C1-C6 alkyl group (preferably a methyl group or an ethyl group) or a deuterated C1-C6 alkyl group (preferably a deuterated methyl group or a deuterated ethyl group) or a C3-C6 cycloalkyl group (preferably a cyclopropyl group).

67. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: M1 is O or S.

68. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: o is 1 or 2.

69. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: o is 1.

70. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R L , R L’ Each independently represents a C1-C6 alkyl group.

71. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R L , R L’ Together with the atoms to which they are attached, they form a 3-6 membered ring.

72. A compound according to claim 38 or 39, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R L , R L’ Together with the atoms to which they are attached, they form a 3-membered ring or a 4-membered ring.

73. A compound, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, having the following structure:

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