Novel PRMT5 inhibitor and application thereof

Abstract

The present invention 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 invention describes compounds of Formula (I) or pharmaceutically acceptable salts, hydrates, or solvates thereof, as well as methods of synthesis and use of the compounds. # imgabs0 #

Description

Novel PRMT5 inhibitors and their applications

[0001] This application claims priority from the following Chinese patent applications:

[0002] (1) Chinese patent application number 202210951874.X, filed with the State Intellectual Property Office of China on August 9, 2022, entitled “Novel PRMT5 inhibitors and their applications”;

[0003] (2) Chinese patent application number 202211173943.5, filed with the State Intellectual Property Office of China on September 26, 2022, entitled “Novel PRMT5 inhibitors and their applications”;

[0004] (3) Chinese patent application number 202211473887.7, filed with the State Intellectual Property Office of China on November 22, 2022, entitled “Novel PRMT5 inhibitors and their applications”;

[0005] (4) Chinese patent application number 202310080068.4, filed with the State Intellectual Property Office of China on January 17, 2023, entitled “Novel PRMT5 inhibitors and their applications”;

[0006] (5) Chinese patent application number 202310402301.6, filed with the State Intellectual Property Office of China on April 14, 2023, entitled “Novel PRMT5 inhibitors and their applications”;

[0007] (6) The Chinese patent application filed with the State Intellectual Property Office of China on July 10, 2023, with application number 202310842267.4 and invention name “Novel PRMT5 inhibitors and their applications”, all contents of which are incorporated herein by reference. Technical Field

[0008] The present application relates to the field of drug synthesis, and specifically to a PRMT5 inhibitor and its application. Background Art

[0009] 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).

[0010] 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.

[0011] 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.

[0012] 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.

[0013] 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.

[0014] 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.

[0015] Summary of the Invention

[0016] To solve the technical problem of the present invention, the present invention provides a class of compounds with novel structures that have excellent inhibitory activity against PRMT5.

[0017] Specifically, the compound represented by formula (I) of the present invention, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative,

[0018] Where W represents N or CR W ;

[0019] Where X3 represents N or CR X3 ; X4 represents N or CR X4 ; X5 represents N or CR X5 ; X6 represents N or CRX6 ;

[0020] Among them, when X3 represents CR X3 When R X3 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0021] Among them, when X4 represents CR X4 When R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a Rb , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0022] Among them, when X5 represents CR X5 When R X5 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)ORa 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0023] Among them, when X6 represents CR X6 When R X6 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[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 have 0-3 heteroatoms selected from O, N, and S; further, the ring may be substituted by 0-3 substituents selected from the following groups: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[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 have 0-3 heteroatoms selected from O, N, and S; further, the ring may be substituted with 0-3 substituents selected from the following groups: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0026] Wherein, the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X5 and X6, and the ring may have 0-3 heteroatoms selected from O, N, and S; further, the ring may be substituted by 0-3 substituents selected from the following groups: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NRa R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0027] Wherein, R' represents 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic monoheterocyclic group, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0028] Preferably, R' represents -CHR 2 R 3 ;

[0029] Among them, R 1represents hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C 10 Cycloalkyl;

[0030] Among them, R 2 、R 3 Each independently represents hydrogen, deuterium, -OR a , halogen, -CN, -C1-C6 alkyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0031] Where W represents CR W When R W Selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, halogenated C1-C6 alkoxy;

[0032] Where X1 represents N or CR X1 ;

[0033] Where X2 represents N or CR X2 ;

[0034] Among them, Y1 represents CR Y1 R Y1’ NR Y1 , O, S, Se;

[0035] Among them, Y2 represents CR Y2 R Y2’ NR Y2 , O, S, Se;

[0036] Among them, Y3 represents CR Y3 R Y3’ NR Y3 , O, S, Se;

[0037] Among them, R X1 、R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -SO3R a 、-NR a R b , -SF5;

[0038] Among them, R Y1 、R Y1’ 、R Y2 、R Y2’ 、R Y3 、R Y3’ Each independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -SO3R a 、-NR a R b , -SF5;

[0039] in, Indicates a single bond or a double bond;

[0040] Among them, R a 、R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a 、R b Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

[0041] In addition, the present invention provides a compound, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, which has the following structure:

[0042] Where W represents N or CR W ;

[0043] Where X3 represents N or CR X3 ; X4 represents N or CR X4 ; X5 represents N or CR X5 ; X6 represents N or CR X6 ;

[0044] Among them, when X3 represents CR X3 When R X3 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 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)Ra 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0045] Among them, when X4 represents CR X4 When R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0046] Among them, when X5 represents CR X5 When R X5represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0047] Among them, when X6 represents CR X6 When R X6 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0048] Wherein, R' represents 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic monoheterocyclic group, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0049] Preferably, R' represents -CHR 2 R 3 ;

[0050] Among them, R 1 represents hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C 10 Cycloalkyl;

[0051] Among them, R 2 、R 3 Each independently represents hydrogen, deuterium, -OR a , halogen, -CN, -C1-C6 alkyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl;

[0052] Where W represents CR W When R W Selected from hydrogen, deuterium, C1-C6 alkyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, halogenated C1-C6 alkoxy;

[0053] Where X1 represents N or CR X1 ;

[0054] Where X2 represents N or CR X2 ;

[0055] Among them, Y1 represents CR Y1 R Y1’ NR Y1 , O, S, Se;

[0056] Among them, Y2 represents CR Y2 R Y2’ NR Y2 , O, S, Se;

[0057] Among them, Y3 represents CR Y3 R Y3’ NR Y3 , O, S, Se;

[0058] Among them, R X1 、R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -SO3R a 、-NR a R b , -SF5;

[0059] Among them, R Y1 、R Y1’ 、R Y2 、R Y2’ 、R Y3 、R Y3’ Each independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a Rb , halogen, -SO3R a 、-NR a R b , -SF5;

[0060] in, Indicates a single bond or a double bond;

[0061] Among them, R a 、R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a 、R b Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

[0062] In the preferred technical solution of formula I or II, W represents CH or N.

[0063] In the preferred technical solution of formula I or II, wherein X1 represents CR X1 or N, where R X1 represents hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, or halogenated C1-C6 alkyl.

[0064] In the preferred technical solution of formula I or II, X2 represents CH or CD.

[0065] In the preferred technical solution of formula I or II, X3 represents CH, CD or N.

[0066] In the preferred technical solution of formula I or II, wherein X4 represents CR X4 or N where R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5, -SO3R a 、-SR a , cyano 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 、-P(O)R a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

[0067] In the preferred technical solution of formula I or II, wherein X5 represents CR X5 or N where R X5 represents hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5, or cyano.

[0068] In the preferred technical solution of formula I or II, X6 represents CH, CD or N.

[0069] In the preferred technical solution of Formula I or II, the chemical bond between Y1 and Y2 is a double bond.

[0070] In the preferred technical solution of formula I or II, wherein Y1 represents CR Y1 , where R Y1 It represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5, -S(O)2CH3 or cyano.

[0071] In the preferred technical solution of formula I or II, Y2 represents N.

[0072] In the preferred technical solution of formula I or II, wherein Y3 represents CH or CD.

[0073] In the preferred technical solution of formula I or II, wherein R' represents -CHR 2 R 3 , where R 2 、R 3 Each independently represents hydrogen, deuterium, C1-C6 alkyl, or 0-3 selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NRa R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

[0074] In the preferred technical solution of formula I or II, wherein R' represents -CHR 2 R 3 , where R 2 represents hydrogen, deuterium, C1-C6 alkyl; R 3 represents hydrogen, C1-C6 alkyl, or 0-3 selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

[0075] In the preferred technical solution of formula I or II, wherein R' represents -CHR 2R 3 , where R 2 represents hydrogen, deuterium, C1-C6 alkyl; R 3 represents 0-3 selected from 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 、-S(O)2R a 、-S(O)R a , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

[0076] In the preferred technical solution of formula I or II, wherein R' represents -CHR 2 R 3 , where R 2 represents hydrogen, deuterium, C1-C6 alkyl; R 3 represents 0-3 selected from 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 、-S(O)2R a 、-S(O)R a , -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 CORb or -CONR a R b The following groups are substituted:

[0077] In the preferred technical solution of formula I or II, wherein R' represents 0-3 selected from deuterated, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-CN、NR a R b , halogenated C1-C6 alkyl, C1-C6 alkyl substituted by halogenated C1-C6 alkoxy.

[0078] In the preferred technical solution of formula I or II, wherein R' represents 0-3 selected from deuterated, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-CN、NR a R b , C3-C substituted by halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy 10 Cycloalkyl.

[0079] In the preferred technical solution of formula I or II, wherein R' represents 0-3 selected from deuterated, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-CN、NR a R b , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl substituted by halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy.

[0080] In the preferred technical solution of formula I or II, wherein R' represents 0-3 selected from deuterated, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-CN、NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy substituted 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

[0081] In the preferred technical solution of formula I or II, wherein R' represents 0-3 selected from deuterated, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-CN、NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, substituted following groups:

[0082] In the preferred technical solution of formula I or II, wherein R' represents any one of the following groups:

[0083] Specifically, the present invention provides the following compounds:

[0084] In the above preferred technical solution of the present invention, at least one or more hydrogen atoms in the isotope derivative are deuterium atoms.

[0085] In addition, the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises any one of the above-mentioned compounds of the present invention, its pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotope derivative and a pharmaceutically acceptable carrier.

[0086] Unless otherwise indicated, the compounds of the present invention may be interpreted to include, in addition to the specific structures of the compounds, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotope isomers (e.g., deuterated compounds), solvates, hydrates, prodrugs, and metabolites. In other words, pharmaceutically acceptable salts of the compounds, their stereoisomers, isotope isomers, solvates, hydrates, prodrugs, and metabolites also fall within the scope of protection of the compounds.

[0087] Preferably, the pharmaceutical composition of the present invention 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.

[0088] In addition, the present invention also provides a compound of the present invention, 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.

[0089] definition:

[0090] 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.

[0091] The term "haloalkyl" refers to an alkyl group as defined above wherein one or more hydrogen atoms are replaced by a halogen atom.

[0092] 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. "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.

[0093] 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.

[0094] 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, and dihydroindanyl. The cycloalkyl group is optionally substituted with one or more halogen atoms. Furthermore, the term "cycloalkyl" as used herein includes bridged ring systems and spirocyclic ring systems.

[0095] 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.

[0096] 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.). Furthermore, 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".

[0097] The term "cycloalkoxy" refers to a cycloalkyl group as defined above bound to an oxygen atom, such as cyclopropyloxy.

[0098] The term "haloalkoxy" refers to an alkoxy group as defined above in which one or more hydrogen atoms are replaced by a halo.

[0099] 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.

[0100] 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.

[0101] "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.

[0102] 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.

[0103] 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.

[0104] 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, 4-chlorobutyl, 3-bromopropyl, and the like.

[0105] "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.

[0106] Optical isomers - diastereomers - geometric isomers - tautomers:

[0107] The compounds of formula (I) may contain asymmetric centers and may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is intended to encompass all such isomeric forms of the compounds of formula (I).

[0108] Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are intended to include both E and Z geometric isomers.

[0109] Some of the compounds of the present invention may contain one or more than one ring system and may therefore exist as cis- and trans-isomers. The present invention is intended to include all such cis- and trans-isomers.

[0110] Some compounds described herein may have different sites of attachment to hydrogen atoms, known as tautomers. Examples of such are the ketone and its enol form, known as keto-enol tautomers. Individual tautomers as well as mixtures thereof are encompassed within the compounds of the present invention.

[0111] The compounds of the present invention 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.

[0112] Alternatively, any enantiomer of a compound of the invention may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

[0113] Stable isotope-labeled analogs: One or more protons in the compounds of the present invention may be replaced with deuterium atoms to provide deuterated analogs with improved pharmacological activity.

[0114] Salt and dosage form

[0115] It will be understood that, as used herein, references to the compounds of the present invention also include the pharmaceutically acceptable salts.

[0116] application

[0117] The compounds of the present invention can be used to treat PRMT5-related diseases. The compounds of the present invention can be prepared by the following reaction formula:

[0118] Method A:

[0119] Method A-SFC

[0120] Method B:

[0121] Method B-SFC

[0122] Method C:

[0123] Method C-SFC:

[0124] Among them, R 1 , R', A ring, W, X1, X2, X 3 、X 4 、X 5 、X 6 , Y1, Y2, and Y3 are as defined in claim 1, and PG is a protecting group.

[0125] 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.

[0126] Method B: Compound BP can be obtained by reacting acid chloride B-1 with amine B-2. The base used can be Et3N, DIPEA, or pyridine, and the solvent can be THF, 1,4-dioxane, DCM, or DCE. A catalyst such as DMPK can also be added to promote the reaction. Similarly, if the amine used is a racemate, the product can be resolved by chiral SFC, and the stereochemistry of the resulting isomers will be randomly assigned to R or S.

[0127] Method C: Compound CP can be obtained via an amino acid condensation reaction between carboxylic acid C-1 and amine C-2, followed by a one-step deprotection reaction. The condensation agent used in the condensation reaction can be HATU or PyBrOP, the base used can be DIPEA or TEA, and the solvent used can be DMF or DMAc. The protecting group selected is PMB or Boc. The reagent used for PMB deprotection is TFA or 5% methanesulfonic acid + TFA. The reagent used for Boc deprotection is TFA or HCl / EA, HCl / 1,4-dioxane, or TMSOTf + 2,6-lutidine. Similarly, if the amine used is a racemate, the product will be resolved by chiral SFC, and the stereochemistry of the resulting isomers will be randomly assigned to R or S.

[0128] Analytical HPLC

[0129] 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;

[0130] Preparative HPLC-MS

[0131] 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;

[0132] Mass spectrometer: Agilent G6125B.

[0133] The compounds of the present invention 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.

[0134] 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.

[0135] The following preparations and examples illustrate the present invention but do not limit it in any way.

[0136] The features and advantages of the subject matter of the present invention 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 without departing from the scope of the claims. Therefore, the description is to be regarded as illustrative in nature, not restrictive. The full scope of the subject matter of the present invention is set forth in the claims.

[0137] The present invention can be more easily understood by referring to the following examples, which are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0138] intermediates

[0139] Intermediate 1: 1-(pyrimidin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine

[0140] (5-(Trifluoromethyl)pyridin-2-yl)methanamine (5.0 g, 28 mmol) was dissolved in dichloromethane (100 ml), 1-(pyrimidin-2-yl)ethyl-1-one (5.0 g, 42.0 mmol) and potassium acetate (3.3 g, 33.6 mmol) were added, and the mixture was stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (9.0 g, 42.0 mmol) was added, and stirring was continued for 5 hours. After the reaction was completed, the mixture was poured into ice water and the mixture was washed with dichloromethane. The mixture was extracted with chloromethane (100 ml × 2), and the combined organic phases were washed with saturated brine (100 ml × 2), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by a rapid purification instrument (petroleum ether: ethyl acetate = 40:60) to give the target product 1-(pyrimidin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine (3.1 g, 10.9 mmol, 39% yield) as a yellow oil.

[0141] LCMS (ESI) m / z: 283 [M+H] +

[0142] Intermediate 1A and Intermediate 1B: Synthesis of (S)-1-(pyrimidin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine and (R)-1-(pyrimidin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine

[0143] 1-(Pyrimidin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine (1 g, 3.5 mmol) was prepared by chiral chromatography (Chromatographic column: CHIRAL ART Cellulose-SB, 2×25 cm, 5 μm, mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: methanol, flow rate: 20 ml / min, elution gradient: mobile phase B from 8% to 8% in 8 minutes, detection wavelength: 220 nm) to obtain public intermediate 1A (S)-1-(pyrimidin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine (450 mg, 1.6 mmol, 45%) and public intermediate 1B (R)-1-(pyrimidin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine (500 mg, 1.7 mmol, 50%) as yellow oils.

[0144] LCMS (ESI) m / z: 283 [M+H] +

[0145] Intermediate 2: (1-methylpyrazol-4-yl){[5-(trifluoromethyl)(2-pyridinyl)]methyl}amine

[0146] A mixture of 5-(trifluoromethyl)pyridine-2-carbaldehyde (5.00 g, 28.55 mmol), 1-methyl-1H-pyrazol-4-ylamine (3.33 g, 34.26 mmol), and dichloromethane (50.00 ml) was stirred at room temperature overnight. Sodium borohydride (1.62 g, 42.83 mmol) was then added, and the mixture was stirred at room temperature for 2 hours. The mixture was then diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution. The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated in vacuo to provide (1-methylpyrazol-4-yl){[5-(trifluoromethyl)(2-pyridyl)]methyl}amine (2.00 g, 22% yield).

[0147] LCMS(ESI):257[M+H] +

[0148] The intermediate amines in the following table can be prepared by using the synthetic steps described in Intermediate 2, replacing only the corresponding starting materials aldehyde or amine

[0149] Intermediate 6: N-(6-(trifluoromethyl)pyridazin-3-ylmethyl)cyclopropylamine

[0150] Step 1: 6-(Trifluoromethyl)pyridazine-3-methanol

[0151] At room temperature, methyl 6-(trifluoromethyl)pyridazine-3-carboxylate (200 mg, 0.9703 mmol) was dissolved in a mixed solution of tetrahydrofuran and methanol (6 ml, 2:1), and sodium borohydride (45 mg, 1.164 mmol) was added. After reacting at 25°C for 16 hours, the mixture was poured into water (30 ml) and extracted with ethyl acetate (50 ml x 2). 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 (0-10% ethyl acetate / petroleum ether) to give 6-(trifluoromethyl)pyridazine-3-methanol (0.1 g, yield: 58%).

[0152] LCMS (ESI) m / z: 179.10 [M+H] +

[0153] Step 2: (6-(trifluoromethyl)pyridazin-3-yl)methyl 4-methylbenzenesulfonate

[0154] 6-(Trifluoromethyl)pyridazine-3-methanol (400 mg, 2.246 mmol) and p-toluenesulfonyl chloride (655 mg, 3.369 mmol) were dissolved in THF (10 mL), and triethylamine (348 mg, 3.369 mmol) was added. The reaction was stirred at 25°C for 2 hours. When LCMS indicated the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (0-10% ethyl acetate / petroleum ether) to provide (6-(trifluoromethyl)pyridazin-3-yl)methyl 4-methylbenzenesulfonate (500 mg, yield: 67%).

[0155] LCMS (ESI) m / z: 333.1 [M+H] +

[0156] Step 3: N-(6-(trifluoromethyl)pyridazin-3-ylmethyl)cyclopropylamine

[0157] At room temperature, (6-(trifluoromethyl)pyridazin-3-yl)methyl 4-methylbenzenesulfonate (500 mg, 1.505 mmol) was dissolved in DMF (10 mL), and cyclopropylamine (438 mg, 7.523 mmol) and cesium carbonate (1.25 g, 3.762 mmol) were added. The reaction was stirred at room temperature for 2 hours. When LCMS showed 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 (0-10% ethyl acetate / petroleum ether) to provide N-(6-(trifluoromethyl)pyridazin-3-ylmethyl)cyclopropylamine (120 mg, yield: 36.7%).

[0158] LCMS (ESI) m / z: 218.1 [M+H] +

[0159] The intermediate amines in the following table can be prepared by adopting the synthetic steps described for intermediate 6, replacing only the corresponding starting materials:

[0160] Intermediate 16 N-methyl-1-(6-(trifluoromethyl)pyridazin-3-yl)ethan-1-amine

[0161] Step 1: A reaction system of 3-chloro-6-(trifluoromethyl)pyridazine (1000 mg, 5.48 mmol), tributyl(1-ethoxyvinyl)stannane (2370 mg, 6.57 mmol), bistriphenylphosphine palladium dichloride (192.27 mg, 0.27 mmol), and 15 mL of dioxane was reacted at 100°C for 8 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and the mixture was extracted three times with ethyl acetate (60 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-(1-ethoxyvinyl)-6-(trifluoromethyl)pyridazine (800 mg, 3.65 mmol, 66.93% yield) as a colorless oil.

[0162] LCMS(ESI):219[M+H] +

[0163] Step 2: 3-(1-Ethoxyvinyl)-6-(trifluoromethyl)pyridazine (800 mg, 3.67 mmol) was added to a 4M hydrochloric acid solution in dioxane (15 mL) and stirred for 2 hours. After the reaction, the resulting mixture was concentrated under reduced pressure. Purification by column chromatography (petroleum ether:ethyl acetate = 5:1) afforded 1-(6-(trifluoromethyl)pyridazin-3-yl)ethan-1-one (400 mg, 2.09 mmol, 57.38% yield) as a white solid.

[0164] LCMS(ESI):191[M+H] +

[0165] Step 3: A solution of 1-(6-(trifluoromethyl)pyridazin-3-yl)ethan-1-one (400 mg, 2.1 mmol), methylamine (78 mg, 2.52 mmol), tetraisopropyl titanate (1200 mg, 4.21 mmol), and 8 mL of 1,2-dichloroethane was stirred at 80°C for 2 hours. After complete conversion as determined by LCMS, the mixture was cooled to room temperature and a methanol solution (10 mL) of sodium borohydride (239 mg, 6.31 mmol) was added dropwise with stirring in an ice bath. Stirring was continued for two hours. After the reaction was complete, the solvent was removed by rotary evaporation and the mixture was extracted three times with ethyl acetate (60 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography (petroleum ether:ethyl acetate=1:2) gave N-methyl-1-(6-(trifluoromethyl)pyridazin-3-yl)ethan-1-amine (60 mg, 0.229 mmol, yield 15.44%) as a white solid.

[0166] LCMS(ESI):206[M+H] +

[0167] The following intermediate amines can be prepared by using the synthetic steps described for intermediate 15, replacing only the corresponding starting materials:

[0168] Intermediate 29 (R)-1-(4-cyclopropylphenyl)-N-methylethanol-1-amine

[0169] Step 1: Synthesis of tert-butyl (R)-(1-(4-bromophenyl)ethyl)(methyl)carbamate

[0170] Under an N2 atmosphere, NaH (2.66 g, 66.6 mmol, 60% purity) was added to a tetrahydrofuran solution of tert-butyl (R)-(1-(4-bromophenyl)ethyl)carbamate (CAS: 578729-21-2, 10.0 g, 33.3 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Iodomethane (7.24 g, 50.0 mmol) was then added to the reaction mixture, and the reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into water (150 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. Purification on a silica gel column (petroleum ether:ethyl acetate = 10:1) afforded tert-butyl (R)-(1-(4-bromophenyl)ethyl)(methyl)carbamate (8.0 g, 76% yield) as a yellow oil.

[0171] LCMS (ESI) m / z: 315.2 [M+H] +

[0172] Step 2: Synthesis of tert-butyl (R)-(1-(4-cyclopropylphenyl)ethyl)(methyl)carbamate

[0173] Under N2 atmosphere, Pd(dppf)Cl2 (325 mg, 0.477 mmol) was added to a mixed solution of tert-butyl (R)-(1-(4-bromophenyl)ethyl)(methyl)carbamate (1.5 g, 4.77 mmol), cyclopropyl trifluoroborate potassium salt (1.77 g, 11.7 mmol), cesium carbonate (4.76 g, 14.3 mmol) in toluene (30 ml) and water (5 ml). The reaction solution was reacted at 100°C for 16 hours. After the reaction was completed, the reaction solution was poured into water (80 ml) and extracted with ethyl acetate (50 ml×3). The organic phases were combined. The residue was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1) to give tert-butyl (R)-(1-(4-cyclopropylphenyl)ethyl)(methyl)carbamate (600 mg, yield: 46%) as a white solid.

[0174] LCMS (ESI) m / z: 276.3 [M+H] +

[0175] Step 3: Synthesis of (R)-1-(4-cyclopropylphenyl)-N-methylethanol-1-amine

[0176] At room temperature, hydrochloric acid / ethyl acetate (2.7 ml, 4 M, 10.9 mmol) was added to a solution of tert-butyl (R)-(1-(4-cyclopropylphenyl)ethyl)(methyl)carbamate (500 mg, 1.82 mmol) in dichloromethane (10 ml), and the reaction solution was reacted at room temperature for 5 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to give a crude product (R)-1-(4-cyclopropylphenyl)-N-methylethanol-1-amine hydrochloride (350 mg, crude product), which was used directly in the next step without purification.

[0177] LCMS (ESI) m / z: 176.20 [M+H] +

[0178] Intermediate 30 (R)-N-methyl-1-(4-(trifluoromethyl)phenyl)ethan-1-amine

[0179] Step 1: Dissolve (R)-1-(4-(trifluoromethyl)phenyl)ethan-1-amine (CAS: 578027-35-7, 2000 mg, 10.57 mmol), triethylamine (4271 mg, 42.29 mmol), and Boc anhydride (2768 mg, 12.69 mmol) in DCM (50 mL) and stir at room temperature for 2 hours. After completion of the reaction, extract with ethyl acetate (30 mL x 3). The combined organic phases are washed with saturated brine and dried over anhydrous sodium sulfate. The combined organic phases are concentrated under reduced pressure to yield tert-butyl (R)-(1-(4-(trifluoromethyl)phenyl)ethyl)carbamate (2000 mg, 58.85% yield) as a white solid.

[0180] LCMS(ESI):290[M+H] +

[0181] Step 2: Dissolve tert-butyl (R)-(1-(4-(trifluoromethyl)phenyl)ethyl)carbamate (2000 mg, 6.91 mmol) in tetrahydrofuran (15 mL). Slowly add sodium hydroxide (497.71 mg, 20.74 mmol) and stir for 1 hour. Add iodomethane (1180 mg, 8.30 mmol) dropwise and stir at room temperature for 2 hours. After the reaction is complete, extract with ethyl acetate (30 mL x 3). Combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate the combined organic phases under reduced pressure to obtain tert-butyl (R)-methyl(1-(4-(trifluoromethyl)phenyl)ethyl)carbamate (800 mg, 38.09% yield) as a white solid.

[0182] LCMS(ESI):304[M+H] +

[0183] Step 3: (R)-tert-Butyl methyl(1-(4-(trifluoromethyl)phenyl)ethyl)carbamate (800 mg, 2.64 mmol) was added to a 4M HCl solution in dioxane (20 mL) and stirred for 2 hours. After the reaction, the resulting mixture was concentrated under reduced pressure to obtain (R)-N-methyl-1-(4-(trifluoromethyl)phenyl)ethan-1-amine (300 mg, 55.98% yield) as a white solid.

[0184] LCMS(ESI):204[M+H] +

[0185] The following intermediate amines can be prepared by using the synthetic steps described for intermediate 30, replacing only the corresponding starting materials:

[0186] By adopting the third step of the synthesis of intermediate 15 and replacing only the corresponding starting materials, the intermediate amines in the following table can be prepared:

[0187] Intermediate 37 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester

[0188] Method 1:

[0189] Step 1: Synthesis of methyl 3-(2-ethoxy-2-oxoethylideneamino)-4-nitrobenzoate

[0190] At room temperature, methyl 3-amino-4-nitrobenzoate (4.5 g, 22.94 mmol) and ethyl glyoxylate (9.4 g, 45.88 mmol) were first added to a 250 ml round-bottom flask. Then, toluene (100 ml) was poured into the flask, and anhydrous magnesium sulfate (5.6 g, 45.88 mmol) was added. After the resulting mixture was stirred at 100°C for 16 hours, the reaction solution was filtered, and the filtrate was concentrated and dried. It was then purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1) ​​to obtain methyl 3-(2-ethoxy-2-oxoethylideneamino)-4-nitrobenzoate (2.4 g, yield: 37.3%) as a yellow solid.

[0191] LCMS (ESI) m / z: 281.2 [M+H] +

[0192] Step 2: Synthesis of ethyl 1-(5-methoxycarbonyl)-2-nitrophenyl)-1H-imidazole-5-carboxylate

[0193] Methyl 3-(2-ethoxy-2-oxoethylideneamino)-4-nitrobenzoate (2.4 g, 8.564 mmol) was dissolved in tetrahydrofuran (40 mL) at room temperature. p-Toluenesulfonylmethyl isocyanide (2.5 g, 12.85 mmol) and potassium carbonate (3.0 g, 21.41 mmol) were then added sequentially. The resulting reaction system was stirred at 75°C for 48 hours. After completion of the reaction, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain ethyl 1-(5-methoxycarbonyl)-2-nitrophenyl)-1H-imidazole-5-carboxylate (1.2 g, yield: 43.9%) as a yellow solid.

[0194] LCMS (ESI) m / z: 320.0 [M+H] +

[0195] Step 3: Synthesis of methyl 4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate

[0196] At room temperature, ethyl 1-(5-methoxycarbonyl)-2-nitrophenyl)-1H-imidazole-5-carboxylate (400 mg, 1.253 mmol) and sodium bisulfite (881 mg, 5.011 mmol) were dissolved in a mixed solvent (20 ml) of acetic acid and water (1:1). The mixture was then heated to 105° C. and maintained at this temperature for 16 hours. After the reaction was completed, the system was poured into water (10 ml) and filtered. The filter cake was washed with water and dried to obtain methyl 4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate (280 mg, yield: 91.9%) as a light yellow solid.

[0197] LCMS (ESI) m / z: 244.2 [M+H] +

[0198] Step 4: Synthesis of methyl 4-chloroimidazo[1,5-a]quinoxaline-8-carboxylate

[0199] At room temperature, 4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (280 mg, 1.19 mmol) was first dissolved in phosphorus oxychloride (5 ml), and the reaction system was then heated to 100° C. and maintained at this temperature with stirring for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and diluted with a small amount of acetonitrile, poured into water (30 ml), and then adjusted to pH=8 with saturated aqueous sodium bicarbonate solution. The mixture was then extracted with ethyl acetate (30 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The resulting filtrate was concentrated and spin-dried to give 4-chloroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (130 mg, yield: 41.7%) as a brown solid.

[0200] LCMS (ESI) m / z: 262.0 [M+H] +

[0201] Step 5: Synthesis of methyl 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate

[0202] Methyl 4-chloroimidazo[1,5-a]quinoxaline-8-carboxylate (130 mg, 0.4968 mmol) was dissolved in DMSO (3 mL) at room temperature. 4-Methoxybenzylamine (136 mg, 0.9936 mmol) and DIEA (197 mg, 1.490 mmol) were then added sequentially to the reaction system. The resulting mixture was reacted at 90°C for 16 hours. Upon completion, the reaction solution was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate, volume ratio 1:1) to obtain methyl 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate (85 mg, yield: 47.21%) as a yellow solid.

[0203] LCMS (ESI) m / z: 363.3 [M+H] +

[0204] Step 6: Synthesis of 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid

[0205] At room temperature, methyl 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate (85 mg, 0.2346 mmol) was first dissolved in a mixture of tetrahydrofuran and water (3.6 ml, volume ratio of 5:1), and then lithium hydroxide monohydrate (20.0 mg, 0.4691 mmol) was added. The resulting mixture was reacted at 50° C. for 5 hours. After the reaction was completed, the reaction solution was adjusted to pH = 6 with 4M hydrochloric acid and then concentrated under reduced pressure to give a crude product 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (85 mg), which was used directly in the next reaction without purification.

[0206] LCMS (ESI) m / z: 349.2 [M+H] +

[0207] Method 2:

[0208] Step 1: Synthesis of imidazo[1,5-a]imidazo[1,5-d]1,4-diazapiperazine-5,10-dione

[0209] Imidazole-5-carboxylic acid (100 g, 892.14 mmol) was added to thionyl chloride (500 ml) and stirred at 80°C for 12 h. The mixture was concentrated to give imidazo[1,5-a]imidazo[1,5-d]1,4-diazapiperazine-5,10-dione (70 g, 0.37 mol, 42% yield) as a yellow solid.

[0210] LCMS (ESI) m / z: 189 [M+H] +

[0211] Step 2: Synthesis of N-(4-bromo-2-fluorophenyl)imidazol-5-ylcarboxamide

[0212] To a mixture of 4-bromo-2-fluorophenylamine (60.60 g, 318.91 mmol) in tetrahydrofuran (600 ml) was slowly added dropwise sodium bistrimethylsilylamide (318.91 ml, 637.82 mmol, 2 mol / L) at 0°C over a period of 1 hour. Imidazo[1,5-a]imidazo[1,5-d]1,4-diazapiperazine-5,10-dione (60 g, 318.91 mmol) was then added. The mixture was stirred at room temperature for 12 hours, poured into water, filtered, and the crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 40%) to give N-(4-bromo-2-fluorophenyl)imidazol-5-ylformamide (60 g, 0.21 mol, 66% yield) as a white solid.

[0213] LCMS (ESI) m / z: 284 [M+H]+

[0214] Step 3: Synthesis of 8-bromo-10-hydroimidazo[1,5-a]quinoxaline-4-ol

[0215] N-(4-Bromo-2-fluorophenyl)imidazol-5-ylformamide (60 g, 211.20 mmol) and sodium hydride (16.88 g, 422.40 mmol, 60% content) were stirred in dimethylacetamide (600 ml) at 140° C. for 12 hours. The mixture was poured into water and filtered to give 8-bromo-10-hydroimidazo[1,5-a]quinoxaline-4-ol (50 g, 90% yield) as a yellow solid.

[0216] LCMS (ESI) m / z: 264 [M+H] +

[0217] Step 4: Synthesis of 8-bromo-4-chloro-10-hydroimidazo[1,5-a]quinoxaline

[0218] Phosphorus oxychloride (500 ml) was added to a mixture of 8-bromo-10-hydroimidazo[1,5-a]quinoxaline-4-ol (50 g, 189.34 mmol) and N,N-diisopropylethylamine (48.85 g, 378.67 mmol), and the mixture was stirred at 90° C. for 2 hours, followed by concentration. The residue was dissolved in acetonitrile and slowly added dropwise to ice water to precipitate a solid, which was filtered to give 8-bromo-4-chloro-10-hydroimidazo[1,5-a]quinoxaline (50 g, yield 93%).

[0219] LCMS (ESI) m / z: 282 [M+H] + .

[0220] Step 5: Synthesis of (8-bromo(10-hydroimidazo[1,5-a]quinoxalin-4-yl))[(4-methoxyphenyl)methyl]amine

[0221] 8-Bromo-4-chloro-10-hydroimidazo[1,5-a]quinoxaline (50 g, 176.98 mmol) and 4-methoxybenzylamine (29.13 g, 212.38 mmol) were added to dimethyl sulfoxide (500 ml), and N,N-diisopropylethylamine (45.66 g, 353.96 mmol) was added. The mixture was stirred at 80 degrees for 2 hours, then poured into water and filtered to give (8-bromo(10-hydroimidazo[1,5-a]quinoxaline-4-yl))[(4-methoxyphenyl)methyl]amine (50 g, yield 74%) as a yellow oil.

[0222] LCMS (ESI) m / z: 384 [M+H] +

[0223] Step 6: Synthesis of methyl 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate

[0224] (8-Bromo(10-hydroimidazo[1,5-a]quinoxaline-4-yl))[(4-methoxyphenyl)methyl]amine (50 g, 130.47 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (10.83 g, 13.05 mmol), and potassium acetate (25.57 g, 260.93 mmol) were added to a solution of dimethylformamide (50 ml) and methanol (250 ml). The system was reacted at 100° C. under a carbon monoxide atmosphere (4 MPa) for 12 hours, then poured into water and filtered. The mixture was purified by silica gel chromatography (petroleum ether:ethyl acetate = 80%) to give methyl 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (30 g, 63% yield) as a yellow solid.

[0225] LCMS (ESI) m / z: 363 [M+H] +

[0226] Step 7: Synthesis of 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0227] 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (30 g, 82.87 mmol) was added to a mixed solution of methanol, water, and tetrahydrofuran (1:1:1, 150 ml), and potassium hydroxide (92.40 g, 165.0 mmol) was added. The mixture was reacted at 60°C for 12 hours. The organic solvent was removed by vacuum concentration and then poured into water. The mixture was extracted with ethyl acetate (100 ml × 3) and concentrated in vacuo to give 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (25 g, yield 86%).

[0228] LCMS (ESI) m / z: 349 [M+H] +

[0229] The following intermediate carboxylic acids can be prepared by using the synthetic steps described in Method 2 for Intermediate 37, replacing only the corresponding starting materials:

[0230] Intermediate 45 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylic acid

[0231] Step 1: Synthesis of methyl 1-(5-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylate

[0232] At room temperature, methyl 3-amino-4-nitrobenzoate (5 g, 25.12 mmol) and methyl 1H-pyrrole-2-carboxylate (4.711 g, 37.68 mmol) were added to a 250 ml round-bottom flask. Then, N,N-dimethylformamide (100 ml) was poured into the flask, and cesium carbonate (24.5 g, 75.37 mmol) was added. The resulting mixture was stirred at 70°C for 6 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain methyl 1-(5-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylate (3.0 g, yield: 39.2%) as a yellow solid.

[0233] LCMS (ESI) m / z: 305.2 [M+H] +

[0234] Step 2: Synthesis of methyl 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-8-carboxylate

[0235] At room temperature, 1-(5-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylic acid methyl ester (3.0 g, 22.94 mmol) was first dissolved in acetic acid (60 ml), and then iron powder (7.7 g, 137.64 mmol) was added to the system. The resulting reaction system was stirred at 110°C for 4 hours. After the reaction was completed, the reaction solution was poured into water (100 ml) and filtered. The filter cake was washed with water and dried to obtain a gray solid 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-8-carboxylic acid methyl ester (1.8 g, yield: 32.4%).

[0236] LCMS (ESI) m / z: 243.1 [M+H] +

[0237] Step 3: Synthesis of methyl 4-chloropyrrolo[1,2-a]quinoxaline-8-carboxylate

[0238] At room temperature, 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-8-carboxylic acid methyl ester (1.8 g, 7.43 mmol) was first dissolved in phosphorus oxychloride (20 ml). The mixture was then heated to 90°C and maintained at this temperature for 3 hours. After the reaction was completed, the system was poured into water (50 ml) and filtered. The filter cake was washed with water and dried to obtain a brown solid 4-chloropyrrolo[1,2-a]quinoxaline-8-carboxylic acid methyl ester (1.3 g, yield: 67.2%).

[0239] LCMS (ESI) m / z: 261.2 [M+H] +

[0240] Step 4: Synthesis of methyl 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylate

[0241] Methyl 4-chloropyrrolo[1,2-a]quinoxaline-8-carboxylate (1.3 g, 5.000 mmol) was dissolved in DMSO (25 mL) at room temperature. 4-Methoxybenzylamine (1.027 g, 7.500 mmol) and DIEA (1.935 g, 15.00 mmol) were then added sequentially to the reaction system. The resulting mixture was reacted at 90°C for 8 hours. Upon completion, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate, volume ratio 1:1) to obtain methyl 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate (1.4 g, yield: 77.7%) as a yellow solid.

[0242] LCMS (ESI) m / z: 361.1 [M+H] +

[0243] Step 5: Synthesis of 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylic acid

[0244] At room temperature, methyl 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylate (130 mg, 0.3601 mmol) was dissolved in a mixture of tetrahydrofuran, methanol and water (4 ml, volume ratio of 2:2:1), and then lithium hydroxide monohydrate (25.9 mg, 1.080 mmol) was added. The resulting mixture was reacted at 25°C for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH = 6 with 4M hydrochloric acid and then concentrated under reduced pressure to obtain a crude product 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylic acid (100 mg, crude product), which was used directly in the next reaction without purification.

[0245] LCMS (ESI) m / z: 348.1 [M+H] +

[0246] The following intermediate carboxylic acids can be prepared by using the synthetic steps described for intermediate 45, replacing only the corresponding starting materials:

[0247] Intermediate 52 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0248] Step 1: Synthesis of methyl 3-(2-methyl-1H-imidazol-1-yl)-4-nitrobenzoate

[0249] Methyl 3-fluoro-4-nitrobenzoate (20.0 g, 100 mmol) was dissolved in acetonitrile (100 ml), followed by the addition of 2-methyl-1H-imidazole (8.2 g, 100 mmol) and potassium carbonate (27.6 g, 200 mmol). The mixture was stirred at 100° C. for 12 hours. The reaction was monitored by LCMS. The reaction solution was poured into water (300 ml), extracted with ethyl acetate (200 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and chromatographed on silica gel (petroleum ether:ethyl acetate=10%) to give methyl 3-(2-methyl-1H-imidazole-1-yl)-4-nitrobenzoate (25.0 g, 95% yield) as a yellow solid.

[0250] LCMS (ESI) m / z: 262 [M+H] +

[0251] Step 2: Synthesis of methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate

[0252] At room temperature, methyl 3-(2-methyl-1H-imidazol-1-yl)-4-nitrobenzoate (25 g, 95.8 mmol) was dissolved in methanol (300 ml), and then Raney nickel (2 g) was added. The mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction was monitored by LCMS. The residue was filtered to obtain a filtrate, which was concentrated and purified by silica gel chromatography (petroleum ether:ethyl acetate=20%) to give methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate (20.5 g, 93% yield) as a yellow solid.

[0253] LCMS (ESI) m / z: 232 [M+H] +

[0254] Step 3: Synthesis of 1-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester

[0255] Methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate (2.0 g, 8.7 mmol) was dissolved in o-dichlorobenzene (40 ml) at room temperature, and carbonyldiimidazole (2.8 g, 17.4 mmol) was then added. The mixture was stirred at 180°C for 12 hours. The reaction was monitored by liquid chromatography-mass spectrometry. The mixture was filtered to obtain a filter cake, which was then slurried with ethyl acetate (5 ml) to afford methyl 1-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate (920.0 mg, 41% yield) as a black solid.

[0256] LCMS (ESI) m / z: 258 [M+H] +

[0257] Step 4: Synthesis of methyl 4-chloro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate

[0258] Methyl 1-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate (100.0 mg, 0.39 mmol) was dissolved in phosphorus oxychloride (5 ml) at room temperature, and the mixture was stirred at 120°C for 4 hours. The reaction was monitored by liquid chromatography-mass spectrometry. The reaction solution was concentrated under reduced pressure, diluted with a small amount of acetonitrile, poured into water (5 ml), filtered, and the filter cake was washed with water and dried in vacuo to give methyl 4-chloro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate (60.0 mg, 56% yield) as a black solid.

[0259] LCMS (ESI) m / z: 276 [M+H] +

[0260] Step 5: Synthesis of methyl 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate

[0261] Methyl 4-chloro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate (60 mg, 0.22 mmol) was dissolved in dimethyl sulfoxide (2 ml) at room temperature, followed by the addition of (4-methoxyphenyl)methanamine (60 mg, 0.44 mmol) and N,N-diisopropylethylamine (67 mg, 0.52 mmol). The mixture was stirred at 100°C for 1 hour. The reaction was monitored by liquid chromatography-mass spectrometry. The reaction solution was poured into 10 ml of water and extracted with ethyl acetate (10 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (petroleum ether:ethyl acetate = 40%) to give methyl 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate (60 mg, 73% yield) as a black solid.

[0262] LCMS (ESI) m / z: 377 [M+H] +

[0263] Step 6: Synthesis of 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0264] At room temperature, methyl 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylate (60 mg, 0.16 mmol) was dissolved in methanol (1 ml), tetrahydrofuran (1 ml) and water (1 ml), and potassium hydroxide (26 mg, 0.44 mmol) was added. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by liquid chromatography-mass spectrometry. The reaction solution was poured into 10 ml of water, acidified by the addition of formic acid, and extracted with ethyl acetate (10 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (50 mg, 86% yield) as a white solid.

[0265] LCMS (ESI) m / z: 363 [M+H] +

[0266] The following intermediate carboxylic acids can be prepared by using the synthetic steps described for intermediate 52, replacing only the corresponding starting materials:

[0267] Intermediate 54: 4-amino-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylic acid

[0268] Step 1: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylate

[0269] A solution of methyl 4-amino-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylate (1.20 g, 4.34 mmol), di-tert-butyl dicarbonate (1.89 g, 8.67 mmol) and triethylamine (1.30 g, 13.01 mmol) in dichloromethane (10 ml) was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was poured into water (5 ml) and extracted with ethyl acetate (5 ml). The organic layer was dried over anhydrous sodium sulfate and filtered, then concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 70:30) to give methyl 4-((tert-butoxycarbonyl)amino)-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylate (1.00 g, 61% yield) as a white solid.

[0270] LCMS(ESI):376[M+H] +

[0271] Step 2: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylate

[0272] Under nitrogen atmosphere, 4-((tert-butyloxycarbonyl)amino)-7-chloroimidazo[1,5-a]quinoxaline-8-carboxylate)carbonylamino]-7-chloro-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (0.20 g, 0.53 mmol), potassium ferricyanide (0.05 g, 0.16 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.09 g, 0.21 mmol), methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl A mixture of 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (0.10 g, 51%) was stirred at 100° C. for 2 hours with 1,1′-biphenylyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (0.17 g, 0.21 mmol) and potassium acetate (0.01 g, 0.07 mmol) in dioxane / water (4.00 ml) and stirred at 100° C. for 2 hours, then concentrated and purified by column chromatography (petroleum ether:ethyl acetate=70:30) to give methyl 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylate (0.10 g, 51%) as a white solid.

[0273] LCMS(ESI):368[M+H] +

[0274] Step 3: Synthesis of methyl 4-amino-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylate

[0275] Trifluoroacetic acid (0.10 ml) was added to a solution of methyl 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylate (0.20 g, 0.54 mmol) in dichloromethane (0.50 ml), and the reaction was stirred at room temperature for 2 hours and then concentrated to give methyl 4-amino-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylate (0.05 g, crude product).

[0276] LCMS(ESI):268[M+H] +

[0277] Step 4: Synthesis of 4-amino-7-cyanoimidazolo[1,5-a]quinoxaline-8-carboxylic acid

[0278] A mixture of methyl 4-amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylate (0.20 g, 0.75 mmol), potassium hydroxide (0.07 g, 1.50 mmol), tetrahydrofuran / methanol / water (1 ml / 1 ml / 1 ml) was stirred at room temperature for 2 hours. After the reaction was completed, the system was concentrated to give a crude product of 4-amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylic acid (210 mg, crude product). The crude product was used directly in the next step without purification.

[0279] LCMS(ESI):254[M+H] +

[0280] Intermediate 55 4-amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0281] Step 1: Synthesis of methyl 4-{[(4-methoxyphenyl)methyl]amino}-7-methyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate

[0282] A mixture of methyl 7-chloro-4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (200 mg, 0.5 mmol), potassium carbonate (300 mg, 2 mmol), dichloro[1,1'-bis(tert-butylphosphino)ferrocenepalladium(II)] (0.08 g, 0.1 mmol), and trimethylboroxane (0.01 g, 0.10 mmol) was stirred in dioxane (2.00 ml) at 100° C. for 12 hours, then poured into water, extracted with ethyl acetate (5 ml), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (petroleum ether:ethyl acetate=30%) to give methyl 4-{[(4-methoxyphenyl)methyl]amino}-7-methyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (100 mg, 53%).

[0283] LCMS(ESI):268[M+H] +

[0284] Step 2: Synthesis of 4-((4-methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0285] Methyl 4-{[(4-methoxyphenyl)methyl]amino}-7-methyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylate (500 mg, 1.86 mmol) was dissolved in methanol:tetrahydrofuran:saturated potassium hydroxide aqueous solution (1 ml:1 ml:1 ml). The reaction solution was reacted at 60° C. for 12 hours. After completion, the reaction solution was spin-dried and the pH was adjusted to 3 with formic acid. The solution was filtered to give 4-((4-methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (52 mg, 12% yield).

[0286] LCMS(ESI):363[M+H] +

[0287] Step 3: Synthesis of 4-amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0288] 4-((4-Methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (500 mg, 1.86 mmol) was dissolved in trifluoroacetic acid solution (5 ml), and the reaction solution was stirred at 100° C. for 12 hours. After completion, the solution was dried to give 4-amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (52 mg, 0.23 mmol).

[0289] LCMS(ESI):363[M+H] +

[0290] The following intermediate acid was prepared using the method used in the third step of intermediate 55:

[0291] Intermediate 62 4-Amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid

[0292] Step 1: Synthesis of 6-bromo-2-chloro-3-hydrazinoquinoxaline

[0293] 6-Bromo-2,3-dichloroquinoxaline (278.0 mg, 1.0 mmol) was placed in a 25 mL single-necked flask. Hydrazine hydrate (156 mg, 2.5 mmol, 80% wt) was added and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the mixture was filtered and the filter cake was washed with water (10 mL x 2) and ethyl acetate (5 mL x 2) to yield 6-bromo-2-chloro-3-hydrazinoquinoxaline (150 mg).

[0294] LCMS (ESI) m / z: 273.0 / 275.0 [M+H] +

[0295] Step 2: Synthesis of 8-bromo-4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline

[0296] 6-Bromo-2-chloro-3-hydrazinoquinoxaline (116.0 mg, 0.5 mmol) was placed in a 25 mL single-necked vial at room temperature. Triethyl orthoformate (4.0 mL) was added. After the addition was complete, the reaction was heated to 100°C and allowed to react for 1 hour. After LCMS indicated completion of the reaction, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with methanol (3.0 mL x 3) and dried to yield 8-bromo-4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline (110 mg).

[0297] 1 H NMR (400MHz, CDCl3) δ10.21(s,1H),8.84(d,1H),7.98(d,1H),7.90(dd,1H).

[0298] Step 3: Synthesis of 8-bromo-N-(4-methoxybenzyl)-[1,2,4]triazolo[4,3-a]quinoxaline-4-amine

[0299] 8-Bromo-4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline (1.70 g, 6.00 mmol) was dissolved in DMSO (15.0 ml), and p-methoxybenzylamine (1.23 g, 9.00 mmol) and DIEA (2.32 g, 18.00 mmol) were added. The reaction system was reacted at 90°C for 4 hours. After the reaction was completed, water (60 ml) was added and the mixture was extracted with ethyl acetate (40 ml x 3). The organic phase was dried over sodium sulfate, filtered, and evaporated to dryness to give crude 8-bromo-N-(4-methoxybenzyl)-[1,2,4]triazolo[4,3-a]quinoxalin-4-amine (2.20 g).

[0300] LCMS (ESI) m / z: 384.1 / 386.1 [M+H] +

[0301] Step 4: Synthesis of methyl 4-((4-methoxybenzyl)amino)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate

[0302] To a solution of 8-bromo-N-(4-methoxybenzyl)-[1,2,4]triazolo[4,3-a]quinoxaline-4-amine (2.2 g, 5.74 mmol) in MeOH (30 mL) and DMF (30 mL) were added potassium acetate (1.7 g, 17.2 mmol) and Pd(dppf)Cl2 (420 mg, 0.57 mmol). The mixture was stirred at 100°C under a CO atmosphere for 12 h. After removing the methanol by vortexing, 100 mL of water was added and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and dried over anhydrous Na2SO4. The crude product was slurried in ethyl acetate (20 mL) to give methyl 4-((4-methoxybenzyl)amino)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate (1.1 g, 53% yield).

[0303] LCMS (ESI) m / z: 364.2 [M+H] +

[0304] Step 5: Synthesis of methyl 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate.

[0305] Methyl 4-((4-methoxybenzyl)amino)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate (300.0 mg, 0.78 mmol) was placed in a 25 mL single-necked flask. TFA (5.0 mL) was added and the reaction system was heated to 80°C and stirred at this temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated to dryness to obtain crude methyl 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate (190 mg).

[0306] LCMS (ESI) m / z: 244.3 [M+H] +

[0307] Step 6: Synthesis of 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid.

[0308] To the crude product from the previous step, methyl 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate (190 mg, 0.78 mmol), THF (5.0 mL) and methanol (5.0 mL) were added. The pH was adjusted to 7 with 3M aqueous potassium hydroxide solution. Lithium hydroxide (65.0 mg, 1.56 mmol) was then added and the reaction was stirred at 50°C for 16 hours. After the reaction was complete, the methanol and THF were removed by vortexing, and the pH was adjusted to 6.5 with 1M dilute hydrochloric acid. The mixture was filtered, and the filter cake was washed with water (5.0 mL x 3), dried, and dehydrated to yield crude 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid (120 mg).

[0309] LCMS (ESI) m / z: 230.1 [M+H] +

[0310] Intermediate 63 5-aminoimidazo[1,5-c]quinazoline-9-carboxylic acid

[0311] Step 1: Synthesis of 6-bromo-N-(4-methoxybenzyl)-4-methylquinazolin-2-amine

[0312] At room temperature, the compound 6-bromo-2-chloro-4-methylquinazoline (0.5 g, 1.942 mmol) was dissolved in DMSO (15 ml), and DIEA (768 mg, 5.825 mmol) and 4-methoxybenzylamine (600 mg, 3.883 mmol) were added. The reaction was stirred at room temperature for 16 hours, and water (50 ml) was added. The mixture was 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. The product was purified by column chromatography (0-10% methanol / dichloromethane) to give 6-bromo-N-(4-methoxybenzyl)-4-methylquinazoline-2-amine (500 mg, yield: 72%).

[0313] LCMS (ESI) m / z: 359.2 [M+H] +

[0314] Step 2: Synthesis of 9-bromo-N-(4-methoxybenzyl)imidazo[1,5-c]quinazolin-5-amine

[0315] At room temperature, compound 6-bromo-N-(4-methoxybenzyl)-4-methylquinazolin-2-amine (0.5 g, 1.396 mmol) was dissolved in DMSO (20 ml), and glycine (211 mg, 2.792 mmol), tert-butyl hydroperoxide (719 mg, 5.583 mmol), tetrabutylammonium iodide (104 mg, 0.2792 mmol) and acetic acid (251 mg, 4.1 87 mmol), under nitrogen protection, the reaction was stirred at 90 ° C for 16 hours, water (60 ml) was added, and the mixture was 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 and purified by column chromatography (0-10% methanol / dichloromethane) to give 9-bromo-N-(4-methoxybenzyl)imidazo[1,5-c]quinazolin-5-amine (300 mg, yield: 56%).

[0316] LCMS (ESI) m / z: 384.2 [M+H] +

[0317] Step 3: Synthesis of methyl 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylate

[0318] To a solution of 9-bromo-N-(4-methoxybenzyl)imidazo[1,5-c]quinazolin-5-amine (300 mg, 0.785 mmol) in MeOH (10 mL) and DMF (10 mL) was added potassium acetate (230 mg, 2.36 mmol) and Pd(dppf)Cl2 (58 mg, 0.0785 mmol) at room temperature. The mixture was stirred at 100°C under a CO atmosphere for 12 hours. After removing the methanol by vortexing, water (60 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (0-10% methanol / dichloromethane) afforded methyl 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylate (200 mg, yield: 56%).

[0319] LCMS (ESI) m / z: 363.2 [M+H] +

[0320] Step 4: Synthesis of methyl 5-aminoimidazo[1,5-c]quinazoline-9-carboxylate

[0321] At room temperature, the compound 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylic acid methyl ester (200 mg, 0.5519 mmol) was placed in a 20 ml round-bottom flask, trifluoroacetic acid (2 ml) was added and the mixture was stirred at 78°C for 3 hours. After the trifluoroacetic acid was removed by vortexing, water (5 ml) was added and the mixture was filtered. The filter cake was washed with water to obtain 5-aminoimidazo[1,5-c]quinazoline-9-carboxylic acid methyl ester (200 mg, crude product).

[0322] LCMS (ESI) m / z: 243.2 [M+H] +

[0323] Step 5: Synthesis of 5-aminoimidazo[1,5-c]quinazoline-9-carboxylic acid

[0324] At room temperature, the compound 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylic acid methyl ester (200 mg, 0.8257 mmol) was dissolved in a mixed solvent of methanol / tetrahydrofuran / water (9 ml, 4:4:1), and lithium hydroxide (40 mg, 1.651 mmol) was added. The mixture was stirred at 78°C for 3 hours. After removing the trifluoroacetic acid by vortexing, water (5 ml) was added and the mixture was filtered. The filter cake was washed with water to obtain 5-aminoimidazo[1,5-c]quinazoline-9-carboxylic acid (200 mg, crude product).

[0325] LCMS (ESI) m / z: 243.2 [M+H] +

[0326] Example 1

[0327] 4-amino-N-cyclopropyl-N-(5-trifluoromethylpyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0328] Step 1: Synthesis of N-cyclopropyl-4-(4-methoxybenzyl)amino)-N-(5-trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0329] At room temperature, 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (85 mg, 0.24 mmol) was dissolved in N,N-dimethylacetamide (3 ml), and then cyclopropyl{[5-(trifluoromethyl)(2-pyridyl)]methyl}amine (20.0 mg, 0.469 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (230 mg, 0.488 mmol) and N,N-diisopropylethylamine (96 mg, 0.7320 mmol) were added to the system in sequence. The mixture was reacted at 50°C for 3 hours. After completion of the reaction, the reaction solution was poured into water (15 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether: ethyl acetate, volume ratio: 1:1) to obtain a yellow solid (N-cyclopropyl-4-(4-methoxybenzyl)amino)-N-(5-trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (100 mg, yield: 75%).

[0330] LCMS (ESI) m / z: 559.3 [M+H] +

[0331] Step 2: Synthesis of 4-amino-N-cyclopropyl-N-(5-trifluoromethylpyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0332] N-(4-(4-methoxybenzyl)amino)-N-(5-trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (100 mg, 0.183 mmol) was dissolved in trifluoroacetic acid (2 mL) at room temperature. The resulting reaction mixture was allowed to react at 50°C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and poured into water (10 mL). The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by reverse phase column chromatography (water:acetonitrile, volume ratio 5:95) to obtain 4-amino-N-cyclopropyl-N-(5-trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (4.98 mg, 3.96% yield) as a white solid.

[0333] LCMS (ESI) m / z: 427.3 [M+H] +

[0334] 1H NMR (400MHz, CDCl3) δ8.91–8.84(m,1H),8.63(s,1H),8.10(d,J=1.8Hz,1H),7.93(dd,J=8.2,2.3Hz,1H),7.76–7.67(m,2H ),7.60(d,J=8.4Hz,1H),7.49(d,J=8.2Hz,1H),5.39(s,2H),4.97(s,2H),1.10(s,1H),0.67(d,J=6.8Hz,2H),0.59(s,2H).

[0335] The following examples can be prepared by using the same synthetic steps as described in Example 1, replacing only the corresponding starting materials:

[0336] Example 18

[0337] 4-amino-N-cyclopropyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide

[0338] 4-Aminoimidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxylic acid (240 mg, 1.047 mmol) was dissolved in N,N-dimethylacetamide (5 ml) at room temperature, and N-(1-(4-(trifluoromethyl)phenyl)ethyl)cyclopropylamine (200 mg, 0.8724 mmol), tripyrrolidinylphosphonium bromide hexafluorophosphate (493 mg, 1.047 mmol) and N,N-diisopropylethylamine (345 mg, 2.617 mmol) were added. The mixture was stirred at 25°C for 2 hours, the reaction solution was poured into water (50 ml), extracted with ethyl acetate (20 ml x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (dichloromethane:methanol=10:1) to give 4-amino-N-cyclopropyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide (50 mg, 13.01% yield).

[0339] 1H NMR (400MHz, DMSO-d6) δ9.28(s,1H),8.66(s,1H),8.42(s,1H),7.99(s,1H),7.74(d,J=8.2Hz,2H),7.68(s,2H),7.63(d,J=8.2Hz,2H), 5.57(d,J=7.3Hz,1H),3.17(d,J=5.2Hz,1H),2.89(s,1H),1.82(d,J=7.2Hz,3H),0.36(d,J=42.1Hz,3H),0.12(dd,J=10.2,5.8Hz,1H).

[0340] 19 F NMR(376MHz,DMSO-d6)δ-60.77.

[0341] LCMS (ESI) m / z: 441.5 [M+H] +

[0342] The following examples can be prepared by using the same synthetic steps as described in Example 18, replacing only the corresponding starting materials:

[0343] Example 47 (R)-4-amino-7-fluoro-N-(1-(5-fluoropyridin-2-yl)ethyl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0344] 4-Amino-7-fluoroimidazo[1,5-a]quinoxaline-8-carboxylic acid (287.41 mg, 1.17 mmol), TCFH (491.32 mg, 1.75 mmol), and NMI (191.71 mg, 2.33 mmol) were dissolved in dimethylacetamide (3 ml), and (R)-1-(5-fluoropyridin-2-yl)-N-methylethan-1-amine (180 mg, 1.17 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the system was cooled to room temperature and extracted with ethyl acetate three times (10 ml each time). The organic phases were combined, washed with saturated brine (10 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by high-performance liquid chromatography (HPLC): Kinetex 5m EVO C18 column, 30 mm × 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 20% B to 47% B over 10 minutes; wavelength: 254 / 220 nm; retention time (minimum): 9.35. (R)-4-amino-7-fluoro-N-(1-(5-fluoropyridin-2-yl)ethyl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide (17.9 mg, 1.17 mmol, 3.84% yield) was obtained as a white solid.

[0345] 1 H NMR(400MHz,DMSO-d6)δ9.35(s,1H),9.13(s,1H),8.34-8.32(m,1H),8.15-8.13(m,1H ),8.05-8.04(m,1H),7.85–7.65(m,2H),7.63–7.45(m,2H),7.34(s,2H),7.23-7.22(m 1H),4.96(S,2H),2.92–2.90(m,1H),0.60-0.49(M,4H).

[0346] LCMS (ESI): 426.85 [M+H] +

[0347] The following examples can be prepared by using the same synthetic steps as described in Example 47, replacing only the corresponding starting materials:

[0348] Example 6 Method 2: (4-amino(10-hydropyrazolo[1,5-a]quinoxalin-8-yl))-N-cyclopropyl-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide

[0349] Step 1: N-cyclopropyl(4-{[(4-methoxyphenyl)methyl]amino}(10-hydropyrazolo[1,5-a]quinoxalin-8-yl))-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide

[0350] 4-{[(4-Methoxyphenyl)methyl]amino}-10-hydropyrazolo[1,5-a]quinoxaline-8-carboxylic acid (200.0 mg, 0.57 mmol) and cyclopropyl{[5-(trifluoromethyl)(2-pyridyl)]methyl}amine (124.1 mg, 0.57 mmol) were dissolved in 3 ml of N,N-dimethylformamide solution, and then HATU (327.25 mg, 0.86 mmol) and DIEA (222.2 mg, 1.72 mmol) were added thereto. After the completion of the reaction monitored by TLC and LCMS, the reaction solution was slowly added to 10 ml of water and extracted with ethyl acetate (10 ml×3). The organic layers were combined and dried over anhydrous Na2SO4. After filtration and concentration, N-cyclopropyl(4-{[(4-methoxyphenyl)methyl]amino}(10-hydropyrazolo[1,5-a]quinoxaline-8-yl))-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide (200.0 mg, yield: 48%) was obtained.

[0351] LCMS (ESI) m / z: 509 [M+H] +

[0352] Step 2: Synthesis of (4-amino(10-hydropyrazolo[1,5-a]quinoxaline-8-yl))-N-cyclopropyl-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide

[0353] A solution of N-cyclopropyl(4-{[(4-methoxyphenyl)methyl]amino}(10-hydropyrazolo[1,5-a]quinoxalin-8-yl))-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide (100.00 mg, 0.18 mmol) in TFA (2 ml) was stirred overnight at 60° C. After the reaction was complete, the mixture was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate. The organic layer was collected and dried over Na2SO4, concentrated and purified by PREP_HPLC (column: XBridge Shield RP18 OBD column, 30×150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 ml / min; gradient: 20% B to 55% B, 55% B in 10 minutes; wavelength: 220 nm; RT1 (min): 8.48) to give (4-amino(10-hydropyrazolo[1,5-a]quinoxalin-8-yl))-N-cyclopropyl-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide (21.30 mg, 27% yield) as a white solid.

[0354] 1 H NMR (400MHz, DMSO-d6): δppm 8.95(s,1H),8.06(s,1H),8.50-8.40(m,1H),8.20-8.10(m,2H),7.80-7.5 2(m,3H),7.20(s,1H),4.90(s,2H),3.12-3.09(m,1H),0.56-0.51(m,4H).

[0355] LCMS (ESI) m / z: 427.35 [M+H] +

[0356] The following examples can be prepared by using the same synthetic steps as those described in Method 2 of Example 6, replacing only the corresponding starting materials:

[0357] Example 62: 4-amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0358] 4-{[(4-Methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carbonyl chloride (100 mg, 0.41 mmol) was dissolved in 1,2-dichloroethane (2 ml) and then added dropwise to a solution of N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)cyclopropaneamine (93 mg, 0.41 mmol) and pyridine (97 mg, 1.22 mmol) in 1,2-dioxolane (10 ml). The mixture was stirred at 60°C for 2 hours. After the reaction, the filtrate was concentrated, and the crude product was purified by reverse phase chromatography (acetonitrile: water = 50:50) to give 4-amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide (23 mg, 0.05 mmol, 12.85% yield) as a white solid.

[0359] 1 H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.95-8.94(m,1H),8.36-8.35(m,1H),8.18-8.15(m,1H),7.92-7.91(m,1H),7.68-7.6 1(m,1H),7.57-7.55(m,1H),7.43-7.41(m,3H),5.46-5.41(m,1H),3.10-3.08(m,1H),1.86-1.85(m,3H),0.54-0.34(m,4H).

[0360] LCMS (ESI): 441.30 [M+H] +

[0361] The following examples can be prepared by using the synthetic steps described in Example 62, replacing only the corresponding starting materials:

[0362] Example 66 Method di-4-amino-7-chloro-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolo[1,2-a]quinoxaline-8-carboxamide

[0363] Step 1: Synthesis of 7-chloro-4-((4-methoxybenzyl)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolo[1,2-a]quinoxaline-8-carboxamide

[0364] At room temperature, 7-chloro-4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylic acid (180 mg, 0.472 mmol) was first dissolved in DCM (3 ml), and then thionyl chloride (280.76 mg, 2.36 mmol) was added to the system in sequence. The resulting mixture was reacted at 50° C. for 3 hours. After the reaction was completed, the reaction solution was spin-dried under low pressure to remove thionyl chloride and dissolved in dichloromethane (2 ml). 1-(pyrimidin-2-yl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)ethane-1-amine (199.65 mg, 0.708 mmol) and triethylamine (287.0 mg, 2.838 The obtained product was dissolved in dichloromethane (1 ml), and the dried product was added dropwise to the system. The resulting mixture was reacted at 25°C for 3 hours. After the reaction was completed, the product was extracted with ethyl acetate (10 ml × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (petroleum ether: ethyl acetate, volume ratio of 1:3) to obtain 7-chloro-4-((4-methoxybenzyl)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolo[1,2-a]quinoxaline-8-carboxamide (80.0 mg, yield: 26.2%) as a yellow solid.

[0365] LCMS (ESI) m / z: 646.3 [M+H] +

[0366] Step 2: Synthesis of 4-amino-7-chloro-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolo[1,2-a]quinoxaline-8-carboxamide

[0367] At room temperature, 7-chloro-4-((4-methoxybenzyl)amino)-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolo[1,2-a]quinoxaline-8-carboxamide (80 mg, 0.12 mmol) was dissolved in TFA (2 ml). The resulting reactants were reacted at 75°C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure and poured into water (10 ml), which was then adjusted with saturated sodium bicarbonate solution. The reaction mixture was stirred for 2 hours until pH = 8, extracted with ethyl acetate (10 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was further purified by reverse phase column chromatography (water:acetonitrile volume ratio 5:95) to give 4-amino-7-chloro-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolo[1,2-a]quinoxaline-8-carboxamide (11.1 mg, 17.5% yield) as a white solid.

[0368] 1 H NMR (400MHz, DMSO-d6) δ8.89–8.86(m,1H),8.79(d,J=4.8Hz,1H),8.69(d,J=4. 8Hz,H),8.30–8.20(m,1H),8.14–8.08(m,1H),8.01(s,1H),7.74(d,J=8.4Hz,1 H),7.45–7.38(m,1H),.32–7.26(m,2H),7.22–7.13(m,1H),7.12–7.00(m,1H), 6.77–6.65(m,1H),5.18–5.03(m,2H),.60(d,J=16.8Hz,1H),1.62–1.54(m,3H).

[0369] LCMS (ESI) m / z: 526.9 [M+H] +

[0370] Example 23 Method II N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}(4-amino-7-chloro(10-hydroimidazo[1,5-a]quinoxalin-8-yl))-N-methylformamide

[0371] Step 1: Dissolve (R)-N-methyl-1-(4-(trifluoromethyl)phenyl)ethan-1-amine (100.00 mg, 0.49 mmol) and 4-amino-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (111.22 mg, 0.49 mmol) in N,N-dimethylformamide (2.00 ml) at room temperature, add N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (277.80 mg, 0.73 mmol) and N,N-diisopropylethylamine (188.97 mg, 1.46 mmol), and stir the reaction at 25°C for 16 hours. After completion of the reaction, dilute with ethyl acetate and wash continuously with saturated sodium bicarbonate. The organic layer was collected and dried over anhydrous sodium sulfate, concentrated and purified by PREP_HPLC (column: YMC Triart C18 ExRs 5m, 30mm×150mm; mobile phase A: water (10mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 60ml / minml / min; gradient: 35% B to 57% B in 10 minutes; wavelength: 254nm / 220nm; retention time (minute): 8.42) to give N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}(4-amino-7-chloro(10-hydroimidazo[1,5-a]quinoxalin-8-yl))-N-methylformamide (33.84 mg, 0.57mmol, yield 13%) as a white solid.

[0372] 1 H NMR(400MHz,DMSO-d6)δ9.21-9.10(m,1H),8.43-8.30(m,1H),7.94-7.91(m,1H),7.80-7.71(m,2H),7.7 0-7.60(m,3H),7.57–7.54(m,1H),7.50-7.48(m,1H),6.04-4.83(m,1H),2.56(s,3H),1.65-1.61(m,3H).

[0373] LCMS (ESI): 448.10 [M+H] + .

[0374] The following examples can be prepared by using the same synthetic steps as those described in Method 2 of Example 23, replacing only the corresponding starting materials:

[0375] Example 80 6-amino(7-hydroimidazo[1,2-c]quinazolin-2-yl)-N-(pyrimidin-2-ylethyl)-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide

[0376] Step 1: {6-[tert-Butoxy)carbonylamino](7-hydrogenimino[1,2-c]quinazolin-2-yl)}-N-(pyrimidin-2-ylethyl)-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide

[0377] 6-[(tert-Butoxy)-N-[(tert-Butyl)oxycarbonyl]carbonylamino]-7-hydroimidazo[1,2-c]quinazoline-2-carboxylate lithium (50 mg, 0.15 mmol) was dissolved in DMF (2 ml), and then (pyrimidin-2-ylethyl)[5-(trifluoromethyl)(2-pyridyl)methyl]amine (52 mg, 0.18 mmol), triethylamine (47 mg, 0.46 mmol) and tripyrrolidinylphosphonium bromide hexafluorophosphate (86 mg, 0.18 mmol) were added to the system in sequence. The mixture was stirred at 4 ℃ for 2 hours. The reaction was carried out at room temperature for 1 hour. After completion of the reaction, the system was poured into water (10 ml) and extracted with ethyl acetate (10 ml × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to give {6-[tert-butoxy)carbonylamino](7-hydrogenimino[1,2-c]quinazolin-2-yl)}-N-(pyrimidin-2-ylethyl)-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide (60 mg, crude product) as a white solid.

[0378] LCMS (ESI) m / z: 593.2 [M+H] +

[0379] Step 2: 6-amino(7-hydroimidazo[1,2-c]quinazolin-2-yl)-N-(pyrimidin-2-ylethyl)-N-{[5-(trifluoromethyl)(2-pyridinyl)]methyl}formamide

[0380] At room temperature, {6-[tert-butoxy)carbonylamino](7-hydroimidazo[1,2-c]quinazolin-2-yl)}-N-(pyrimidin-2-ylethyl)-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide (50 mg, 0.084 mmol) was dissolved in ethyl acetate (2 ml), and HCl / EA (0.2 ml, 0.84 mmol) was added thereto. After reacting at room temperature for 2 hours, the reaction solution was poured into water (10 ml), adjusted to pH = 8 with saturated sodium carbonate solution, extracted with ethyl acetate (10 ml×3), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase column chromatography (acetonitrile:water=5:95-70:30) to give 6-amino(7-hydroimidazo[1,2-c]quinazolin-2-yl)- N-(Pyrimidin-2-ylethyl)-N-{[5-(trifluoromethyl)(2-pyridinyl)]methyl}formamide (3 mg, 0.006 mmol, 7% yield) was obtained as a white solid.

[0381] LCMS (ESI) m / z: 493.3 [M+H] +

[0382] Example 97 4-amino-N-cyclopropyl-7-fluoro-N-(6-(trifluoromethyl)pyridin-3-ylmethyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0383] At room temperature, the compound 4-amino-7-fluoro-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (50 mg, 0.202 mmol) was dissolved in DMF (3 ml), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46 mg, 0.239 mmol) and 1-hydroxybenzotriazole (32 mg, 0.239 mmol) were added, followed by the addition of DIEA (95 mg, 0.736 mmol), and the reaction was stirred at room temperature for 0.5 hour. N-(6-(trifluoromethyl)pyridazin-3-ylmethyl)cyclopropylamine (40 mg, 0.184 mmol) was then added, and the mixture was reacted at room temperature for 16 hours. When LCMS showed the reaction was complete, water (20 mL) was poured into the mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated and purified by column chromatography (0-5% methanol / dichloromethane) to give 4-amino-N-cyclopropyl-7-fluoro-N-(6-(trifluoromethyl)pyridin-3-ylmethyl)imidazo[1,5-a]quinoxaline-8-carboxamide (15 mg, yield: 4.2%).

[0384] 1H NMR (400MHz, DMSO-d6) δ9.13(s,1H),8.81(s,1H),8.34(d,J=6.6Hz,1H),8.08(d,J=8.0Hz,1H),7.96(d ,J=16.4Hz,2H),7.60(s,2H),7.24(d,J=11.2Hz,1H),4.90(s,2H),2.81(s,1H),0.53(d,J=12.7Hz,4H).

[0385] LCMS (ESI) m / z: 445.2 [M+H] +

[0386] The following examples can be prepared by using the same synthetic steps as described in Example 97, replacing only the corresponding starting materials:

[0387] Example 81 (R)-4-amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide and

[0388] Example 82 (S)-4-amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0389] 4-Amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide (23 mg) was separated by chiral HPLC (CHIRALPAK I-3 The reaction mixture was stirred at 40 ℃ for 1 hr at 40 ℃ for 2 h. The resulting mixture was stirred at 40 ℃ for 1 hr at 40 ℃ for 2 h. The resulting mixture was stirred at 40 ℃ for 3 hr at 40 ℃ for 1 hr. The mixture was stirred at 40 ℃ for 2 hr. The mixture was stirred at 40 ℃ for 3 hr. The mixture was stirred at 40 ℃ for 1 hr. The mixture was stirred at 40 ℃ for 2 hr. The mixture was stirred at 40 ℃ for 3 hr. The mixture was stirred at 40 ℃ for 1 hr.

[0390] Pre-peak Example 81 (R)-4-amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0391] 1 H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.95-8.94(m,1H),8.36-8.35(m,1H),8.18-8.15(m,1H),7.92-7.91(m,1H),7.68-7.6 1(m,1H),7.57-7.55(m,1H),7.43-7.41(m,3H),5.46-5.41(m,1H),3.10-3.08(m,1H),1.86-1.85(m,3H),0.54-0.34(m,4H).

[0392] LCMS (ESI): 441.30 [M+H] +

[0393] Later Peak Example 82 (S)-4-amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0394] 1 H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.95-8.93(m,1H),8.36-8.35(m,1H),8.17-8.15(m,1H),7.92-7.90(m,1H),7.68-7.6 1(m,1H),7.57-7.56(m,1H),7.44-7.41(m,3H),5.46-5.41(m,1H),3.10-3.06(m,1H),1.86-1.85(m,3H),0.57-0.34(m,4H).

[0395] LCMS (ESI) m / z: 441.30 [M+H] + .

[0396] Using the procedures described in Example 81 and Example 82 and the corresponding chiral SFC separation conditions, the compounds shown in the following table were obtained:

[0397] Biochemical evaluation

[0398] 1. Experimental study on the inhibitory activity of compounds on tumor cell proliferation

[0399] Test Example 1: Inhibitory activity of compounds on HCT-116 MTAP(- / -) deficient cell proliferation

[0400] Materials and cells: HCT-116 MTAP(- / -)-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).

[0401] Cell culture: HCT116 MTAP(- / -)-deficient 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 for experiments.

[0402] Cell proliferation inhibitory activity assay: The Cell-Titer Glo assay was used to detect the inhibitory activity of compounds against HCT-116 MTAP(- / -)-deficient cells. The cell concentration was adjusted, and 40 μL was inoculated into each well of a 384-well plate. The plate was incubated overnight at 37°C and 5% CO2. 40 nL of compound was added to each well to a final concentration of 0-10,000 nM (starting concentration 10,000 nM, 3-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 viability. The test results are shown in Table 1.

[0403] Test Example 2: Experimental study on the inhibitory activity of compounds on HCT-116 wild-type cell proliferation

[0404] 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).

[0405] 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.

[0406] 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.

[0407] 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.

[0408] Table 1

[0409] 2. Pharmacokinetic Experiments in Mice

[0410] 1. Test compounds

[0411] The compounds used in this test are from the specific examples of the present invention.

[0412] 2. Experimental Animals

[0413] ICR male mice, N=3 / group; original source: Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd.

[0414] 3. Drug preparation and administration

[0415] 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.

[0416] 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.

[0417] 4. Sample Collection

[0418] 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.

[0419] 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.

[0420] Table 2: Pharmacokinetic data

[0421] Although the preferred embodiment has been described above, it will be apparent to those skilled in the art that modifications may be made without departing from the invention. Such modifications are considered to be possible variations within the scope of the invention.

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, in, W stands for N or CR W ; Where X3 represents N or CR X3 ; X4 represents N or CR X4 ; X5 represents N or CR X5 ; X6 represents N or CR X6 ; Among them, when X3 represents CR X3 When R X3 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X4 represents CR X4 When R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X5 represents CR X5 When R X5 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X6 represents CR X6 When R X6 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Wherein the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X3 and X4, and the ring may have 0-3 heteroatoms selected from O, N, and S; further, the ring may be substituted by 0-3 substituents selected from the following groups: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Wherein the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X4 and X5, and the ring may have 0-3 heteroatoms selected from O, N, and S; further, the ring may be substituted by 0-3 substituents selected from the following groups: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Wherein the ring A may be optionally fused with a 5-6 membered saturated or unsaturated ring at the chemical bond between X5 and X6, and the ring may have 0-3 heteroatoms selected from O, N, and S; further, the ring may be substituted by 0-3 substituents selected from the following groups: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Wherein, R' represents 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic monoheterocyclic group, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Preferably, R' represents -CHR 2 R 3 ; Among them, R 1 represents hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C 10 Cycloalkyl; Among them, R 2 、R 3 Each independently represents hydrogen, deuterium, -OR a , halogen, -CN, -C1-C6 alkyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Where W represents CR W When R W Selected from hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, halogenated C1-C6 alkoxy; Where X1 represents N or CR X1 ; Where X2 represents N or CR X2 ; Among them, Y1 represents CR Y1 R Y1’ NR Y1 , O, S, Se; Among them, Y2 represents CR Y2 R Y2’ NR Y2 , O, S, Se; Among them, Y3 represents CR Y3 R Y3’ NR Y3 , O, S, Se; Among them, R X1 、R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -SO3R a 、-NR a R b , -SF5; Among them, R Y1 、R Y1’ 、R Y2 、R Y2’ 、R Y3 、R Y3’ Each independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -SO3R a 、-NR a R b , -SF5; in, Indicates a single bond or a double bond; Among them, R a 、R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a 、R b Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, which has the following formula (II): in, W stands for N or CR W ; Where X3 represents N or CR X3 ; X4 represents N or CR X4 ; X5 represents N or CR X5 ; X6 represents N or CR X6 ; Among them, when X3 represents CR X3 When R X3 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X4 represents CR X4 When R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-4 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X5 represents CR X5 When R X5 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Among them, when X6 represents CR X6 When R X6 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-P(O)R a R b 、-CN、-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-C 10 Cycloalkyl, -OR a , oxo, hydroxy (C1-C6 alkyl), NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Wherein, R' represents 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic monoheterocyclic group, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Preferably, R' represents -CHR 2 R 3 ; Among them, R 1 represents hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, C3-C 10 Cycloalkyl; Among them, R 2 、R 3 Each independently represents hydrogen, deuterium, -OR a , halogen, -CN, -C1-C6 alkyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, hydroxy C1-C6 alkyl or 0-3 substituents selected from the following: deuterated, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl; Where W represents CR W When R W Selected from hydrogen, deuterium, C1-C6 alkyl, halogen, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-SF5、-NR a R b , halogenated C1-C6 alkyl, hydroxy C1-C6 alkyl, halogenated C1-C6 alkoxy; Where X1 represents N or CR X1 ; Where X2 represents N or CR X2 ; Among them, Y1 represents CR Y1 R Y1’ NR Y1 , O, S, Se; Among them, Y2 represents CR Y2 R Y2’ NR Y2 , O, S, Se; Among them, Y3 represents CR Y3 R Y3’ NR Y3 , O, S, Se; Among them, R X1 、R X2 Each independently represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -SO3R a 、-NR a R b , -SF5; Among them, R Y1 、R Y1’ 、R Y2 、R Y2’ 、R Y3 、R Y3’ Each independently represents absence, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxy C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a 、-SR a 、-S(O)2R a 、-S(O)R a 、-CN、-OC(O)R a 、-OCONR a R b , halogen, -SO3R a 、-NR a R b , -SF5; in, Indicates a single bond or a double bond; Among them, R a 、R b Each independently represents hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halo(C1-C6 alkyl), or R a 、 R b Together with the atoms to which they are attached, they form a 3-14 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S, and N.

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

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X1 represents CR X1 or N, where R X1 represents hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, or halogenated C1-C6 alkyl.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X2 represents CH or CD.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X3 represents CH, CD or N.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X4 means CR X4 or N where R X4 represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5, -SO3R a 、-SR a , cyano 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 、-P(O)R a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocycloalkyl, 6-10 membered heterocycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X5 means CR X5 or N where R X5 represents hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5, or cyano.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: X6 represents CH, CD or N.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: The chemical bond between Y1 and Y2 is a double bond.

11. The compound according to claim 10, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Y1 represents CR Y1 , where R Y1 It represents hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5, -S(O)2CH3 or cyano.

12. The compound according to claim 11, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein Y2 represents N.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: Y3 represents CH or CD.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R' represents -CHR 2 R 3 , where R 2 、R 3 Each independently represents hydrogen, deuterium, C1-C6 alkyl, or 0-3 selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

15. The compound according to claim 14, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein R' represents -CHR 2 R 3 ,in, R 2 represents hydrogen, deuterium, C1-C6 alkyl; R 3 represents hydrogen, C1-C6 alkyl, or 0-3 selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxy C1-C6 alkyl, NR a R b , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

16. The compound according to claim 15, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein R' represents -CHR 2 R 3 ,in, R 2 represents hydrogen, deuterium, C1-C6 alkyl; R 3 represents 0-3 selected from 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 、-S(O)2R a 、-S(O)R a , -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a 、-SR a 、-S(O)2R a 、-S(O)R a 、-SF5、-C(O)R a 、-C(O)OR a 、-OC(O)R a 、-OC(O)NR a R b 、-NR a COR b or -CONR a R b Replaced by C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

17. The compound according to claim 16, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein R' represents -CHR 2 R 3 ,in, R 2 represents hydrogen, deuterium, C1-C6 alkyl; R 3 represents 0-3 selected from 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 、-S(O)2R a 、-S(O)R a , -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 The following groups are substituted:

18. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R' represents 0-3 selected from deuterated, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-CN、NR a R b , halogenated C1-C6 alkyl, C1-C6 alkyl substituted by halogenated C1-C6 alkoxy.

19. The compound according to claim 17, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R' represents 0-3 selected from deuterated, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-CN、NR a R b , C3-C substituted by halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy 10 Cycloalkyl.

20. The compound according to claim 19, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R' represents 0-3 selected from deuterated, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-CN、NR a R b , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl substituted by halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy.

21. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R' represents 0-3 selected from deuterated, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-CN、NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy substituted 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl.

22. The compound according to claim 21, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R' represents 0-3 selected from deuterated, halogen, C1-C6 alkyl, hydroxy C1-C6 alkyl, -OR a 、-CN、NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, substituted following groups:

23. The compound according to claim 1, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, wherein: R' represents any of the following groups:

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof, characterized in that Selected from any of the following compound structures:

25. The isotopic derivative of the compound according to any one of claims 1 to 24, characterized in that At least one or more hydrogen atoms in the isotope derivative are deuterium atoms.

26. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to any one of claims 1 to 25, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotope derivative thereof, and a pharmaceutically acceptable carrier.

27. The pharmaceutical composition according to claim 26, characterized in that A second active substance may also be included, 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.

28. A method for treating a disease by inhibiting the action of PRMT5 using a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotopic derivative thereof.

29. The method of claim 28, wherein the disease is a tumor.

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