Novel prmt5 inhibitors and uses thereof

Abstract

Described herein are novel molecules having protein arginine methyltransferase 5 inhibitory activity, as well as methods of synthesis and use of the compounds. In particular, described herein are compounds of Formula (I), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as well as methods of synthesis and use of the compounds.

Description

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

[0002] (1) A Chinese patent application filed on August 9, 2022 with the China National Intellectual Property Administration, application number 202210951874.X, entitled “Novel PRMT5 Inhibitor and Its Application”;

[0003] (2) A Chinese patent application filed on September 26, 2022 with the China National Intellectual Property Administration, application number 202211173943.5, entitled “Novel PRMT5 Inhibitor and Its Application”;

[0004] (3) A Chinese patent application filed on November 22, 2022 with the China National Intellectual Property Administration, application number 202211473887.7, entitled “Novel PRMT5 Inhibitor and Its Application”;

[0005] (4) A Chinese patent application filed on January 17, 2023 with the China National Intellectual Property Administration, application number 202310080068.4, entitled “Novel PRMT5 Inhibitor and Its Application”;

[0006] (5) A Chinese patent application filed on April 14, 2023 with the China National Intellectual Property Administration, application number 202310402301.6, entitled “Novel PRMT5 Inhibitor and Its Application”;

[0007] (6) The entire contents of Chinese patent application filed on July 10, 2023 with the State Intellectual Property Office of China, application number 202310842267.4, entitled “Novel PRMT5 Inhibitor and Its Application”, are incorporated herein by reference. Technical Field

[0008] This application belongs to the field of drug synthesis, specifically relating to a PRMT5 inhibitor and its application. Background Technology

[0009] Epigenetic alterations are key mediators driving and maintaining malignant tumor phenotypes. Changes in DNA methylation, histone acetylation and methylation, non-coding RNA, and post-translational modifications are all epigenetic drivers of cancer development, independent of DNA sequence alterations. Arginine methylation is an important class of post-translational modifications that influence 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, which transfers a methyl group from S-adenosylmethionine (AdoMet) to histone and non-histone arginine side chains. Nine PRMT genes have been annotated in the human genome, classified into type I (PRMT1, 2, 3, 4, 6, and 8), type II (PRMT5 and PRMT9), and type III (PRMT7) enzymes based on the type of methylarginine produced. PRMT5 is primarily a type II enzyme that catalyzes the symmetrical dimethylation of arginine. PRMT5 was first discovered in a two-hybrid assay for proteins interacting with Janus tyrosine kinase (Jak2).

[0010] PRMT5 is a universal transcriptional repressor that forms complexes with other transcription factors, including BRG1 and Hbrm, Blimp1, and Snail. PRMT5 participates in a variety of cell biological processes through the methylation of various substrates in the cytoplasm and nucleus, 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 markers, 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. The core component of this protein complex is MEP50. MEP50 is essential for the enzymatic activity of PRMT5. Research has found that PRMT5 can methylate proteins involved in RNA splicing, such as SmD3, and can be used to track the chemical activity of PRMT5 in cellular organisms.

[0011] PRMT5 plays a crucial role in tumorigenesis. Studies have found that PRMT5 expression is upregulated in various tumors, including lymphoma, lung cancer, breast cancer, and colorectal cancer. Furthermore, PRMT5 expression is increased in mantle cell lymphoma (MCL) patient samples, and PRMT5 knockout inhibits MCL cell proliferation, indicating that PRMT5 plays an important role in MCL. PRMT5 overexpression promotes cell proliferation, while PRMT5 knockout inhibits the proliferation of melanoma, breast cancer, and lung cancer cell lines. Therefore, PRMT5 is a potential target for cancer therapy.

[0012] Loss of methylthioadenosine phosphorylase (MTAP) confers cellular selectivity for PRMT5 and its binding protein WDR77. MTAP is frequently lost due to its proximity to the normally absent tumor suppressor gene CDKN2A. Cells carrying MTAP deficiency exhibit increased intracellular concentrations of methylthioadenosine (MTA, a metabolite cleaved by MTAP). MTA has a structurally similar composition to S-adenosylmethionine (SAM), and with increasing concentrations, MTA acts as an intrinsically selective inhibitor, suppressing the binding of SAM to PRMT5 and consequently inhibiting PRMT5 methyltransferase activity.

[0013] The most significant structural difference between MTAP-deficient cancer cells and MTAP wild-type cancer cells lies in the PRMT5-MTA complex generated due to the accumulation of MTA concentration in MTAP-deficient cancer cells. Inhibitors developed targeting the PRMT5-MTA complex can selectively target MTAP-deficient cancer cells with minimal impact on normal cells, significantly improving the therapeutic index.

[0014] Therefore, the identification and development of small molecules that inhibit PRMT5 activity will serve as a treatment for various PRMT5-related diseases or conditions, such as cancer. Summary of the Invention

[0015] To address the technical problem of this invention, this invention provides a novel type of compound with excellent inhibitory activity against PRMT5.

[0016] Specifically, the compounds represented by formula (I) of this invention, including their pharmaceutically acceptable salts, esters, prodrugs, stereoisomers, or isotopic derivatives,

[0017]

[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 CRX5 X6 represents N or CR X6 ;

[0020] Where X3 represents CR X3 At that time, R X3 Indicates 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, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl;

[0021] Where X4 represents CR X4 At that time, R X4 Indicates 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, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl;

[0022] Where X5 represents CR X5 At that time, R X5 Indicates 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, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, -OR a Oxygenated, hydroxyl (C1-C6 alkyl), NR a R b -CN, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, -SO3R a -SR a -SF5, -C(O)Ra -C(O)OR a -OC(O)R a -OC(O)NR a R b -NR a COR b Or -CONR a R b Replaced C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl;

[0023] Where X6 represents CR X6 At that time, R X6 Indicates 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, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl;

[0024] The ring A may also have 5-6 saturated or unsaturated rings fused at the chemical bonds between X3 and X4, and the ring may also contain 0-3 heteroatoms selected from O, N, and S; furthermore, the ring may be substituted by 0-3 groups 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, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl;

[0025] The ring A may also have 5-6 saturated or unsaturated rings fused at the chemical bonds between X4 and X5, and the ring may also contain 0-3 heteroatoms selected from O, N, and S; furthermore, the ring may be substituted by 0-3 groups 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, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl;

[0026] The ring A may also have 5-6 saturated or unsaturated rings fused at the chemical bonds between X5 and X6, and the ring may also contain 0-3 heteroatoms selected from O, N, and S; furthermore, the ring may be substituted by 0-3 groups 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, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, -OR aOxygenated, hydroxyl (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 C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl;

[0027] Wherein, R' represents the presence of 0-3 substituents selected from the following: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic monoheterocyclic groups, -OR a , oxo, hydroxyl 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 The substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl;

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

[0029] Among them, R 1This indicates hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl;

[0030] Among them, R 2 R 3 Each can be used independently to represent hydrogen, deuterium, and -OR. a Halogen, -CN, -C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, or substituted with 0-3 substituents selected from the following: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl 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 C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl;

[0031] Where W represents CR W At that time, 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, hydroxylated C1-C6 alkyl, halogenated C1-C6 alkoxy;

[0032] Where X1 represents N or CR X1 ;

[0033] Where X2 represents N or CR X2 ;

[0034] Where Y1 represents CR Y1 R Y1’ NR Y1 、O、S、Se;

[0035] Where Y2 represents CR Y2 R Y2’ NR Y2 、O、S、Se;

[0036] Where Y3 represents CR Y3 R Y3’ NR Y3 、O、S、Se;

[0037] Among them, R X1 R X2 Each of these can be independently represented as hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxyl-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 of these independently represents the absence of, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and -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 or double bond;

[0040] Among them, R a R b Each can independently represent hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated (C1-C6 alkyl), or R. a R b Together with the atoms attached to it, they form 3-14 saturated or unsaturated rings, which may 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, having the structure of the following formula (II):

[0042]

[0043] Where W represents N or CR W ;

[0044] 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 ;

[0045] Where X3 represents CR X3 At that time, R X3 Indicates 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, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl;

[0046] Where X4 represents CR X4 At that time, R X4 Indicates 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, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl;

[0047] Where X5 represents CR X5 At that time, R X5 Indicates 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, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl;

[0048] Where X6 represents CR X6 At that time, R X6 Indicates 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 bHalogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl;

[0049] Wherein, R' represents the presence of 0-3 substituents selected from the following: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 3-6 membered saturated or unsaturated aliphatic monoheterocyclic groups, -OR a , oxo, hydroxyl 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 The substituted C1-C6 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl;

[0050] Preferably, R' represents -CHR 2 R 3 ;

[0051] Among them, R 1 This indicates hydrogen, deuterium, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl C1-C6 alkyl, C3-C 10 cycloalkyl;

[0052] Among them, R 2 R 3 Each can be used independently to represent hydrogen, deuterium, and -OR. a Halogen, -CN, -C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, or substituted with 0-3 substituents selected from the following: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl 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 C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl;

[0053] Where W represents CR W At that time, 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, hydroxylated C1-C6 alkyl, halogenated C1-C6 alkoxy;

[0054] Where X1 represents N or CR X1 ;

[0055] Where X2 represents N or CR X2 ;

[0056] Where Y1 represents CR Y1 R Y1’ NR Y1 、O、S、Se;

[0057] Where Y2 represents CR Y2 R Y2’ NR Y2 、O、S、Se;

[0058] Where Y3 represents CR Y3 R Y3’ NR Y3 、O、S、Se;

[0059] Among them, R X1 R X2 Each of these can be independently represented as hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxyl-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;

[0060] Among them, R Y1 R Y1’ R Y2 R Y2’ R Y3 R Y3’ Each of these independently represents the absence of, hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, and -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;

[0061] in, Indicates a single or double bond;

[0062] Among them, R a R b Each can independently represent hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated (C1-C6 alkyl), or R. a R b Together with the atoms attached to it, they form 3-14 saturated or unsaturated rings, which may contain 0-2 heteroatoms selected from O, S, and N.

[0063] In the preferred embodiment of formula I or II, W represents CH or N.

[0064] In the preferred embodiment of formula I or II, X1 represents CR X1 Or N, where R X1 It represents hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 alkoxy, and halogenated C1-C6 alkyl.

[0065] In the preferred embodiment of formula I or II, X2 represents CH or CD.

[0066] In the preferred embodiment of formula I or II, X3 represents CH, CD, or N.

[0067] In the preferred embodiment of formula I or II, X4 represents CR X4 Or N, where R X4 This indicates 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 Cyanoyl or selected from 0-4 or fewer substituents: deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl, C6-C 10 Cycloalkenyl, 4-10 membered heterocyclic alkyl, 6-10 membered heterocyclic alkenyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0068] In the preferred embodiment of formula I or II, X5 represents CR X5 Or N, where R X5 It can represent hydrogen, deuterium, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, halogen, SF5, or cyano.

[0069] In the preferred embodiment of formula I or II, X6 represents CH, CD, or N.

[0070] In the preferred embodiment of formula I or II, the chemical bond between Y1 and Y2 is a double bond.

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

[0072] In the preferred technical solution of formula I or II, Y2 represents N.

[0073] In the preferred embodiment of formula I or II, Y3 represents CH or CD.

[0074] In the preferred embodiment of formula I or II, R' represents -CHR. 2 R 3 , where R 2 R 3 Each independently represents hydrogen, deuterium, C1-C6 alkyl, or is selected by 0-3 elements from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl 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 C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0075] In the preferred embodiment of formula I or II, R' represents -CHR. 2 R 3 , where R 2 Indicates hydrogen, deuterium, and C1-C6 alkyl; R 3 It represents hydrogen, C1-C6 alkyl, or 0-3 elements selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl 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 C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0076] In the preferred embodiment of formula I or II, R' represents -CHR. 2R 3 , where R 2 Indicates hydrogen, deuterium, and C1-C6 alkyl; R 3 Indicates 0-3 elements selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl 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 C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0077] In the preferred embodiment of formula I or II, R' represents -CHR. 2 R 3 , where R 2 Indicates hydrogen, deuterium, and C1-C6 alkyl; R 3 Indicates 0-3 elements selected from deuterated, halogenated, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, -OR a , oxo, hydroxyl 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 replaced:

[0078] In the preferred embodiment of formula I or II, R' represents a radical selected from 0-3 deuterated, halogenated, C1-C6 alkyl, or hydroxyl C1-C6 alkyl groups, -OR a -CN, NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy-substituted C1-C6 alkyl.

[0079] In the preferred embodiment of formula I or II, R' represents a radical selected from 0-3 deuterated, halogenated, C1-C6 alkyl, or hydroxyl C1-C6 alkyl groups, -OR a -CN, NR a R b , C3-C substituted C1-C6 alkyl, C1-C6 alkoxy 10 Cycloalkyl.

[0080] In the preferred embodiment of formula I or II, R' represents a radical selected from 0-3 deuterated, halogenated, C1-C6 alkyl, or hydroxyl C1-C6 alkyl groups, -OR a -CN, NR a R b Cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl substituted with C1-C6 alkyl or C1-C6 alkoxy groups.

[0081] In the preferred embodiment of formula I or II, R' represents a radical selected from 0-3 deuterated, halogenated, C1-C6 alkyl, or hydroxyl C1-C6 alkyl groups, -OR a -CN, NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy-substituted 4-10 membered heterocyclic alkyl, C6-C 10 Aryl, 5-10 heteroaryl.

[0082] In the preferred embodiment of formula I or II, R' represents a radical selected from 0-3 deuterated, halogenated, C1-C6 alkyl, or hydroxyl C1-C6 alkyl groups, -OR a -CN, NR a R b Halo-C1-C6 alkyl groups, halo-C1-C6 alkoxy groups, and substituted groups of the following:

[0083]

[0084] In the preferred embodiment of formula I or II, R' represents any one of the following groups:

[0085]

[0086] Specifically, the present invention provides the following compounds:

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096] In the preferred embodiment of the present invention described above, the isotope derivative contains at least one or more deuterium atoms.

[0097] In addition, the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition comprises any of the compounds described above, a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotope derivative thereof, and a pharmaceutically acceptable carrier.

[0098] Unless otherwise indicated, the compounds of the present invention, in addition to their specific structures, may also be interpreted as pharmaceutically acceptable salts, stereoisomers (e.g., deuterated compounds), solvates, hydrates, prodrugs, and metabolites of the compound, i.e., pharmaceutically acceptable salts, stereoisomers, isotopic isomers, solvates, hydrates, prodrugs, and metabolites of the compound, which also fall within the scope of protection of the compound.

[0099] Preferably, the pharmaceutical composition of the present invention may further include a second active substance, wherein the second active substance is an antitumor drug, and the antitumor drug includes one or more of chemotherapy drugs, targeted tumor therapy drugs, or tumor therapy antibody drugs.

[0100] In addition, the present invention also provides a method for treating a disease by inhibiting the action of PRMT5, wherein the compound of the present invention is a pharmaceutically acceptable salt, ester, prodrug, stereoisomer or isotope derivative thereof, preferably a tumor.

[0101] definition:

[0102] Unless otherwise stated, the term "alkyl" itself, or as part of another substituent, refers to a straight-chain (i.e., unbranched) or branched, or cyclic hydrocarbon group, or a combination thereof, which may be saturated, monounsaturated or polyunsaturated, and may include divalent or polyvalent groups having a specified number of carbon atoms (i.e., C1-C2). 10 This refers to one to ten carbon atoms. Examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclohexylmethyl, cyclopropylmethyl, and homologues and isomers such as n-pentyl, n-hexyl, n-heptyl, n-octyl. An unsaturated alkyl group is an alkyl group having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotonyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers. An alkyl group defined as a hydrocarbon group is called a "homoalkyl". The alkyl group is optionally substituted with one or more halogen atoms.

[0103] The term "halogenated alkyl" refers to an alkyl group as defined above, in which one or more hydrogen atoms are replaced by halogen atoms.

[0104] The term "alkylene" itself, or as part of another substituent, refers to a divalent group derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2C≡CCH2-, and -CH2CH2CH(CH2CH2CH3)CH2-. Alkyl (or alkylene) groups typically have 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred in this invention. "Lower alkyl" or "lower alkylene" refers to a shorter-chain alkyl or alkylene group, typically having eight or fewer carbon atoms. The alkylene group may optionally be substituted with one or more halogen atoms.

[0105] 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, propynyl, 3-methyl-1-pentynyl, 2-heptynyl, etc. The alkynyl group may optionally be substituted with one or more halogen atoms.

[0106] The term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbon ring, each having 3 to 10 carbon atoms. "Fused analogues" of cycloalkyl refer to a monocyclic ring fused with an aryl or heteroaryl group, wherein the linking site is in the non-aromatic portion. Examples of cycloalkyl and their fused analogues include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, decahydronaphthyl, dihydroindenyl, etc. The cycloalkyl group may optionally be substituted with one or more halogen atoms. Further, the term "cycloalkyl" in this invention includes bridged ring systems and spirocyclic systems.

[0107] The term "alkoxy group" refers to a straight-chain or branched alkoxy group that indicates the number of carbon atoms. 1-6 Alkyl groups, for example, include methoxy, ethoxy, propoxy, isopropoxy, etc.

[0108] Unless otherwise stated, the term "heteroalkyl" on its own or in combination with another term refers to a stable straight-chain or branched, or cyclic, hydrocarbon group, or combination thereof, consisting of at least one carbon atom and at least one heteroatom selected from O, N, P, Si, and S, wherein the nitrogen atom, phosphorus atom, or sulfur atom may optionally be oxidized and the nitrogen atom may optionally be quaternized. The heteroatoms O, N, P, S, and Si may be placed at any position within the heteroalkyl group or at a position where the alkyl group 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 can be consecutive. For example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene" itself, or in combination with other terms, refers to a divalent group 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 end 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's molecular formula is written does not indicate the orientation of the linking group. For example, the molecular formula -C(O)OR'- represents -C(O)OR'- and -R'OC(O)-. As stated above, heteroalkyl as used herein includes those groups attached to the remainder of the molecule by a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R", -OR', -SR', and / or -SO2R'. Where “heteroalkyl” is referred to, followed by specific heteroalkyl groups such as -NR'R", it should be understood that the terms heteroalkyl and -NR'R are not repetitive and are not mutually exclusive. Rather, these specific heteroalkyl groups are referred to for clarity. Therefore, the term “heteroalkyl” should not be construed herein as excluding specific heteroalkyl groups such as -NR'R".

[0109] The term "cycloalkoxy" refers to a cycloalkyl group as defined above, such as a cyclopropoxy group, which is bonded to an oxygen atom.

[0110] The term "haloalkoxy" refers to an alkoxy group as defined above in which one or more hydrogen atoms are halogenated.

[0111] The term "aryl" refers to a monocyclic or bicyclic aryl group containing only a carbon atom. "Fused analogues" of aryl refer to the fusion of an aryl group with a monocyclic cycloalkyl group or a monocyclic heterocyclic group, where the connecting point is located at the aryl moiety. Examples of aryl groups and their fused-ring analogues include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1,4-benzodioxane, etc.

[0112] The term "heteroaryl" refers to a monocyclic or bicyclic aryl group containing at least one heteroatom selected from N, O, and S. "Fused analogues" of heteroaryls refer to the fusion of a heteroaryl group with a monocyclic cycloalkyl group or a monocyclic heterocyclic group, wherein the connecting point is located at the aryl moiety. Examples of heteroaryls include pyrroleyl, isozolyl, isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazoleyl, triazolyl, tetrazolyl, furanyl, triazinyl, thiopheneyl, pyrimidinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiopheneyl, furano(2,3-b)pyridinyl, quinolinyl, indolyl, isoquinolinyl, etc.

[0113] "Substituted or Unsubstituted": The alkyl, aryl, and heteroaryl groups defined are either unsubstituted or substituted by at least one substituent selected from the group consisting of substituents. The substituents are 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, arylalkoxy groups having 7 to 10 carbon atoms, arylcarbonyl groups, aminocarbonyl groups, and groups having 2 to 10 carbon atoms. Alkenyl groups with 5 to 5 carbon atoms, alkylthio groups with 1 to 6 carbon atoms, aminosulfinyl groups, aminosulfonyl groups, hydroxyl groups, -SF5, hydroxyalkyl groups with 1 to 4 carbon atoms, nitro groups, amino groups, carboxyl groups, alkoxycarbonyl groups with 2 to 5 carbon atoms, alkoxyalkyl groups with 1 to 4 carbon atoms, alkylsulfonyl groups with 1 to 4 carbon atoms, alkanoylamino groups with 1 to 6 carbon atoms, and in... Alkylaminoalkyl groups having 1 to 6 carbon atoms in both the alkanoyl and alkyl moieties; alkanoyl(alkyl)aminoalkyl groups having 1 to 6 carbon atoms in both the alkanoyl and alkyl moieties; alkylsulfonylamino groups having 1 to 4 carbon atoms; monoalkylaminocarbonyl or dialkylaminocarbonyl groups having 1 to 6 carbon atoms; monoalkylaminosulfinyl or dialkylaminosulfinyl groups having 1 to 6 carbon atoms; monoalkylaminosulfonyl or... Dialkylaminosulfonyl, aminoalkyl having 1 to 4 carbon atoms, monoalkylamino or dialkylamino having 1 to 6 carbon atoms, monoalkylaminoalkyl or dialkylaminoalkyl having 1 to 6 carbon atoms in each alkyl moiety, aralkyl having 7 to 10 carbon atoms, heteroarylalkyl having 1 to 4 carbon atoms in the alkyl moiety, heteroarylalkoxy having 1 to 4 carbon atoms in the alkoxy moiety, and alkylsulfonamide having 1 to 4 carbon atoms.

[0114] As used herein, the terms "heterocyclic," "heterocyclic," "heterocyclic alkyl," or "heterocyclic group" refer to a saturated, partially saturated, or unsaturated group (but not aromatic) having a monocyclic or fused ring (including bridged and spirocyclic systems, having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen within the ring; in fused ring systems, one or more rings may be cycloalkyl, aryl, or heteroaryl, provided the junction passes through a non-aromatic ring). In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized. To provide N-oxide, sulfinyl, and sulfonyl moieties. Examples of "heterocyclic groups" and their fused and analogues include pyrrolidinyl, piperidinyl, piperazinyl, imidazoalkyl, 2,3-dihydrofuran(2,3-b)pyridinyl, benzoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, etc. The term also includes non-aromatic, partially unsaturated monocyclic compounds such as 2- or 4-pyridones linked by a nitrogen atom or N-substituted -(1H,3H)-pyrimidine-2,4-diones (N-substituted uracil).

[0115] As used herein, the terms “substituted heterocyclic” or “substituted heterocyclic alkyl” or “substituted heterocyclic group” refer to a heterocyclic group substituted by 1 to 5 (e.g., 1 to 3) substituents, which are the same substituents defined as substituted cycloalkyl.

[0116] Unless otherwise stated, the terms "halogenated" or "halogen" on their own or as part of another substituent refer to a fluorine, chlorine, bromine, or iodine atom. Additionally, the term "halogenated alkyl" refers to both monohalogenated and polyhalogenated alkyl groups. For example, the term "halogenated (C1-C6)alkyl" refers to, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0117] A "prodrug" is a substance that is converted into a parent drug substance in the body. Prodrugs are frequently used in certain situations because they are easier to administer than the parent drug. For example, a prodrug may be bioavailable orally while the parent drug is not. In pharmaceutical compositions, prodrugs may also have higher solubility than the parent drug. Examples of prodrugs, but not limited to, include any compound of Formula I administered as an ester (prodrug) to facilitate transcellular transport, where water solubility is detrimental to migration within the cell membrane, but which is beneficial within the cell, is subsequently metabolized and hydrolyzed into the active substance, a carboxylic acid. Another example of a prodrug can be a short peptide (polyamino acid) with bonded acid groups, wherein the peptide is metabolized to release the active moiety.

[0118] Optical isomers - diastereomers - geometric isomers - tautomers:

[0119] Compounds of formula (I) may contain an asymmetric center and thus may exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomeric forms. This invention should encompass all such isomers of compounds of formula (I).

[0120] Some of the compounds described herein contain olefinic double bonds, which, unless otherwise stated, refer to both E and Z geometric isomers.

[0121] Some compounds of this invention may contain one or more ring systems, and therefore may have cis- and trans-isomers. This invention aims to include all of these cis- and trans-isomers.

[0122] Some of the compounds described herein can exist at different sites of hydrogen atom bonding, referred to as tautomers. Examples of such tautomers include ketones and their enol forms, known as keto-enol tautomers. Individual tautomers and mixtures thereof are included in the compounds of this invention.

[0123] The compounds of the present invention can be isolated into diastereoisomeric pairs of enantiomers, for example by fractional crystallization from a suitable solvent, such as methanol or ethyl acetate or mixtures thereof. A pair of enantiomers thus obtained can be separated into individual stereoisomers by conventional methods, such as using an optically active amine or acid as a resolving agent or in a chiral HPLC column.

[0124] Alternatively, any enantiomer of the compounds of the present invention can be obtained by stereo-directional synthesis using optically pure raw materials or reagents with known configurations.

[0125] Stable isotope-labeled analogs: One or more protons in the compounds of the present invention may be replaced with deuterium atoms, thereby providing deuterated analogs with improved pharmacological activity.

[0126] Salt and dosage form

[0127] It should be understood that, as used herein, the compounds mentioned in this invention also include pharmaceutically acceptable salts.

[0128] application

[0129] The compounds of this invention can be used to treat PRMT5-related diseases. The compounds of this invention can be prepared by the following reaction:

[0130] Method A:

[0131]

[0132] Method A-SFC

[0133]

[0134] Method B:

[0135]

[0136] Method B-SFC

[0137]

[0138] Method C:

[0139]

[0140] Method C-SFC:

[0141]

[0142] Among them, R 1 R', A ring, W, X1, X2, X 3 X 4 X 5 X 6 Y1, Y2, and Y3 are defined as in claim 1, where PG is a protecting group.

[0143] Method A: Compound AP can be obtained by an 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 mixture, it will be resolved by chiral SFC, and the stereochemistry of the resulting isomer will be randomly assigned as R or S.

[0144] Method B: Compound BP can be obtained by reacting acyl 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. Catalysts such as DMPK can also be added to promote the reaction. Similarly, if the amine used is racemic, the product will be resolved by chiral SFC, and the stereochemistry of the resulting isomer will be randomly assigned as R or S.

[0145] Method CCompound CP can be obtained through an amino acid condensation reaction of a carboxylic acid (C-1) and an amine (C-2) followed by a one-step deprotecting reaction. The condensing agent used in the condensation reaction can be HATU or PyBrOP, the base can be DIPEA or TEA, and the solvent can be DMF or DMAc. The selected protecting group is PMB or Boc. The reagent used for deprotecting PMB is TFA or 5% methanesulfonic acid + TFA, and the reagent used for deprotecting Boc is TFA or HCl / EA, HCl / 1,4-dioxane, or TMSOTf + 2,6-lutidine, etc. Similarly, if the amine used is a racemic mixture, the product will be resolved by chiral SFC, and the stereochemistry of the resulting isomer will be randomly assigned as R or S.

[0146] Analytical HPLC

[0147] Equipment: Agilent 1260; Column specifications: 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: from 10% B to 90% B; duration: 12 min; detector: DAD detector; wavelength: 254 / 220 nm;

[0148] Preparative HPLC-MS

[0149] HPLC equipment: Waters 2489; Column specifications: UltimateμXB-C18 (130A, 5µm, 30mm×150mm); Binary solvent system, mobile phase A: water (0.1% v / v ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60-100 mL / min; gradient: from 10% B to 90% B; detector: DAD detector; wavelength: 254 / 220 nm;

[0150] Mass spectrometer: Agilent G6125B.

[0151] 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, the reagents, solvents and reaction conditions specifically mentioned can be substituted, and, if necessary, the reactive sites can be protected and deprotected.

[0152] The following abbreviations have the following meanings: ACN refers to acetonitrile; EA refers to ethyl acetate; CDI refers to N,N'-carbonyldiimidazole; DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL-H represents diisobutylaluminum hydride; DIEA refers to diisopropylethylamine; DMAP refers to N,N-dimethylaminopyridine; DME refers to 1,2-dimethoxyethane; DMF refers to N,N-dimethylformamide; DMA and DMAc refer to N,N-dimethylformamide; DMPE refers to 1,2-bis(dimethyl)-dimethylformamide. Phosphinyl) ethane; DMSO stands for dimethyl sulfoxide; DPPB refers to 1,4-bis(diphenylphosphine)butane; dppe refers to 1,2-bis(diphenylphosphine)ethane; dppf refers to 1,1'-bis(diphenylphosphine)ferrocene; dppm refers to 1,1'-bis(diphenylphosphine)methane; DIAD refers to diisopropyl azodicarboxylate; EDCI represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; HATU represents 2-(7-aza-1H-benzotriazol-1-yl)-1,1, 3,3-Tetramethylurea hexafluorophosphate; HMPA represents hexamethylphosphoramide; IPA refers to isopropanol; LDA refers to lithium diisopropylamino; LHMDS refers to lithium di(trimethylsilyl)amino; LAH refers to lithium aluminum hydride; NCS refers to N-chlorosuccinimide; NaHMDS refers to sodium di(trimethylsilyl)amino; PyBOP refers to benzotriazol-1-yl-oxytripyrrolylphosphobenzotriazolium hexafluorophosphate; PyBrOP refers to tripyrrolylphosphonium bromide hexafluorophosphate; TDA-I refers to... (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-methylbenzenesulfonylmethylisocyanate; (Boc)2O refers to ditert-butyl dicarbonate; PE refers to petroleum ether; o / n refers to overnight reaction.

[0153] The following preparation and examples illustrate the present invention, but do not limit the invention in any way.

[0154] The features and advantages of the subject matter of the invention will become more apparent from the detailed description of the selected embodiments. As will be appreciated, the disclosed and claimed subject matter is susceptible to modification in various aspects without departing from the scope of the claims. Therefore, the description should be considered illustrative in nature, not restrictive. The full scope of the subject matter of the invention is set forth in the claims.

[0155] The present invention can be more readily understood by referring to the following embodiments, which are for illustrative purposes only and are not intended to limit the scope of the invention.

[0156] intermediate

[0157] Intermediate 1: 1-(pyrimidin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine

[0158]

[0159] Dissolve 5.0 g (28 mmol) of (5-(trifluoromethyl)pyridin-2-yl)methylamine in 100 mL of dichloromethane, add 5.0 g (42.0 mmol) of 1-(pyrimidin-2-yl)ethyl-1-one and 3.3 g (33.6 mmol) of potassium acetate, stir the mixture at room temperature for 1 hour, then add 9.0 g (42.0 mmol) of sodium triacetoxyborohydride, and continue stirring for 5 hours. After the reaction is complete, pour the mixture into ice water. Extracted with chloromethane (100 mL × 2), the organic phases were combined and washed with saturated brine (100 mL × 2), then dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by a rapid purifier (petroleum ether: ethyl acetate = 40:60) to obtain the target product 1-(pyrimidin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine (3.1 g, 10.9 mmol, yield 39%) as a yellow oil.

[0160] LCMS(ESI) m / z: 283 [M+H] +

[0161] Synthesis of Intermediates 1A and 1B: (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

[0162]

[0163] 1-(pyrimidin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine (1 g, 3.5 mmol) was prepared chirally (column: CHIRAL ART). Cellulose-SB, 2×25cm, 5μm, mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B: methanol, flow rate: 20 mL / min, elution gradient: mobile phase B increased from 8% to 8% within 8 minutes, detection wavelength: 220 nm) yielded common intermediate 1A(S)-1-(pyrimidin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine (450 mg, 1.6 mmol, 45%) and common intermediate 1B(R)-1-(pyrimidin-2-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)methyl)ethyl-1-amine (500 mg, 1.7 mmol, 50%) as a yellow oil.

[0164] LCMS(ESI) m / z: 283 [M+H] +

[0165] Intermediate 2: (1-methylpyrazol-4-yl){[5-(trifluoromethyl)(2-pyridyl)]methyl}amine

[0166]

[0167] A mixture of 5-(trifluoromethyl)pyridin-2-carboxaldehyde (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 overnight at room temperature. 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 continuously with a saturated sodium bicarbonate solution. The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under vacuum to give (1-methylpyrazol-4-yl){[5-(trifluoromethyl)(2-pyridyl)]methyl}amine (2.00 g, 22% yield).

[0168] LCMS(ESI):257[M+H] +

[0169] Using the synthetic steps described in Intermediate 2, by simply changing the corresponding starting material aldehyde or amine, the intermediate amines listed in the table below can be prepared.

[0170]

[0171] Intermediate 6: N-(6-(trifluoromethyl)pyridazine-3-ylmethyl)cyclopropylamine

[0172]

[0173] Step 1: 6-(trifluoromethyl)pyridazine-3-methanol

[0174] At room temperature, methyl 6-(trifluoromethyl)pyridazine-3-carboxylate (200 mg, 0.9703 mmol) was dissolved in a mixture of tetrahydrofuran and methanol (6 mL, 2:1), sodium borohydride (45 mg, 1.164 mmol) was added, and the mixture was reacted at 25 °C for 16 hours. The solution was then poured into water (30 mL), and the mixture was 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 obtain the crude product. The crude product was purified by column chromatography (0-10% ethyl acetate / petroleum ether) to give 6-(trifluoromethyl)pyridazine-3-methanol (0.1 g, yield: 58%).

[0175] LCMS(ESI) m / z: 179.10 [M+H] +

[0176] Step 2: (6-(trifluoromethyl)pyridazine-3-yl)methyl-4-methylbenzenesulfonate

[0177] 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 mixture was stirred at 25 °C for 2 h. After the reaction was complete as indicated by LCMS, 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 give (6-(trifluoromethyl)pyridazine-3-yl)methyl 4-methylbenzenesulfonate (500 mg, yield: 67%).

[0178] LCMS(ESI) m / z: 333.1 [M+H] +

[0179] Step 3: N-(6-(trifluoromethyl)pyridazine-3-ylmethyl)cyclopropylamine

[0180] At room temperature, 500 mg (1.505 mmol) of 6-(trifluoromethyl)pyridazin-3-yl)methyl 4-methylbenzenesulfonate was dissolved in 10 mL of DMF, 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 h. When the reaction was complete as indicated by LCMS, 10 mL of water 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 give N-(6-(trifluoromethyl)pyridazin-3-ylmethyl)cyclopropylamine (120 mg, yield: 36.7%).

[0181] LCMS(ESI) m / z: 218.1 [M+H] +

[0182] Using the synthetic steps described in intermediate 6, by simply changing the corresponding starting materials, the intermediate amines in the table below can be prepared:

[0183]

[0184]

[0185]

[0186]

[0187] Intermediate 16N-methyl-1-(6-(trifluoromethyl)pyridazin-3-yl)ethyl-1-amine

[0188]

[0189] Step 1: The reaction mixture of 3-chloro-6-(trifluoromethyl)pyridazine (1000 mg, 5.48 mmol), tributyl(1-ethoxyvinyl)stanane (2370 mg, 6.57 mmol), bis(triphenylphosphine)palladium dichloride (192.27 mg, 0.27 mmol), and 15 mL of dioxane was reacted at 100 °C for 8 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 combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The combined organic phases were concentrated under reduced pressure to obtain 3-(1-ethoxyvinyl)-6-(trifluoromethyl)pyridazine (800 mg, 3.65 mmol, yield 66.93%), a colorless oil.

[0190] LCMS(ESI):219[M+H] +

[0191] Step 2: 3-(1-ethoxyvinyl)-6-(trifluoromethyl)pyridazine (800 mg, 3.67 mmol) was added to 15 mL of 4M dioxane hydrochloride solution and stirred for 2 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. Purification by column chromatography (petroleum ether: ethyl acetate = 5:1) yielded 1-(6-(trifluoromethyl)pyridazine-3-yl)ethyl-1-one (400 mg, 2.09 mmol, yield 57.38%), a white solid.

[0192] LCMS(ESI):191[M+H] +

[0193] Step 3: A solution of 1-(6-(trifluoromethyl)pyridazin-3-yl)ethyl-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. After the addition was complete, stirring was continued for another 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 combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The combined organic phases were then concentrated under reduced pressure. Column chromatography (petroleum ether: ethyl acetate = 1:2) yielded N-methyl-1-(6-(trifluoromethyl)pyridazin-3-yl)ethyl-1-amine (60 mg, 0.229 mmol, yield 15.44%), a white solid.

[0194] LCMS(ESI):206[M+H] +

[0195] Using the synthetic steps described in Intermediate 15, by simply changing the corresponding starting materials, the intermediate amines in the table below can be prepared:

[0196]

[0197]

[0198]

[0199] Intermediate 29(R)-1-(4-cyclopropylphenyl)-N-methylethanol-1-amine

[0200]

[0201] Step 1: Synthesis of tert-butyl(R)-(1-(4-bromophenyl)ethyl)(methyl)carbamate

[0202] Under a nitrogen 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 mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give a yellow oily compound tert-butyl(R)-(1-(4-bromophenyl)ethyl)(methyl)carbamate (8.0 g, yield: 76%).

[0203] LCMS(ESI) m / z: 315.2 [M+H] +

[0204] Step 2: Synthesis of tert-butyl(R)-(1-(4-cyclopropylphenyl)ethyl)(methyl)carbamate

[0205] Under a nitrogen 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), potassium cyclopropanetrifluoroborate (1.77 g, 11.7 mmol), cesium carbonate (4.76 g, 14.3 mmol), toluene (30 mL), and water (5 mL). The reaction was carried out 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, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a white solid tert-butyl(R)-(1-(4-cyclopropylphenyl)ethyl)(methyl)carbamate (600 mg, yield: 46%).

[0206] LCMS(ESI) m / z: 276.3 [M+H] +

[0207] Step 3: Synthesis of (R)-1-(4-cyclopropylphenyl)-N-methylethanol-1-amine

[0208] 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). The reaction mixture was reacted at room temperature for 5 hours. After the reaction was completed, the reaction mixture was directly concentrated under reduced pressure to obtain the 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.

[0209] LCMS(ESI) m / z: 176.20 [M+H] +

[0210] Intermediate 30(R)-N-methyl-1-(4-(trifluoromethyl)phenyl)ethyl-1-amine

[0211]

[0212] Step 1: (R)-1-(4-(trifluoromethyl)phenyl)ethyl-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) were dissolved in DCM (50 mL) and stirred at room temperature for 2 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The combined organic phases were concentrated under reduced pressure to give (R)-(1-(4-(trifluoromethyl)phenyl)ethyl)carbamate tert-butyl ester (2000 mg, yield 58.85%), a white solid.

[0213] LCMS(ESI):290[M+H] +

[0214] Step 2: Dissolve (R)-(1-(4-(trifluoromethyl)phenyl)ethyl)carbamate tert-butyl ester (2000 mg, 6.91 mmol) in tetrahydrofuran (15 mL), slowly add sodium hydrogen (497.71 mg, 20.74 mmol), stir for 1 hour, then add iodomethane (1180 mg, 8.30 mmol) dropwise, stirring at room temperature for 2 hours after the addition is complete. After the reaction is complete, extract with ethyl acetate (30 mL × 3). Combine the organic phases, wash with saturated brine and dry with anhydrous sodium sulfate, then concentrate the combined organic phases under reduced pressure to give (R)-methyl(1-(4-(trifluoromethyl)phenyl)ethyl)carbamate tert-butyl ester (800 mg, yield 38.09%), a white solid.

[0215] LCMS(ESI):304[M+H] +

[0216] Step 3: 800 mg (2.64 mmol) of (R)-methyl-1-(4-(trifluoromethyl)phenyl)ethyl)carbamate tert-butyl ester was added to 20 mL of 4 M HCl dioxane solution and stirred for 2 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. (R)-N-methyl-1-(4-(trifluoromethyl)phenyl)ethyl-1-amine (300 mg, yield 55.98%) was obtained as a white solid.

[0217] LCMS(ESI):204[M+H] +

[0218] Using the synthetic steps described in intermediate 30, and only changing the corresponding starting materials, the intermediate amines in the table below can be prepared:

[0219]

[0220]

[0221] By using the third step of the synthesis of intermediate 15, and only changing the corresponding starting materials, the intermediate amines listed in the table below can be prepared:

[0222]

[0223]

[0224] Intermediate 37 methyl 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid

[0225] Method 1:

[0226]

[0227] Step 1: Synthesis of methyl 3-(2-ethoxy-2-oxoethyleneamino)-4-nitrobenzene

[0228] At room temperature, methyl 3-amino-4-nitrobenzene (4.5 g, 22.94 mmol) and ethyl glyoxylate (9.4 g, 45.88 mmol) were added to a 250 mL round-bottom flask. Then, toluene (100 mL) and anhydrous magnesium sulfate (5.6 g, 45.88 mmol) were added to the flask. The resulting mixture was stirred at 100 °C for 16 hours. The reaction solution was filtered, the filtrate was concentrated and evaporated to dryness, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a yellow solid methyl 3-(2-ethoxy-2-oxoethyleneamino)-4-nitrobenzene (2.4 g, yield: 37.3%).

[0229] LCMS(ESI) m / z: 281.2 [M+H]+

[0230] Step 2: Synthesis of ethyl 1-(5-methoxycarbonyl)-2-nitrophenyl)-1H-imidazolium-5-carboxylate

[0231] At room temperature, methyl 3-(2-ethoxy-2-oxoethyleneamino)-4-nitrobenzoate (2.4 g, 8.564 mmol) was first dissolved in tetrahydrofuran (40 mL). Then, p-methylbenzenesulfonylmethylisocyanate (2.5 g, 12.85 mmol) and potassium carbonate (3.0 g, 21.41 mmol) were added to the system sequentially. The resulting reaction system was then stirred at 75 °C for 48 hours. After the reaction was completed, 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, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain a yellow solid ethyl 1-(5-methoxycarbonyl)-2-nitrophenyl)-1H-imidazolium-5-carboxylate (1.2 g, yield: 43.9%).

[0232] LCMS(ESI) m / z: 320.0 [M+H] +

[0233] Step 3: Synthesis of methyl 4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate

[0234] At room temperature, ethyl 1-(5-methoxycarbonyl)-2-nitrophenyl)-1H-imidazolium-5-carboxylate (400 mg, 1.253 mmol) and sodium bisulfite (881 mg, 5.011 mmol) were dissolved in a mixed solvent of acetic acid and water (1:1) (20 mL). The mixture was then heated to 105 °C and maintained at this temperature for 16 hours. After the reaction was complete, the system was poured into water (10 mL), filtered, and the resulting filter cake was washed with water and dried to obtain a pale yellow solid, methyl 4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate (280 mg, yield: 91.9%).

[0235] LCMS(ESI) m / z: 244.2 [M+H] +

[0236] Step 4: Synthesis of methyl 4-chloroimidozopo[1,5-a]quinoxaline-8-carboxylate

[0237] At room temperature, methyl 4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylate (280 mg, 1.19 mmol) was dissolved in phosphorus oxychloride (5 mL). The reaction system was then heated to 100 °C and stirred for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, diluted with a small amount of acetonitrile, and poured into water (30 mL). The pH was then adjusted to 8 with a saturated sodium bicarbonate aqueous solution. The solution was then extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated and evaporated to dryness to obtain brown solid methyl 4-chloroimidazo[1,5-a]quinoxaline-8-carboxylate (130 mg, yield: 41.7%).

[0238] LCMS(ESI) m / z: 262.0 [M+H] +

[0239] Step 5: Synthesis of methyl 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid

[0240] At room temperature, methyl 4-chloroimidozolo[1,5-a]quinoxaline-8-carboxylate (130 mg, 0.4968 mmol) was first dissolved in DMSO (3 mL). Then, 4-methoxybenzylamine (136 mg, 0.9936 mmol) and DIEA (197 mg, 1.490 mmol) were added sequentially to the reaction system. The resulting mixture was reacted at 90 °C for 16 hours. After the reaction was completed, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried with 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 a yellow solid methyl 4-((4-methoxybenzyl)amino)imidozolo[1,5-a]quinoxaline-8-carboxylate (85 mg, yield: 47.21%).

[0241] LCMS(ESI) m / z: 363.3 [M+H] +

[0242] Step 6: Synthesis of 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid

[0243] At room temperature, methyl 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (85 mg, 0.2346 mmol) was dissolved in a mixture of tetrahydrofuran and water (3.6 mL, volume ratio 5:1), followed by the addition of lithium hydroxide monohydrate (20.0 mg, 0.4691 mmol). The resulting mixture was reacted at 50 °C for 5 hours. After the reaction was complete, the reaction solution was adjusted to pH 6 with 4M hydrochloric acid, and then concentrated under reduced pressure to obtain the 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.

[0244] LCMS(ESI) m / z: 349.2 [M+H] +

[0245] Method 2:

[0246]

[0247] Step 1: Synthesis of imidazo[1,5-a]imidazo[1,5-d]1,4-diazapiperazine-5,10-dione

[0248] Imidazole-5-carboxylic acid (100 g, 892.14 mmol) was added to thionyl chloride (500 mL), and the mixture was stirred at 80 °C for 12 hours. The mixture was then concentrated to give imidazo[1,5-a]imidazo[1,5-d]1,4-diazapiperazine-5,10-dione (70 g, 0.37 mol, yield 42%) as a yellow solid.

[0249] LCMS(ESI) m / z: 189 [M+H] +

[0250] Step 2: Synthesis of N-(4-bromo-2-fluorophenyl)imidazol-5-ylformamide

[0251] In a mixture of 4-bromo-2-fluorophenylamine (60.60 g, 318.91 mmol) and tetrahydrofuran (600 mL), sodium bis(trimethylsilylamino) (318.91 mL, 637.82 mmol, 2 mol / L) was slowly added dropwise over 1 hour. Then, imidazo[1,5-a]imidazo[1,5-d]1,4-diazapiperazine-5,10-dione (60 g, 318.91 mmol) was added. The mixture was stirred at room temperature for 12 hours, then poured into water and filtered. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 40%) to give N-(4-bromo-2-fluorophenyl)imidazo-5-ylformamide (60 g, 0.21 mol, yield 66%) as a white solid.

[0252] LCMS(ESI)m / z:284[M+H]+

[0253] Step 3: Synthesis of 8-bromo-10-hydroimidazo[1,5-a]quinoxaline-4-ol

[0254] N-(4-bromo-2-fluorophenyl)imidazol-5-ylformamide (60 g, 211.20 mmol) and sodium hydride (16.88 g, 422.40 mmol, 60% purity) were stirred in dimethylacetamide (600 mL) at 140 °C for 12 hours. The mixture was poured into water and filtered to obtain 8-bromo-10-hydroimidazo[1,5-a]quinoxaline-4-ol (50 g, 90% yield) as a yellow solid.

[0255] LCMS(ESI) m / z: 264 [M+H] +

[0256] Step 4: Synthesis of 8-bromo-4-chloro-10-hydroimidazo[1,5-a]quinoxaline

[0257] 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. The mixture was then concentrated, and the residue was dissolved in acetonitrile and slowly added dropwise to ice water. The solid precipitated and was filtered to give 8-bromo-4-chloro-10-hydroimidazo[1,5-a]quinoxaline (50 g, 93% yield).

[0258] LCMS(ESI) m / z: 282 [M+H] + .

[0259] Step 5: Synthesis of (8-bromo(10-hydroimidazo[1,5-a]quinoxalin-4-yl))[(4-methoxyphenyl)methyl]amine

[0260] 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), followed by N,N-diisopropylethylamine (45.66 g, 353.96 mmol). The mixture was stirred at 80°C for 2 hours, then poured into water and filtered to obtain a yellow oily (8-bromo(10-hydroimidazo[1,5-a]quinoxaline-4-yl))[(4-methoxyphenyl)methyl]amine (50 g, 74% yield).

[0261] LCMS(ESI) m / z: 384 [M+H] +

[0262] Step 6: Synthesis of methyl 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidozolo[1,5-a]quinoxaline-8-carboxylic acid

[0263] (8-bromo(10-hydroimidazo[1,5-a]quinoxaline-4-yl))[(4-methoxyphenyl)methyl]amine (50 g, 130.47 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (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 for 12 h under a carbon monoxide atmosphere (4 MPa). The mixture was then poured into water and filtered. The methyl ester of 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (30 g, 63% yield) was purified by silica gel chromatography (petroleum ether: ethyl acetate = 80%) to obtain methyl 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (30 g, 63% yield) as a yellow solid.

[0264] LCMS(ESI) m / z: 363 [M+H] +

[0265] Step 7: Synthesis of 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidozolo[1,5-a]quinoxaline-8-carboxylic acid

[0266] Methyl 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (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 reaction was carried out at 60 °C for 12 hours. After removing the organic solvent by vacuum concentration, the solution was poured into water, extracted with ethyl acetate (100 mL × 3), and concentrated under vacuum to obtain 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (25 g, 86% yield).

[0267] LCMS(ESI) m / z: 349 [M+H] +

[0268] Using the synthetic steps described in Method 2 for intermediate 37, and only changing the corresponding starting materials, the intermediate carboxylic acids in the table below can be prepared:

[0269]

[0270]

[0271] Intermediate 454-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylic acid

[0272]

[0273] Step 1: Synthesis of methyl 1-(5-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylic acid

[0274] At room temperature, methyl 3-amino-4-nitrobenzoate (5 g, 25.12 mmol) and methyl 1H-pyrrole-2-carboxylic acid (4.711 g, 37.68 mmol) were first added to a 250 mL round-bottom flask. Then, N,N-dimethylformamide (100 mL) and cesium carbonate (24.5 g, 75.37 mmol) were added to the flask. The resulting mixture was stirred at 70 °C for 6 hours. The reaction solution was filtered, the filtrate was concentrated and evaporated to dryness, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to give a yellow solid methyl 1-(5-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylic acid (3.0 g, yield: 39.2%).

[0275] LCMS(ESI) m / z: 305.2 [M+H] +

[0276] Step 2: Synthesis of methyl 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaloline-8-carboxylate

[0277] At room temperature, methyl 1-(5-(methoxycarbonyl)-2-nitrophenyl)-1H-pyrrole-2-carboxylic acid (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 sequentially. The resulting reaction system was then stirred at 110 °C for 4 hours. After the reaction was completed, the reaction solution was poured into water (100 mL) and filtered. The resulting filter cake was washed with water and dried to obtain a gray solid methyl 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaline-8-carboxylic acid (1.8 g, yield: 32.4%).

[0278] LCMS(ESI) m / z: 243.1 [M+H] +

[0279] Step 3: Synthesis of methyl 4-chloropyrrolo[1,2-a]quinoxaline-8-carboxylic acid

[0280] At room temperature, methyl 4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxaloline-8-carboxylate (1.8 g, 7.43 mmol) was 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 complete, the system was poured into water (50 mL), filtered, and the resulting filter cake was washed with water and dried to obtain brown solid methyl 4-chloropyrrolo[1,2-a]quinoxaloline-8-carboxylate (1.3 g, yield: 67.2%).

[0281] LCMS(ESI) m / z: 261.2 [M+H] +

[0282] Step 4: Synthesis of methyl 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylic acid

[0283] At room temperature, methyl 4-chloropyrrolo[1,2-a]quinoxaline-8-carboxylate (1.3 g, 5.000 mmol) was first dissolved in DMSO (25 mL). Then, 4-methoxybenzylamine (1.027 g, 7.500 mmol) and DIEA (1.935 g, 15.00 mmol) were added sequentially to the reaction system. The resulting mixture was reacted at 90 °C for 8 hours. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried with 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 a yellow solid methyl 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylate (1.4 g, yield: 77.7%).

[0284] LCMS(ESI) m / z: 361.1 [M+H] +

[0285] Step 5: Synthesis of 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylic acid

[0286] At room temperature, methyl 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylic acid (130 mg, 0.3601 mmol) was dissolved in a mixture of tetrahydrofuran, methanol, and water (4 mL, volume ratio 2:2:1). 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 the crude product 4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaline-8-carboxylic acid (100 mg, crude product). No purification was required, and it was directly used in the next reaction.

[0287] LCMS(ESI) m / z: 348.1 [M+H] +

[0288] Using the same synthetic steps as described for intermediate 45, but changing only the corresponding starting materials, the intermediate carboxylic acids in the table below can be prepared:

[0289]

[0290]

[0291] Intermediate 52 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0292]

[0293] Step 1: Synthesis of methyl 3-(2-methyl-1H-imidazol-1-yl)-4-nitrobenzoate

[0294] Methyl 3-fluoro-4-nitrobenzene (20.0 g, 100 mmol) was dissolved in acetonitrile (100 mL), followed by the addition of 2-methyl-1H-imidazolium (8.2 g, 100 mmol) and potassium carbonate (27.6 g, 200 mmol). The mixture was stirred at 100 °C for 12 h. The reaction was monitored by LCMS. The reaction mixture 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 subjected to silica gel chromatography (petroleum ether: ethyl acetate = 10%) to give methyl 3-(2-methyl-1H-imidazol-1-yl)-4-nitrobenzene (25.0 g, 95% yield) as a yellow solid.

[0295] LCMS(ESI) m / z: 262 [M+H] +

[0296] Step 2: Synthesis of methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate

[0297] 25 g (95.8 mmol) of methyl 3-(2-methyl-1H-imidazol-1-yl)-4-nitrobenzoate was dissolved in 300 mL of methanol at room temperature, followed by the addition of Raney nickel (2 g). 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 a yellow solid, methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate (20.5 g, 93% yield).

[0298] LCMS(ESI)m / z:232[M+H] +

[0299] Step 3: Synthesis of methyl 1-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid ester

[0300] At room temperature, methyl 4-amino-3-(2-methyl-1H-imidazol-1-yl)benzoate (2.0 g, 8.7 mmol) was dissolved in o-dichlorobenzene (40 mL), followed by the addition of carbonyl diimidazole (2.8 g, 17.4 mmol). The mixture was stirred at 180 °C for 12 h. The reaction was monitored by liquid chromatography-mass spectrometry. The mixture was filtered, and the filter cake was slurried with ethyl acetate (5 mL) to give methyl 1-methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (920.0 mg, 41% yield) as a black solid.

[0301] LCMS(ESI) m / z: 258 [M+H] +

[0302] Step 4: Synthesis of methyl 4-chloro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid ester

[0303] 1-Methyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (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, the filter cake was washed with water, and dried under vacuum to give 4-chloro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (60.0 mg, yield 56%) as a black solid.

[0304] LCMS(ESI) m / z: 276 [M+H] +

[0305] Step 5: Synthesis of methyl 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0306] 4-Chloro-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (60 mg, 0.22 mmol) was dissolved in dimethyl sulfoxide (2 mL) at room temperature, followed by the addition of (4-methoxyphenyl)methylamine (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 mixture was poured into (10 mL) of water, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (petroleum ether: ethyl acetate = 40%) to give 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid methyl ester (60 mg, 73% yield) as a black solid.

[0307] LCMS(ESI) m / z: 377 [M+H] +

[0308] Step 6: Synthesis of 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0309] Methyl 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (60 mg, 0.16 mmol) was dissolved in methanol (1 mL), tetrahydrofuran (1 mL), and water (1 mL) at room temperature, followed by the addition of potassium hydroxide (26 mg, 0.44 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was monitored by liquid chromatography-mass spectrometry. The reaction mixture was poured into 10 mL of water, adjusted to acidity with formic acid, and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 50 mg, 86% yield, of 4-((4-methoxybenzyl)amino)-1-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid as a white solid.

[0310] LCMS(ESI) m / z: 363 [M+H] +

[0311] Using the same synthetic steps as described for intermediate 52, but changing only the corresponding starting materials, the intermediate carboxylic acids in the table below can be prepared:

[0312]

[0313] Intermediate 54 4-Amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0314]

[0315] Step 1: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-7-chloroimidazolo[1,5-a]quinoxaline-8-carboxylic acid

[0316] A solution of methyl 4-amino-7-chloroimidazolo[1,5-a]quinoxaline-8-carboxylic acid (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 the reaction was complete, the solution was poured into water (5 mL), extracted with ethyl acetate (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 70:30) to give methyl 4-((tert-butoxycarbonyl)amino)-7-chloroimidazolo[1,5-a]quinoxaline-8-carboxylic acid (1.00 g, 61% yield) as a white solid.

[0317] LCMS(ESI): 376 [M+H] +

[0318] Step 2: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0319] Under a nitrogen atmosphere, methyl 4-((tert-butoxycarbonyl)amino)-7-chloroimidazole[1,5-a]quinoxaline-8-carboxylate (0.20 g, 0.53 mmol), potassium ferricyanide (0.05 g, 0.16 mmol), 2-di-tert-butylphospho-2',4',6'-triisopropylbiphenyl (0.09 g, 0.21 mmol), and methanesulfonic acid (2-di-tert-butylphospho-2',4',6'-triisopropyl) were prepared. A mixture of dioxane / water (4.00 mL) of 1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.17 g, 0.21 mmol) and potassium acetate (0.01 g, 0.07 mmol) was stirred at 100 °C for 2 h, then concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 70:30) to give methyl 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylic acid (0.10 g, 51%) as a white solid.

[0320] LCMS(ESI):368[M+H] +

[0321] Step 3: Synthesis of methyl 4-amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0322] Trifluoroacetic acid (0.10 mL) was added to a solution of methyl 4-((tert-butoxycarbonyl)amino)-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylate (0.20 g, 0.54 mmol) in dichloromethane (0.50 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated to give methyl 4-amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylate (0.05 g, crude product).

[0323] LCMS(ESI):268[M+H] +

[0324] Step 4: Synthesis of 4-amino-7-cyanoimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0325] 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), and tetrahydrofuran / methanol / water (1 mL / 1 mL / 1 mL) was stirred at room temperature for 2 hours. After the reaction was complete, the system was concentrated to obtain crude 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.

[0326] LCMS(ESI):254[M+H] +

[0327] Intermediate 55 4-Amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0328]

[0329] Step 1: Synthesis of methyl 4-{[(4-methoxyphenyl)methyl]amino}-7-methyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0330] A mixture of methyl 7-chloro-4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (200 mg, 0.5 mmol), potassium carbonate (300 mg, 2 mmol), dichloro[1,1'-bis(o-tert-butylphosphine)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-carboxylic acid (100 mg, 53%).

[0331] LCMS(ESI):268[M+H] +

[0332] Step 2: Synthesis of 4-((4-methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0333] Methyl 4-{[(4-methoxyphenyl)methyl]amino}-7-methyl-10-hydroimidazo[1,5-a]quinoxaline-8-carboxylic acid (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 h. After the reaction was completed, the solution was evaporated to dryness, the pH was adjusted to 3 with formic acid, and the solution was filtered to obtain 4-((4-methoxybenzyl)amino)-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (52 mg, 12% yield).

[0334] LCMS(ESI):363[M+H] +

[0335] Step 3: Synthesis of 4-amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid

[0336] 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). The reaction solution was stirred at 100 °C for 12 hours. After the reaction was completed, the solution was evaporated to dryness to obtain 4-amino-7-methylimidazo[1,5-a]quinoxaline-8-carboxylic acid (52 mg, 0.23 mmol).

[0337] LCMS(ESI):363[M+H] +

[0338] Using the method employed in step 3 of intermediate 55, the following intermediate acid was prepared:

[0339]

[0340]

[0341] Intermediate 62 4-Amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid

[0342]

[0343] Step 1: Synthesis of 6-bromo-2-chloro-3-hydrazinoquinoxaline

[0344] At room temperature, 6-bromo-2,3-dichloroquinoxaline (278.0 mg, 1.0 mmol) was placed in a 25 mL single-necked flask, and hydrazine hydrate (156 mg, 2.5 mmol, 80% wt) was added. After the addition was complete, 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 × 2) and ethyl acetate (5 mL × 2) to give 6-bromo-2-chloro-3-hydrazinoquinoxaline (150 mg).

[0345] LCMS(ESI) m / z: 273.0 / 275.0 [M+H] +

[0346] Step 2: Synthesis of 8-bromo-4-chloro-[1,2,4]triazole[4,3-a]quinoxaline

[0347] At room temperature, 116.0 mg (0.5 mmol) of 6-bromo-2-chloro-3-hydrazinoquinoxaline was placed in a 25 mL single-necked flask, and 4.0 mL of triethyl orthoformate was added. After the addition was complete, the reaction was heated to 100 °C and reacted at this temperature for 1 hour. When LC-MS showed that the reaction was complete, the reaction was cooled to room temperature, filtered, and the filter cake was washed with methanol (3.0 mL × 3), dried, and 8-bromo-4-chloro-[1,2,4]triazole[4,3-a]quinoxaline (110 mg) was obtained.

[0348] 1 H NMR (400MHz, CDCl3) δ10.21(s,1H),8.84(d,1H),7.98(d,1H),7.90(dd,1H).

[0349] Step 3: Synthesis of 8-bromo-N-(4-methoxybenzyl)-[1,2,4]triazolo[4,3-a]quinoxaline-4-amine

[0350] 8-Bromo-4-chloro-[1,2,4]triazol[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 h. After the reaction was completed, water (60 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phase was dried over sodium sulfate, filtered, and evaporated to dryness to obtain crude 8-bromo-N-(4-methoxybenzyl)-[1,2,4]triazol[4,3-a]quinoxaline-4-amine (2.20 g).

[0351] LCMS(ESI) m / z: 384.1 / 386.1 [M+H] +

[0352] Step 4: Synthesis of methyl 4-((4-methoxybenzyl)amino)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate

[0353] Potassium acetate (1.7 g, 17.2 mmol) and Pd(dppf)Cl2 (420 mg, 0.57 mmol) were added 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). The mixture was stirred at 100 °C for 12 hours under a CO atmosphere. After removing methanol by rotary evaporation, 100 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and dried with anhydrous Na2SO4. The crude product was then slurried with ethyl acetate (20 mL) to give methyl 4-((4-methoxybenzyl)amino)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate (1.1 g, yield: 53%).

[0354] LCMS(ESI) m / z: 364.2 [M+H]+

[0355] Step 5: Synthesis of methyl 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate.

[0356] 300.0 mg (0.78 mmol) of methyl 4-((4-methoxybenzyl)amino)-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylate was placed in a 25 mL single-necked flask, and 5.0 mL of TFA was added. The reaction mixture was heated to 80 °C and stirred at this temperature for 16 hours. After the reaction was complete, 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).

[0357] LCMS(ESI) m / z: 244.3 [M+H] +

[0358] Step 6: Synthesis of 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid.

[0359] In the previous step, crude methyl 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid (190 mg, 0.78 mmol) was added with THF (5.0 mL) and methanol (5.0 mL). The pH was adjusted to 7 with 3M potassium hydroxide aqueous solution, and then lithium hydroxide (65.0 mg, 1.56 mmol) was added. The reaction was stirred at 50°C for 16 hours. After the reaction was complete, the methanol and THF in the system were removed by rotary evaporation, and the pH was adjusted to 6.5 with 1M dilute hydrochloric acid solution. The mixture was filtered, and the filter cake was washed with water (5.0 mL × 3). The filter cake was dried, and the water was removed to obtain crude 4-amino-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid (120 mg).

[0360] LCMS(ESI) m / z: 230.1 [M+H] +

[0361] Intermediate 63 5-Aminoimidazo[1,5-c]quinazolin-9-carboxylic acid

[0362]

[0363] Step 1: Synthesis of 6-bromo-N-(4-methoxybenzyl)-4-methylquinazoline-2-amine

[0364] At room temperature, 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 mixture was stirred at room temperature for 16 hours, water (50 mL) was added, and 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 and purified by column chromatography (0-10% methanol / dichloromethane) to give 6-bromo-N-(4-methoxybenzyl)-4-methylquinazoline-2-amine (500 mg, yield: 72%).

[0365] LCMS(ESI) m / z: 359.2 [M+H] +

[0366] Step 2: Synthesis of 9-bromo-N-(4-methoxybenzyl)imidazo[1,5-c]quinazolin-5-amine

[0367] At room temperature, 0.5 g (1.396 mmol) of compound 6-bromo-N-(4-methoxybenzyl)-4-methylquinazoline-2-amine was dissolved in 20 mL of DMSO, and glycine (211 mg, 2.792 mmol), tert-butanol hydroperoxide (719 mg, 5.583 mmol), tetrabutylammonium iodide (104 mg, 0.2792 mmol), and acetic acid (251 mg, 4.1 mmol) were added. The mixture was stirred at 90°C for 16 hours under nitrogen protection (87 mmol), 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%).

[0368] LCMS(ESI) m / z: 384.2 [M+H] +

[0369] Step 3: Synthesis of methyl 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazolin-9-carboxylic acid

[0370] At room temperature, potassium acetate (230 mg, 2.36 mmol) and Pd(dppf)Cl2 (58 mg, 0.0785 mmol) were added to a solution of 9-bromo-N-(4-methoxybenzyl)imidazo[1,5-c]quinazoline-5-amine (300 mg, 0.785 mmol) in MeOH (10 mL) and DMF (10 mL). The mixture was stirred at 100 °C for 12 hours under a CO atmosphere. After removing methanol by rotary evaporation, 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 methyl 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylic acid (200 mg, yield: 56%).

[0371] LCMS(ESI) m / z: 363.2 [M+H] +

[0372] Step 4: Synthesis of methyl 5-aminoimidazo[1,5-c]quinazolin-9-carboxylate

[0373] At room temperature, methyl 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylate (200 mg, 0.5519 mmol) was placed in a 20 mL round-bottom flask, and trifluoroacetic acid (2 mL) was added. The mixture was stirred at 78 °C for 3 hours. After removing the trifluoroacetic acid, water (5 mL) was added, and the mixture was filtered. The filter cake was washed with water to obtain methyl 5-aminoimidazo[1,5-c]quinazoline-9-carboxylate (200 mg, crude product).

[0374] LCMS(ESI) m / z: 243.2 [M+H] +

[0375] Step 5: Synthesis of 5-aminoimidazo[1,5-c]quinazolin-9-carboxylic acid

[0376] At room temperature, methyl 5-((4-methoxybenzyl)amino)imidazo[1,5-c]quinazoline-9-carboxylic acid (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 trifluoroacetic acid, 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).

[0377] LCMS(ESI) m / z: 243.2 [M+H] +

[0378] Example 1

[0379] 4-Amino-N-cyclopropyl-N-(5-trifluoromethylpyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0380]

[0381] Step 1: Synthesis of N-cyclopropyl-4-(4-methoxybenzyl)amino)-N-(5-trifluoromethyl)pyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0382] At room temperature, 4-((4-methoxybenzyl)amino)imidazo[1,5-a]quinoxaline-8-carboxylic acid (85 mg, 0.24 mmol) was first dissolved in N,N-dimethylacetamide (3 mL). Then, cyclopropyl{[5-(trifluoromethyl)(2-pyridyl)]methyl}amine (20.0 mg, 0.469 mmol), tripyrrolidinylphosphonium hexafluorophosphate bromide (230 mg, 0.488 mmol), and N,N-diisopropylethylamine (96 mg, 0.7320 mmol) were added sequentially to the system. The resulting mixture... The reaction was carried out at 50°C for 3 hours. After the reaction was completed, 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 the crude product, which was then purified by silica gel column chromatography (petroleum ether and ethyl acetate in a volume ratio of 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%).

[0383] LCMS(ESI) m / z: 559.3 [M+H] +

[0384] Step 2: Synthesis of 4-amino-N-cyclopropyl-N-(5-trifluoromethylpyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0385] At room temperature, N-cyclopropyl-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). The resulting reaction mixture was reacted at 50 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and poured into water (10 mL). The pH was then adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by reversed-phase column chromatography (water:acetonitrile volume ratio 5:95) to obtain a white solid 4-amino-N-cyclopropyl-N-(5-trifluoromethylpyridin-2-yl)methyl)imidazo[1,5-a]quinoxaline-8-carboxamide (4.98 mg, yield 3.96%).

[0386] LCMS(ESI) m / z: 427.3 [M+H] +

[0387] 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).

[0388] Using the same synthesis steps as described in Example 1, but changing only the corresponding starting materials, the examples in the table below can be prepared:

[0389]

[0390]

[0391]

[0392]

[0393] Example 18

[0394] 4-Amino-N-cyclopropyl-N-(1-(4-(trifluoromethyl)phenyl)ethyl)imidazo[1,5-a]pyrido[3,4-e]pyrazine-8-carboxamide

[0395]

[0396] At room temperature, 4-aminoimidazo[1,5-a]pyrido[3,4-e]pyrazin-8-carboxylic acid (240 mg, 1.047 mmol) was dissolved in N,N-dimethylacetamide (5 mL), and N-(1-(4-(trifluoromethyl)phenyl)ethyl)cyclopropylamine (200 mg, 0.8724 mmol), tripyrrolidinylphosphonium 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 × 3), the organic phases were combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude product, and subjected to 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).

[0397] 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).

[0398] 19 F NMR(376MHz,DMSO-d6)δ-60.77.

[0399] LCMS(ESI) m / z: 441.5 [M+H] +

[0400] Using the same synthesis steps as described in Example 18, but changing only the corresponding starting materials, the examples in the table below can be prepared:

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408] Example 47 (R)-4-amino-7-fluoro-N-(1-(5-fluoropyridin-2-yl)ethyl)-N-methylimidazo[1,5-a]quinoxaline-8-carboxamide

[0409]

[0410] 4-Amino-7-fluoroimidazolo[1,5-a]quinoxaloline-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), followed by the addition of (R)-1-(5-fluoropyridin-2-yl)-N-methylethyl-1-amine (180 mg, 1.17 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the system was cooled to room temperature and extracted three times with ethyl acetate, 10 mL each time. The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (HPLC): column specifications: Kinetex 5m EVO C18, 30mm × 150mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 10 min 20% B to 47% B; wavelength: 254 / 220 nm; retention time (min): 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, yield 3.84%) was obtained as a white solid.

[0411] 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(m1H),4.96(S,2H),2.92–2.90(m,1H),0.60-0.49(M,4H).

[0412] LCMS(ESI): 426.85 [M+H] +

[0413] Using the same synthesis steps as described in Example 47, but changing only the corresponding starting materials, the examples in the table below can be prepared:

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420] Example 6 Method 2: (4-amino(10-hydropyrazolo[1,5-a]quinoxaline-8-yl))-N-cyclopropyl-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide

[0421]

[0422] Step 1: N-cyclopropyl(4-{[(4-methoxyphenyl)methyl]amino}(10-hydropyrazolo[1,5-a]quinoxaline-8-yl))-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide

[0423] 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 to the solution. After the reaction was 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 with anhydrous Na2SO4. After filtration and concentration, N-cyclopropyl(4-{[(4-methoxyphenyl)methyl]amino}(10-hydropyrazolo[1,5-a]quinoxalin-8-yl))-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide (200.0 mg, yield: 48%) was obtained.

[0424] LCMS(ESI) m / z: 509 [M+H] +

[0425] Step 2: Synthesis of (4-amino(10-hydropyrazolo[1,5-a]quinoxaline-8-yl))-N-cyclopropyl-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide

[0426] A 2 mL solution of TFA containing 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) was stirred overnight at 60 °C. After the reaction was complete, the solution was diluted with ethyl acetate and washed continuously 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 over 10 min; wavelength: 220 nm; RT1 (min): 8.48) to give (4-amino(10-hydropyrazolo[1,5-a]quinoxaline-8-yl))-N-cyclopropyl-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide (21.30 mg, yield 27%) as a white solid.

[0427] 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).

[0428] LCMS(ESI) m / z: 427.35 [M+H] +

[0429] Using the same synthesis steps as described in Method 2 of Example 6, but changing only the corresponding starting materials, the examples in the table below can be prepared:

[0430]

[0431] Example 62 4-Amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0432]

[0433] 4-{[(4-methoxyphenyl)methyl]amino}-10-hydroimidazole[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 N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)cyclopropaneamine (93 mg, 0.41 mmol) and pyridine (97 mg, 1.22 mmol) in 1,2-dioxane (10 mL). The mixture was stirred at 60 °C for 2 hours. After the reaction was completed, the filtrate was concentrated, and the crude product was purified by reversed-phase chromatography (acetonitrile:water = 50:50) to obtain 4-amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide (23 mg, 0.05 mmol, yield 12.85%), which was a white solid.

[0434] 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).

[0435] LCMS(ESI): 441.30 [M+H] +

[0436] By using the synthesis steps described in Example 62, and only changing the corresponding starting materials, the examples in the table below can be prepared:

[0437]

[0438]

[0439] Example 66 Method 2: 4-Amino-7-chloro-N-(1-(pyrimidin-2-yl)ethyl)-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)pyrrolo[1,2-a]quinoxaline-8-carboxamide

[0440]

[0441] 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

[0442] At room temperature, 7-chloro-4-((4-methoxybenzyl)amino)pyrrolo[1,2-a]quinoxaloline-8-carboxylic acid (180 mg, 0.472 mmol) was dissolved in DCM (3 mL), followed by the sequential addition of thionyl chloride (280.76 mg, 2.36 mmol). The resulting mixture was reacted at 50 °C for 3 hours. After the reaction was complete, the reaction solution was evaporated to dryness 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 mmol) were then added. The solution was dissolved in dichloromethane (1 ml) and the dissolved mixture was added dropwise to the system. The resulting mixture was reacted at 25 °C for 3 hours. After the reaction was completed, it 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 the crude product, which was purified by silica gel column chromatography (petroleum ether and ethyl acetate in a volume ratio of 1:3) to obtain a yellow solid 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%).

[0443] LCMS(ESI) m / z: 646.3 [M+H] +

[0444] 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

[0445] At room temperature, 80 mg (0.12 mmol) 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 was dissolved in 2 mL of TFA. The resulting reaction mixture was reacted at 75 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and poured into 10 mL of water. Then, it was adjusted with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate (10 mL × 3), the organic phases were combined, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by reversed-phase column chromatography (water:acetonitrile volume ratio 5:95) to obtain a white solid 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, yield 17.5%).

[0446] 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).

[0447] LCMS(ESI) m / z: 526.9 [M+H] +

[0448] Example 23 Method 2: N-{(1R)-1-[4-(trifluoromethyl)phenyl]ethyl}(4-amino-7-chloro(10-hydroimidazo[1,5-a]quinoxalin-8-yl))-N-methylformamide

[0449]

[0450] Step 1: At room temperature, (R)-N-methyl-1-(4-(trifluoromethyl)phenyl)ethyl-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) were dissolved in N,N-dimethylformamide (2.00 mL), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (277.80 mg, 0.73 mmol) and N,N-diisopropylethylamine (188.97 mg, 1.46 mmol) were added. The mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the mixture was diluted with ethyl acetate and washed 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 (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 35% B to 57% B over 10 min; wavelength: 254 nm / 220 nm; retention time (min): 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, 0.57 mmol, yield 13%) as a white solid.

[0451] 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).

[0452] LCMS(ESI): 448.10 [M+H] + .

[0453] Using the same synthesis steps as described in Method 2 of Example 23, but changing only the corresponding starting materials, the examples in the table below can be prepared:

[0454]

[0455]

[0456]

[0457]

[0458]

[0459] Example 80 6-Amino(7-hydroimidazo[1,2-c]quinazolin-2-yl)-N-(pyrimidin-2-ylethyl)-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide

[0460]

[0461] Step 1: {6-[tert-butoxy)carbonylamino](7-hydroimino[1,2-c]quinazolin-2-yl)}-N-(pyrimidin-2-ylethyl)-N-{[5-(trifluoromethyl)(2-pyridyl)]methyl}formamide

[0462] Lithium 6-[(tert-butoxy)-N-[(tert-butyl)oxycarbonyl]carbonylamino]-7-hydroimidazo[1,2-c]quinazolin-2-carboxylate (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 hexafluorophosphate bromide (86 mg, 0.18 mmol) were added sequentially to the system. The mixture was then... The reaction was carried out at room temperature for 1 hour. After the reaction was completed, 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 then purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain {6-[tert-butoxy)carbonylamino](7-hydroimino[1,2-c]quinazolin-2-yl)}-N-(pyrimidin-2-ylethyl)-N-{[5-(trifluoromethyl)(2-pyridinyl)]methyl}formamide (60 mg, crude product), which was a white solid.

[0463] LCMS(ESI) m / z: 593.2 [M+H] +

[0464] Step 2: 6-Amino(7-hydroimidazo[1,2-c]quinazolin-2-yl)-N-(pyrimidin-2-ylethyl)-N-{[5-(trifluoromethyl)(2-pyridinyl)]methyl}formamide

[0465] At room temperature, {6-[tert-butoxy)carbonylamino](7-hydroimino[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. After reacting at room temperature for 2 hours, the reaction solution was poured into water (10 mL) and saturated with sodium carbonate. The solution was adjusted to pH 8, extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reversed-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, yield 7%) as a white solid.

[0466] LCMS(ESI) m / z: 493.3 [M+H] +

[0467] Example 97 4-Amino-N-cyclopropyl-7-fluoro-N-(6-(trifluoromethyl)pyridin-3-ylmethyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0468]

[0469] At room temperature, 4-amino-7-fluoro-10-hydroimidazole[1,5-a]quinoxaline-8-carboxylic acid (50 mg, 0.202 mmol) was dissolved in DMF (3 mL), followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (46 mg, 0.239 mmol) and 1-hydroxybenzotriazole (32 mg, 0.239 mmol), and then DIEA (95 mg, 0.736 mmol). The mixture was stirred at room temperature for 0.5 hours. Then N-(6-(trifluoromethyl)pyridazin-3-ylmethyl)cyclopropylamine (40 mg, 0.184 mmol) was added, and the mixture was reacted at room temperature for 16 hours. When the reaction was complete as indicated by LCMS, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (0-5% methanol / dichloromethane) to obtain 4-amino-N-cyclopropyl-7-fluoro-N-(6-(trifluoromethyl)pyridin-3-ylmethyl)imidazo[1,5-a]quinoxaline-8-carboxamide (15 mg, yield: 4.2%).

[0470] 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).

[0471] LCMS(ESI) m / z: 445.2 [M+H] +

[0472] By employing the same synthesis steps as described in Example 97, and only changing the corresponding starting materials, the examples in the table below can be prepared:

[0473]

[0474] Example 81 (R)-4-amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide and

[0475] Example 82 (S)-4-amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0476]

[0477] 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). 4.6 × 50 mm, 3 μm, mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol, mobile phase A: mobile phase B = 40:60, flow rate: 1.0 mL / min, retention time: first peak 1.57 min, second peak 2.23 min) yielded the first peak (R)-4-amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide (4.79 mg, 0.01 mmol), a white solid, and the second peak (S)-4-amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide (3.72 mg, 0.01 mmol), a white solid.

[0478] Front Example 81(R)-4-amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0479] 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).

[0480] LCMS(ESI): 441.30 [M+H] +

[0481] Back Peak Example 82 (S)-4-amino-N-cyclopropyl-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)imidazo[1,5-a]quinoxaline-8-carboxamide

[0482] 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).

[0483] LCMS(ESI) m / z: 441.30 [M+H] + .

[0484] Using the operations described in Examples 81 and 82 and the corresponding chiral SFC resolution conditions, the compounds in the table below were obtained:

[0485]

[0486]

[0487]

[0488]

[0489] Biochemical evaluation

[0490] I. Experiments on the inhibitory activity of compounds on tumor cell proliferation

[0491] Test Example 1: Inhibitory Activity of Compounds on the Proliferation of HCT-116 MTAP(- / -) Deficit Cells

[0492] Materials and Cells: HCT-116 MTAP(- / -) deletion 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); Cell-Titer Glo kit was purchased from Prometheus (USA).

[0493] Cell culture: HCT116 MTAP(- / -) deletion cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum + 1% penicillin-streptomycin at 37°C and 5% CO2. Only cells in the logarithmic growth phase were used for experiments.

[0494] Cell proliferation inhibition activity assay: The inhibitory activity of the compound on the proliferation of HCT-116 MTAP(- / -) deletion cells was detected using the Cell-Titer Glo reagent kit. Cell concentrations were adjusted to 40 μL per well in 384-well plates and incubated overnight at 37°C and 5% CO2. 40 nL of the compound was added to each well to achieve a final concentration of 0-10,000 nM (initial concentration 10,000 nM, 3-fold dilution, 10 spots). The cell plates with 0.1% DMSO were incubated at 37°C and 5% CO2 for 8 days. Cell viability was then assessed using 40 μL of Cell-Titer Glo reagent. The results are shown in Table 1.

[0495] Test Example 2: Experiment on the inhibitory activity of the compound on the proliferation of HCT-116 wild-type cells

[0496] 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); Cell-Titer Glo kit was purchased from Prometheus (USA).

[0497] 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. Only cells in the logarithmic growth phase were used for experiments.

[0498] Cell proliferation activity assay: The inhibitory activity of the compound on the proliferation of HCT-116 wild-type cells was detected using the Cell-Titer Glo reagent kit. Cell concentrations were adjusted, and 40 μL was seeded per well in 384-well plates and incubated overnight at 37°C and 5% CO2. 40 nL of the compound was added to each well to achieve a final concentration of 0-10,000 nM (initial concentration 10,000 nM, 2-fold dilution, 10 spots). The cell plates with 0.1% DMSO were incubated at 37°C and 5% CO2 for 8 days. Cell viability was then assessed using 40 μL of Cell-Titer Glo reagent. The results are shown in Table 1.

[0499] Table 1 below shows the inhibitory activities of the compounds in the examples on the proliferation of HCT116 MTAP(- / -) deficient cells and HCT116 wild-type cells.

[0500] Table 1

[0501]

[0502]

[0503]

[0504]

[0505] II. Mouse Pharmacokinetic Experiment

[0506] 1. Test compound

[0507] The compounds used in this experiment were derived from compounds in specific embodiments of this invention.

[0508] 2. Experimental animals

[0509] ICR mice, male, N=3 / group; Original source: Zhejiang Vital International Laboratory Animal Technology Co., Ltd.

[0510] 3. Drug preparation and administration

[0511] ICR mice were given a single oral (PO) administration: The compound was weighed and dissolved in dimethyl sulfoxide, and a certain volume of polyethylene glycol 400 and water for injection were added. The solution was then adjusted to a clear solution with a small amount of 1 mol / L hydrochloric acid solution. Three mice were given the solution by gavage after fasting overnight. The dosage was 10 mg / kg.

[0512] ICR mice were administered a single intravenous (IV) injection: The compound was weighed and dissolved in dimethyl sulfoxide, and a certain volume of polyethylene glycol 400 and water for injection were added. The solution was then adjusted to a clear solution with a small amount of 1 mol / L hydrochloric acid solution. Three mice were fasted overnight and then administered the compound via tail vein injection at a dose of 3 mg / kg.

[0513] 4. Sample Collection

[0514] Approximately 30 μL of blood was collected via the dorsal pedis vein at each time point. Dipotassium EDTA was used as an anticoagulant. After collection, the samples were placed on ice and centrifuged within 1 hour to separate the plasma (centrifugation conditions: 4000 g / min; 5 minutes; 4°C). Blood collection time points were 0.0833 (IV injection), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Samples were stored at -20°C.

[0515] 30 μL of plasma sample (10 μL sample + 20 μL blank plasma sample) was added to 200 μL of ice-cold acetonitrile containing internal standard. After vortexing for 30 seconds, the sample was centrifuged at 4000 g / min for 20 minutes. 100 μL of the supernatant was transferred to a 96-well plate, and 200 μL of ultrapure water was added. After vortexing for 30 seconds, 5 μL or 10 μL was injected into LC-MS / MS for analysis.

[0516] Table 2: Pharmacokinetic Data

[0517]

[0518]

[0519] While preferred embodiments have been described above, it will be apparent to those skilled in the art that modifications can be made without departing from the invention. Such modifications are considered possible variations that are included within the scope of the invention.

Claims

1. The pharmaceutically acceptable salts and stereoisomers of the compound represented by formula (I), in, W indicates 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 ; Where X3 represents CR X3 At that time, R X3 Indicates hydrogen, 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, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, or selected from 0 to 4 substituents: halogen, C1-C6 alkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl; Where X4 represents CR X4 At that time, R X4 Indicates hydrogen, 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, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, or selected from 0 to 4 substituents: halogen, C1-C6 alkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl; Where X5 represents CR X5 At that time, R X5 Indicates hydrogen, 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, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, or selected from 0 to 4 substituents: halogen, C1-C6 alkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl; Where X6 represents CR X6 At that time, R X6 Indicates hydrogen, 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, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, or selected from 0 to 4 substituents: halogen, C1-C6 alkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl; The ring A may also have 5-6 saturated or unsaturated rings fused at the chemical bonds between X3 and X4, and the ring may also have 0-3 heteroatoms selected from N. The ring A may also have 5-6 saturated or unsaturated rings fused at the chemical bonds between X4 and X5, and the ring may also contain 0-3 heteroatoms selected from N. The ring A may also have 5-6 saturated or unsaturated rings fused at the chemical bonds between X5 and X6, and the ring may also contain 0-3 heteroatoms selected from N. Wherein, R' represents the presence of 0-3 substituents selected from the following: halogen, C1-C6 alkyl, -OR a , oxo, hydroxyl 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 C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, R' represents -CHR 2 R 3 ; Among them, R 1 This indicates hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, C3-C 10 cycloalkyl; Among them, R 2 R 3 Each independently represents hydrogen, -OR a Halogen, -CN, C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, or substituents selected from 0 to 3 of the following: halogen, C1-C6 alkyl, -OR a , oxo, hydroxyl 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 C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl; Where W represents CR W At that time, R W Selected from hydrogen, 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, hydroxylated C1-C6 alkyl, halogenated C1-C6 alkoxy; Where X1 represents N or CR X1 ; Where X2 represents N or CR X2 ; Where Y1 represents CR Y1 R Y1’ or NR Y1 ; Where Y2 represents CR Y2 R Y2’ or NR Y2 ; Where Y3 represents CR Y3 R Y3’ or NR Y3 ; Among them, R X1 R X2 Each of these can be independently represented as hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxylated C1-C6 alkyl, or -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 of these independently represents the absence of, hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxylated C1-C6 alkyl, -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 or double bond; Among them, R a R b Each can be used independently to represent hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated (C1-C6 alkyl). Wherein, the compound represented by formula (I) is not one of the following compounds: 。 2. The compound according to claim 1, and its pharmaceutically acceptable salts and stereoisomers, having the structure of formula (II): in, W indicates 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 ; Where X3 represents CR X3 At that time, R X3 Indicates hydrogen, 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, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, or selected from 0 to 4 substituents: halogen, C1-C6 alkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl; Where X4 represents CR X4 At that time, R X4 Indicates hydrogen, 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, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, or selected from 0 to 4 substituents: halogen, C1-C6 alkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl; Where X5 represents CR X5 At that time, R X5 Indicates hydrogen, 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, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, or selected from 0 to 4 substituents: halogen, C1-C6 alkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl; Where X6 represents CR X6 At that time, R X6 Indicates hydrogen, 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, halogenated C1-C6 alkoxy, hydroxyl C1-C6 alkyl, or selected from 0 to 4 substituents: halogen, C1-C6 alkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 cycloalkyl; Wherein, R' represents the presence of 0-3 substituents selected from the following: halogen, C1-C6 alkyl, -OR a , oxo, hydroxyl 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 C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl; Alternatively, R' represents -CHR 2 R 3 ; Among them, R 1 This indicates hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxylated C1-C6 alkyl, C3-C 10 cycloalkyl; Among them, R 2 R 3 Each independently represents hydrogen, -OR a Halogen, -CN, C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxy-C1-C6 alkyl, or substituents selected from 0 to 3 of the following: halogen, C1-C6 alkyl, -OR a , oxo, hydroxyl 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 C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl; Where W represents CR W At that time, R W Selected from hydrogen, 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, hydroxylated C1-C6 alkyl, halogenated C1-C6 alkoxy; Where X1 represents N or CR X1 ; Where X2 represents N or CR X2 ; Where Y1 represents CR Y1 R Y1’ or NR Y1 ; Where Y2 represents CR Y2 R Y2’ or NR Y2 ; Where Y3 represents CR Y3 R Y3’ or NR Y3 ; Among them, R X1 R X2 Each of these can be independently represented as hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxylated C1-C6 alkyl, or -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 of these can be used independently to represent non-existence, hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and hydroxy-C1-C6 alkyl. in, Indicates a single or double bond; Among them, R a R b Each can be independently represented as hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, or halogenated (C1-C6 alkyl).

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

4. The compound according to claim 1 or 2, and its pharmaceutically acceptable salts and stereoisomers, wherein, W represents N.

5. The compound according to claim 1 or 2, wherein, a pharmaceutically acceptable salt or stereoisomer thereof, X1 indicates CR X1 Or N, where R X1 It represents hydrogen, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, and halogenated C1-C6 alkyl.

6. The compound according to claim 1 or 2, wherein, a pharmaceutically acceptable salt or stereoisomer thereof, X1 indicates CR X1 , where R X1 It represents hydrogen, halogen, C1-C6 alkyl, and halogenated C1-C6 alkyl.

7. The compound according to claim 1 or 2, wherein, a pharmaceutically acceptable salt or stereoisomer thereof, X1 indicates CR X1 , where R X1 It represents hydrogen and C1-C6 alkyl groups.

8. The compound according to claim 1 or 2, wherein, a pharmaceutically acceptable salt or stereoisomer thereof, X2 represents CH.

9. The compound according to claim 1 or 2, wherein, a pharmaceutically acceptable salt or stereoisomer thereof, X3 represents CH or N.

10. The compound according to claim 1 or 2, wherein, a pharmaceutically acceptable salt or stereoisomer thereof, X3 represents CH.

11. The compound according to claim 1, and its pharmaceutically acceptable salts and stereoisomers, wherein, X4 indicates CR X4 Or N, where R X4 It represents hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halogen, SF5, cyano, or substituted with 0 to 4 or fewer substituents: halogen, C1-C6 alkyl, -OR a Oxygenated, hydroxyl (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 C3-C 10 Cycloalkyl.

12. The compound according to claim 1, and its pharmaceutically acceptable salts and stereoisomers, wherein, X4 indicates CR X4 , where R X4 It indicates a halogenated C1-C6 alkyl group.

13. The compound according to claim 1, and its pharmaceutically acceptable salts and stereoisomers, wherein, X5 indicates CR X5 Or N, where R X5 It represents hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, halogen, SF5, or cyano.

14. The compound according to claim 1, and its pharmaceutically acceptable salts and stereoisomers, wherein, X5 represents CH.

15. The compound according to claim 1, and its pharmaceutically acceptable salts and stereoisomers, wherein, X6 represents CH or N.

16. The compound according to claim 1, and its pharmaceutically acceptable salts and stereoisomers, wherein, X6 represents CH.

17. The compound according to claim 1 or 2, wherein, a pharmaceutically acceptable salt or stereoisomer thereof, The chemical bond between Y1 and Y2 is a double bond.

18. The compound according to claim 17, and its pharmaceutically acceptable salts and stereoisomers, wherein, Y1 represents CH.

19. The compound according to claim 18, its pharmaceutically acceptable salt and stereoisomer, wherein, Y2 represents N.

20. The compound according to claim 1 or 2, wherein, a pharmaceutically acceptable salt or stereoisomer thereof, Y3 represents CH.

21. The compound according to claim 1 or 2, wherein, a pharmaceutically acceptable salt or stereoisomer thereof, R' indicates -CHR 2 R 3 , where R 2 R 3 Each independently represents hydrogen, C1-C6 alkyl, or is represented by 0-3 elements selected from halogen, C1-C6 alkyl, -OR a , oxo, hydroxyl 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 C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl.

22. The compound according to claim 21, wherein its pharmaceutically acceptable salt and stereoisomer, R' indicates -CHR 2 R 3 , where R 2 Indicates hydrogen, C1-C6 alkyl; R 3 It represents hydrogen, C1-C6 alkyl, or 0-3 elements selected from halogen, C1-C6 alkyl, -OR a , oxo, hydroxyl 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 C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl.

23. The compound according to claim 22, wherein its pharmaceutically acceptable salt and stereoisomer, R' indicates -CHR 2 R 3 , where R 2 Indicates hydrogen, C1-C6 alkyl; R 3 Indicates that it is selected from 0-3 ions chosen from halogens, C1-C6 alkyl groups, and -OR. a 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 Replaced C3-C 10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 heteroaryl.

24. The compound according to claim 23, and its pharmaceutically acceptable salts and stereoisomers, wherein, R' indicates -CHR 2 R 3 , where R 2 Indicates hydrogen, C1-C6 alkyl; R 3 This indicates C3-C atoms substituted with 0-3 alkyl groups selected from halogens, C1-C6 alkyl groups, or halo-C1-C6 alkyl groups. 10 Cycloalkyl.

25. The compound according to claim 22, and its pharmaceutically acceptable salts and stereoisomers, wherein, R' indicates -CHR 2 R 3 , where R 2 Indicates hydrogen, C1-C6 alkyl; R 3 Indicates that it is selected from 0-3 ions chosen from halogens, C1-C6 alkyl groups, and -OR. a 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 replaced: 。 26. The compound according to claim 23, and its pharmaceutically acceptable salts and stereoisomers, wherein, R' indicates -CHR 2 R 3 , where R 2 Indicates hydrogen, C1-C6 alkyl; R 3 express .

27. The compound according to claim 1 or 2, wherein, a pharmaceutically acceptable salt or stereoisomer thereof, R' indicates that the 0-3 elements are selected from halogen, C1-C6 alkyl, hydroxyC1-C6 alkyl, -OR a -CN, NR a R b , C3-C substituted C1-C6 alkyl, C1-C6 alkoxy 10 Cycloalkyl.

28. The compound according to claim 27, wherein, a pharmaceutically acceptable salt or stereoisomer thereof, R' indicates that the 0-3 elements are selected from halogen, C1-C6 alkyl, hydroxyC1-C6 alkyl, -OR a -CN, NR a R b Cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl substituted with C1-C6 alkyl or C1-C6 alkoxy groups.

29. The compound according to claim 1 or 2, wherein, a pharmaceutically acceptable salt or stereoisomer thereof, R' indicates that the 0-3 elements are selected from halogen, C1-C6 alkyl, hydroxyC1-C6 alkyl, -OR a -CN, NR a R b , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy-substituted 4-10 membered heterocyclic alkyl, C6-C 10 Aryl, 5-10 heteroaryl.

30. The compound according to claim 1, and its pharmaceutically acceptable salts and stereoisomers, wherein, R' indicates that the 0-3 elements are selected from halogen, C1-C6 alkyl, hydroxyC1-C6 alkyl, -OR a -CN, NR a R b The following groups are substituted with halogenated C1-C6 alkyl or halogenated C1-C6 alkoxy groups: 。 31. The compound according to claim 1, and its pharmaceutically acceptable salts and stereoisomers, wherein, R' represents any of the following groups: 。 32. The compound according to claim 1 or 2, wherein, a pharmaceutically acceptable salt or stereoisomer thereof, R 1 It represents hydrogen, C1-C6 alkyl, and halogenated C1-C6 alkyl.

33. A compound, its pharmaceutically acceptable salts and stereoisomers, wherein, The compound is selected from any of the following structures: 。 34. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the compound of any one of claims 1-33, a pharmaceutically acceptable salt, a stereoisomer, and a pharmaceutically acceptable carrier.

35. The pharmaceutical composition according to claim 34, characterized in that, It also includes a second active substance, which is an anti-tumor drug, including one or more of chemotherapy drugs, targeted tumor therapy drugs, or tumor therapy antibody drugs.

36. Use of any one of the compounds according to claims 1-33, including pharmaceutically acceptable salts and stereoisomers, for the preparation of a medicament for treating a disease by inhibiting PRMT5 action.

37. The use according to claim 36, wherein the disease is a tumor.

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