Novel prmt5 inhibitors and uses thereof

Abstract

The present disclosure describes novel molecules having protein arginine methyltransferase 5 inhibitory activity, as well as methods of synthesis and use of the compounds. In particular, the present disclosure describes a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as well as methods of 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 discloses a compound represented by formula (I), and pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives thereof,

[0010] Wherein, the dotted line represents a single bond or a double bond;

[0011] Where X1 represents N or CR X1 ;

[0012] Where X2 represents N or CR X2 ;

[0013] Where X3 represents N or CR X3 ;

[0014] Among them, X4 represents N or CR X4 ;

[0015] Among them, X5 represents N or CR X5 ;

[0016] Among them, X6 represents N or CR X6 ;

[0017] Wherein, Y represents CH or N;

[0018] Among them, R 4 Indicates H or D;

[0019] 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 、-S(O)(=NR a )R b 、-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 ;

[0020] 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 、-S(O)(=NR a )R b 、-SF5、-NR a Rb , 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;

[0021] Among them, R X4 Indicates -LR X4-1 ;

[0022] Among them, L means non-existent or CR a R b 、SiR a R b 、O、S、Se、NR a ;

[0023] 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 、-S(O)(=NR a )R b 、-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;

[0024] 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 、-S(O)(=NR a )R b 、-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, -ORa , 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;

[0025] 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 、-S(O)(=NR a )R b 、-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 bsubstituted by a substituent;

[0026] Among them, R 1 represents hydrogen or substituted by 0-3 of any of the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl (e.g. C3-C6 cycloalkyl), 3-10 membered substituted or unsubstituted saturated or unsaturated heterocyclic group (e.g. 3-6 membered saturated or unsaturated heterocyclic group), substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, -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 、-S(O)(=NR a )R b 、-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;

[0027] Preferably, R 1 Indicates -CHR s R t or -CDR s R t ;

[0028] 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, -ORa , 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 、-S(O)(=NR a )R b 、-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;

[0029] 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);

[0030] Among them, M1 represents CR a R b 、-SiR a R b NR a , O, S or Se;

[0031] Wherein, M2 represents C or Si;

[0032] Among them, R L 、R L’ Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxy, carboxyl, halogenated C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl); 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, -ORa 、-SR a 、-S(O)2R a 、-S(O)R a 、-S(O)(=NR a )R b 、-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;

[0033] Among them, R T 、R T’ Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxy, carboxyl, halogenated C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl); or R T 、R T’ 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 、-S(O)(=NR a )R b 、-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;

[0034] Among them, R L 、R L’ Yes, R. T 、R T’At least one of the pairs forms a 3-10 membered saturated or unsaturated ring with the atoms connected thereto, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, S, and Se; further, the ring may optionally be substituted 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 、-S(O)(=NR a )R b 、-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;

[0035] Where o represents 0, 1 or 2;

[0036] 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.

[0037] In addition, the present disclosure provides a compound represented by formula (I-2), and its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives,

[0038] Where X1 represents N or CR X1 ;

[0039] Where X2 represents N or CR X2 ;

[0040] Where X3 represents N or CR X3 ;

[0041] Among them, X4 represents N or CR X4 ;

[0042] Among them, X5 represents N or CR X5 ;

[0043] Among them, X6 represents N or CR X6 ;

[0044] Wherein, Y represents CH or N;

[0045] Among them, R 4 Indicates H or D;

[0046] 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 、-S(O)(=NR a )R b 、-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 ;

[0047] 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 、-S(O)(=NR a )R b 、-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;

[0048] Among them, R X4 Indicates -LR X4-1 ;

[0049] Among them, L means non-existent or CR a R b 、SiR a R b 、O、S、Se、NR a ;

[0050] 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 、-S(O)(=NR a )R b 、-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;

[0051] Among them, R 1 represents hydrogen or substituted by 0-3 of any of the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl (e.g. C3-C6 cycloalkyl), 3-10 membered substituted or unsubstituted saturated or unsaturated heterocyclic group (e.g. 3-6 membered saturated or unsaturated heterocyclic group), substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, -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 、-S(O)(=NR a )R b 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NRa 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;

[0052] Preferably, R 1 Indicates -CHR s R t or -CDR s R t ;

[0053] 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 、-S(O)(=NR a )R b 、-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;

[0054] 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);

[0055] Among them, M1 represents CR a R b 、-SiR a R b NR a , O, S or Se;

[0056] Wherein, M2 represents C or Si;

[0057] Among them, R L 、R L’ Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxy, carboxyl, halogenated C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl); 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 、-S(O)(=NR a )R b 、-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;

[0058] Among them, R T 、R T’ Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxy, carboxyl, halogenated C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl); or R T 、R T’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 、-S(O)(=NR a )R b 、-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;

[0059] Among them, R L 、R L’ Yes, R. T 、R T’ At least one of the pairs forms a 3-10 membered saturated or unsaturated ring with the atoms connected thereto, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, S, and Se; further, the ring may optionally be substituted 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 、-S(O)(=NR a )R b 、-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;

[0060] Where o represents 0, 1 or 2;

[0061] Among them, Ra 、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.

[0062] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X 1 Indicates N.

[0063] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X1 represents CR X1 , where R X1 It represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, NH2, -N(CH3)2.

[0064] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X 2 Indicates CR X2 , where R X2 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, NH2, -N(CH3)2; preferably, R X2 It represents hydrogen or C1-C6 alkyl.

[0065] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X 3 Indicates N.

[0066] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X 3 Indicates CR X3 , where R X3 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, NH2, -N(CH3)2; preferably, R X3 It represents hydrogen, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl.

[0067] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X 5 Indicates N.

[0068] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X 5 Indicates CR X5 , where R X5 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, NH2, -N(CH3)2; preferably, R X5 It represents hydrogen, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl.

[0069] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X 6 Indicates N.

[0070] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X 6 Indicates CR X6 , where R X6 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, NH2, -N(CH3)2; preferably, R X6 It represents hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, or halogenated C1-C6 alkylthio.

[0071] In the preferred technical solution shown in the above formula (I) or formula (I-2), 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 、-S(O)(=NR a )R b 、-SF5、-NR a R b 、-C(O)OR a 、-OC(O)Ra 、-OCONR a R b 、-NR a COR b 、-CONR 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.

[0072] In the preferred technical solution shown in the above formula (I) or formula (I-2), 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, halogenated C1-C6 alkylthio, -SF5, -P(O)(CH3)2.

[0073] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1It represents hydrogen, halogen (preferably F), CN, -CF3, -CF2CF3, -NH2, -NHCH3, -N(CH3)2, -OCH3, -OCF3, -SF5, -SCF3, -P(O)(CH3)2.

[0074] In the preferred technical solution shown in the above formula (I) or formula (I-2), 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.

[0075] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups:

[0076] 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.

[0077] In the preferred technical solution shown in the above formula (I) or formula (I-2), 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.

[0078] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X 4 Represents CLR X4-1 , wherein L represents O, S or NH, N(CH3), R X4-1 Represents the following groups:

[0079] Furthermore, R X4-1 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.

[0080] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups:

[0081] Among them, W1 represents CR C R D NR C 、O、S、SiR C R D ;

[0082] Wherein, W2 represents -(CR M R N ) i -;

[0083] 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;

[0084] 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;

[0085] Among them, R M 、R N Each independently represents hydrogen or C1-C6 alkyl;

[0086] Here, i represents an integer of 1 or 2.

[0087] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups:

[0088] Among them, the R X4-1 It may be arbitrarily substituted with 0, 1, or 2 substituents selected from halogen, C0-C6 alkylhydroxy, C0-C6 alkylcyano, C1-C6 alkyl, and halo-C1-C6 alkyl.

[0089] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups:

[0090] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein R L 、R L’ Together with the atoms to which they are attached, they form a ring with the following structure:

[0091] 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 、-S(O)(=NR a )R b 、-CN、-C(O)OR a 、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5 substituents.

[0092] In the preferred technical solution shown in the above formula (I) or formula (I-2), wherein R T 、R T’ Together with the atoms to which they are attached, they form a ring with the following structure:

[0093] 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 、-S(O)(=NR a )R b 、-CN、-C(O)OR a 、-OC(O)R a 、-OCONR a Rb , halogen, -OSO3R a 、-NR a R b , -SF5 substituents.

[0094] In addition, the present disclosure provides a compound having any of the following structures, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof,

[0095] Where X1 represents N or CR X1 ;

[0096] Where X3 represents N or CR X3 ;

[0097] Among them, X4 represents N or CR X4 ;

[0098] Among them, X5 represents N or CR X5 ;

[0099] Among them, X6 represents N or CR X6 ;

[0100] Among them, R 4 Indicates H or D;

[0101] Among them, R X1 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 、-S(O)(=NR a )R b 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5;

[0102] 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 、-SRa 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-S(O)(=NR a )R b 、-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;

[0103] Among them, R X4 Indicates -LR X4-1 ;

[0104] Among them, L means non-existent or CR a R b , O, S, NR a ;

[0105] 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 、-S(O)(=NRa )R b 、-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;

[0106] Among them, R 1 represents hydrogen or substituted by 0-3 of any of the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl (e.g. C3-C6 cycloalkyl), 3-10 membered substituted or unsubstituted saturated or unsaturated heterocyclic group (e.g. 3-6 membered saturated or unsaturated heterocyclic group), substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, -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 、-S(O)(=NR a )R b 、-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;

[0107] Preferably, R 1 Indicates -CHR s R t or -CDR s R t ;

[0108] 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 、-S(O)(=NR a )R b 、-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;

[0109] Among them, M 1 Indicates CR aR b NR a , O, S or Se; wherein R T 、R T’ Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxy, carboxyl, halogenated C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl); or R T 、R T’ 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 、-S(O)(=NR a )R b 、-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;

[0110] Where o represents 0, 1 or 2;

[0111] 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.

[0112] In addition, the present disclosure provides a compound having any of the following structures, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof,

[0113] Where X1 represents N or CR X1 ;

[0114] Where X3 represents N or CR X3 ;

[0115] Among them, X4 represents N or CR X4 ;

[0116] Among them, X5 represents N or CR X5 ;

[0117] Among them, X6 represents N or CR X6 ;

[0118] Among them, R 4 Indicates H or D;

[0119] Among them, R X1 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 、-S(O)(=NR a )R b 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -OSO3R a 、-NR a R b , -SF5;

[0120] 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 、-S(O)(=NR a )R b 、-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;

[0121] Among them, R X4 Indicates -LR X4-1 ;

[0122] Among them, L means non-existent or CR a R b , O, S, NR a ;

[0123] 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 、-S(O)(=NR a )R b 、-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 saturated or unsaturated heterocyclic group, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0124] Among them, R 1 represents hydrogen or substituted by 0-3 of any of the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl (e.g. C3-C6 cycloalkyl), 3-10 membered substituted or unsubstituted saturated or unsaturated heterocyclic group (e.g. 3-6 membered saturated or unsaturated heterocyclic group), substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, -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 、-S(O)(=NR a )R b 、-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;

[0125] Preferably, R 1 Indicates -CHR s R tor -CDR s R t ;

[0126] 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 、-S(O)(=NR a )R b 、-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;

[0127] Among them, M 1 Indicates CR a R b NR a , O, S or Se;

[0128] Among them, R L 、R L’ Each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxy, carboxyl, halogenated C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl); 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 、-S(O)(=NR a )R b 、-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;

[0129] 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.

[0130] In the preferred technical solutions of formula (I-3) to formula (I-16), wherein X 1 Indicates N.

[0131] In the preferred technical solutions of formula (I-3) to formula (I-16), wherein X1 represents CR X1 , where R X1 It represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, NH2, -N(CH3)2.

[0132] In the preferred technical solutions of formula (I-3) to formula (I-16), wherein X 3 Indicates N.

[0133] In the preferred technical solutions of formula (I-3) to formula (I-16), wherein X 3 Indicates CR X3 , where R X3 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, NH2, -N(CH3)2; preferably, R X3 It represents hydrogen, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl.

[0134] In the preferred technical solutions of formula (I-3) to formula (I-16), wherein X 5 Indicates N.

[0135] In the preferred technical solutions of formula (I-3) to formula (I-16), wherein X 5 Indicates CR X5 , where R X5 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, NH2, -N(CH3)2; preferably, R X5 It represents hydrogen, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl.

[0136] In the preferred technical solutions of formula (I-3) to formula (I-16), wherein X 6 Indicates N.

[0137] In the preferred technical solutions of formula (I-3) to formula (I-16), wherein X 6 Indicates CR X6 , where R X6 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, NH2, -N(CH3)2; preferably, R X6 It represents hydrogen, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl.

[0138] In the preferred technical solutions of formula (I-3) to formula (I-16), 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 、-SRa 、-P(O)R a R b 、-CN、-S(O)2R a 、-S(O)R a 、-S(O)(=NR a )R b 、-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.

[0139] In the preferred technical solutions of formula (I-3) to formula (I-16), 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.

[0140] In the preferred technical solutions of formula (I-3) to formula (I-16), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1It represents hydrogen, halogen (preferably F), -CF3, -NH2, -NHCH3, -N(CH3)2, -OCH3, -OCF3, -SF5, -P(O)(CH3)2.

[0141] In the preferred technical solutions of formula (I-3) to formula (I-16), 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.

[0142] In the preferred technical solutions of formula (I-3) to formula (I-16), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups:

[0143] 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.

[0144] In the preferred technical solutions of formula (I-3) to formula (I-16), 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 aR 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.

[0145] Among them, X 4 Represents CLR X4-1 , wherein L represents O, S or NH, N(CH3), R X4-1 Represents the following groups:

[0146] Furthermore, R X4-1 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.

[0147] In the preferred technical solutions of formula (I-3) to formula (I-16), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups:

[0148] Among them, W1 represents CR C R D NR C ,O,S;

[0149] Wherein, W2 represents -(CR M R N ) i -;

[0150] 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;

[0151] 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;

[0152] Among them, R M 、R N Each independently represents hydrogen or C1-C6 alkyl;

[0153] Here, i represents an integer of 1 or 2.

[0154] In the preferred technical solutions of formula (I-3) to formula (I-16), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups:

[0155] 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.

[0156] In the preferred technical solutions of formula (I-3) to formula (I-16), wherein X 4 Represents CLR X4-1 , where L means non-existent, R X4-1 Represents the following groups:

[0157] Specifically, the present disclosure provides the following compounds, and pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives thereof, having the following structures:

[0158] In addition, the present disclosure provides a method for treating and / or preventing a disease associated with abnormal PRMT5 expression, comprising administering to an individual in need thereof a therapeutically and / or preventive effective amount of a compound of the present disclosure or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof. Preferably, the disease associated with abnormal PRMT5 expression is a tumor or cancer.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] definition:

[0163] 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 10Refers 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.

[0164] The term "haloalkyl" refers to an alkyl group as defined above wherein one or more hydrogen atoms are replaced by a halogen atom.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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".

[0170] The term "cycloalkoxy" refers to a cycloalkyl group as defined above bound to an oxygen atom, such as cyclopropyloxy.

[0171] The term "haloalkoxy" refers to an alkoxy group as defined above in which one or more hydrogen atoms are replaced by a halo.

[0172] 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.

[0173] 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.

[0174] "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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] "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.

[0179] Optical isomers - diastereomers - geometric isomers - tautomers:

[0180] 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).

[0181] Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are intended to include both E and Z geometric isomers.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] Salt and dosage form

[0188] It should be understood that, as used herein, references to the compounds of the present disclosure also include the pharmaceutically acceptable salts.

[0189] application

[0190] The compounds disclosed herein can be used to treat PRMT5-related diseases.

[0191] The compounds of the present disclosure can be prepared by the following reaction formula:

[0192] Method A:

[0193] Method A-SFC

[0194] Among them, X1, X2, X3, X4, X5, X6, Y, R 1 、R 2 、R 3 , M1, R L 、R L’ , o are defined as the compound of formula (I) above.

[0195] 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.

[0196] Analytical HPLC

[0197] 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; Flow duration: 12 min; Detector: DAD; Wavelength: 254 / 220 nm;

[0198] Preparative HPLC-MS

[0199] 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;

[0200] Mass spectrometer: Agilent G6125B.

[0201] 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.

[0202] 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.

[0203] The following preparations and examples illustrate the present disclosure but do not limit it in any way.

[0204] 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.

[0205] 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.

[0206] Intermediate 1 Methyl[10-(trifluoromethyl)spiro[cyclopropane-1,1'-isochromane]-7-yl]amine

[0207] Step 1: A dioxane hydrochloride solution (0.2 ml, 4 M) was added dropwise to a solution of (1-ethoxycyclopropane)trimethylsilane (20 g, 0.115 mol) in methanol (80 ml) and stirred at room temperature for 15 minutes. After the reaction was complete, water (160 ml), sodium benzenesulfinate (37.7 g, 0.23 mol) and formic acid (43 ml, 1.15 mol) were added directly to the reaction solution. The reaction solution was continued to react for 48 hours. After the reaction was complete, the reaction solution was poured into water (300 ml) and extracted with dichloromethane (200 ml × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product solid. The solid was then slurried with petroleum ether (50 ml) to obtain compound 1-hydroxycyclopropanebenzenesulfonic acid (18 g, two-step yield: 73%).

[0208] LCMS (ESI) m / z: 215.2 [M+H]+

[0209] Step 2: Under nitrogen protection, in an ice bath, isopropylmagnesium chloride lithium chloride tetrahydrofuran solution (39 ml, 50.70 mmol, 1.3 M) was added to a solution of 1-bromo-2-iodo-4-(trifluoromethyl)benzene (17.84 g. 50.85 mmol) in tetrahydrofuran (150 ml), and the reaction solution was reacted at 0 ° C for 1 hour, and then the reaction solution was cooled to -78 ° C, and a solution of 1-hydroxycyclopropanebenzenesulfonic acid (4.8 g, 24.21 mmol) in tetrahydrofuran (20 ml) was slowly added dropwise to the reaction mixture. The reaction solution was reacted at -78 ° C for 30 minutes, then warmed to room temperature and continued to react for 6 hours. The reaction solution was quenched with saturated ammonium chloride solution (100 ml) and water (150 ml), extracted with ethyl acetate (200 ml × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude solid product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0 to 10:1) to obtain a yellow oily compound 1-[2-bromo-5-(trifluoromethyl)phenyl]cyclopropane-1-ol (4.1 g, yield 60%).

[0210] LCMS (ESI) m / z: 263.0 [M-OH] +

[0211] 1 H NMR (400MHz, CDCl3) δ7.71 (d, J = 8.4Hz, 1H), 7.69–7.63 (m, 1H), 7.46–7.39 (m, 1H), 1.35–1.27 (m, 2H), 1.06–0.99 (m, 2H).

[0212] Step 3: 1-[2-bromo-5-(trifluoromethyl)phenyl]cyclopropan-1-ol (1.7 g, 6.048 mmol) was dissolved in tetrahydrofuran (20 ml) at room temperature, and potassium hydroxide (0.67 g, 12.09 mmol), tetrabutylammonium hydrogen sulfate (0.4 g, 1.210 mmol) and 3-bromopropene (1.5 g, 12.09 mmol) were added. The reaction was carried out at 25°C for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and 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 obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 1-{[2-bromo-5-(trifluoromethyl)phenyl]cyclopropyloxy}prop-2-ene (1.8 g, yield: 92.6%).

[0213] LCMS (ESI) m / z: 322.1 [M+H] +

[0214] Step 4: To a solution of 1-{[2-bromo-5-(trifluoromethyl)phenyl]cyclopropyloxy}prop-2-ene (1.7 g, 5.39 mmol) in N,N-dimethylformamide (20 ml) were added DIEA (2.1 g, 15.88 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.63 g, 1.059 mmol) and palladium acetate (0.12 g, 0.5294 mmol). Under N2 atmosphere, the mixture was stirred at 90°C for 16 hours. The reaction solution was poured into 60 ml of water and extracted with ethyl acetate (20 ml × 3). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give 7-methylene-10-trifluoromethylspiro[cyclopropane-1,1'-isobenzopyranane] (1 g, yield: 78.6%).

[0215] LCMS (ESI) m / z: 241 [M+H] +

[0216] Step 5: 7-Methylene-10-trifluoromethylspiro[cyclopropane-1,1'-isobenzopyranane] (1 g, 4.163 mmol) was dissolved in a mixture of acetone (10 mL) and water (2 mL) at room temperature. N-methylmorpholine-N-oxide (1.5 g, 12.49 mmol) and potassium osmate (0.16 g, 0.4163 mmol) were added. The reaction was stirred at 25°C under a nitrogen atmosphere for 16 hours. After completion of the reaction, solid sodium sulfite (5 g) was added to the reaction solution, stirred for 10 minutes, and concentrated under reduced pressure to remove a certain amount of acetone. The solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 7-hydroxymethyl-10-trifluoromethylspiro[cyclopropane-1,1'-isobenzopyranane]-7-ol (0.6 g, yield: 52.5%).

[0217] LCMS (ESI) m / z: 256 [M-18] +

[0218] Step 6: 7-Hydroxymethyl-10-trifluoromethylspiro[cyclopropane-1,1'-isobenzo]-7-ol (1 g, 3.646 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 ml) and water (3 ml) at room temperature, and sodium metaperiodate (3.183 g, 14.59 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 give a crude product. 7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-one (0.45 g, yield: 51%) was obtained by column chromatography (petroleum ether:ethyl acetate = 3:1).

[0219] LCMS (ESI) m / z: 243.2 [M+H] +

[0220] The following intermediates were prepared by using the preparation method and steps of intermediate 1, with only the corresponding raw material intermediates being replaced:

[0221] Intermediate 3

[0222] Step 1: 5-bromo-2-chloro-4-iodopyridine (25 g, 78.6 mmol) was dissolved in tetrahydrofuran (250 ml) at room temperature and replaced with nitrogen three times. Isopropylmagnesium chloride and lithium chloride (60.4 ml, 1.3 M, 78.5 mmol) were slowly added dropwise to the system at -78°C and stirred for 2 hours at -78°C. 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 100°C. The reaction was allowed to proceed to 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 obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-10:1) to obtain 1-(5-bromo-2-chloropyridin-4-yl)cyclobutane-1-ol (10.9 g, yield: 53%) as a light yellow oil.

[0223] 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).

[0224] Step 2: 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. 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 x 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. 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.

[0225] LCMS(ESI):[M+H] + =301.9 / 303.9.

[0226] Step 3: 2-[1-(Allyloxy)cyclobutyl]-1-bromo-4-(trifluoromethyl)benzene (9.5 g, 31.20 mmol) was dissolved in N,N-dimethylformamide (30 ml) at room temperature, and potassium carbonate (9.7 g, 70.19 mmol), palladium(II) acetate (0.71 g, 3.11 mmol) and tricyclohexylphosphine tetrafluoroborate (1.14 g, 3.11 mmol) were added. Under N2 atmosphere, the mixture was stirred at 70°C for 16 hours. The reaction solution was poured into 1000 ml of water and extracted with ethyl acetate (800 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 7'-chloro-4'-methylene-3', 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine] (3.6 g, yield: 43.4%).

[0227] 1 H NMR (400MHz, DMSO-d6) δ8.81(s,1H),7.65(s,1H),5.91(s,1H),5.22(s,1H),4.32(s,2H),2.47-2.40(m,2H),2.38-2.29(m,2H),2.07-1.98(m,2H).

[0228] Step 4: 7'-Chloro-4'-methylene-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine] (1.5 g, 6.7 mmol) was dissolved in a mixed solvent of tetrahydrofuran (21 ml) and water (7 ml) at room temperature, and N-methylmorpholine-N-oxide (2.76 g, 20.8 mmol) and potassium osmate (0.21 g, 0.67 mmol) were added. The reaction was stirred at 25° C. under nitrogen for 16 hours. After completion of the reaction, solid sodium sulfite (1.3 g) was added and stirred for ten minutes. The mixture was concentrated under reduced pressure to remove a certain amount of tetrahydrofuran, poured into water (40 ml), and extracted with ethyl acetate (60 ml × 4). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product 7'-chloro-4'-(hydroxymethyl)-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-ol (1.1 g, crude product).

[0229] LCMS(ESI):[M+H] + =256.12.

[0230] Step 5: 7'-chloro-4'-(hydroxymethyl)-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-ol (1.1 g, 4.3 mmol) was dissolved in a mixed solvent of tetrahydrofuran (40 ml) and water (4 ml) at room temperature. Sodium periodate (2.89 g, 13.36 mmol) was added and stirred at 25°C under nitrogen 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 = 3:1) gave 7'-chlorospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'(3'H)-one (0.7 g, yield: 52% (2 steps)).

[0231] 1 H NMR (400MHz, DMSO-d6) δ8.80(s,1H),7.88(s,1H),4.41(s,2H),2.51-2.47(m,4H),2.05-2.01(m,2H).

[0232] Intermediate 4N-methyl-2'-morpholino-5',6'-dihydrospiro[cyclobutane-1,8'-pyrano[3,4-b]pyridine]5'-amine

[0233] Step 1: Dissolve 2,3-dibromo-6-chloropyridine (25 g, 92.3 mmol) in tetrahydrofuran (250 ml) at room temperature, replace with nitrogen three times, slowly add isopropylmagnesium chloride lithium chloride (70.9 ml, 1.3 M, 92.3 mmol) dropwise to the system at -78°C, stir and react for 2 hours at -78°C, then add a solution of cyclobutanone (6.5 g, 92.3 mmol) in tetrahydrofuran (30 ml) to the above reaction solution, and the reaction will gradually reach The reaction was carried out at room temperature for 16 hours. When the reaction was complete, 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-(3-bromo-6-chloropyridin-2-yl)cyclobutane-1-ol (8.6 g, yield: 53%) as a light yellow oil.

[0234] 1H NMR (400MHz, DMSO-d6) δ7.84(d,J=7.6Hz,1H),7.55(d,J=7.6Hz,1H),5.61(s,1 H),2.64–2.53(m,2H),2.38–2.30(m,2H),2.03–1.97(m,1H),1.60–1.52(m,1H).

[0235] Step 2: 1-(3-Bromo-6-chloropyridin-2-yl)cyclobutan-1-ol (8.6 g, 32.8 mmol) was dissolved in tetrahydrofuran (100 ml) at room temperature, and potassium hydroxide (3.45 g, 65.6 mmol), tetrabutylammonium hydrogen sulfate (2.09 g, 3.3 mmol) and 3-bromopropene (3.7 g, 32.8 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 (100 ml) and extracted with ethyl acetate (100 ml x 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. Column chromatography (petroleum ether:ethyl acetate = 10:1) gave 2-[1-(allyloxy)cyclobutyl]-3-bromo-6-chloropyridinylbenzene (6.8 g, yield: 81.6%) as a light yellow oil.

[0236] 1 H NMR (400MHz, DMSO-d6) δ7.94(d,J=7.6Hz,1H),7.59(d,J=7.6Hz,1H),5.82–5.69(m,1H),5.24–5.14(m ,1H),5.07–4.97(m,1H),3.59–3.48(m,2H),2.56–2.44(m,4H),2.01–1.94(m,1H),1.65–1.55(m,1H).

[0237] Step 3: 2-[1-(allyloxy)cyclobutyl]-3-bromo-6-chloropyridinylbenzene (6.8 g, 22.7 mmol) was dissolved in morpholine (12 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 = 3:1) gave 4-(6-(1-(allyloxy)cyclobutyl)-5-bromopyridin-2-yl)morpholine (4.6 g, yield: 60.6%, 1.1 g starting material) as a pale yellow oil.

[0238] 1H NMR (400MHz, DMSO-d6) δ7.58(d,J=7.6Hz,1H),6.78(d,J=7.6Hz,1H),5.89–5.70(m,1H),5.26–5.16(m,1 H),5.09–4.94(m,1H),3.69–3.66(m,4H),3.55–3.50(m,2H),3.45–3.41(m,4H),2.50–2.44(m,2H),2.42– 2.35(m,2H),1.97–1.90(m,1H),1.61–1.53(m,1H).

[0239] Step 4: 4-(6-(1-(allyloxy)cyclobutyl)-5-bromopyridin-2-yl)morpholine (4.6 g, 13.1 mmol) was dissolved in DMF (20 ml) at room temperature, and potassium carbonate (5.4 g, 39.3 mmol) and 1,1-bis(diphenylphosphine)dichloropalladium iron (0.95 g, 1.3 mmol) were added. Under N2 atmosphere, the mixture was stirred at 70°C for 16 hours. The reaction solution was cooled and poured into 200 ml of water, extracted with ethyl acetate (80 ml × 3), the organic phases were combined, and dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a light yellow oily product 5'-methylene-2'-morpholinyl-5', 6'-dihydrospiro[cyclobutane-1,8'-pyrano[3,4-b]pyridine] (2.6 g pure product, yield: 73.4%).

[0240] 1 H NMR (400MHz, DMSO-d6) δ7.70(d,J=7.6Hz,1H),6.85(d,J=7.6Hz,1H),6.01(s,1H),5.06(s,1H),4.37( s,2H),3.72–3.69(m,4H),3.48–3.45(m,4H),2.33–2.27(m,4H),1.99-1.94(m,1H),1.94–1.87(m,1H).

[0241] Step 5: 5'-Methylene-2'-morpholinyl-5',6'-dihydrospiro[cyclobutane-1,8'-pyrano[3,4-b]pyridine] (2.6 g, 9.6 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 ml) and water (10 ml) at room temperature, and N-methylmorpholine-N-oxide (3.4 g, 28.8 mmol) and potassium osmate (0.3 g, 1 mmol) were added. Under N2, the reaction was stirred at 25°C for 16 hours. After the reaction was completed, solid sodium sulfite (1.5 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 (60 ml) and extracted with ethyl acetate (80 ml × 4). The organic phases were combined and dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product 5'-(hydroxymethyl)-2'-morpholinyl-5', 6'-dihydrospiro[cyclobutane-1,8'-pyrano[3,4-b]pyridine]-5'-ol (2.1 g, crude product).

[0242] LCMS (ESI): 307.17 [M+H] +

[0243] Step 6: 5'-(Hydroxymethyl)-2'-morpholino-5',6'-dihydrospiro[cyclobutane-1,8'-pyrano[3,4-b]pyridine]-5'-ol (2.1 g, 6.9 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 ml) and water (0.8 ml) at room temperature. Sodium periodate (4.5 g, 20.7 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 2'-morpholinospiro[cyclobutane-1,8'-pyrano[3,4-b]pyridine]-5'(6-hydro)-one (970 mg, yield: 53% (2 steps)) as a pale yellow solid.

[0244] LCMS (ESI): 275.2 [M+H] +

[0245] Step 7: 2'-morpholinospiro[cyclobutane-1,8'-pyrano[3,4-b]pyridine]-5'(6-H)-one (200 mg, 0.73 mmol) was dissolved in 1.2-dichloroethane (5 ml) at room temperature, and tetraethoxytitanium (410 mg, 1.8 mmol) and methylamine tetrahydrofuran solution (2 ml, 30%) were added. The reaction was stirred at room temperature for 16 hours, then sodium borohydride (42 mg, 1.1 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-2'-morpholinoline-5',6'-dihydrospiro[cyclobutane-1,8'-pyrano[3,4-b]pyridine]5'-amine (80 mg, yield: 37.9%).

[0246] LCMS (ESI) m / z: 290.2 [M+H] +

[0247] The following intermediates were prepared by using the preparation method and steps of intermediate 4, with only the corresponding raw material intermediates being replaced:

[0248] Intermediate 6N, 9,9-trimethyl-6,9-dihydro-7H-[1,3]dioxacyclo[4,5-h]isochroman-6-amine

[0249] Step 1: 5-Bromobenzo[d][1,3]dioxazole (5.0 g, 24.87 mmol) was dissolved in tetrahydrofuran (50 ml) at room temperature and replaced with nitrogen three times. Lithium diisopropylamide (1.68 ml, 2 M, 27.36 mmol) was slowly added dropwise to the system at -65°C and stirred for 2 hours at -65°C. Then, acetone (1.59 g, 27.36 mmol) was slowly added dropwise to the reaction solution and reacted at -65°C for 1 hour and gradually increased to 10% by volume. The reaction was allowed to proceed at room temperature for 16 hours. When the reaction was complete, the reaction solution was quenched with ammonium chloride solution (50 ml), poured into water (100 ml), and extracted with ethyl acetate (100 ml x 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 2-(5-bromobenzo[d][1,3]dihydroxy-4-yl)propan-2-ol (3.8 g, yield: 58.96%).

[0250] 1H NMR (400MHz, CDCl3) δ7.09-7.08 (d, 1H, J = 7.08), 6.58-6.56 (d, 1H, J = 6.57), 5.92 (s, 2H), 1.74 (s, 6H).

[0251] Step 2: 2-(5-Bromobenzo[d][1,3]dihydroxy-4-yl)propan-2-ol (4 g, 15.44 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature. Potassium hydroxide (1.73 g, 30.88 mmol), tetrabutylammonium hydrogen sulfate (1.05 g, 3.09 mmol), and 3-bromopropene (2.24 g, 18.53 mmol) were added. The mixture was reacted at 80°C for 16 hours. After completion of the reaction, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (60 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. 4-(2-(allyloxy)propan-2-yl)-5-bromobenzo[d][1,3]dioxazole (1.5 g, yield: 32.48%) was obtained by column chromatography (petroleum ether:ethyl acetate = 10:1).

[0252] 1 H NMR (400MHz, CDCl3) δ7.15-7.13(d,1H,J=7.14),6.60-6.58(d,1H,J=6.59),6.04-5.96(m,1H),5.91(s, 2H),5.29-5.23(dd,1H,J=5.26),5.14-5.10(dd,1H,J=5.12),3.76-3.74(td,2H,J=3.75),1.73(s,6H).

[0253] Step 3: To a solution of 4-(2-(allyloxy)propan-2-yl)-5-bromobenzo[d][1,3]dioxazole (100 mg, 0.33 mmol) in N,N-dimethylformamide (3 mL) at room temperature were added potassium carbonate (92 mg, 0.67 mmol), tricyclohexylphosphine tetrafluoroborate (12 mg, 0.03 mmol), and palladium acetate (8 mg, 0.03 mmol). The mixture was stirred at 110° C. under a N atmosphere for 3 hours. After the reaction was completed, the reaction solution was poured into 200 ml of water and extracted with ethyl acetate (100 ml × 3). The organic phases were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. Column chromatography (petroleum ether: ethyl acetate = 10:1) gave 9,9-dimethyl-6-methylene-6,9-dihydro-7H-[1,3]dioxacyclo[4,5-h]isochroman (35 mg, yield: 47.98%).

[0254] 1H NMR (400MHz, CDCl3) δ7.17-7.15(d,1H,J=7.16),6.74-6.72(d,1H,J=6.73),5.96(s,2H),5.42(s,1H),4.92(s,1H),4.33(s,2H),1.59(s,6H).

[0255] Step 4: 9,9-dimethyl-6-methylene-6,9-dihydro-7H-[1,3]dioxacyclo[4,5-h]isochroman (0.4 g, 1.83 mmol) was dissolved in a mixed solvent of tetrahydrofuran (6 ml) and water (2 ml) at room temperature, and N-methylmorpholine-N-oxide (0.64 g, 5.5 mmol) and potassium osmate (0.057 g, 0.18 mmol) were added. Under nitrogen, the reaction was stirred at 25°C for 16 hours. After completion of the reaction, solid sodium sulfite (0.3 g) was added to the reaction solution, stirred for ten minutes, and concentrated under reduced pressure to remove a certain amount of tetrahydrofuran. The solution was poured into water (10 ml) and extracted with ethyl acetate (80 ml × 4). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of 6-(hydroxymethyl)-9,9-dimethyl-6,9-dihydro-7H-[1,3]dioxacyclo[4,5-h]isochroman-6-ol (0.38 g, crude product).

[0256] LCMS(ESI):[MH]+251.10 / 251.07.=

[0257] Step 5: 6-(Hydroxymethyl)-9,9-dimethyl-6,9-dihydro-7H-[1,3]dioxacyclo[4,5-h]isochroman-6-ol (0.38 g, 1.51 mmol) was dissolved in a mixed solvent of tetrahydrofuran (15 ml) and water (1.5 ml) at room temperature, and sodium periodate (0.97 g, 4.52 mmol) was added. 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. 9,9-dimethyl-7H-[1,3]dioxacyclo[4,5-h]isochroman-6(9H)-one (0.3 g, yield: 90.44%) was obtained by column chromatography (petroleum ether:ethyl acetate = 2:1).

[0258] 1 H NMR (400MHz, CDCl3) δ7.71-7.69(d,1H,J=7.70),6.85-6.83(d,1H,J=6.84),6.07(s,2H),4.36(s,2H),1.66(s,6H).

[0259] Step 6: 9,9-dimethyl-7H-[1,3]dioxo[4,5-h]isochroman-6(9H)-one (0.27 g, 1.22 mmol) and methylamine methanol solution (0.63 g, 6.13 mmol) were dissolved in a mixed solvent of 1,2-dichloroethane (12 ml) at room temperature, tetraethyl titanate (0.56 g, 2.45 mmol) was added, and the mixture was stirred at 50°C for 2 hours. After the reaction was completed, the mixture was cooled to 0°C and sodium borohydride (0.07 g, 1 .84 mmol), stirred at 0 ° C for 0.5 hours. After the reaction was completed, saturated ammonium chloride solution (40 ml) was added and extracted with dichloromethane (30 ml × 4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Column chromatography (petroleum ether: ethyl acetate = 2: 1) gave N, 9,9-trimethyl-6,9-dihydro-7H-[1,3]dioxacyclo[4,5-h]isochroman-6-amine (0.1 g, yield: 34.67%).

[0260] LCMS (ESI): [MH]+236.21

[0261] The following intermediates were prepared by using the preparation method and steps of intermediate 6, with only the corresponding raw material intermediates being replaced:

[0262] Synthesis of Intermediate 81 N-methyl-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanhydro]-4'-amine

[0263] Step 1: Synthesis of 1-(2-bromo-5-(trifluoromethyl)phenyl)cyclobutane-1-ol

[0264] 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.

[0265] LCMS (ESI) m / z: 295.1 [M-OH] +

[0266] Step 2: Synthesis of 2-[1-(allyloxy)cyclobutyl]-1-bromo-4-(trifluoromethyl)benzene

[0267] 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).

[0268] LCMS (ESI) m / z: 335.1 [M+H] +

[0269] Step 3: Synthesis of 4'-methylene-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromatic hexacyclic]

[0270] 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).

[0271] LCMS (ESI) m / z: 255.1 [M+H] +

[0272] Step 4: Synthesis of 4'-(hydroxymethyl)-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-ol

[0273] 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).

[0274] LCMS (ESI) m / z: 289.0 [M+H]+

[0275] Step 5: Synthesis of 7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-one

[0276] 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).

[0277] LCMS (ESI) m / z: 257.1 [M+H] +

[0278] Step 6: Preparation of N-methyl-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanol]-4'-amine

[0279] 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%).

[0280] LCMS (ESI) m / z: 272.1 [M+H] +

[0281] The following intermediates were prepared by using the preparation method and steps of intermediate 8, with only the corresponding raw material intermediates being replaced:

[0282] Intermediate 17 N-methyl-7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-amine

[0283] 7-(Trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-one (160 mg, 0.6606 mmol) was dissolved in 1,2-dichloroethane (20 mL) at room temperature, and titanium(IV) ethoxide (0.38 g, 1.65 mmol) and methylamine tetrahydrofuran solution (2 mL) were added. The reaction mixture was stirred at room temperature for 16 hours, and then sodium borohydride (51 mg, 1.321 mmol) was added. The mixture was stirred for an additional 20 minutes. Upon completion, the reaction mixture was diluted with ethyl acetate, filtered, washed, and the combined filtrates were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product. Column chromatography (dichloromethane:methanol = 10:1) afforded N-methyl-7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-amine (60 mg, 35% yield).

[0284] LCMS (ESI) m / z: 258.2 [M+H] +

[0285] The following intermediates were prepared by using the preparation method and steps of intermediate 17, with only the corresponding raw material intermediates being replaced:

[0286] Intermediate 18 (S)-(7'-chloro-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-yl)(methyl)carbamic acid tert-butyl ester

[0287] Step 1: To a solution of triethylamine (1.17 g, 11.56 mmol) in dichloromethane (25 ml) was added formic acid (0.62 g, 13.55 mmol) at 0°C, followed by 7'-chlorospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridin]-4'(3'H)-one (1 g, 4.47 mmol) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine(p-isopropylbenzene)ruthenium chloride (338 mg). , 0.65 mmol), the mixture was reacted at 25°C for 2 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 sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain (R)-7'-chloro-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-ol (0.9 g, yield: 90%).

[0288] LCMS (ESI) m / z: [M+H] + =226.12.

[0289] Step 2: (R)-7'-chloro-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-ol (1 g, 4.4 mmol) was dissolved in tetrahydrofuran (40 ml) at room temperature, triphenylphosphine (1.4 g, 5.32 mmol) and bis(tert-butyloxycarbonyl)amine (1.16 g, 5.36 mmol) were added, and the mixture was reacted at zero temperature under a nitrogen atmosphere for 10 minutes. Diisopropyl azodicarboxylate (1.07 g, 5.30 mmol) was slowly added dropwise to the reaction system. The mixture was reacted at 25°C for 16 hours. After the reaction was completed, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 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 silica gel column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain tert-butyl (S)-(7'-chloro-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-yl)aminodicarboxylate (0.77 g, yield: 40.7%).

[0290] LCMS (ESI) m / z: [M+H] + =425.26.

[0291] Step 3: tert-Butyl (S)-(7'-chloro-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridin]-4'-yl)carbamate (1 g, 2.23 mmol) was dissolved in acetonitrile (16 mL) at room temperature, and lithium bromide (1 g, 11.56 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 and poured into water (50 mL). Extraction was performed 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'-chloro-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridin]-4'-yl)carbamate (0.76 g, 95% yield).

[0292] LCMS (ESI) m / z: [M+H] + =325.22.

[0293] Step 4: Dissolve tert-butyl (S)-(7'-chloro-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-yl)carbamate (0.76 g, 2.36 mmol) in N,N-dimethylformamide (30 ml) at room temperature under nitrogen protection, cool to zero degrees, and add 60% sodium hydride (190 mg, 4.7 mmol). After stirring for 30 minutes, iodomethane (502 mg, 3.52 mmol) was added to the reaction solution and reacted at room temperature for 4 hours. After the reaction was completed, the reaction solution was poured into water (40 mL) and extracted with ethyl acetate (30 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 = 3:1) gave (S)-(7'-chloro-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-yl)(methyl)carbamic acid tert-butyl ester (0.5 g, yield: 62.5%).

[0294] LCMS (ESI) m / z: [M+H] + =339.14 / 339.24.

[0295] The following intermediates were prepared by using the preparation method and steps of intermediate 18, with only the corresponding raw material intermediates being replaced:

[0296] Intermediate 22 (4'S)-7'-(3-oxa-6-azabicyclo[3.1.1]heptane-6-yl)-N-methyl-3',4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-amine

[0297] Step 1: Tert-butyl (S)-(7'-chloro-3',4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridin]-4'-yl)(methyl)carbamate (300 mg, 0.89 mmol) and 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride (132 mg, 1.33 mmol) were dissolved in N,N-dimethylformamide (5.0 ml), followed by the addition of cesium carbonate (865 mg, 2.66 mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-KN)palladium (86 mg, 0.09 mmol) and stirred at 110°C for 18 hours under nitrogen atmosphere. LCMS monitoring showed approximately 80% product. The reaction mixture was returned to room temperature and filtered. The mother liquor was diluted with ethyl acetate (50 mL), washed with water (3 x 25 mL), washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to afford tert-butyl ((4'S)-7'-(3-oxa-6-azabicyclo[3.1.1]heptane-6-yl)-3',4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridin-4'-yl)(methyl)carbamate (300 mg, 84% yield) as a yellow solid.

[0298] LCMS(ESI):[M+H] + m / z=402.40.

[0299] Step 2: To a solution of tert-butyl ((4'S)-7'-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)-3',4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridin-4'-yl)(methyl)carbamate (300 mg, 0.75 mmol) in dichloromethane (12.0 mL) was added trifluoroacetic acid (3.0 mL) dropwise. The mixture was allowed to react at room temperature for 1 hour. LCMS monitoring indicated approximately 90% product. The reaction solution was concentrated and purified by reverse phase column (A: 0.5% formic acid / water; B: acetonitrile; gradient elution from 5% to 10% B over 10 minutes) and lyophilized to give (4'S)-7'-(3-oxa-6-azabicyclo[3.1.1]hept-6-yl)-N-methyl-3',4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-amine (200 mg, yield: 89%) as a light yellow solid.

[0300] LCMS(ESI):[M+H-MeNH] + m / z=271.27.

[0301] The following intermediates were prepared by adopting the preparation method and steps of intermediate 22, replacing only the corresponding raw material intermediates:

[0302] Intermediate 31 (S)-4-(4'-(tert-Butyloxycarbonyl)(methyl)amino)-3'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-7'-yl)piperazine-1-carboxylate

[0303] Step 1: Tert-butyl (S)-(7'-chloro-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-yl)(methyl)carbamate (500 mg, 1.48 mmol) was dissolved in dimethyl sulfoxide (1.0 ml), benzyl piperazine-1-carboxylate (975 mg, 4.43 mmol), potassium fluoride (87 mg, 1.48 mmol) and N,N-diisopropylethylamine (583 mg, 4.43 mmol) were added, and the mixture was stirred at 120°C for 48 hours. After the reaction was completed, the reaction solution was poured into water (40 ml), 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 column chromatography (petroleum ether: ethyl acetate = 3:1) to give benzyl (S)-4-(4'-(tert-butoxycarbonyl)(methyl)amino)-3'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-7'-yl)piperazine-1-carboxylate (0.5 g, yield: 78.4%).

[0304] LCMS (ESI) m / z: [M+H] + =523.33. Step 2: Benzyl (S)-4-(4'-(tert-butoxycarbonyl)(methyl)amino)-3'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridinyl]-7'-yl)piperazine-1-carboxylate (500 mg, 0.89 mmol) was dissolved in dichloromethane (3.00 ml). Trifluoroacetic acid (1.00 ml) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under vacuum, and the mixture was pumped with an oil pump for 10 minutes. The crude product was used directly in the next step without purification, yielding benzyl (S)-4-(4'-(tert-butoxycarbonyl)(methyl)amino)-3'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridinyl]-7'-yl)piperazine-1-carboxylate (0.4 g, 99.0% yield).

[0305] LCMS (ESI) m / z: [M+H] + =392.35.

[0306] The following intermediates were prepared by using the preparation method and steps of intermediate 31, with only the corresponding raw material intermediates being replaced:

[0307] Intermediate 34 (S)-N-methyl-7'-(3,3,3-trifluoropropyl-1-propyn-1-yl)spiro[cyclopropane-1,1'-isochroman]-4'-amine

[0308] The following intermediates were prepared by using the preparation method and steps of intermediate 34, with only the corresponding raw material intermediates being replaced:

[0309] Intermediate 40 (S)-N-methyl-7'-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-3',4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-amine

[0310] Step 1: tert-Butyl (S)-(7'-chloro-3',4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridin]-4'-yl)(methyl)carbamate (300 mg, 0.89 mmol) and 4-(trifluoromethyl)-1H-pyrazole (181 mg, 1.33 mmol) were dissolved in 1,4-dioxane (20.0 mL). Potassium phosphate (244 mg, 1.15 mmol), cuprous iodide (219 mg, 1.15 mmol), and trans-N,N-dimethylcyclohexane-1,2-diamine (164 mg, 1.15 mmol) were then added. The mixture was stirred at reflux under nitrogen for 20 hours. LCMS monitoring indicated approximately 80% product. The reaction mixture was cooled to room temperature and filtered. The mother liquor was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 20%) to give tert-butyl (S)-methyl(7'-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-3',4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-yl)carbamate (350 mg, yield: 90%) as a white solid.

[0311] LCMS(ESI):[M+H] + m / z=439.3

[0312] Step 2: Trifluoroacetic acid (3.0 ml) was added dropwise to a solution of tert-butyl ((S)-methyl (7'-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-3', 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-yl)carbamate (350 mg, 0.80 mmol) in dichloromethane (12.0 ml). After the addition was complete, the mixture was reacted at room temperature for 1 hour. The resulting product was concentrated and purified by reverse phase column chromatography (A: 0.5% formic acid / water; B: acetonitrile; gradient elution from 5% to 100% B over 10 minutes) and lyophilized to afford (S)-N-methyl-7'-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-3',4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-amine (210 mg, 74% yield) as a light yellow solid.

[0313] LCMS(ESI):[M+H] + m / z=339.2.

[0314] The following intermediates were prepared by adopting the preparation method and steps of intermediate 40, replacing only the corresponding raw material intermediates:

[0315] Intermediate 43 (S)-N-methyl-7'-(1-methyl-1H-pyrazol-4-yl)-3',4'-dihydrospiro[cyclobutane-1,1'-pyranone[4,3-c]pyridine]-4'-amine

[0316] Step 1: Under N2 atmosphere, tert-butyl (S)-(7'-chloro-3',4'-dihydrospiro[cyclobutane-1,1'-pyranone[4,3-c]pyridin]-4'-yl)(methyl)carbamate (150 mg, 0.56 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (175 mg, 0.84 mmol) were dissolved in 1,4-dihydro- 1,1-Bis(diphenylphosphino)ferrocenepalladium dichloride (40 mg, 0.056 mmol) and potassium carbonate (230 mg, 1.68 mmol) were added to a solution of hexacyclic ring (5 mL) and water (1 mL). The reaction mixture was stirred at 80°C for 16 hours, 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 the anhydrous sodium sulfate, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain tert-butyl (S)-methyl (7'-(1-methyl-1H-pyrazol-4-yl)-3',4'-dihydrospiro[cyclobutane-1,1'-pyranone[4,3-c]pyridinyl]-4'-yl)carbamate (130 mg, 85% yield) as a yellow solid.

[0317] LCMS(ESI):[M+H] + m / z=385.2.

[0318] Step 2: To a solution of (tert-butyl (S)-methyl (7'-(1-methyl-1H-pyrazol-4-yl)-3',4'-dihydrospiro[cyclobutane-1,1'-pyrone[4,3-c]pyridine]-4'-yl) carbamate (130 mg) in dichloromethane (5 mL) was added dropwise a solution of dioxane hydrochloride (1.0 mL, 4 M) and the mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated to give a yellow solid product (S)-N-methyl-7'-(1-methyl-1H-pyrazol-4-yl)-3',4'-dihydrospiro[cyclobutane-1,1'-pyrone[4,3-c]pyridine]-4'-amine (180 mg, crude product). The product was used directly in the next step without purification.

[0319] LCMS(ESI):[M+H] + m / z=285.2.

[0320] The following intermediates were prepared by adopting the preparation method and steps of intermediate 43, replacing only the corresponding raw material intermediates:

[0321] Intermediate 53 1-Methyl-N-(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochroman]-4'-yl)-1H-pyrazol-4-amine

[0322] 7'-(Trifluoromethyl)spiro[cyclobutane-1,1'-isochromatin]-4'-one (500 mg, 1.95 mmol) was dissolved in methanol (5.0 mL). 1-Methyl-1H-pyrazol-4-amine (189 mg, 1.95 mmol) and formic acid (0.10 mL) were added, and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (363 mg, 5.85 mmol) was then added, and the mixture was stirred at room temperature for 3 hours. LCMS determined the target molecular weight. The reaction mixture was directly applied to silica gel and eluted with a gradient of 50%-100% ethyl acetate:petroleum ether to afford 1-methyl-N-(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromatin]-4'-yl)-1H-pyrazol-4-amine (480.00 mg, yield: 73%) as a light red oil.

[0323] LCMS(ESI):[M+H] + =338.26.

[0324] 1H NMR(400MHz,Chloroform-d)δ7.66(s,1H),7.52–7.44(m,2H),7.17(d,J=1.0Hz,1H),6.98(s,1H),4.05(t,J=3.4Hz,1H),3.97(dd ,J=11.8,3.4Hz,1H),3.87(dd,J=11.8,3.2Hz,1H),3.81(s,3H),2.58–2.45(m,3H),2.39–2.31(m,1H),2.20(m,1H),2.03(m,1H).

[0325] Intermediate 75 (S)-N-methyl-7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-amine

[0326] To a solution of tert-butyl (S)-methyl (7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-yl)(methyl)carbamate (150 mg) in dichloromethane (5 mL) was added dropwise a solution of dioxane hydrochloride (1.0 mL, 4 M) and allowed to react at room temperature for 2 hours. The reaction solution was concentrated to give a yellow solid product (S)-N-methyl-7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-amine (190 mg, crude product). The product was used directly in the next step without purification.

[0327] LCMS(ESI):[M+H] + m / z=258.2.

[0328] The following intermediates were prepared by using the preparation method and steps of intermediate 76, replacing only the corresponding raw material intermediates:

[0329] Intermediate 82 (S)-4'-(methylamino)spiro[cyclopropane-1,1'-isochroman]-7'-carbonitrile

[0330] Step 1: Under nitrogen, tetrakistriphenylphosphine palladium (157 mg, 0.136 mmol) was added to a solution of tert-butyl (S)-(7'-bromospiro[cyclopropane-1,1'-isochroman]-4'-yl)(methyl)carbamate (500 mg, 1.36 mmol) and zinc cyanide (95 mg, 0.82 mmol) in DMF (5 mL). The atmosphere was replaced with nitrogen three times, and the reaction was incubated at 90°C for 16 hours. After completion of the reaction, the mixture was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the anhydrous sodium sulfate, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1) to give tert-butyl (S)-(7'-cyanospiro[cyclopropane-1,1'-isochroman]-4'-yl)(methyl)carbamate (210 mg, 49% yield) as a yellow solid.

[0331] LCMS(ESI):[M+H] + m / z=315.2.

[0332] Step 2: To a solution of (S)-(7'-cyanospiro[cyclopropane-1,1'-isochroman]-4'-yl)(methyl)carbamate (210 mg) in dichloromethane (5 mL) was added a solution of dioxane hydrochloride (1.0 mL, 4 M) and allowed to react at room temperature for 2 hours. The reaction solution was concentrated to give a yellow solid product, (S)-4'-(methylamino)spiro[cyclopropane-1,1'-isochroman]-7'-carbonitrile (250 mg, crude product). The product was used directly in the next step without purification.

[0333] LCMS(ESI):[M+H] + m / z=215.2.

[0334] Intermediate 83 (S)-4'-(methylamino)spiro[cyclopropane-1,1'-yisochroman]-7'-carboxamide

[0335] Intermediate 85 N-(methyl-d3)-7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-d-4'-amine

[0336] Step 1: To a methanol solution (15 ml) of 7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-one (1 g, 4.13 mmol) was added NaBD4 (186 mg, 4.54 mmol) at 0°C. The reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was directly concentrated to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 3:1) to give a yellow solid product 7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-d-4'-ol (510 mg, yield: 50%).

[0337] LCMS (ESI) m / z: 246.2 [M+H] +

[0338] Step 2: Under N2 protection, a toluene solution (10 ml) of DPPA (2.47 g, 8.98 mmol) was slowly added dropwise to a toluene (30 ml) solution of 7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-d-4'-ol (2 g, 8.16 mmol) and DBU (1.36 g, 8.98 mmol). The reaction solution was reacted at room temperature for 16 hours. After the reaction was completed, water (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml × 2). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The yellow solid product 4'-azido-7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-d (1.3 g, yield: 59%) was separated by column chromatography (petroleum ether: ethyl acetate = 1:0 to 3:1).

[0339] Step 3: Under N2 protection, PPh3 (1.89 g, 7.22 mmol) was added to a solution of 4'-azido-7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-d (1.3 g, 4.81 mmol) in THF (15 ml) and stirred at room temperature for 1 hour. Then, KOH (670 mg, 12 mmol) aqueous solution (5 ml) was added to the reaction solution. The reaction solution was continued to stir at room temperature for 16 hours. After the reaction was completed, water (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml × 3). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The yellow solid product 7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-d-4'-amine (700 mg, yield: 60%) was isolated by column chromatography (petroleum ether: ethyl acetate = 1:0 to 1:0).

[0340] LCMS (ESI) m / z: 245.2 [M+H] +

[0341] Step 4: (Boc)2O (940 mg, 4.3 mmol) was added to a solution of 7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-d-4'-amine (700 mg, 2.87 mmol) and triethylamine (870 mg, 8.61 mmol) in dichloromethane (15 mL). The reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The yellow solid product, tert-butyl (7'-(trifluoromethyl)spiro[cyclopropane-1,1'-isochroman]-4'-yl-4'-d)carbamate (890 mg, yield: 90%) was isolated by column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1).

[0342] LCMS (ESI) m / z: 345.2 [M+H] +

[0343] Step 5: At 0°C, NaH (155 mg, purity 60%, 3.88 mmol) was added to a solution of tert-butyl (7'-(trifluoromethyl) spiro[cyclopropane-1,1'-isochroman]-4'-yl-4'-d) carbamate (890 mg, 2.58 mmol) in tetrahydrofuran (15 ml) and stirred at 0°C for 30 minutes. Then, CD3I (560 mg, 3.88 mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, water (30 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 ml × 3). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 1:0 to 5:1) to isolate the yellow solid product tert-butyl (methyl-d3) (7'-(trifluoromethyl) spiro [cyclopropane-1,1'-isochroman] -4'-yl-4'-d) carbamate (650 mg, yield: 70%).

[0344] LCMS (ESI) m / z: 362.2 [M+H] +

[0345] Step 6: To a solution of tert-butyl (methyl-d3) (7'-(trifluoromethyl) spiro[cyclopropane-1,1'-isochroman]-4'-yl-4'-d) carbamate (650 mg) in dichloromethane (15 ml) was added a hydrochloric acid solution of dioxane (3.0 ml, 4 M) dropwise and reacted at room temperature for 5 hours. The reaction solution was concentrated to give a yellow solid product N-(methyl-d3) (7'-(trifluoromethyl) spiro[cyclopropane-1,1'-isochroman]-4'-d-4'-amine (720 mg, crude product). It was used directly in the next step without purification.

[0346] LCMS(ESI):[M+H]+ m / z=262.2

[0347] The following intermediates were prepared by adopting the preparation method and steps of intermediate 86, replacing only the corresponding raw material intermediates:

[0348] Example 1 4-amino-N-methyl-N-(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochroman]-4'-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0349] At room temperature, the compound 4-amino-1-methylpyrazolo[4,5-c]quinoline-8-carboxylic acid (100 mg, 0.442 mmol) was dissolved in DMF (3 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (85 mg, 0.442 mmol) and 1-hydroxybenzotriazole (60 mg, 0.442 mmol) were added, followed by the addition of DIEA (87 mg, 0.66 mmol), and the reaction was stirred at room temperature for 0.5 hour. N-methyl-7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromanhydro]-4'-amine (60 mg, 0.221 mmol) was then added, and the mixture was reacted at room temperature for 16 hours. When LCMS showed the reaction was complete, water (40 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-methyl-N-(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochroman]-4'-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (25 mg, yield: 13.1%) as a white solid.

[0350] LCMS (ESI) m / z: 496.2 [M+H] +

[0351] 1 H NMR (400MHz, DMSO-d6) δ9.19(d,J=18.9Hz,1H),8.36(d,1H),7.89(d,J=15.1Hz,2H),7.68(d,1H),7.63 –7.35(m,5H),5.31(d,J=341.0Hz,1H),4.07(d,2H),2.73(s,3H),2.48–2.29(m,3H),2.26–1.93(m,3H).

[0352] The following compounds were prepared by using the method or part of the method used in Example 1, except that the corresponding materials were replaced:

[0353] Example 17 4-amino-N-(1-methyl-1H-pyrazol-4-yl)-N-(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochroman]-4'-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0354] Step 1: 4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid (200 mg, 0.88 mmol) was dissolved in dichloromethane (2.0 ml) and 4M hydrochloric acid ethyl ether (0.3 ml) solution was added. The reaction mixture was stirred at 20 ° C for 30 minutes. The reaction solution was concentrated and dissolved in dichloromethane (1.0 ml), and oxalyl chloride (566 mg, 4.38 mmol) and N,N-dimethylformamide (6.41 mg, 0.09 mmol) were added at 0 ° C as catalyst. The reactants were stirred at room temperature for 16 hours. The reaction was monitored by LCMS (methanol), and LCMS showed 80% of methyl ester product. The reaction solution was directly concentrated to give a gray solid crude product 4-aminoimidazo[1,5-a]quinoxaline-8-carbonyl chloride hydrochloride (210 mg, yield: 97%).

[0355] LCMS(ESI):[M+H] + =243.14.

[0356] Step 2: 1-Methyl-N-(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromatic]-4'-yl)-1H-pyrazol-4-amine (120 mg, 0.36 mmol) was dissolved in tetrahydrofuran (10.0 ml) and N,N-diisopropylethylamine (230 mg, 1.78 mmol) and 4-aminoimidazo[1,5-a]quinoxaline-8-carbonyl chloride hydrochloride (105 mg, 0.43 mmol) were added. The reaction mixture was stirred at 20°C for 16 hours. The reaction was monitored by LCMS (methanol), which showed 35% product. The reaction was concentrated and purified on a silica gel column, eluting with 10-15% methanol / dichloromethane for 20 minutes to obtain a product with a purity of 70%. The product was dissolved in 3 ml of N,N-dimethylformamide and further purified by HPLC (0.5% aqueous ammonium bicarbonate solution / acetonitrile, 60% to 70%). After freeze-drying, a white solid 4-amino-N-(1-methyl-1H-pyrazol-4-yl)-N-(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochromatic]-4'-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (83.27 mg, yield: 52%) was obtained.

[0357] LCMS(ESI):[M+H] + =548.3.

[0358] 1 H NMR(400MHz,DMSO-d6)δppm 9.08(s,1H),8.20(s,1H),7.88(s,1H),7.75-7.65(m,3H),7.41.7.32(m,3H),7.29-7.23(m,2H), 6.95(s,1H),5.86(s,1H),4.16-4.12(m,1H),3.99-3.97(m,1H),3.50(s,3H),2.51-2.04(m,6H).

[0359] The following compounds were prepared by using the method or part of the method used in Example 17, except that the corresponding materials were replaced:

[0360] Example 19 4-amino-7-fluoro-N,1-dimethyl-N-(7-(trifluoromethyl)-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran]-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0361] Step 1: N-methyl-7-(trifluoromethyl)-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran]-4-amine (300 mg, 0.99 mmol) was dissolved in N,N-dimethylacetamide (8.0 ml) solution, and 4-amino-7-fluoro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (311 mg, 1.19 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (335 mg, 1.19 mmol) and N-methylimidazole (409 mg, 4.98 mmol) were added. The reaction mixture was stirred at 50° C. for 16 hours, water (50 ml) was added to the reaction solution, extracted with ethyl acetate (30 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by HPLC (0.5% formic acid aqueous solution / acetonitrile, 40% to 50%). After freeze-drying, a white solid 4-amino-7-fluoro-N,1-dimethyl-N-(7-(trifluoromethyl)-2',3',5',6'-tetrahydrospiro[isochroman-1,4'-pyran]-4-yl)imidazo[1,5-a]quinoxaline-8-carboxamide (220 mg, yield: 41%) was obtained.

[0362] LCMS(ESI):[M+H] + =544.3.

[0363] 1 H NMR (400MHz, DMSO-d6) δ8.17-8.14(m,1H),7.96(s,1.75H),7.78-7.65(m,3.37H),7.55(d,J=8.2Hz,1H),7.33-7.30(m,1.3H),5 .75(s,0.5H),4.81(s,0.5H),4.23-4.01(m,2H),3.77-3.65(m,4H),3.99-3.97(m,3H),2.75(d,J=2.74,3H),2.34-1.89(m,4H).

[0364] The following compounds were prepared by using the method or part of the method used in Example 19, replacing only the corresponding materials:

[0365] Example 21 4-amino-N-(1-methyl-1H-pyrazol-4-yl)-N-(7'-(trifluoromethyl)spiro[cyclobutane-1,1'-isochroman]-4'-yl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0366] Step 1: Tert-butyl (S)-(7'-chloro-3'-, 4'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-4'-yl)(methyl)carbamate (500 mg, 1.48 mmol) was dissolved in dimethyl sulfoxide (1.0 ml), benzyl piperazine-1-carboxylate (975 mg, 4.43 mmol), potassium fluoride (87 mg, 1.48 mmol) and N,N-diisopropylethylamine (583 mg, 4.43 mmol) were added, and the mixture was stirred at 120°C for 48 hours. After the reaction was completed, the reaction solution was poured into water (40 ml), 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 give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give benzyl (S)-4-(4'-(tert-butoxycarbonyl)(methyl)amino)-3'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-7'-yl)piperazine-1-carboxylate (0.5 g, yield: 78.4%).

[0367] LCMS (ESI) m / z: [M+H] + =523.33.

[0368] Step 2: Benzyl (S)-4-(4'-(tert-butoxycarbonyl)(methyl)amino)-3'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridin]-7'-yl)piperazine-1-carboxylate (500 mg, 0.89 mmol) was dissolved in dichloromethane (3.00 mL). Trifluoroacetic acid (1.00 mL) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under vacuum, and the mixture was pumped with an oil pump for 10 minutes. The crude product was used in the next step without purification to provide benzyl (S)-4-(4'-(tert-butoxycarbonyl)(methyl)amino)-3'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridin]-7'-yl)piperazine-1-carboxylate (0.4 g, 99.0% yield).

[0369] LCMS (ESI) m / z: [M+H] + =392.35.

[0370] Step 3: 4-Amino-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (259 mg, 1.14 mmol) was dissolved in N,N-dimethylformamide (5.00 ml), and chloro-N,N,N',N'-tetramethylformamidoammonium hexafluorophosphate (325 mg, 1.14 mmol), N-methylimidazole (392 mg, 4.73 mmol) and N,N-diisopropylethylamine (374 mg, 2.84 mmol) were added respectively, and the mixture was stirred at room temperature for 20 minutes, and then benzyl (S)-4-(4'-(tert-butoxycarbonyl)(methyl)amino)-3'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-7'-yl)piperazine-1-carboxylate (400 mg, 0.95 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 (30 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. Column chromatography (dichloromethane:methanol = 15:1) gave benzyl (S)-4-(4'-(4-amino-N-methylimidazo[1,5-a]quinoxaline-8-carboxamido)-3'-dihydrospiro[cyclobutane-1,1'-pyrano[4,3-c]pyridine]-7'-yl)piperazine-1-carboxylate (245 mg, yield: 41.0%).

[0371] LCMS (ESI) m / z: [M+H] + =633.35.

[0372] Step 4: Benzyl (S)-4-(4'-(4-amino-N-methylimidazo[1,5-a]quinoxaline-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 trifluoroacetic acid (1.00 ml) and the reaction mixture was stirred at 50°C for 16 hours. After completion of the reaction, the solvent was removed in vacuo, and 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 (3.37 mg, yield: 20.0%) as a white solid.

[0373] LCMS (ESI) m / z: [M+H] + =499.30.

[0374] 1H NMR (400MHz, DMSO-d6) δ9.21(s,1H),8.33(s,1H),8.04(d,J=47.4Hz,1H),7.90(s,1H),7.43(d,J=17.8Hz,4H),6.79(d,J=22.6Hz,1H),5. 60-4.69(m,1H),3.95(d,J=30.0Hz,2H),3.45(s,4H),2.79(s,4H),2.71(s,3H),2.36-2.27(m,3H),2.06-1.93(m,3H),1.45-0.85(m,1H).

[0375] After chiral SFC separation, the compounds in the following table were obtained:

[0376] Biochemical evaluation

[0377] 1. Experimental study on the inhibitory activity of compounds on tumor cell proliferation

[0378] Test Example 1: Inhibitory activity of compounds on HCT-116MTAP(- / -) cell proliferation

[0379] Materials and cells: HCT-116MTAP(- / -) deficient cells were purchased from Kangyuan Bochuang (China); RPMI-1640 medium, fetal bovine serum, and penicillin-streptomycin 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).

[0380] Cell Culture: HCT116 MTAP(- / -)-deficient cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C and 5% CO2. Cells in the logarithmic growth phase were used for experiments. Cell Proliferation Inhibitory Activity Assay: Compounds were assayed for their inhibitory activity against HCT-116 MTAP(- / -)-deficient cells using the Cell-Titer Glo assay. Cell concentrations were adjusted, and 40 μL of compound was seeded per well in a 384-well plate. The plates were incubated 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 at 10,000 nM, 3-fold dilutions, 10 points) with 0.1% DMSO. The plates were incubated at 37°C and 5% CO2 for 8 days. Cell viability was assessed by adding 40 μL of Cell-Titer Glo reagent. The results are shown in Table 1.

[0381] Test Example 2: Experimental study on the inhibitory activity of compounds on HCT-116 wild-type cell proliferation

[0382] Materials and cells: HCT-116 wild-type cells were purchased from Kangyuan Bochuang (China); RPMI-1640 medium, fetal bovine serum, and penicillin-streptomycin 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).

[0383] Cell culture: HCT-116 wild-type cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C and 5% CO2. Cells in the logarithmic growth phase were used in experiments.

[0384] 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. 40 nL of compound was added to each well to a final concentration of 0-10,000 nM (starting concentration 10,000 nM, 2-fold dilution, 10 points) with a DMSO content of 0.1%. The cell plates were incubated at 37°C and 5% CO2 for 8 days. 40 μL of Cell-Titer Glo reagent was added to detect cell activity. The test results are shown in Table 1.

[0385] 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.

[0386] NA means not tested.

[0387] As shown in Table 1, the compounds of the present disclosure have good inhibitory activity against the proliferation of MTAP-deficient HCT116 cells and have good selectivity relative to MTAP wild-type HCT116 cells.

[0388] Test Example 3: Inhibitory activity of compounds on LU99 MTAP(- / -) deficient cell proliferation

[0389] Materials and Cells: The 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 the Cell-Titer Glo kit was purchased from Promega (USA). Cell Culture: LU99 MTAP(- / -)-deficient cells were cultured in a medium supplemented with 10% fetal bovine serum at 37°C and 5% CO2. Cells in the logarithmic growth phase were used in experiments.

[0390] 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.

[0391] Test Example 4: Inhibitory activity of compounds on the proliferation of LU99 MTAP-overexpressing cells

[0392] 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).

[0393] 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.

[0394] 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

[0395] As shown in Table 2, the compounds of the examples of the present disclosure have good inhibitory activity against the proliferation of MTAP-deficient LU99 cells and have good selectivity over MTAP-overexpressing LU99 cells.

[0396] 2. Pharmacokinetic Experiments in Mice

[0397] 1. Test compounds

[0398] The compounds used in this test are from the compounds of the specific examples disclosed in this disclosure.

[0399] 2. Experimental Animals

[0400] ICR male mice, N=3 / group; original source: Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd.

[0401] 3. Drug preparation and administration

[0402] Single oral (PO) administration in ICR mice: Weigh the compound and dissolve it in dimethyl sulfoxide. Add a certain volume of polyethylene glycol 400 and water for injection, and adjust the solution to a clear solution with a small amount of 1 mol / L hydrochloric acid solution. Administer the compound to three mice by gavage after an overnight fast at a dose of 10 mg / kg.

[0403] Single intravenous (IV) administration in ICR mice: Weigh the compound and dissolve it in dimethyl sulfoxide. Add a certain volume of polyethylene glycol 400 and water for injection, and adjust the solution to a clear solution with a small amount of 1 mol / L hydrochloric acid solution. Administer 3 mg / kg of the compound to the tail vein of 3 mice after an overnight fast.

[0404] 4. Sample Collection

[0405] Approximately 30 μL of blood was collected from the dorsal foot vein at each time point. Anticoagulated with dipotassium EDTA, placed on ice, and centrifuged within 1 hour to separate plasma (centrifugation conditions: 4000 g / min, 5 minutes, 4°C). Blood was collected at 0.0833 (intravenous injection), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Samples were stored at -20°C.

[0406] To 30 μL of plasma sample (10 μL sample + 20 μL blank plasma sample), add 200 μL of ice-cold acetonitrile containing internal standard, vortex for 30 seconds, and centrifuge at 4000 g / min for 20 minutes. Transfer 100 μL of the supernatant to a 96-well plate, add 200 μL of ultrapure water, vortex for 30 seconds, and inject 5 μL or 10 μL into LC-MS / MS for analysis.

[0407] Table 2: Pharmacokinetic data

[0408] 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), its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives, Among them, The dashed line represents a single bond or a double bond; wherein, X1 represents N or CR X1 ; wherein, X2 represents N or CR X2 ; wherein, X3 represents N or CR X3 ; wherein, X4 represents N or CR X4 ; wherein, X5 represents N or CR X5 ; wherein, X6 represents N or CR X6 ; wherein, Y represents CH or N; wherein, R 4 represents H or D; Wherein, R X1 and 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 , -S(O)(=NR a )R b , -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, 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 , -S(O)(=NR a )R b , -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 substituted by 0-4 of the following substituents: deuteration, 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 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 represents -L-R X4-1 ; wherein, L represents absent or CR a R b , SiR a R b , O, S, Se, NR a ; Wherein, 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 -S(O)(=NR a )R b -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 substituted with 0 to 4 of the following substituents: deuterium, 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 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, the ring A can also optionally be fused with a 5- or 6-membered saturated or unsaturated ring at the chemical bond between X3 and X4, and this ring can contain 0-3 heteroatoms selected from O, N, and S; among them, the ring can also optionally be substituted by 0, 1, 2, or 3 substituents 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 、-S(O)(=NR a )R b 、-SF5、-NR a R b 、halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or substituted by 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 and substituted by substituents; Among them, the ring A can also optionally be fused with a 5- or 6-membered saturated or unsaturated ring at the chemical bond between X4 and X5, and this ring can contain 0-3 heteroatoms selected from O, N, and S; among them, the ring can also optionally be substituted by 0, 1, 2, or 3 substituents 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 、-S(O)(=NR a )R b 、-SF5、-NR a R b 、halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or substituted by 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 ; Wherein, R 1 represents hydrogen or is substituted by 0 - 3 of any of the following substituents: deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl (e.g., C3-C6 cycloalkyl), 3-10 membered substituted or unsubstituted saturated or unsaturated heterocyclic group (e.g., 3-6 membered saturated or unsaturated heterocyclic group), substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halo C1-C6 alkyl, halo C1-C6 alkoxy, -SO3R a , -SR a , -S(O)2R a , -S(O)R a , -S(O)(=NR a )R b , -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 represents -CHR s R t or -CDR s R t ; wherein, R s , R t each independently represents hydrogen, deuterium, -OR a , halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, -C3-C 10 cycloalkyl or is substituted with 0-3 of any of the following substituents: deuteration, 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, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, -SO3R a , -SR a , -S(O)2R a , -S(O)R a , -S(O)(=NR a )R b , -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; Wherein, R 2 and R 3 each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxyl, carboxyl, halo C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl); Among them, M1 represents CR a R b , -SiR a R b , NR a , O, S or Se; wherein, M2 represents C or Si; wherein, R L and R L’ each independently represent hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxyl, carboxyl, halo C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl); or R L and R L’ together with the atom to which they are attached form a 3-10 membered saturated or unsaturated ring, and the ring may further optionally contain 0, 1, or 2 heteroatoms selected from O, N, S, Se; further, the ring may further optionally be substituted by 0, 1, or 2 substituents selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo C1-C6 alkyl, halo 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 , -S(O)(=NR a )R b , -CN, -C(O)OR a , -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b , -SF5; Wherein, R T and R T’ each independently represents hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxyl, carboxyl, halo C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl); or R T and R T’ together with the atom to which they are attached form a 3-10 membered saturated or unsaturated ring, and the ring may further optionally contain 0, 1, or 2 heteroatoms selected from O, N, S, Se; further, the ring may further optionally be substituted by 0, 1, or 2 substituents selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo C1-C6 alkyl, halo 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 , -S(O)(=NR a )R b , -CN, -C(O)OR a , -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b 、-SF5; Wherein, R L and R L’ pair up, and at least one pair of R T and R T’ forms a 3- to 10-membered saturated or unsaturated ring with the atoms connected thereto, and the ring may further optionally contain 0, 1, or 2 heteroatoms selected from O, N, S, and Se; further, the ring may further optionally be substituted with 0, 1, or 2 substituents 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 , -S(O)(=NR a )R b , -CN, -C(O)OR a , -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b , and -SF5; wherein, o represents 0, 1 or 2; wherein, R a and R b each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a and R b together with the atoms to which they are attached form a 3- to 14-membered saturated or unsaturated monocyclic ring, a 3- to 14-membered saturated or unsaturated spiro ring, or a 3- to 14-membered saturated or unsaturated fused ring, and each of said rings may optionally contain 0 to 2 heteroatoms selected from O, S, and N.

2. A compound represented by formula (I-2), a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, Among them, X1 represents N or CR X1 ; wherein, X2 represents N or CR X2 ; wherein, X3 represents N or CR X3 ; wherein, X4 represents N or CR X4 ; wherein, X5 represents N or CR X5 ; Wherein, X6 represents N or CR X6 ; wherein, Y represents CH or N; wherein, R 4 represents H or D; Wherein, R X1 and 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 , -S(O)(=NR a )R b , -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, 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 、-S(O)(=NR a )R b 、-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 substituted with 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 and is substituted 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 represents -L-R X4-1 ; wherein, L represents absent or CR a R b , SiR a R b , O, S, Se, NR a ; Wherein, 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 、-S(O)(=NR a )R b 、-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 substituted with 0-4 of the following substituents: deuterium, 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 C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl; Wherein, R 1 represents hydrogen or is substituted by 0 - 3 of any of the following substituents: deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl (e.g., C3-C6 cycloalkyl), 3-10 membered substituted or unsubstituted saturated or unsaturated heterocyclic group (e.g., 3-6 membered saturated or unsaturated heterocyclic group), substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halo C1-C6 alkyl, halo C1-C6 alkoxy, -SO3R a , -SR a , -S(O)2R a , -S(O)R a , -S(O)(=NR a )R b , -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 represents -CHR s R t or -CDR s R t ; wherein, R s and R t each independently represent hydrogen, deuterium, -OR a , halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, -C3-C 10 cycloalkyl or is substituted with 0-3 of any of the following substituents: deuteration, 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, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, -SO3R a , -SR a , -S(O)2R a , -S(O)R a , -S(O)(=NR a )R b , -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 heteroalkyl, C6-C 10 aryl, 5-10 membered heteroaryl; wherein, R 2 and R 3 each independently represent hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxy, carboxy, halo C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl); Among them, M1 represents CR a R b , -SiR a R b , NR a , O, S or Se; wherein, M2 represents C or Si; wherein, R L and R L’ each independently represent hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxyl, carboxyl, halo C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl); or R L and R L’ together with the atoms to which they are attached form a 3-10 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, S, Se; further, the ring may optionally be substituted by 0, 1, or 2 substituents selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo C1-C6 alkyl, halo 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 , -S(O)(=NR a )R b , -CN, -C(O)OR a , -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b , -SF5; wherein, R T and R T’ each independently represents hydrogen, deuterium, a C1-C6 alkyl group, a halogen, a hydroxyl group, a carboxyl group, a halogenated C1-C6 alkyl group, a hydroxy(C1-C6 alkyl) group, a mercapto(C1-C6 alkyl) group; or R T and R T’ together with the atoms to which they are attached form a 3-10 membered saturated or unsaturated ring, and the ring may further optionally contain 0, 1, or 2 heteroatoms selected from O, N, S, and Se; further, the ring may further optionally be substituted by 0, 1, or 2 substituents selected from deuterium, a C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a halogenated C1-C6 alkoxy group, a hydroxy C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C6 cycloalkyl group, -OR a , -SR a , -S(O)2R a , -S(O)R a , -S(O)(=NR a )R b , -CN, -C(O)OR a , -OC(O)R a , -OCONR a R b , a halogen, -OSO3R a , -NR a R b , -SF5; Wherein, R L and R L’ pair, R T and R T’ Among the pairs, at least one pair forms a 3- to 10-membered saturated or unsaturated ring with the atoms connected thereto, and the ring may also optionally contain 0, 1, or 2 heteroatoms selected from O, N, S, and Se; further, the ring may also optionally be substituted by 0, 1, or 2 substituents 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 , -S(O)(=NR a )R b , -CN, -C(O)OR a , -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b , -SF5; wherein, o represents 0, 1 or 2; Wherein, R a and R b each independently represents hydrogen, deuterium, a halogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halo(C1-C6 alkyl) group, or R a and R b together with the atoms to which they are attached form a 3- to 14-membered saturated or unsaturated monocyclic ring, a 3- to 14-membered saturated or unsaturated spiro ring, or a 3- to 14-membered saturated or unsaturated fused ring, and each of said rings may optionally contain 0-2 heteroatoms selected from O, S, and N.

3. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 1 represents N.

4. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotope derivatives, wherein, X1 represents CR X1 , where R X1 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halogenated C1-C6 alkoxy, cyano, NH2, -N(CH3)2.

5. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotope derivatives, wherein, X 2 represents CR X2 , wherein R X2 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halo C1-C6 alkoxy, cyano, NH2, -N(CH3)2; preferably, R X2 represents hydrogen, C1-C6 alkyl.

6. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives, wherein, X 3 represents N.

7. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 3 represents CR X3 , wherein R X3 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, cyano, NH2, -N(CH3)2; preferably, R X3 represents hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl.

8. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 5 represents N.

9. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives, wherein, X 5 represents CR X5 , wherein R X5 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, cyano, NH2, -N(CH3)2; preferably, R X5 represents hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl.

10. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 6 represents N.

11. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotope derivative, wherein, X 6 represents CR X6 , where R X6 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, cyano, NH2, -N(CH3)2; preferably, R X6 represents hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halo-C1-C6 alkylthio.

12. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotope derivatives, wherein, X 4 represents C-L-R X4-1 , wherein L represents absent, and 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 , -S(O)(=NR a )R b , -SF5, -NR a R b , -C(O)OR a , -OC(O)R a , -OCONR a R b , -NR a COR b , -CONR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl or substituted by 0-4 of the following substituents: deuterium, 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 C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl.

13. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, and a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 4 represents C-L-R X4-1 , wherein, L represents absent, and R X4-1 represents hydrogen, deuterium, C1-C6 alkyl, halogen, halo-C1-C6 alkyl, -CN, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, C1-C6 alkoxy, halo-C1-C6 alkoxy, halo-C1-C6 alkylthio, -SF5, -P(O)(CH3)2.

14. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 4 represents C-L-R X4-1 , wherein L represents absent, and R X4-1 represents hydrogen, halogen (preferably F), CN, -CF3, -CF2CF3, -NH2, -NHCH3, -N(CH3)2, -OCH3, -OCF3, -SF5, -SCF3, -P(O)(CH3)2.

15. The compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein, X 4 represents C-L-R X4-1 , wherein L represents absent, and R X4-1 is selected from 0 to 4 of the following substituents: deuterium, 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, halo-C1-C6 alkyl, halo-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 C6-C 10 aryl or 5-10 membered heteroaryl.

16. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative, wherein, X 4 represents C-L-R X4-1 , where L represents absence and R X4-1 represents the following groups: Further, R X4 may optionally be substituted with 0, 1 or 2 substituents selected from halogen, hydroxy, C1-C6 alkyl, halo-C1-C6 alkyl and halo-C1-C6 alkoxy.

17. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, and a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 4 represents C-L-R X4-1 , wherein L represents absent, and R X4-1 is selected from 0 to 4 of the following substituents: deuterium, 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, halo-C1-C6 alkyl, halo-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 C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4- to 10-membered saturated or unsaturated heterocycle.

18. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, and a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 4 represents C-L-R X4-1 , wherein, L represents O, S or NH, N(CH3), and R X4-1 represents the following groups: Further, R X4-1 may optionally be substituted with 0, 1, or 2 groups independently selected from halogen, hydroxy, C1-C6 alkyl, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy.

19. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 4 represents C-L-R X4-1 , where L represents absence and R X4-1 represents the following groups: Among them, W1 represents CR C R D , NR C , O, S, SiR C R D ; Among them, W2 represents -(CR M R N ) i -; wherein, R1′, R2′, R3′, R4′, R5′, R6′, R7′, R8′ each independently represent hydrogen, deuterium, halogen, C1-C6 alkyl, hydroxy; or, respectively, R1′ and R2′; R3′ and R4′; R5′ and R6′; 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, 2 heteroatoms selected from O, S, N; further, the ring may optionally be substituted by 0, 1, 2 substituents selected from deuterium, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy; Wherein, R C and R D each independently represent hydrogen, deuterium, a halogen, a C1-C6 alkyl group, or a hydroxyl group; or R S and R T together with the atom to which they are attached form a 3- to 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, a halogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, and a hydroxyl group; wherein, R M and R N each independently represents hydrogen or a C1-C6 alkyl group; wherein, i represents an integer of 1 or 2.

20. A compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives, wherein, X 4 represents C-L-R X4-1 , where L represents absent and R X4-1 represents the following groups: Among them, the described R X4-1 may be arbitrarily substituted by 0, 1 or 2 substituents selected from halogen, C0-C6 alkyl hydroxy, C0-C6 alkyl cyano, C1-C6 alkyl, and halogenated C1-C6 alkyl.

21. The compound of formula (I) according to claim 1, its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives, wherein, X 4 represents C-L-R X4-1 , where L represents non-existence and R X4-1 represents the following groups:

22. The compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotope derivatives, wherein, R L and R L’ together with the atoms to which they are attached form a ring having the following structure: wherein, * represents R L and R L’ are jointly connected atomic sites. Further, the above-mentioned cyclic structure can also be arbitrarily substituted by 0, 1, or 2 substituents 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 , -S(O)(=NR a )R b , -CN, -C(O)OR a , -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b .

23. The compound represented by formula (I) according to claim 1 or formula (I-2) according to claim 2, its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives, wherein, R T and R T’ together with the atoms attached thereto form a ring having the following structure: wherein, * represents R T and R T’ are jointly connected atomic sites. Further, the above-mentioned cyclic structure can also be arbitrarily substituted by 0, 1, or 2 substituents 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 , -S(O)(=NR a )R b , -CN, -C(O)OR a , -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b , -SF5.

24. A compound having any one of the following structures, its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives, Among them, X1 represents N or CR X1 ; wherein, X3 represents N or CR X3 ; wherein, X4 represents N or CR X4 ; wherein, X5 represents N or CR X5 ; Wherein, X6 represents N or CR X6 ; wherein, R 4 represents H or D; wherein, R X1 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 , -S(O)(=NR a )R b , -CN, -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b , -SF5; Wherein, R X3 and R X5 and 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 , -S(O)(=NR a )R b , -SF5, -NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl or substituted by 0 to 4 of the following substituents: deuterium, 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 and is substituted 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 represents -L-R X4-1 ; wherein, L represents absent or CR a R b , O, S, NR a ; Wherein, 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 -S(O)(=NR a )R b -SF5, -NR a R b halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl or is substituted with 0 to 4 of the following substituents: deuterium, 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 C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl; Wherein, R 1 represents hydrogen or is substituted by 0 to 3 of any of the following substituents: deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl (e.g., C3-C6 cycloalkyl), 3- to 10-membered substituted or unsubstituted saturated or unsaturated heterocyclic group (e.g., 3- to 6-membered saturated or unsaturated heterocyclic group), substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halo C1-C6 alkyl, halo C1-C6 alkoxy, -SO3R a , -SR a , -S(O)2R a , -S(O)R a , -S(O)(=NR a )R b , -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- to 10-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl; Preferably, R 1 represents -CHR s R t or -CDR s R t ; Wherein, R s and R t each independently represents hydrogen, deuterium, -OR a , halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, -C3-C 10 cycloalkyl or is substituted with 0-3 of any 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, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, -SO3R a , -SR a , -S(O)2R a , -S(O)R a , -S(O)(=NR a )R b , -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 heteroalkyl, C6-C 10 aryl, 5-10 membered heteroaryl; Among them, M 1 represents CR a R b , NR a , O, S or Se; Wherein, R T and R T’ each independently represent hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxyl, carboxyl, halo C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl); or R T and R T’ together with the atoms to which they are attached form a 3-10 membered saturated or unsaturated ring, and the ring may also optionally contain 0, 1, or 2 heteroatoms selected from O, N, S, Se; further, the ring may also optionally be substituted by 0, 1, or 2 substituents selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo C1-C6 alkyl, halo 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 , -S(O)(=NR a )R b , -CN, -C(O)OR a , -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b , -SF5; wherein, o represents 0, 1 or 2; wherein, R a and R b each independently represents hydrogen, deuterium, a halogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halo(C1-C6 alkyl) group, or R a and R b together with the atom to which they are attached form a 3- to 14-membered saturated or unsaturated monocyclic ring, a 3- to 14-membered saturated or unsaturated spiro ring, or a 3- to 14-membered saturated or unsaturated fused ring, and each of said rings may optionally contain 0 to 2 heteroatoms selected from O, S, and N.

25. A compound having any one of the following structures, its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives, Among them, X1 represents N or CR X1 ; Wherein, X3 represents N or CR X3 ; wherein, X4 represents N or CR X4 ; wherein, X5 represents N or CR X5 ; Wherein, X6 represents N or CR X6 ; wherein, R 4 represents H or D; wherein, R X1 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 , -S(O)(=NR a )R b , -CN, -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b , -SF5; wherein, 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 、-S(O)(=NR a )R b 、-SF5、-NR a R b 、halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl or substituted by 0-4 of the following substituents: deuterium, 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 C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl; wherein, R X4 represents -L-R X4-1 ; wherein, L represents absent or CR a R b , O, S, NR a ; wherein, 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 , -S(O)(=NR a )R b , -SF5, -NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl or substituted by 0-4 of the following substituents: deuterium, 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 C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl; wherein, R 1 represents hydrogen or is substituted by 0 - 3 of any of the following substituents: deuterium, halogen, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C 10 cycloalkyl (e.g., C3 - C6 cycloalkyl), 3 - 10 - membered substituted or unsubstituted saturated or unsaturated heterocyclic group (e.g., 3 - 6 - membered saturated or unsaturated heterocyclic group), substituted or unsubstituted C6 - C 10 aryl, substituted or unsubstituted 5 - 10 - membered heteroaryl, -OR a , oxo, hydroxy C1 - C6 alkyl, NR a R b , -CN, halo C1 - C6 alkyl, halo C1 - C6 alkoxy, -SO3R a , -SR a , -S(O)2R a , -S(O)R a , -S(O)(=NR a )R b , -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 represents -CHR s R t or -CDR s R t ; wherein, R s and R t each independently represents hydrogen, deuterium, -OR a , halogen, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, -C3-C 10 cycloalkyl or a 4- to 10-membered heterocycloalkyl, C6-C a aryl, 5- to 10-membered heteroaryl which is substituted with 0 to 3 of any of the following substituents: deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy-C1-C6 alkyl, NR b R a , -CN, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, -SO3R a , -SR a , -S(O)2R a , -S(O)R a , -S(O)(=NR b )R a , -SF5, -C(O)R a , -C(O)OR a , -OC(O)R a , -OC(O)NR b R a , -NR b COR a or -CONR b R 10 ; Among them, M 1 represents CR a R b , NR a , O, S or Se; wherein, R L and R L’ each independently represent hydrogen, deuterium, C1-C6 alkyl, halogen, hydroxyl, carboxyl, halo C1-C6 alkyl, hydroxy(C1-C6 alkyl), mercapto(C1-C6 alkyl); or R L and R L’ together with the atoms to which they are attached form a 3-10 membered saturated or unsaturated ring, and the ring may optionally contain 0, 1, or 2 heteroatoms selected from O, N, S, Se; further, the ring may optionally be substituted by 0, 1, or 2 substituents selected from deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo C1-C6 alkyl, halo 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 , -S(O)(=NR a )R b , -CN, -C(O)OR a , -OC(O)R a , -OCONR a R b , halogen, -OSO3R a , -NR a R b , -SF5; wherein, R a and R b each independently represents hydrogen, deuterium, a halogen, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halo(C1-C6 alkyl) group, or R a and R b together with the atom to which they are attached form a 3- to 14-membered saturated or unsaturated monocyclic ring, a 3- to 14-membered saturated or unsaturated spiro ring, or a 3- to 14-membered saturated or unsaturated fused ring, and each of said rings may optionally contain 0 to 2 heteroatoms selected from O, S, and N.

26. A compound according to claim 24 or 25, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 1 represents N.

27. A compound according to claim 24 or 25, and its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotope derivatives, wherein, X1 represents CR X1 , where R X1 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, cyano, NH2, -N(CH3)2.

28. A compound according to claim 24 or 25, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 3 represents N.

29. A compound according to claim 24 or 25, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 3 represents CR X3 , wherein R X3 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, cyano, NH2, -N(CH3)2; preferably, R X3 represents hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl.

30. A compound according to claim 24 or 25, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 5 represents N.

31. A compound according to claim 24 or 25, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 5 represents CR X5 , wherein R X5 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, cyano, NH2, -N(CH3)2; preferably, R X5 represents hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl.

32. A compound according to claim 24 or 25, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 6 represents N.

33. A compound according to claim 24 or 25, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 6 represents CR X6 , wherein R X6 represents hydrogen, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, hydroxy, C1-C6 alkoxy, halo-C1-C6 alkoxy, cyano, NH2, -N(CH3)2; preferably, R X6 represents hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl.

34. A compound according to claim 24 or 25, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 4 represents C-L-R X4-1 , where L represents absent, and 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 , -S(O)(=NR a )R b , -SF5, -NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogenated C1-C6 alkylthio, hydroxy C1-C6 alkyl or substituted by 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 substituted C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4-10 membered saturated or unsaturated heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl.

35. A compound according to claim 24 or 25, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 4 represents C-L-R X4-1 , wherein, L represents absent, and R X4-1 represents hydrogen, deuterium, C1-C6 alkyl, halogen, halo-C1-C6 alkyl, -CN, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, C1-C6 alkoxy, halo-C1-C6 alkoxy, -SF5, -P(O)(CH3)2.

36. The compound according to claim 24, its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives, wherein, X 4 represents C-L-R X4-1 , wherein, L represents absence, and R X4-1 represents hydrogen, halogen (preferably F), -CF3, -NH2, -NHCH3, -N(CH3)2, -OCH3, -OCF3, -SF5, -P(O)(CH3)2.

37. A compound according to claim 24 or 25, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 4 [0001010] 4 represents C-L-R X4-1 [0001011] X4-1 , where L represents absent, and R X4-1 [0001012] X4-1 is selected from 0 to 4 of the following substituents: deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a [0001013] a , oxo, hydroxy(C1-C6 alkyl), NR a [0001014] a R b [0001015] b , -CN, halo C1-C6 alkyl, halo C1-C6 alkoxy, -SO3R a [0001016] a , -SR a [0001017] a , -SF5, -C(O)R a [0001018] a , -C(O)OR a [0001019] a , -OC(O)R a [0001020] a , -OC(O)NR a [0001021] a R b [0001022] b , -NR a [0001023] a COR b [0001024] b or -CONR a [0001025] a R b [0001026] b substituted C6-C 10 [0001027] 10 aryl or 5-10 membered heteroaryl.

38. A compound according to claim 24 or 25, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 4 represents C-L-R X4-1 , where L represents absent and R X4-1 represents the following groups: Further, R X4 may optionally be substituted with 0, 1 or 2 substituents selected from halogen, hydroxy, -CN, C1-C6 alkyl, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy.

39. A compound according to claim 24 or 25, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 4 represents C-L-R X4-1 , where L represents absent, and R X4-1 is selected from 0 to 4 of the following substituents: deuterium, 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, halo C1-C6 alkyl, halo 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 and is substituted C3-C 10 cycloalkyl, C6-C 10 cycloalkenyl, 4- to 10-membered saturated or unsaturated heterocycle.

40. A compound according to claim 24 or 25, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 4 represents C-L-R X4-1 , wherein, L represents O, S or NH, N(CH3), and R X4-1 represents the following groups: Further, R X4-1 may optionally be substituted with 0, 1 or 2 substituents selected from halogen, hydroxy, -CN, C1-C6 alkyl, halo C1-C6 alkyl, and halo C1-C6 alkoxy.

41. A compound according to claim 24 or 25, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 4 represents C-L-R X4-1 , wherein, L represents absent, and R X4-1 represents the following groups: Among them, W1 represents CR C R D , NR C , O, S; Among them, W2 represents -(CR M R N ) i -; wherein, R1′, R2′, R3′, R4′, R5′, R6′, R7′, R8′ each independently represent hydrogen, deuterium, halogen, C1-C6 alkyl, hydroxy; or, respectively, R1′ and R2′; R3′ and R4′; R5′ and R6′; 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, 2 heteroatoms selected from O, S, N; further, the ring may optionally be substituted by 0, 1, 2 substituents selected from deuterium, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy; wherein, R C , R D each independently represents hydrogen, deuterium, a halogen, a C1-C6 alkyl group, or a hydroxyl group; or R S , R T together with the atom to which they are attached form a 3- to 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, a halogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group, and a hydroxyl group; wherein, R M and R N each independently represents hydrogen or a C1-C6 alkyl group; wherein, i represents an integer of 1 or 2.

42. A compound according to claim 24 or 25, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 4 represents C-L-R X4-1 , wherein, L represents absent, and R X4-1 represents the following groups: wherein, the said R X4-1 may optionally be substituted by 0, 1, or 2 substituents selected from halogen, hydroxyl, cyano, C1-C6 alkyl, and halo-C1-C6 alkyl.

43. A compound according to claim 24 or 25, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein, X 4 represents C-L-R X4-1 , where L represents absence, and R X4-1 represents the following groups:

44. A compound, its pharmaceutically acceptable salts, esters, prodrugs, stereoisomers or isotopic derivatives, having the following structure:

45. A method for treating and / or preventing a disease associated with abnormal PRMT5 expression, which comprises administering to an individual in need thereof a therapeutically and / or prophylactically effective amount of a compound or a tautomeric form thereof, or a pharmaceutically acceptable salt form thereof, as described in any one of claims 1-44.

46. The method according to claim 45, wherein the disease associated with abnormal PRMT5 expression is a tumor or cancer.

47. The method according to claim 46, wherein the tumor or cancer is selected from any one of the following: cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung cancer: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal cancer: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary cancer: kidney cancer (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver cancer: Liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract cancer: gallbladder cancer, ampullary cancer, cholangiocarcinoma; Bone Cancer: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteocartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; Nervous system cancer: skull cancer (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meningeal cancer (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological cancer: uterine cancer (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), fallopian tube cancer (carcinoma); Blood Cancer: blood cancer (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin cancer: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid; and adrenal cancer, neuroblastoma.

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