Quinoline compound, preparation method, application and pharmaceutical composition thereof

Abstract

The invention belongs to the field of chemical medicines, and particularly relates to a quinoline compound, a preparation method, application and a pharmaceutical composition thereof. The invention provides a quinoline compound as shown in a formula I. The quinoline compound has excellent DNA methyltransferase 1 (DNMT1) inhibitory activity and good selectivity, can be used as a novel DNMT1 inhibitor, and provides a new choice for development and application of drugs for treating diseases driven by DNMT1. Formula I.

Description

Technical Field

[0001] This invention belongs to the field of chemical medicine, specifically relating to a quinoline compound, its preparation method and uses, and its pharmaceutical composition. Background Technology

[0002] DNA methylation, an important form of epigenetic modification, mainly occurs at the C5 position (5-methylcytosine, 5mC) of DNA CpG islands. It plays a crucial role in gene expression regulation, genomic imprinting maintenance, X chromosome inactivation, and genome stability. DNMT1 has been identified as a key enzyme in maintaining DNA methylation in various diseases; DNMT1 ensures the stability of epigenetic information transmission by recognizing hemimethylated DNA and precisely transmitting methylation patterns during DNA replication (maintaining methylation). At the molecular level, CpG methylation can inhibit gene expression in two ways: firstly, it directly hinders the binding of transcription factors to DNA through steric hindrance. For example, Yimeng Yin's team, through systematic analysis of 542 human methylation-sensitive SELEX transcription factors, found that embryonic development-related transcription factors (such as bHLH, bZIP, and ETS family members) tend to bind to methylated CpG sites (this preference stems from the interaction between the 5mC hydrophobic methyl group and the transcription factor binding domain). However, methylated CpGs inhibit the binding of major transcription factors such as bHLH, bZIP, and ETS due to steric hindrance. On the other hand, methyl-binding proteins are recruited to form dense chromatin structures. For instance, during tumorigenesis, the degree of unmethylation of CpG sequences outside the CpG islands of tumor suppressor genes increases, while CpGs within the islands are highly methylated, leading to increased chromosome helicity and loss of tumor suppressor gene expression. Furthermore, gene knockout studies have revealed the central role of DNMT1 in development and cell differentiation. Biallelic deletion of DNMT1 in mice leads to embryonic death at E8.5, with the embryonic genome exhibiting over 95% demethylation and complete arrest of the cell differentiation process. Similarly, when DNMT1 expression levels in human differentiated cells fall below a critical threshold (20%), it triggers genome-wide demethylation, abnormal mitosis, and cell death. These findings not only confirm the indispensability of DNMT1 in maintaining epigenetic homeostasis but also suggest that its expression level needs to be precisely regulated to ensure normal cellular function.

[0003] Currently available DNMT1 inhibitors are nucleoside analogs such as 5-azacytidine and 5-aza-2'-deoxycytidine. These inhibitors work by integrating themselves into DNA, forming a covalent complex with DNMT1, which is then recognized as an incorrect protein by the proteasome and degraded, thus inhibiting DNMT1 activity. As the complex degrades, DNA is also damaged, resulting in significant toxic side effects, including bone marrow suppression, nausea, vomiting, and fatigue. In addition, there are natural products containing a large number of hydroxyl groups, such as epigallocatechin gallate (EGCG) and caffeic acid phenethyl ester (CAPE), which inhibit DNMT1 activity through multiple mechanisms; however, these molecules suffer from severe off-target effects and poor activity. Besides these two categories, recent years have seen some progress in the development of small molecule inhibitors targeting DNMT1. For example, carbazole, quinoline, desaturated purine, and dicyanpyridine small molecule inhibitors have been successfully obtained and have shown certain antitumor activity in vitro and in vivo. Although various DNMT1 inhibitors have been developed for research on multiple diseases, these small molecule inhibitors still need further improvement in terms of activity and selectivity. For example, carbazoles only inhibit DNMT1 enzyme activity at the micromolar level, while quinoline inhibitors have a higher IC50 value for DNMT1. 50 It reached 382 nM, but for G9a IC 50 The value was as low as 8 nM, indicating that its selectivity needs further improvement. In conclusion, the development of selective DNMT1 inhibitors has significant scientific and clinical application value, and is expected to provide new strategies and means for the treatment of various DNMT1-driven diseases. Summary of the Invention

[0004] To address the problems in the prior art, the present invention provides a quinoline compound, its preparation method, its uses, and a pharmaceutical composition thereof.

[0005] The compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopic label thereof, or a crystal form thereof, or a prodrug thereof: Formula I R1 is selected from hydrogen, substituted or unsubstituted C1-C. 10 Alkoxy group, wherein the substituent is selected from halogen or benzyl group; R2 is selected from hydrogen, -OL1R6, ; Alternatively, R1 and R2 linked together form a substituted or unsubstituted 5-10 membered cycloalkyl group or a substituted or unsubstituted 5-10 membered heterocycloalkyl group, wherein the substituents are selected from C1-C2. 10 Alkyl, C1-C 10 Alkoxy, C1-C10 Amine, halogen, benzyl, -L1CO-R8; L1 is a covalent bond or -(CH2) 1-10 ; R3 is selected from substituted or unsubstituted 5-10 membered heterocyclic alkyl groups, or substituted or unsubstituted C3-C groups. 10 cycloalkyl, substituted or unsubstituted C6-C 20 aryl, wherein the substituents are selected from C1-C 10 Alkyl, C3-C 10 cycloalkyl, halogen, ; R4 is selected from hydrogen, substituted or unsubstituted C1-C. 10 Alkyl, substituted or unsubstituted C1-C 10 Ester group, wherein the substituents are selected from hydroxyl, C1-C 10 Alkyl groups, halogens; R5 is selected from hydrogen, substituted or unsubstituted C1-C. 10 Alkyl groups, wherein the substituents are selected from hydroxyl, C1-C... 10 Alkyl groups, halogens; Alternatively, R4 and R5 may connect to form substituted or unsubstituted C6-C. 10 aryl, wherein the substituents are selected from C1-C 10 Alkyl, C1-C 10 Alkoxy groups, halogens; When R3 is selected from substituted or unsubstituted C6-C 20 In the aryl case, R1, R2, R4, and R5 are not all hydrogen atoms simultaneously; R6 is selected from substituted or unsubstituted 4-10 membered heterocyclic alkyl groups, wherein the substituents are selected from C1-C2. 10 alkyl; R7 is selected from substituted or unsubstituted C1-C. 10 Alkyl groups, wherein the substituents are selected from halogens, C1-C... 10 amino group; R8 is selected from substituted or unsubstituted C1-C. 10 Amino, substituted or unsubstituted 5-10 membered heterocyclic alkyl groups The substituents are selected from C1-C1. 10 Alkyl groups, halogens; R9 is selected from hydrogen or an amino protecting group; R 10 Selected from substituted or unsubstituted C1-C 10 Alkyl groups, wherein the substituents are selected from halogens; M is selected from carbon, nitrogen, and sulfur atoms; w is selected from 1 and 2; x is selected from 1 and 2; y is selected from 0, 1, and 2; z is selected from 1 and 2.

[0006] Preferably, R1 is selected from hydrogen or methoxy groups; R2 is selected from hydrogen, -OCH2R6, ; Alternatively, substituted or unsubstituted 5-6 membered cycloalkyl groups or substituted or unsubstituted 5-6 membered heterocycloalkyl groups formed by the connection of R1 and R2, wherein the substituents are selected from methyl, benzyl, and -CH2CO-R8; R3 is selected from substituted or unsubstituted 5-6 membered heterocyclic alkyl groups, substituted or unsubstituted C4-C6 cycloalkyl groups, and substituted or unsubstituted C6 aryl groups, wherein the substituents are selected from C1-C2 alkyl groups, C3 cycloalkyl groups, halogens, and other similar groups. ; R4 is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted C1 ester group, wherein the substituent is selected from hydroxyl; R5 is selected from hydrogen; Alternatively, a C6 aryl group formed by the connection of R4 and R5; When R3 is selected from substituted or unsubstituted C6 aryl groups, R1, R2, R4, and R5 are not all hydrogen at the same time; R6 is selected from substituted or unsubstituted 4-5 membered heterocyclic alkyl groups, wherein the substituent is selected from methyl; R7 is selected from methyl; R8 is selected from substituted or unsubstituted amino groups, substituted or unsubstituted 5-9 membered heterocyclic alkyl groups, The substituents are selected from methyl and fluorine. R9 is selected from hydrogen and Boc; R 10 Selected from C1-C3 alkyl groups; M is selected from carbon atom and nitrogen atom; w is selected from 1 and 2; x is selected from 1 and 2; y is selected from 0, 1, and 2; z is selected from 1 and 2.

[0007] Preferably, R1 is selected from methoxy groups; R2 is selected from -OCH2R6. ; Alternatively, a 6-membered heterocyclic alkyl group formed by connecting R1 and R2, wherein the heteroatom is oxygen; R3 is selected from substituted or unsubstituted 6-membered heterocyclic alkyl groups, substituted or unsubstituted C6 aryl groups, wherein the substituent is selected from C1-C2 alkyl groups, N-methylpiperazinyl groups, and the heteroatom is nitrogen; R4 is selected from hydrogen, substituted or unsubstituted methyl groups, wherein the substituent is selected from hydroxyl groups; R5 is selected from hydrogen; R6 is selected from substituted or unsubstituted 4-5 membered heterocyclic alkyl groups, wherein the substituent is selected from methyl and the heteroatom is nitrogen; R7 is selected from methyl; w is selected from 1; x is selected from 1; y is selected from 1; z is selected from 1.

[0008] Preferably, the compound has the structural formula shown in Formula II: Formula II R3 is selected from substituted or unsubstituted 6-membered heterocyclic alkyl, substituted or unsubstituted C4-C6 cycloalkyl, substituted or unsubstituted C6 aryl, wherein the substituent is selected from C1-C2 alkyl, C3 cycloalkyl, halogen, N-methylpiperazinyl, and the heteroatom is nitrogen or oxygen. R4 is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted C1 ester group, wherein the substituent is selected from hydroxyl; R5 is selected from hydrogen; Alternatively, a C6 aryl group formed by the connection of R4 and R5.

[0009] Preferably, R3 is selected from substituted or unsubstituted 6-membered heterocyclic alkyl groups, substituted or unsubstituted C6 aryl groups, wherein the substituent is selected from C1-C2 alkyl groups, N-methylpiperazinyl groups, and the heteroatom is nitrogen. R4 is selected from hydrogen, substituted or unsubstituted methyl groups, wherein the substituent is selected from hydroxyl groups; R5 is selected from hydrogen.

[0010] Preferably, the compound represented by Formula I has one of the following structures: .

[0011] The present invention also provides a method for preparing the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopic label thereof, or a crystal form thereof, or a prodrug thereof, comprising the following steps: Step 1: React compound a with compound b to obtain compound c; Step 2: Compound c undergoes a deprotection reaction to yield compound d; Step 3: React compound d with an aldehyde compound and a reducing agent to obtain compound e; Step 4: Compound e is reacted with R-boronate pinacol ester to obtain compound f; the structure of R in R-boronate pinacol ester is as follows: ; Step 5: React compound f with H2N-R3 to obtain the compound shown in Formula II.

[0012] Preferably, in step 1, the reaction is carried out under the action of a base, which is selected from at least one of cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, and diisopropylethylamine. And / or, in step 1, the solvent for the reaction is selected from... N , N - At least one of dimethylformamide, dichloromethane, acetonitrile, tetrahydrofuran, and dioxane; And / or, in step 1, the reaction temperature is 40-80℃ and the reaction time is 3-8 h; And / or, in step 2, the reaction is carried out under the action of an acid, the acid being selected from at least one of hydrochloric acid and trifluoroacetic acid; And / or, in step 2, the solvent for the reaction is at least one of dichloromethane, acetonitrile, tetrahydrofuran, dioxane, methanol, and ethanol; And / or, in step 2, the reaction temperature is 20-25°C and the reaction time is 2-6 h; And / or, in step 3, the reducing agent is selected from at least one of sodium triacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride; And / or, in step 3, the solvent for the reaction is selected from at least one of dichloromethane and methanol; And / or, in step 3, the reaction temperature is 20-25°C and the reaction time is 8-12 h; And / or, in step 4, the reaction is carried out under the action of a base, the base being selected from sodium carbonate; And / or, in step 4, the reaction is carried out in the presence of a catalyst selected from at least one of tetra(triphenylphosphine)palladium and 1,1'-bis(diphenylphosphine)palladium dichloride; And / or, in step 4, the solvent for the reaction is at least one of 1,4-dioxane and water; And / or, in step 4, the reaction temperature is 70-90℃ and the reaction time is 4-6 h; And / or, in step 5, the catalyst for the reaction is selected from chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) and methanesulfonic acid(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II); And / or, in step 5, the reaction is carried out under the action of a base, the base being selected from at least one of cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, and diisopropylethylamine; And / or, in step 5, the solvent for the reaction is at least one of 1,4-dioxane, toluene, and dimethylformamide; And / or, in step 5, the reaction temperature is 80-110℃ and the reaction time is 8-15 h.

[0013] The present invention also provides the use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotope label thereof, or a crystal form thereof, or a prodrug thereof, in the preparation of a DNA methyltransferase 1 inhibitor; said DNA methyltransferase 1 inhibitor is a drug for the prevention and / or treatment of fibrosis, cancer, and hypobaric hypoxia; said fibrosis is at least one of pulmonary fibrosis, liver fibrosis, and renal fibrosis; said cancer is at least one of breast cancer, colorectal cancer, lung cancer, bladder cancer, hematologic malignancy, prostate cancer, ovarian cancer, pancreatic cancer, gastric cancer, and liver cancer; said hypobaric hypoxia is at least one of high-altitude pulmonary hypertension, pulmonary edema, acute mountain sickness, chronic mountain sickness, and cerebral edema.

[0014] The present invention also provides a pharmaceutical composition, which is a formulation made by adding pharmaceutically acceptable excipients to the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotope label thereof, or a crystal form thereof, or a prodrug thereof as the active ingredient.

[0015] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0016] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0017] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0018] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a -C b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C1-C6 alkyl" refers to alkyl groups containing 1 to 6 carbon atoms.

[0019] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted by one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl groups may also be part of other groups, such as C1-C6 alkoxy groups.

[0020] "Cycloalkyl" refers to a saturated or partially saturated cyclic group having 3 to 10 carbon atoms, no heterocyclic atoms, and a single or multiple rings (including fused, bridged, and spirocyclic systems). For polycyclic systems having aromatic and non-aromatic rings without heteroatoms, the term "cycloalkyl" (e.g., 5,6,7,8-tetrahydronaphthalene-5-yl) applies when the linker is located on a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups including polycyclic dicycloalkyl ring systems are dicyclohexyl, dicyclopentyl, dicyclooctyl, etc.

[0021] Halogens are fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0022] "Halogenated alkyl" refers to an alkyl group in which the hydrogen atom can be replaced by one or more halogen atoms. For example, C1-C6 halogenated alkyl refers to alkyl groups containing 1 to 6 carbon atoms in which the hydrogen atom is replaced by one or more halogen atoms.

[0023] "Heterocyclic" and "heterocyclic alkyl" refer to saturated rings or non-aromatic unsaturated rings containing at least one heteroatom and having a single ring or multiple rings (including fused, bridged, and spirocyclic systems); where heteroatoms refer to nitrogen atoms, oxygen atoms, and sulfur atoms; "Alkoxy" refers to a group in which an alkyl group is attached to a linker site via an oxygen atom. For example, methoxy is -OCH3.

[0024] "Ester group" refers to a group that is connected to a carbon chain via a linking site, and the carbon chain contains at least one ester bond (i.e., -COO-).

[0025] "Amino group" refers to a group that is connected to a linking site via a carbon chain or N, and the carbon chain contains at least one N.

[0026] “R a R b "Connected to form a ring" refers to R a and R b At least one atom in each is connected by a chemical bond, such that R a R b Together with the molecular backbone structure in which they reside, they form a ring structure.

[0027] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0028] The terms "salt" and "pharmaceutical salt" refer to acidic and / or basic salts formed by the above-described compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-described compounds or their stereoisomers with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0029] In some embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent to prepare a medicament or pharmaceutical composition for regulating cell function or treating disease. If a group of compounds is used, these compounds may be administered to the test subject simultaneously, separately, or sequentially.

[0030] This invention provides quinoline compounds of Formula I, which have excellent DNMT1 enzyme inhibitory activity and good selectivity. They can be used as novel DNMT1 inhibitors, providing a new option for the treatment of diseases related to DNMT1 activity (e.g., fibrosis, cancer, and diseases caused by low pressure and hypoxia), and have broad application prospects.

[0031] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0032] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0033] In the following examples and experimental cases, reagents and raw materials not specifically described are all commercially available products.

[0034] Example 1: Synthesis of Compound A2 Step 1: Synthesis of intermediate A2-1 (5,6,7,8-tetrahydronaphthyl-2-amine) 1 g (1 eq) of 6-amino-1,2,3,4-tetrahydro-1-naphthone was added to a reaction flask, along with 5 mL (5 eq) of triethylsilane and 4.7 mL (10 eq) of trifluoroacetic acid. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting mixture was diluted with 100 mL of ethyl acetate and extracted with 40 mL of water (2). The combined organic layers were washed with 50 mL of saturated sodium bicarbonate and sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give intermediate A2-1, which could be used directly in the next step without further purification. The yield was 100%.

[0035] Step 2: Synthesis of intermediate A2-2 (3-oxo-3-((5,6,7,8-tetrahydronaphth-2-yl)amino)propionic acid) Intermediate A2-1 (911 mg, 1 eq) and cycloisopropyl malonate (1.1 g, 1.2 eq) were placed in a reaction flask and stirred at 70 °C for 4 h. After the reaction was completed, rapid column chromatography was performed directly to obtain 1.7 g (containing a certain amount of impurities) of crude product A2-2.

[0036] Step 3: Intermediate A2-3 (6,7,8,9-tetrahydrobenzo[ g Quinoline-2,4(1) H ,3 H Synthesis of )-diketones Intermediate A2-2 (1.7 g, 1 eq) and methanesulfonic anhydride (2.55 g, 2 eq) were placed in a reaction flask and stirred at 70 °C for 2 h. After the reaction solution cooled to room temperature, water was added and the mixture was filtered to obtain the solid, yielding intermediate A2-3, which was used in the next step of the reaction.

[0037] Step 4: Intermediate A2-4 (2,4-dichloro-6,7,8,9-tetrahydrobenzo[] g ]Quinoline) synthesis: Phosphorus oxychloride (6 mL) was added to the reaction flask containing crude product A2-3 obtained from the previous filtration, and the mixture was stirred at 110 °C for 12 h. After the reaction was complete, the reaction solution was quenched in ice water (100 mL) and extracted with ethyl acetate (60 mL × 2). The combined organic layers were washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Rapid column chromatography purification (PE / EA = 40% - 60%) yielded intermediate A2-4, providing 1.3 g of a white solid. The total yield was 78% across the four steps. MS (ESI) m / z 410.5 [M + H] + . Step 5: Intermediate A2-5 (4-chloro-2-(5-methylfuran-2-yl)-6,7,8,9-tetrahydrobenzo[ g ]quinoline) synthesis Intermediate A2-4 (1 eq), sodium carbonate (2 eq), and 5% Pd(PPh3)4 were dissolved in Dioxane / H2O = 4 / 1 (10 mL). Finally, 2-methylfuran-5-boronic acid pinacol ester (1 eq) was added to the reaction system. The reaction was carried out under N2 protection at 80 °C for 5 h. A large amount of solid was formed after the reaction was completed. The solvent was removed by concentration under reduced pressure, and the mixture was slurried with ethyl acetate to obtain intermediate A2-5 in 66% yield. MS (ESI) m / z 410.5 [M + H] + . Step 6: Compound A2 (2-(5-methylfuran-2-yl)- N -(1-Methylpiperidin-4-yl)-6,7,8,9-tetrahydrobenzo[ g Synthesis of quinoline-4-amine Take intermediate A2-5 (1 eq) and 5% potassium iodide in a tube, and add... N2 mL of methylpyrrolidone was added to the reaction system, followed by the addition of 4-amino-1-methylpiperidine (5 eq) and DIPEA (3 eq), and the reaction was carried out at 180 °C for 24 h. After the reaction was completed, direct rapid column chromatography (dichloromethane / NH3·MeOH = 100% - 85%) was performed to give compound A2 in 47% yield.

[0038] HRMS (ESI) m / z : calcd forC 24 H 30 N3O + [M + H] + , 376.2383; found, 376.2384. 1 H NMR (400 MHz, Chloroform- d ) δ 7.84 (s, 1H), 7.47 (d, J = 9.8 Hz,2H), 6.67 (s, 1H), 6.17 (dd, J = 3.4, 1.1 Hz, 1H), 5.65 (s, 1H), 3.75 – 3.69 (m, 1H), 3.01 – 2.96 (m, 2H), 2.90 – 2.84 (m, 4H), 2.44 – 2.37 (m, 8H), 2.26– 2.20 (m, 2H), 1.90 – 1.84 (m, 2H), 1.82 – 1.77 (m, 4H). Example 2 Synthesis of Compound A1 The synthesis method is the same as in Example 1, with the substituents adjusted accordingly to obtain the final product.

[0039] 1 H NMR (400 MHz, DMSO- d 6) δ 8.29 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 8.4,1.3 Hz, 1H), 7.64 – 7.55 (m, 1H), 7.40 – 7.31 (m, 1H), 7.13 (d, J = 3.2 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 6.83 (s, 1H), 6.28 (d, J= 3.6 Hz, 1H), 3.76 –3.69 (m, 1H), 3.41 (s, 2H), 3.06 (d, J = 11.7 Hz, 2H), 2.41 (s, 6H), 2.08 –1.99 (m, 2H), 1.89 – 1.76 (m, 2H). Example 3 Synthesis of Compound A3 The synthesis method follows steps 2-6 of Example 1, with adaptive adjustments made to the substituents to obtain the final product.

[0040] HRMS (ESI) m / z: calcd forC 23 H 28 N3O + [M + H] + , 362.2227; found, 362.2225. 1 H NMR (400 MHz, DMSO- d 6) δ 8.23 ​​(s, 1H), 7.74 (s, 1H), 7.32 (s, 1H), 6.84 (s, 1H), 6.33 (s, 1H), 5.76 (s, 1H), 4.21 – 4.09 (m, 1H), 4.08 – 3.86(m, 2H), 3.17 (d, J = 4.2 Hz, 2H), 3.01 (t, J = 7.4 Hz, 4H), 2.67 (s, 3H), 2.42(s, 3H), 2.15 – 1.99 (m, 6H). Example 4 Synthesis of Compound A4 Compound A4-0 (1 eq) and malonic acid (2 eq) were added to a reaction flask, and phosphorus oxychloride (15 mL) was added to the flask. The reaction was carried out at 100 °C for 10 h. Phosphorus oxychloride was removed by vacuum distillation. The remaining residue was dissolved in ice water, and the resulting mixture was quenched with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was obtained. The crude product was purified by plate preparation to obtain intermediate A4-1. Subsequent synthesis was carried out according to steps 5-6 of Example 1, with adaptive adjustments to the substituents to obtain the final product.

[0041] HRMS (ESI) m / z: calcd forC 21 H 24 N3O3 + [M + H] + , 366.1812; found, 366.1810. 1 H NMR (400 MHz, Chloroform- d ) δ 7.28 (s, 1H), 6.93 (d, J = 3.1 Hz,1H), 6.89 (s, 1H), 6.70 (s, 1H), 6.07 (s, 1H), 5.99 (s, 1H), 5.23 (s, 2H),4.49 – 4.45 (m, 1H), 3.64 – 3.51 (m, 2H), 2.85 – 2.78 (m, 2H), 2.37 (s, 3H), 2.30 (s, 3H), 2.23 (t, J = 11.1 Hz, 2H), 2.15 – 2.09 (m, 2H). Example 5 Synthesis of Compound A6 Step 1: Synthesis of intermediate A6-1 (1-methyl-1,2,3,4-tetrahydroquinoline-7-amine) Take 1-methyl-7-nitro-1,2,3,4-tetrahydroquinoline (1 g, 1 eq), dissolve 10% Pd / C in methanol (15 mL), react at room temperature for 2 h under hydrogen atmosphere, filter, and concentrate the filtrate under reduced pressure to obtain gray oily substance A6-1, which can be used directly in the next step without purification, with a yield of 100%.

[0042] Step 2: Intermediate A6-2 (6,8-dichloro-1-methyl-1,2,3,4-tetrahydropyrido[3,2- g ]quinoline) synthesis Intermediate A6-1 (844 mg, 1 eq) and malonic acid (1 g, 2 eq) were added to a reaction flask. Phosphorus oxychloride (15 mL) was added to the flask, and the mixture was reacted at 100 °C for 10 h. Phosphorus oxychloride was removed by vacuum distillation. The remaining residue was dissolved in ice water, and the resulting mixture was quenched with water (100 mL). The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative plate to give intermediate A6-2, yielding 60 mg of white solid, with a yield of 5%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.57 (s, 1H), 7.02 (s, 1H), 6.81 (s, 1H), 3.35 (t, J = 5.9 Hz, 2H), 2.96 (s, 3H), 2.90 – 2.82 (m, 2H), 1.98– 1.90 (m, 2H). Step 3: Intermediate A6-3 (6-chloro-1-methyl-8-(5-methylfuran-2-yl)-1,2,3,4-tetrahydropyrido[3,2- g ]Quinoline) synthesis: Intermediate A6-2 (1 eq), sodium carbonate (2 eq), and 5% Pd(PPh3)4 were dissolved in Dioxane / H2O = 4 / 1 (10 mL). Finally, 2-methylfuran-5-boronic acid pinacol ester (1 eq) was added to the reaction system. The reaction was carried out under N2 protection at 80 °C for 5 h. After the reaction was completed, a large amount of solid was formed. The solvent was removed by concentration under reduced pressure, and the solid was slurried with ethyl acetate to obtain 50 mg of white solid A6-3, yielding a yield of 70%.

[0043] 1 H NMR (400 MHz, Chloroform- d ) δ 7.65 (s, 1H), 7.49 (s, 1H), 7.01 (s,2H), 6.15 (d, J = 3.3 Hz, 1H), 3.40 (t, J = 5.9 Hz, 2H), 3.06 (s, 3H), 2.95 (t, J =6.4 Hz, 2H), 2.44 (s, 3H), 2.04 (q, J = 6.1 Hz, 2H). Step 4: A6 (9-methyl-2-(5-methylfuran-2-yl)- N -(1-Methylpiperidin-4-yl)-6,7,8,9-tetrahydropyrido[3,2-] g Quinoline-4-amine Take intermediate A6-3 (1 eq) and 5% potassium iodide into a sealing tube, and add... N 2 mL of methylpyrrolidone was added to the reaction system, followed by the addition of 4-amino-1-methylpiperidine (5 eq) and DIPEA (3 eq), and the reaction was carried out at 180 °C for 24 h. After the reaction was completed, direct rapid column chromatography (dichloromethane / NH3·MeOH = 100% - 85%) yielded 26 mg of white solid A6, with a yield of 42%.

[0044] HRMS (ESI) m / z : calcd forC 24 H 31 N4O + [M + H] + , 391.2492; found,391.2492. 1 H NMR (400 MHz, Chloroform- d ) δ 8.11 (s, 1H), 7.48 (s, 2H), 6.46 (s,1H), 6.27 (s, 1H), 6.19 (d, J = 3.4 Hz, 1H), 3.75 (s, 1H), 3.31 (t, J = 5.8 Hz,2H), 3.07 – 2.99 (m, 2H), 2.98 (s, 3H), 2.81 (t, J = 6.3 Hz, 2H), 2.55 – 2.30 (m, 8H), 2.26 – 2.17 (m, 2H), 2.01 – 1.85 (m, 4H). Example 6 Synthesis of Compound A5 Compound A5-0 (1 eq) was placed in a reaction flask, and triethylsilane (5 eq) and trifluoroacetic acid (10 eq) were added. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate (100 mL) and extracted with water (40 mL × 2). The combined organic layers were washed with saturated sodium bicarbonate and sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate A5-1. Subsequent synthesis was carried out according to steps 1-4 of Example 5, with adaptive adjustments to the substituents to obtain the final product.

[0045] HRMS (ESI) m / z : calcd for C 23 H 28 N3O2 + [M + H] + , 378.2176; found, 378.2173. 1 H NMR (400 MHz, Chloroform- d ) δ 7.75 (s, 1H), 7.02 (s, 1H), 6.96 (s,1H), 6.73 (s, 1H), 6.13 (dd, J = 3.2, 1.1 Hz, 1H), 4.62 (d, J = 7.6 Hz, 1H), 4.30– 4.23 (m, 2H), 3.65 (s, 1H), 3.00 (t, J = 6.5 Hz, 2H), 2.84 (d, J = 11.7 Hz,2H), 2.44 (s, 3H), 2.35 (s, 3H), 2.33 – 2.25 (m, 2H), 2.22 – 2.14 (m, 2H), 2.11 – 2.05 (m, 2H), 1.75 – 1.61 (m, 2H). Example 7 Synthesis of Compound A7 The synthesis method is the same as steps 2-4 in Example 5, with the substituents adjusted accordingly to obtain the final product.

[0046] Example 8 Synthesis of Compound A8 Step 1: Intermediate A8-1 (6-nitro-3,4-dihydro-2- H Synthesis of -1,4-benzoxazine Dissolve 50 g (1 eq) of 2-amino-4-nitrophenol, 64 g (1.2 eq) of 1,2-dibromoethane, and 79 g (3 eq) of potassium carbonate in water. N , N - Dimethylformamide (100 mL) was stirred at 125 °C for 6 h. The reaction mixture was quenched with water (1000 mL) and extracted with ethyl acetate (800 mL × 3). The combined organic layers were washed with saturated sodium chloride aqueous solution (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give crude product, which was purified by rapid column chromatography (PE / EA = 5 / 1-1 / 1) to give intermediate A8-1. 17 g of brown solid was given, yield 34%. 1 H NMR (400 MHz, DMSO- d 6) δ 7.46 (d, J =2.8 Hz, 1H), 7.39 (dd, J = 8.8, 2.8 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 6.48 (s,1H), 4.24 (t, J = 4.4 Hz, 2H), 3.35 – 3.32 (m, 2H). Step 2: Intermediate A8-2 (4-methyl-6-nitro-3,4-dihydro-2- H Synthesis of -1,4-benzoxazine Dissolve intermediate A8-1 (660 mg, 1 eq) in... N , N Dimethylformamide (7 mL) was stirred at 0 °C, followed by the addition of sodium hydride (296 mg, 2 eq) and stirring for 30 min under the same conditions. Iodomethane (525 mg, 1 eq) was then added to the reaction mixture, and after 5 min, the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with a saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. This crude product was then concentrated by distillation under reduced pressure to give intermediate A8-2, which could be used directly in the next step without further purification. 650 mg of a yellow solid was obtained, with a yield of 90%.

[0047] Step 3: Intermediate A8-3 (4-methyl-6-amino-3,4-dihydro-2-amino-3 ... H Synthesis of -1,4-benzoxazine Intermediate A8-2 (100 mg, 1 eq) was dissolved in a 1:1 mixture of methanol and formic acid (6 mL) and stirred at 50 °C. Then, reduced iron powder (145 mg, 5 eq) was added, and the reaction was allowed to proceed for 3 h. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to obtain intermediate A8-3, which was a gray oily substance with a 100% yield. No further purification was required for the next step. 1 H NMR (400 MHz, Chloroform- d ) δ7.58 (dd, J = 8.8, 2.6 Hz, 1H), 7.50 (d, J = 2.6 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 4.46 – 4.27 (m, 2H), 3.57 – 3.34 (m, 2H). Step 4: Intermediate A8-4 (4-methyl-3,4-dihydro-2-methyl-3,4-dihydro-3 ...dihydro- H -[1,4]oxynitric heterogeneity[2,3- g Quinoline-7,9(6) H 8 H Synthesis of )-diketones Intermediate A8-3 (85 mg, 1 eq) was added to diethyl malonate (2 mL) and reacted at 100 °C for 30 min, followed by heating to 170 °C for 12 h. After the reaction was completed, the mixture was cooled to room temperature. The reaction system was a brown solid. The solid was washed with ethyl acetate and filtered to obtain intermediate A8-4, yielding 50 mg of brown solid, with a yield of 42%.

[0048] Step 5: Intermediate A8-5 (7,9-dichloro-4-methyl-3,4-dihydro-2 ... H -[1,4]oxynitric heterogeneity[2,3- g ]quinoline) synthesis Phenyl dichlorophosphate (5 mL) was placed in a reaction flask, and A8-4 (500 mg, 1 eq) was added. The reaction mixture was then heated to 170 °C and stirred for 21 h. The pH was then adjusted to approximately 7 by adding saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Rapid column chromatography (PE / EA = 100%–40%) yielded intermediate A8-5, providing 320 mg of a yellow solid in 55% yield. 1H NMR (400 MHz, Chloroform- d ) δ 7.39 (s, 1H), 7.17(s, 1H), 7.01 (s, 1H), 4.40 – 4.33 (m, 2H), 3.49 – 3.44 (m, 2H), 3.05 (s, 3H). Step 6: Intermediate A8-6 (9-chloro-4-methyl-7-(5-methylfuran-2-yl)-3,4-dihydro-2-yl) H -[1,4]oxynitric heterogeneity[2,3- g ]quinoline) synthesis Intermediate A8-5 (100 mg, 1 eq), sodium carbonate (79 mg, 2 eq), and 5% Pd(PPh3)4 were dissolved in Dioxane / H2O = 4 / 1 (10 mL). Finally, 2-methylfuran-5-borate pinacol ester (77 mg, 1 eq) was added to the reaction system. The reaction was carried out under N2 protection at 80 °C for 5 h. A large amount of solid was formed after the reaction. The solvent was removed by concentration under reduced pressure, and the mixture was slurried with ethyl acetate to give intermediate A8-6, yielding 100 mg of a yellow solid (85% yield). MS (ESI) m / z 410.5 [M + H] + . Step 7: Compound A8 (4-methyl-7-(5-methylfuran-2-yl)- N -(1-Methylpiperidin-4-yl)-3,4-dihydro-2 H -[1,4]oxynitric heterogeneity[2,3- g Synthesis of quinoline-9-amine Take intermediate A8-6 (100 mg, 1 eq) and 5% potassium iodide in a sealing tube, and add... N 2 mL of methylpyrrolidone was added to the reaction system, followed by the addition of 4-amino-1-methylpiperidine (180 mg, 5 eq) and DIPEA (124 mg, 3 eq), and the reaction was carried out at 180 °C for 24 h. After the reaction was completed, direct rapid column chromatography (dichloromethane / NH3·MeOH = 100% - 85%) yielded 53 mg of yellow solid A8, with a yield of 42%.

[0049] HRMS (ESI) m / z : calcd for C 23 H 29 N4O2 + [M + H] +, 393.2285; found, 393.2284. 1 H NMR (400 MHz, Chloroform- d ) δ 7.36 (s, 1H), 6.93 (s, 1H), 6.63 (s,1H), 6.18 – 6.12 (m, 1H), 5.30 (s, 1H), 4.71 (s, 1H), 4.34 (t, J = 4.6 Hz, 2H),3.68 – 3.60 (m, 1H), 3.40 (t, J = 4.6 Hz, 2H), 3.06 (s, 3H), 2.85 (d, J = 11.8Hz, 2H), 2.43 (s, 3H), 2.35 (s, 3H), 2.31 – 2.25 (m, 2H), 2.19 – 2.14 (m,2H), 1.72 – 1.64 (m, 2H). Example 9 Synthesis of Compound A9 The synthesis method is the same as in Example 8, with the substituents adjusted accordingly to obtain the final product.

[0050] HRMS (ESI) m / z : calcd forC 29 H 33 N4O2 + [M + H] + , 469.2598; found,469.2598. 1 H NMR (400 MHz, Chloroform- d ) δ 7.91 (s, 1H), 7.68 (s, 1H), 7.40 (s,1H), 7.36 – 7.17 (m, 6H), 6.56 (s, 1H), 6.20 (d, J = 3.0 Hz, 1H), 4.41 (s, 2H), 4.21 (t, J = 4.6 Hz, 2H), 3.97 – 3.88 (m, 1H), 3.41 (t, J= 4.6 Hz, 2H), 3.24 –3.13 (m, 2H), 2.80 – 2.68 (m, 2H), 2.54 (s, 3H), 2.42 (s, 3H), 2.32 – 2.25(m, 2H), 2.12 – 2.01 (m, 2H). Example 10 Synthesis of Compound A10 Step 1: Intermediate 1 (methyl 2-(6-nitro-2,3-dihydro-4-methyl) H -benzo[ b Synthesis of [1,4]oxazazine-4-yl)acetate: Take intermediate A8-1 (17 g, 1 eq) and 5% potassium iodide in a reaction flask, and add... N , N - Dimethylformamide (100 mL) was stirred at room temperature, followed by the addition of methyl bromoacetate (11 mL, 1.2 eq) and... N , N -Diisopropylethylamine (31 mL, 2 eq) was reacted at 120 °C for 8 h. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give crude product, and subjected to rapid column chromatography (PE / EA = 100%-60%) to give intermediate 1, yielding 15 g of yellow solid, 50% yield. 1 H NMR (400 MHz, Chloroform- d ) δ 7.61 (dd, J = 8.8, 2.5 Hz, 1H), 7.38 (d, J = 2.6Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.41 – 4.35 (m, 2H), 4.11 (s, 2H), 3.77 (s, 3H), 3.54 – 3.48 (m, 2H). Step 2: Intermediate 2 (methyl 2-(6-amino-2,3-dihydro-4-methyl) H -benzo[ b Synthesis of [1,4]oxazazine-4-yl)acetate Take intermediate 1 (1 g, 1 eq), dissolve 5% Pd / C in methanol (15 mL), react under hydrogen at room temperature for 2 h, filter, and concentrate the filtrate under reduced pressure to obtain a gray oily intermediate 2, which can be used directly in the next step without purification. The yield is 100%. 1 H NMR (400MHz, Chloroform- d ) δ 6.61 (d, J = 8.3 Hz, 1H), 6.02 (dd, J = 8.3, 2.5 Hz, 1H), 5.89 (d, J = 2.5 Hz, 1H), 4.23 – 4.15 (m, 2H), 3.97 (s, 2H), 3.73 (s, 3H), 3.49– 3.42 (m, 2H). Step 3: Intermediate 3 (methyl 2-(7,9-dihydroxy-2,3-dihydro-4-methyl) H -[1,4]oxynitric heterogeneity[2,3- g Synthesis of quinoline-4-yl)acetate Intermediate 2 (500 mg, 1 eq) was mixed with diethyl malonate (721 mg, 3 eq) and reacted at 100 °C for 30 min, followed by heating to 170 °C for 12 h. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was a brown solid. The solid was washed with ethyl acetate, filtered, and the filter cake was collected to give intermediate 3, yielding 320 mg of brown solid, with a yield of 49%. MS (ESI) m / z 291.19 [M + H] + .

[0051] Step 4: Intermediate 4 (methyl 2-(7,9-dichloro-2,3-dihydro-4-) H -[1,4]oxynitric heterogeneity[2,3- g Synthesis of quinoline-4-yl)acetate Phenyl dichlorophosphate (697 mg, 3 eq) was placed in a reaction flask, and intermediate 3 (320 mg, 1 eq) was added. The reaction was then heated to 170 °C and stirred for 21 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to approximately 7 by adding saturated sodium bicarbonate aqueous solution in an ice bath. The mixture was extracted with ethyl acetate (80 mL × 2). The combined organic layers were washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Rapid column chromatography (PE / EA = 100% -60%) yielded intermediate 4, providing 230 mg of a yellow solid, with a yield of 64%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.46(s, 1H), 7.20 (s, 1H), 6.92 (s, 1H), 4.40 – 4.35 (m, 2H), 4.16 (s, 2H), 3.76(s, 3H), 3.62 (t, J = 4.7 Hz, 2H). Step 5: Intermediate 5 (methyl 2-(9-chloro-7-(5-methylfuran-2-yl)-2,3-dihydro-4-yl) H -[1,4]oxynitric heterogeneity[2,3- g Synthesis of quinoline-4-yl)acetate Intermediate 4 (100 mg, 1 eq), sodium carbonate (66 mg, 2 eq), and 5% Pd(PPh3)4 were dissolved in a 1,4-dioxane / water ratio of 4 / 1 (10 mL). Finally, 2-methylfuran-5-boronate pinacol ester (65 mg, 1 eq) was added to the reaction system. The reaction was carried out under N2 protection at 80 °C for 5 h. A large amount of solid was formed after the reaction. The solvent was removed by concentration under reduced pressure, and the mixture was purified by slurrying with ethyl acetate to give intermediate 5, yielding 90 mg of a yellow solid (75% yield). MS (ESI) m / z 373.23 [M + H] + .

[0052] Step 6: Intermediate 6 (methyl 2-[7-(5-methylfuran-2-yl)-9-((1-methylpiperidin-4-yl)amino)-2,3-dihydro-4-yl) H -[1,4]oxynitric heterogeneity[2,3- g Synthesis of quinoline-4-yl]acetate Intermediate 5 (50 mg, 1 eq), 10% RuPhosPdG2, and cesium carbonate (64 mg, 1.5 eq) were dissolved in dry 1,4-dioxane (10 mL), followed by the addition of 4-amino-1-methylpiperidine (18 mg, 1.2 eq). The reaction was carried out under N2 protection at 100 °C for 12 h. After the reaction was completed, palladium was removed by filtration, and intermediate 6 was purified by preparative plate to give 38 mg of white solid, with a yield of 65%. 1 H NMR (400 MHz, Chloroform- d ) δ 7.00 (s, 1H), 6.98 (s, 1H), 6.92 (d, J = 3.2 Hz, 1H), 6.63 (s, 1H), 6.11 (dd, J = 3.3, 1.1 Hz, 1H), 4.48 (d, J = 7.5 Hz, 1H), 4.34 (t, J = 4.6 Hz, 2H), 4.17 (s, 2H), 3.74 (s, 3H), 3.57 (q, J = 7.6, 4.6 Hz, 3H), 2.83(d, J = 11.4 Hz, 2H), 2.43 (s, 3H), 2.34 (s, 3H), 2.26 (t, J = 11.3 Hz, 2H), 2.16(d, J = 12.8 Hz, 2H), 1.65 (d, J = 10.3 Hz, 2H). Step 7: Intermediate 7 (2-[7-(5-methylfuran-2-yl)-9-((1-methylpiperidin-4-yl)amino)-2,3-dihydro-4-yl) H -[1,4]oxynitric heterogeneity[2,3- g Synthesis of quinoline-4-yl]acetic acid Intermediate 6 (600 mg, 1 eq) was dissolved in methanol / tetrahydrofuran / water = 3:2:1 (12 mL), and lithium hydroxide (162 mg, 3 eq) was added. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the pH was adjusted to 3-4 with hydrochloric acid (1 M), and the solvent was removed by vacuum distillation to obtain intermediate 7 with a yield of 100%. It can be used directly in the next step without purification.

[0053] Step 8: A10 ( N , N-Dimethyl-2-[7-(5-methylfuran-2-yl)-9-((1-methylpiperidin-4-yl)amino)-2,3-dihydro-4-yl] H -[1,4]oxynitric heterogeneity[2,3- g Synthesis of quinoline-4-ylacetamide Intermediate 7 (85 mg, 1 eq), dimethylamine hydrochloride (19 mg, 1.2 eq), and HATU (110 mg, 1.5 eq) were dissolved in... N , N -Dimethylformamide (5 mL) was added last to the reaction system. N , N -Diisopropylethylamine (74 mg, 3 eq) was reacted overnight at room temperature. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give crude product, and purified by preparative arbitrage to give compound A10. 30 mg of yellow solid was given, yield 34%.

[0054] HRMS (ESI) m / z : calcd for C 26 H 34 N5O3 + [M + H] + , 464.2656; found, 464.2654. 1 H NMR (400 MHz, Chloroform- d ) δ 7.05 – 6.94 (m, 3H), 6.60 (s, 1H), 6.11 (dd, J = 3.2, 1.2 Hz, 1H), 4.58 (d, J = 7.5 Hz, 1H), 4.34 (t, J = 4.6 Hz, 2H), 4.21 (s, 2H), 3.65 – 3.54 (m, 3H), 3.10 (s, 3H), 2.97 (s, 3H), 2.82 (d, J =11.5 Hz, 2H), 2.43 (s, 3H), 2.33 (s, 3H), 2.26 (t, J = 11.2 Hz, 2H), 2.17 –2.12 (m, 2H), 1.70 – 1.60 (m, 2H). Example 11 Synthesis of Compound A11 The synthesis method of compound A11 is as described in Example 10, with adaptive adjustments to the substituents.

[0055] HRMS (ESI) m / z : calcd for C 29 H 38 N5O3 + [M + H] + , 504.2969; found, 504.2969. 1 H NMR (400 MHz, Chloroform- d ) δ 7.15 (s, 2H), 6.98 (s, 1H), 6.60 (s,1H), 6.13 (d, J = 2.2 Hz, 1H), 4.68 (s, 1H), 4.34 (t, J = 4.7 Hz, 2H), 4.23 (s,2H), 3.60 – 3.51 (m, 5H), 3.49 – 3.45 (m, 2H), 2.89 – 2.76 (m, 2H), 2.43 (s,3H), 2.34 (s, 3H), 2.29 – 2.23 (m, 2H), 2.17 – 2.13 (m, 2H), 1.72 – 1.64 (m,6H), 1.61 – 1.57 (m, 2H). Example 12 Synthesis of Compound A12 The synthesis method of compound A12 is as described in Example 10, with adaptive adjustments made to the substituents.

[0056] HRMS (ESI) m / z : calcd for C 28 H 36 N5O3 + [M + H] + , 490.2813; found, 490.2816. 1 H NMR (400 MHz, Chloroform- d) δ 7.21 (s, 1H), 6.99 (s, 1H), 6.59 (s,1H), 6.13 (d, J = 2.4 Hz, 1H), 4.79 (s, 1H), 4.41 – 4.31 (m, 2H), 4.15 (s, 2H), 3.65 – 3.57 (m, 5H), 3.50 (t, J = 7.1 Hz, 2H), 2.84 (d, J = 11.6 Hz, 2H), 2.42(s, 3H), 2.34 (s, 3H), 2.29 – 2.21 (m, 2H), 2.19 – 2.11 (m, 2H), 2.10 – 2.02(m, 2H), 1.94 – 1.86 (m, 2H), 1.73 – 1.64 (m, 2H). Example 13 Synthesis of Compound A13 The synthesis method of compound A13 is as described in Example 10, with adaptive adjustments made to the substituents.

[0057] HRMS (ESI) m / z : calcd for C 29 H 36 N5O4 + [M + H] + , 518.2762; found, 518.2767. 1 H NMR (400 MHz, Chloroform- d ) δ 7.11 (s, 1H), 7.06 (s, 1H), 6.98 (s, 1H), 6.59 (d, J = 5.4 Hz, 1H), 6.14 (d, J = 3.3 Hz, 1H), 4.94 (s, 1H), 4.74 (s,1H), 4.68 – 4.65(m, 1H), 4.35 (s, 2H), 4.27 (d, J = 17.2 Hz, 1H), 3.95 – 3.88(m, 2H), 3.85 – 3.79 (m, 1H), 3.79 – 3.71 (m, 1H), 3.68 – 3.59 (m, 2H), 2.84(d, J= 10.4 Hz, 2H), 2.43 (s, 3H), 2.34 (s, 3H), 2.29 – 2.23 (m, 2H), 2.18 –2.13 (m, 2H), 2.05 – 1.99 (m, 2H), 1.96 – 1.90 (m, 2H), 1.70 – 1.63 (m, 2H). Example 14 Synthesis of Compound A14 The synthesis method of compound A14 is as described in Example 10, with adaptive adjustments made to the substituents.

[0058] HRMS (ESI) m / z : calcd for C 30 H 38 N5O4 + [M + H] + , 532.2918; found, 532.2924. 1 H NMR (400 MHz, Chloroform- d ) δ 7.42 (s, 1H), 7.39 (s, 1H), 7.00 (s, 1H), 6.56 (s, 1H), 6.25 (d, J = 3.6 Hz, 1H), 4.46 – 4.30 (m, 2H), 4.15 – 4.00(m, 2H), 3.98 – 3.90 (m, 2H), 3.87 – 3.61 (m, 4H), 3.58 – 3.32 (m, 2H), 3.25(s, 2H), 3.07 – 2.95 (m, 2H), 2.46 (s, 3H), 2.40 (s, 3H), 2.31 (t, J = 12.0 Hz, 2H), 2.09 (d, J = 13.1 Hz, 2H), 1.91 – 1.70 (m, 2H). Example 15 Synthesis of Compound A15 The synthesis method of compound A15 is as described in Example 10, with adaptive adjustments made to the substituents.

[0059] HRMS (ESI) m / z : calcd forC 30 H40 N5O4 + [M + H] + , 534.3075; found, 534.3080. 1 H NMR (400 MHz, Chloroform- d ) δ 7.27 (s, 2H), 6.99 (s, 1H), 6.58 (s,1H), 6.16 (d, J = 3.3 Hz, 1H), 5.04 – 4.83 (m, 1H), 4.40 – 4.31 (m, 4H), 3.84 –3.75 (m, 1H), 3.70 – 3.59 (m, 4H), 3.58 – 3.52 (m, 2H), 2.95 (t, J = 11.8 Hz,1H), 2.88 – 2.81 (m, 2H), 2.43 (s, 3H), 2.35 (s, 3H), 2.31 – 2.22 (m, 3H),2.15 (d, J = 13.1 Hz, 3H), 1.71 – 1.64 (m, 2H), 1.22 – 1.16 (m, 4H). Example 16 Synthesis of Compound A16 The synthesis method of compound A16 is as described in Example 10, with adaptive adjustments made to the substituents.

[0060] HRMS (ESI) m / z : calcd for C 29 H 36 F2N5O3 + [M + H] + , 540.2781; found, 540.2779. 1 H NMR (400 MHz, Chloroform- d ) δ 7.22 (s, 2H), 6.99 (s, 1H), 6.60 (s,1H), 6.14 (d, J = 3.2 Hz, 1H), 4.76 (s, 1H), 4.34 (t, J= 4.6 Hz, 2H), 4.28 (s,2H), 3.80 – 3.70 (m, 2H), 3.67 – 3.59 (m, 2H), 3.54 (t, J = 4.7 Hz, 2H), 2.84(d, J = 11.6 Hz, 2H), 2.43 (s, 3H), 2.34 (s, 3H), 2.31 – 2.21 (m, 2H), 2.20 –2.11 (m, 4H), 2.05 (s, 2H), 1.73 – 1.61 (m, 2H). Example 17 Synthesis of Compound A17 The synthesis method of compound A17 is as described in Example 10, with adaptive adjustments made to the substituents.

[0061] 1 H NMR (400 MHz, Chloroform- d ) δ7.28(s, 1H), 7.02 (s, 1H), 6.99 (s,1H), 6.45 (s, 1H), 6.20 (d, J = 3.5 Hz, 1H), 5.51 (s, 1H), 4.33 (t, J = 4.7 Hz,2H), 4.27 (s, 2H), 3.87 – 3.79 (m, 2H), 3.76 – 3.70 (m, 2H), 3.67 – 3.59 (m,3H), 3.56 – 3.51 (m, 4H), 2.90 – 2.83 (m, 2H), 2.44 (s, 3H), 2.35 (s, 3H), 2.31 – 2.25 (m, 2H), 2.13 – 2.08 (m, 2H), 1.75 – 1.67 (m, 2H). Example 18 Synthesis of Compound A18 The synthesis method of compound A18 is as described in Example 10, with adaptive adjustments made to the substituents.

[0062] 1 H NMR (400 MHz, Chloroform- d) δ 7.18 (s, 1H), 7.14 (s, 1H), 7.00 (s, 1H), 6.56 (s, 1H), 6.13 (d, J = 3.3 Hz, 1H), 4.85 (s, 1H), 4.32 (t, J = 4.5 Hz, 2H), 4.20 (s, 2H), 3.56 – 3.51 (m, 5H), 3.47 – 3.43 (m, 2H), 2.83 (d, J = 11.4Hz, 2H), 2.42 (s, 3H), 2.33 (s, 3H), 2.25 (t, J = 11.1 Hz, 2H), 2.17 – 2.11 (m,2H), 1.72 – 1.63 (m, 2H), 1.53 (t, J = 5.9 Hz, 2H), 1.47 – 1.39 (m, 12H). Example 19 Synthesis of Compound A19 The synthesis method of compound A19 is as described in Example 10, with adaptive adjustments made to the substituents.

[0063] HRMS (ESI) m / z : calcd forC 31 H 40 N5O3 + [M + H] + , 530.3126; found, 530.3121. 1 H NMR (400 MHz, Chloroform- d ) δ 7.18 (s, 2H), 7.00 (s, 1H), 6.58 (s,1H), 6.14 (d, J = 3.2 Hz, 1H), 4.83 (s, 1H), 4.34 (t, J = 4.6 Hz, 2H), 4.25 (s,2H), 3.68 – 3.59 (m, 3H), 3.58 – 3.50 (m, 4H), 2.84 (d, J = 11.5 Hz, 2H), 2.42(s, 3H), 2.34 (s, 3H), 2.26 (t, J= 11.1 Hz, 2H), 2.19 – 2.11 (m, 2H), 1.74 –1.61 (m, 2H), 1.48 (t, J = 5.6 Hz, 2H), 1.40 (t, J = 5.8 Hz, 2H), 0.41 – 0.35 (m,4H). Example 20 Synthesis of Compound A20 The synthesis method of compound A20 is as described in Example 10, with adaptive adjustments made to the substituents.

[0064] HRMS (ESI) m / z : calcd for C 34 H 45 N6O5 + [M + H] + , 617.3446; found, 617.3435. 1 H NMR (400 MHz, Chloroform- d ) δ7.27(s, 1H), 7.21 (s, 1H), 6.99 (s,1H), 6.59 (s, 1H), 6.16 (s, 1H), 4.91 (s, 1H), 4.48 (s, 2H), 4.31 (s, 2H), 4.18 (s, 2H), 4.12 – 4.07 (m, 3H), 4.01 (s, 2H), 3.59 – 3.55 (m, 2H), 3.37 –3.32 (m, 2H), 2.85 (s, 2H), 2.43 (s, 3H), 2.34 (s, 3H), 2.29 – 2.22 (m, 2H),2.18 – 2.11 (m, 2H), 1.73 – 1.63 (m, 2H), 1.43 (s, 9H). Example 21 Synthesis of Compound A21 Step 1: Synthesis of Intermediate 8 (2,4-dichloro-6-methoxyquinoline-7-ol) 10 g (1 eq) of 2-methoxy-5-aminophenol and 8.2 g (1.1 eq) of malonic acid were added to a reaction flask. Phosphorus oxychloride (40 mL) was added to the flask, and the mixture was reacted at 95 °C for 12 h. Phosphorus oxychloride was removed by vacuum distillation and quenched with water (300 mL). The mixture was extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. Rapid column chromatography (PE / EA = 100%–40%) yielded intermediate 8, which was a 3 g white solid, with a yield of 17%. MS (ESI) m / z 244.02 [M + H] + .

[0065] Step 2: Synthesis of Intermediate 9 (4-chloro-6-methoxy-2-(5-methylfuran-2-yl)quinoline-7-ol) Intermediate 8 (1 g, 1 eq), sodium carbonate (874 mg, 2 eq), and 5% Pd(PPh3)4 were dissolved in 1,4-dioxane / water = 4 / 1 (24 mL). Finally, 2-methylfuran-5-boronic acid pinacol ester (858 mg, 1 eq) was added to the reaction system. The reaction was carried out under N2 protection at 80 °C for 5 h. A large amount of solid was formed after the reaction. The solvent was removed by concentration under reduced pressure, and the mixture was purified by slurrying with ethyl acetate to give intermediate 9, yielding 1 g of grayish-white solid in 85% yield. MS (ESI) m / z 290.17 [M + H] + .

[0066] Step 3: Synthesis of intermediate 2a (tert-butyl 3-[((4-chloro-6-methoxy-2-(5-methylfuran-2-yl)quinolin-7-yl)oxy)methyl]azacyclobutane-1-carboxylic acid ester) Intermediate 9 (578 mg, 1 eq) N -Boc-3-bromocyclobutane (501 mg, 1 eq) and potassium carbonate (417 mg, 1.5 eq) were dissolved in N , NDimethylformamide (7 mL) was reacted at 60 °C for 5 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, and subjected to rapid column chromatography (PE / EA = 100%–0%) to give 688 mg of white solid, yield 75%. The obtained white solid was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added to the reaction solution and reacted at room temperature for 3 h. The solvent was removed by concentration under reduced pressure, diluted with dichloromethane (10 mL), and neutralized to pH 7 with amine-containing methanol solution. Rapid column chromatography (dichloromethane / NH3·MeOH = 100%–85%) was then performed to give 530 mg of white solid intermediate 2a, yield 95%. MS (ESI) m / z 381.18 [M + H] + . Step 4: Synthesis of intermediate 3a (4-chloro-6-methoxy-7-((1-methylazacyclobutane-3-yl)methoxy)-2-(5-methylfuran-2-yl)quinoline): Intermediate 2a (530 mg, 1 eq) was dissolved in dichloromethane:methanol = 10:1 (10 mL), followed by the addition of 1 mL of 37%–40% formaldehyde aqueous solution. The mixture was stirred at room temperature for 30 min, and then sodium triacetoxyborohydride (906 mg, 3 eq) was added, and the reaction was continued overnight. After the reaction was complete, a large amount of white solid was produced. The filtrate was filtered, concentrated, and purified by rapid column chromatography (DCM / NH3·MeOH = 100%–85%) to give 454 mg of white solid intermediate 3a, with a yield of 80%. MS (ESI) m / z 373.23 [M +H] + .

[0067] Step 5: Compound A21 (6-methoxy-7-((1-methylazacyclobutane-3-yl)methoxy)-2-(5-methylfuran-2-yl)- N Synthesis of (1-methylpiperidin-4-yl)quinoline-4-amine: Intermediate 3a (150 mg, 1 eq), 5% RuPhosPdG2, and cesium carbonate (268 mg, 2 eq) were dissolved in ultradry 1,4-dioxane (10 mL), followed by the addition of 4-amino-1-methylpiperidine (94 mg, 2 eq). The reaction was carried out under N2 protection at 100 °C for 12 h. After the reaction was completed, palladium was removed by filtration, and the mixture was purified by preparative plate to give compound A21 as 88 mg of white solid, with a yield of 48%.

[0068] HRMS (ESI) m / z : calcd forC 26 H 35 N4O3 + [M + H] + , 451.2704; found, 451.2698. 1 H NMR (400 MHz, Methanol- d 4) δ 7.52 (s, 1H), 7.28 (s, 1H), 7.10 (d, J =3.3 Hz, 1H), 6.83 (s, 1H), 6.22 (dd, J = 3.4, 1.1 Hz, 1H), 4.20 (d, J = 5.7 Hz,2H), 3.99 (s, 3H), 3.84 – 3.75 (m, 2H), 3.75 – 3.65 (m, 1H), 3.54 – 3.45 (m,2H), 3.16 – 3.04 (m, 1H), 3.04 – 2.95 (m, 2H), 2.57 (s, 3H), 2.43 (s, 3H), 2.37 (s, 3H), 2.35 – 2.26 (m, 2H), 2.14 (d, J = 12.9 Hz, 2H), 1.87 – 1.73 (m,2H). Example 22 Synthesis of compound A22 The synthesis method of compound A22 is as described in Example 21, with adaptive adjustments to the substituents.

[0069] HRMS (ESI) m / z : calcd forC 27 H 37 N4O3 + [M + H] +, 465.2860; found, 465.2856. 1 H NMR (400 MHz, Methanol- d 4) δ 7.47 (s, 1H), 7.26 (s, 1H), 7.04 (d, J =3.2 Hz, 1H), 6.81 (s, 1H), 6.19 (dd, J = 3.3, 1.2 Hz, 1H), 4.10 – 3.99 (m, 2H), 3.97 (s, 3H), 3.70 – 3.60 (m, 1H), 2.96 (d, J = 11.7 Hz, 2H), 2.88 (dd, J = 9.6,7.9 Hz, 1H), 2.86 – 2.74 (m, 1H), 2.71 – 2.60 (m, 2H), 2.51 (dd, J = 9.6, 5.9Hz, 1H), 2.41 (s, 3H), 2.39 (s, 3H), 2.33 (s, 3H), 2.33 – 2.22 (m, 2H), 2.18– 2.08 (m, 3H), 1.84 – 1.65 (m, 3H). Example 23 Synthesis of Compound A24 The synthesis method of compound A24 is as described in Example 21, with adaptive adjustments to the substituents.

[0070] HRMS (ESI) m / z : calcd for C 30 H 41 N4O3 + [M + H] + , 505.3173; found, 505.3169. 1 H NMR (400 MHz, Methanol- d 4) δ 7.54 (d, J = 2.7 Hz, 1H), 7.32 (d, J = 3.0Hz, 1H), 7.13 (d, J = 3.4 Hz, 1H), 6.84 (d, J= 2.6 Hz, 1H), 6.24 (d, J = 3.3 Hz,1H), 4.48 (s, 1H), 3.97 (s, 3H), 3.78 – 3.68 (m, 1H), 3.42 –3.36 (m, 3H), 3.01 (d, J = 11.6 Hz, 2H), 2.55 (s, 3H), 2.43 (s, 3H), 2.37 (s, 3H), 2.35 –2.28 (m, 2H), 2.18 – 2.11 (m, 2H), 2.08 – 1.95 (m, 4H), 1.86 – 1.76 (m, 2H), 1.74 – 1.63 (m, 4H), 0.89 – 0.86 (m, 2H). Example 24 Synthesis of Compound A25 The synthesis method of compound A25 is as described in Example 21, with adaptive adjustments made to the substituents.

[0071] HRMS (ESI) m / z : calcd for C 32 H 45 N4O3 + [M + H] + , 533.3486; found, 533.3484. 1 H NMR (400 MHz, Methanol- d 4) δ 7.56 (s, 1H), 7.33 (s, 1H), 7.15 (d, J =3.0 Hz, 1H), 6.85 (s, 1H), 6.24 (d, J = 3.3 Hz, 1H), 4.47 (s, 1H), 3.97 (s, 3H), 3.80 – 3.69 (m, 1H), 3.01 (d, J = 11.9 Hz, 2H), 2.76 – 2.57 (m, 4H), 2.44(s, 3H), 2.43 (s, 3H), 2.37 (s, 3H), 2.36 – 2.28 (m, 2H), 2.14 (d, J= 13.1 Hz,2H), 2.00 – 1.92 (m, 2H), 1.87 – 1.71 (m, 6H), 1.71 – 1.64 (m, 2H), 1.62 –1.55 (m, 2H), 1.42 – 1.32 (m, 2H). Example 25 Synthesis of Compound A26 Step 1: Synthesis of intermediate 10 (tert-butyl 6-(((4-nitrophenyl)sulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylic acid ester) 6-Hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (640 mg, 1 eq) and p-nitrobenzenesulfonyl chloride (731 g, 1.1 eq) were dissolved in dichloromethane (20 mL), followed by the addition of triethylamine (626 μL, 1.5 eq), and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the solid was collected by slurrying and filtration in ethyl acetate to give intermediate 10, yielding 1.1 g of white solid, with a yield of 92%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.41 (dd, J = 8.8, 1.8 Hz, 2H), 8.09 (dd, J =8.8, 1.7 Hz, 2H), 4.86 – 4.74 (m, 1H), 3.87 (s, 4H), 2.64 – 2.53 (m, 2H), 2.43 – 2.34 (m, 2H), 1.41 (s, 9H). The subsequent steps are the same as in Example 21, with the substituents adjusted to obtain compound A26.

[0072] 1 H NMR (400 MHz, Methanol- d 4) δ 7.67 (d, J = 1.7 Hz, 1H), 7.49 (s, 1H), 7.17 (dd, J = 3.5, 0.8 Hz, 1H), 7.11 (s, 1H), 6.88 (s, 1H), 6.61 (dd, J= 3.4,1.8 Hz, 1H), 4.75 – 4.67 (m, 1H), 3.96 (s, 3H), 3.69 – 3.60 (m, 1H), 3.46 (s,2H), 3.37 (s, 2H), 2.96 (d, J = 11.6 Hz, 2H), 2.83 – 2.75 (m, 2H), 2.38 – 2.31(m, 8H), 2.30 – 2.23 (m, 2H), 2.13 (d, J = 13.0 Hz, 2H), 1.82 – 1.71 (m, 2H). Example 26 Synthesis of Compound A27 The synthesis method of compound A27 is as described in Example 25, with adaptive adjustments made to the substituents.

[0073] HRMS (ESI) m / z : calcd for C 29 H 37 N4O5 + [M + H] + , 521.2758; found, 521.2756. 1 H NMR (400 MHz, Methanol- d 4) δ 7.48 (s, 1H), 7.34 (d, J = 3.7 Hz, 1H), 7.25 (d, J = 3.7 Hz, 1H), 7.09 (s, 1H), 6.98 (s, 1H), 4.72 – 4.66 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.73 – 3.65 (m, 1H), 3.45 (s, 2H), 3.36 (s, 2H), 2.99– 2.93 (m, 2H), 2.83 – 2.76 (m, 2H), 2.37 – 2.32 (m, 8H), 2.28 (dd, J = 12.3, 2.4 Hz, 2H), 2.12 (d, J = 12.9 Hz, 2H), 1.81 – 1.70 (m, 2H). Example 27 Synthesis of Compound A28 The synthesis method of compound A28 is as described in Example 25, with adaptive adjustments made to the substituents.

[0074] HRMS (ESI) m / z : calcd for C 28 H 37 N4O4 + [M + H] + , 493.2809; found, 493.2804. 1 H NMR (400 MHz, Methanol- d 4) δ 7.50 (s, 1H), 7.14 (d, J = 3.4 Hz, 1H),7.11 (s, 1H), 6.90 (s, 1H), 6.49 (d, J = 3.3 Hz, 1H), 4.75 – 4.68 (m, 1H), 4.64(s, 2H), 3.97 (s, 3H), 3.74 – 3.65 (m, 1H), 3.55 (s, 2H), 3.46 (s, 2H), 2.99(d, J = 11.8 Hz, 2H), 2.85 – 2.78 (m, 2H), 2.42 (s, 3H), 2.40 – 2.35 (m, 5H), 2.30 (dd, J = 12.3, 2.5 Hz, 2H), 2.14 (d, J = 13.5 Hz, 2H), 1.83 – 1.73 (m, 2H). Example 28 Synthesis of Compound A29 The synthesis method of compound A29 is as described in Example 25, with adaptive adjustments made to the substituents.

[0075] HRMS (ESI) m / z : C 31 H 37 N4O3 + calcdfor[M + H] + , 513.2860; found, 513.2858. 1 H NMR (400 MHz, Methanol- d4) δ 7.67 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 8.2Hz, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 7.39 – 7.34 (m, 1H), 7.30 – 7.25 (m,1H), 7.15 (s, 1H), 7.05 (s, 1H), 4.77 – 4.69 (m, 1H), 3.97 (s, 3H), 3.76 –3.69 (m, 1H), 3.64 (s, 2H), 3.56 (s, 2H), 3.00 (d, J = 11.9 Hz, 2H), 2.89 –2.81 (m, 2H), 2.48 (s, 3H), 2.44 – 2.38 (m, 2H), 2.38 (s, 3H), 2.36 – 2.28(m, 2H), 2.16 (d, J = 13.0 Hz, 2H), 1.88 – 1.73 (m, 2H). Example 29 Synthesis of Compound A30 The synthesis method of compound A30 is as described in Example 25, with adaptive adjustments made to the substituents.

[0076] HRMS (ESI) m / z : calcd forC 27 H 35 N4O3 + [M + H] + , 463.2704; found, 463.2698. 1 H NMR (400 MHz, Methanol- d 4) δ 7.80 (s, 1H), 7.62 (d, J = 3.5 Hz, 1H), 7.37 (s, 1H), 7.09 (s, 1H), 6.42 (dd, J = 3.6, 1.1 Hz, 1H), 4.82 (d, J = 6.6 Hz,2H), 4.35 – 4.31 (m, 1H), 4.01 (s, 3H), 3.64 – 3.53 (m, 2H), 3.31 (d, J= 1.6Hz, 4H), 3.01 (s, 2H), 2.92 (s, 3H), 2.57 (dd, J = 13.5, 6.1 Hz, 2H), 2.50 (s,3H), 2.39 – 2.31 (m, 2H), 2.15 – 2.03 (m, 2H). Example 30 Synthesis of Compound A31 The synthesis method of compound A31 is as described in Example 25, with adaptive adjustments made to the substituents.

[0077] HRMS (ESI) m / z : calcd forC 29 H 38 N3O3 + [M + H] + , 476.2908; found, 476.2903. 1 H NMR (400 MHz, Chloroform- d ) δ 7.43 (s, 1H), 7.36 (s, 1H), 7.07 (s,1H), 6.73 (s, 1H), 6.17 (dd, J = 3.4, 1.1 Hz, 1H), 5.58 (s, 1H), 4.71 – 4.63(m, 1H), 3.99 (s, 3H), 3.84 (s, 1H), 3.53 (s, 2H), 3.43 (s, 2H), 2.92 – 2.85(m, 2H), 2.45 – 2.37 (m, 8H), 1.99 – 1.88 (m, 2H), 1.85 – 1.77 (m, 2H), 1.72 – 1.64 (m, 3H), 1.40 – 1.32 (m, 2H), 0.98 (d, J = 6.4 Hz, 3H). Example 31 Synthesis of compound A32 The synthesis method of compound A32 is as described in Example 25, with adaptive adjustments to the substituents.

[0078] HRMS (ESI) m / z : calcd forC 29 H 38 N3O3+ [M + H] + , 476.2908; found, 476.2903. 1 H NMR (400 MHz, Chloroform- d ) δ 7.38 (s, 1H), 7.32 (d, J = 3.3 Hz,1H), 7.17 (s, 1H), 6.73 (s, 1H), 6.15 (d, J = 3.3 Hz, 1H), 5.68 (s, 1H), 4.67 –4.59 (m, 1H), 3.95 (s, 3H), 3.90 – 3.84 (m, 1H), 3.59 – 3.51 (m, 1H), 3.44(s, 2H), 3.36 (s, 2H), 2.89 – 2.77 (m, 2H), 2.44 – 2.34 (m, 8H), 2.20 (d, J =12.2 Hz, 2H), 1.87 – 1.78 (m, 2H), 1.48 – 1.39 (m, 3H), 1.22 – 1.12 (m, 2H), 0.95 (d, J = 6.5 Hz, 3H). Example 32 Synthesis of compound A33 The synthesis method of compound A33 is as described in Example 25, with adaptive adjustments made to the substituents.

[0079] HRMS (ESI) m / z : calcd for C 29 H 39 N4O3 + [M + H] + , 491.3017; found, 491.3015. 1 H NMR (400 MHz, Chloroform- d ) δ 7.20 (s, 1H), 6.99 (d, J= 3.3 Hz,1H), 6.89 (s, 1H), 6.78 (s, 1H), 6.14 – 6.13 (m, 1H), 4.75 – 4.66 (m, 4H), 3.96 (s, 3H), 3.69 – 3.60 (m, 1H), 3.29 (s, 2H), 3.23 (s, 2H), 2.99 (d, J =11.3 Hz, 2H), 2.84 – 2.76 (m, 2H), 2.52 – 2.37 (m, 7H), 2.30 (s, 3H), 2.26 –2.19 (m, 4H), 1.70 (q, J = 11.5 Hz, 2H), 1.13 (t, J = 7.2 Hz, 3H). Example 33 Synthesis of Compound A34 The synthesis method of compound A34 is as described in Example 25, with adaptive adjustments to the substituents.

[0080] HRMS (ESI) m / z : calcd for C 30 H 39 N4O3 + [M + H] + , 503.3017; found, 503.3015. 1 H NMR (400 MHz, Chloroform- d ) δ 7.13 (d, J = 3.3 Hz, 1H), 6.95 (s,1H), 6.77 (s, 1H), 6.15 (dd, J = 3.3, 1.1 Hz, 1H), 5.02 (s, 1H), 4.72 – 4.65(m, 1H), 3.94 (s, 3H), 3.72 – 3.63 (m, 1H), 3.37 (s, 2H), 3.30 (s, 2H), 3.08(d, J= 11.6 Hz, 2H), 2.86 – 2.80 (m, 2H), 2.67 (s, 1H), 2.50 – 2.45 (m, 2H), 2.44 (s, 3H), 2.42 – 2.36 (m, 2H), 2.34 (s, 3H), 2.16 (d, J = 12.6 Hz, 2H), 1.70 – 1.60 (m, 2H), 0.52 – 0.47 (m, 2H), 0.46 – 0.41 (m, 2H). Example 34 Synthesis of Compound A35 The synthesis method of compound A35 is as described in Example 25, with adaptive adjustments made to the substituents.

[0081] HRMS (ESI) m / z : calcd forC 27 H 34 N3O4 + [M + H] + , 464.2544; found, 464.2539. 1 H NMR (400 MHz, Chloroform- d ) δ 7.23 (s, 1H), 7.06 (d, J = 3.3 Hz,1H), 7.02 (s, 1H), 6.80 (s, 1H), 6.14 (dd, J = 3.3, 1.1 Hz, 1H), 5.03 (d, J = 7.2Hz, 1H), 4.68 – 4.61 (m, 1H), 4.07 (dt, J = 11.9, 3.5 Hz, 2H), 3.94 (s, 3H), 3.90 – 3.82 (m, 1H), 3.62 (td, J = 11.7, 2.1 Hz, 2H), 3.31 (s, 2H), 3.27 (s,2H), 2.82 – 2.74 (m, 2H), 2.44 – 2.42 (m, 3H), 2.38 (td, J = 7.2, 3.6 Hz, 2H),2.32 (s, 3H), 2.16 (d, J= 12.7Hz, 2H), 1.72 – 1.62 (m, 2H). Example 35 Synthesis of Compound A36 The synthesis method of compound A36 is as described in Example 25, with adaptive adjustments made to the substituents.

[0082] HRMS (ESI) m / z : calcd for C 26 H 30 F2N3O3 + [M + H] + , 470.2250; found, 470.2245. 1 H NMR (400 MHz, Chloroform- d ) δ 7.18 (d, J = 2.9 Hz, 2H), 7.05 (d, J =3.3 Hz, 1H), 6.62 (s, 1H), 6.14 (dd, J = 3.3, 1.2 Hz, 1H), 5.86 (s, 1H), 4.60 –4.52 (m, 1H), 4.13 (s, 1H), 3.86 (s, 3H), 3.23 (d, J = 10.0 Hz, 4H), 3.20 –3.10 (m, 2H), 2.74 – 2.62 (m, 4H), 2.41 (s, 3H), 2.37 – 2.31 (m, 2H), 2.29(s, 3H). Example 36 Synthesis of Compound A37 The synthesis method of compound A37 is as described in Example 25, with adaptive adjustments made to the substituents.

[0083] HRMS (ESI) m / z : calcd for C 28 H 30 N3O3 + [M + H] + , 456.2282; found, 456.2275. 1 H NMR (400 MHz, Chloroform- d) δ 7.39 (dd, J = 13.9, 6.2 Hz, 3H), 7.31(d, J = 7.9 Hz, 2H), 7.23 (s, 1H), 7.15 (d, J = 5.7 Hz, 2H), 6.90 – 6.79 (m, 2H), 6.07 (d, J = 3.3 Hz, 1H), 4.69 – 4.60 (m, 1H), 3.87 (s, 3H), 3.29 (s, 2H), 3.23(s, 2H), 2.81 – 2.73 (m, 2H), 2.42 – 2.36 (m, 2H), 2.34 (s, 3H), 2.30 (s,3H). Example 37 Synthesis of Compound A38 The synthesis method of compound A38 is as described in Example 25, with adaptive adjustments made to the substituents.

[0084] HRMS (ESI) m / z : calcd forC 29 H 32 N3O3 + [M + H] + , 470.2438; found, 470.2433. 1 H NMR (400 MHz, Chloroform- d ) δ 7.27 (d, J = 1.7 Hz, 2H), 7.25 – 7.18(m, 5H), 6.91 (d, J = 3.3 Hz, 1H), 6.06 (d, J = 2.9 Hz, 1H), 4.64 – 4.52 (m, 1H), 3.81 (s, 3H), 3.30 (s, 2H), 3.25 (s, 2H), 2.77 – 2.67 (m, 2H), 2.37 (s, 3H), 2.36 – 2.32 (m, 2H), 2.31 (s, 6H). Example 38 Synthesis of Compound A39 The synthesis method of compound A39 is as described in Example 25, with adaptive adjustments to the substituents.

[0085] HRMS (ESI) m / z : calcd for C 28 H 29 FN3O3 + [M + H] + , 474.2187; found, 474.2185. 1 H NMR (400 MHz, Chloroform- d ) δ 7.31 – 7.24 (m, 1H), 7.20 (d, J = 2.7Hz, 2H), 7.17 (s, 1H), 7.14 – 7.05 (m, 3H), 6.86 (d, J = 3.3 Hz, 1H), 6.06 (d, J = 3.3 Hz, 1H), 4.63 – 4.54 (m, 1H), 3.81 (s, 3H), 3.24 (s, 2H), 3.20 (s, 2H), 2.76 – 2.68 (m, 2H), 2.39 – 2.34 (m, 2H), 2.31 (s, 3H), 2.28 (s, 3H). Example 39 Synthesis of Compound A40 The synthesis method of compound A40 is as described in Example 25, with adaptive adjustments made to the substituents.

[0086] HRMS (ESI) m / z : calcd for C 33 H 40 N5O3 + [M + H] + , 554.3126; found, 554.312. 1 H NMR (400 MHz, Chloroform- d ) δ 7.26 – 7.20 (m, 3H), 7.17 – 7.11 (m,2H), 6.98 (d, J = 8.7 Hz, 2H), 6.86 – 6.76 (m, 2H), 6.05 (d, J = 3.3 Hz, 1H),4.67 – 4.59 (m, 1H), 3.85 (d,J = 4.2 Hz, 2H), 3.26 – 3.22 (m, 5H), 3.19 (d, J =2.2 Hz, 2H), 2.79 – 2.71 (m, 2H), 2.61 (t, J = 5.0 Hz, 4H), 2.43 – 2.35 (m,5H), 2.33 (s, 3H), 2.30 – 2.18 (m, 5H). The technical solution of the present invention will be further explained through experiments below.

[0087] Experimental Example 1: Test of the enzyme activity of quinoline compounds against DNMT1 and G9a I. Experimental Methods The enzyme activity assay of DNMT1 was performed by Shanghai Ruizhi Chemical Research Co., Ltd. A 1x assay buffer (modified Tris buffer) was prepared for subsequent experiments. Quinoline compounds dissolved in DMSO were transferred to the assay plate and serially diluted according to the set concentration. The final DMSO concentration was adjusted to 1%. Subsequently, the enzyme solution was prepared in the 1x assay buffer, and the substrate solution and […] were prepared in the same buffer. 3 H]-SAM solution. Add 10 μL of enzyme solution to the detection plate (or 10 μL of 1x assay buffer for the control group without drug) and incubate at room temperature for 15 min. Then, add 10 μL of substrate solution to each well, followed by 10 μL of [ 3 The reaction was initiated with H-SAM solution and incubated at 37°C for 180 min. After the reaction was complete, 10 μL of cold SAM solution was added to each well to terminate the reaction. Next, the filter plate was pre-incubated with 0.5% PEI for 15 min, followed by vacuum treatment. 40 μL of the reaction mixture was transferred to the filter plate and washed three times with ddH2O (each time under vacuum). Finally, the counts were read using a MicroBeta instrument.

[0088] The enzyme activity assay for G9a was performed by Shanghai Ruizhi Chemical Research Co., Ltd. A 1x assay buffer (modified Tris buffer) was prepared for subsequent experiments. Quinoline compounds dissolved in DMSO were transferred to the assay plate and serially diluted according to the set concentration. Subsequently, the G9a enzyme solution was prepared in the 1x assay buffer, and the substrate mixture was prepared in the same buffer. 5 μL of enzyme solution (or 5 μL of 1x assay buffer for the untreated control group) was added to the assay plate and incubated at room temperature for 15 min. Then, 5 μL of the substrate mixture was added to each well to initiate the reaction and incubated at room temperature for 60 min. Next, a 1x Alphalisa buffer was prepared, and a mixture of acceptor and donor microbeads was prepared in it. 15 μL of the acceptor and donor microbead mixture was added to the assay plate and incubated at room temperature in the dark for 60 min. Finally, the endpoint signal was read using the Alpha mode of an Envision or EnSpire instrument.

[0089] II. Experimental Results The results are shown in Table 1. It can be seen that the quinoline compounds prepared in this invention can inhibit the activity of DNA methyltransferase 1 (DNMT1) at 100 nM, 250 nM and 500 nM. Among them, compounds A5, A21, A22, A26, A28, A30 and A40 have higher inhibition rates on DNMT1.

[0090] As shown in Table 2, compounds A21, A22, A33, and A40 exhibited good inhibitory effects on DNMT1, with compound A40 showing the strongest inhibitory effect (IC50). 50 The value was 36 nM. Compounds A21 and A22 showed good inhibitory effects on G9a, with compound A22 exhibiting the strongest inhibitory effect on G9a, IC50 value 36 nM. 50 The value is 1.24 nM.

[0091] The above results indicate that the quinoline compounds synthesized in this invention have a significant inhibitory effect on DNMT1 and can be used as DNMT1 inhibitors. Among them, compound A40 has a high inhibition rate and selectivity for DNMT1.

[0092] Table 1. Single-concentration inhibition rate of the quinoline compounds of this invention against DNMT1 "-" indicates that it has not been tested. Table 2 shows the IC50 values ​​of some compounds for DNMT1 and G9a. 50 Experimental Example 2 Pharmacokinetic Study of Compound A40 I. Experimental Method Six Balb / c mice (Chengdu Dashuo Experimental Animal Co., Ltd., License No.: SCXK (Chuan) 2020 - 030) were used in this experiment. Each experiment was divided into 2 groups, with 3 mice in each group. Sample preparation: Weigh approximately 2.0 mg of Compound A40, dissolve it in 40.0 µL of DMSO to form a 50 mg / mL stock solution. Take 2 µL of the stock solution and add 10 µL of 30% HS15 solution and 10 µL of PEG300, and finally add 978 µL of sodium chloride injection solution to prepare a 0.1 mg / mL A40 compound solution for intravenous administration; take 20 µL of the stock solution and add 20 µL of 30% HS15 solution and 20 µL of PEG300, and finally add 940 µL of sodium chloride injection solution to prepare a 1.0 mg / mL A40 compound solution for gavage administration. At 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h after administration, a total of 10 times, approximately 0.02 mL of blood was collected and placed on ice after collection.

[0093] Preparation of plasma samples: The collected plasma samples were thawed at room temperature and then vortex - mixed evenly. Take 5 µL of plasma into each EP tube, add 100 µL of acetonitrile containing 20 ng / mL internal standard SAHA to precipitate proteins, vortex for 10 s, centrifuge at 13000 rpm for 10 min, and take the supernatant and load it into the sample vial for measurement.

[0094] Result analysis: The blood drug concentration data at different time points were processed using DAS 2.0 pharmacokinetic software to provide AUC (0-t) 、AUC (0-∞) 、C max (ng / mL), T max (h), T 1 / 2 (h), and parameters such as F% and their mean values and standard deviations.

[0095] II. Experimental Results The results are shown in Table 3. After intravenous injection, A40 has a relatively long half - life. In addition, the oral bioavailability of A40 is 17.93%, indicating that A40 has good drug - like properties.

[0096] Table 3 Pharmacokinetic Parameters of Compound A40 In summary, the quinoline compounds provided by the present invention have excellent DNMT1 enzyme inhibitory activity and good selectivity, and can be used as novel DNMT1 inhibitors, providing a new option for the drug development and application of DNMT1 - driven diseases.

Claims

1. A compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopic label thereof, or a crystal form thereof, or a prodrug thereof: Formula I wherein R1is selected from hydrogen, substituted or unsubstituted C1-C 10 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, halo, cyano, oxo, hydroxy, -ORa, -NRbRc, -N(Rd)C(O) R2is selected from hydrogen, -OL1R6, ; Alternatively, R1 and R2 linked together form a substituted or unsubstituted 5-10 membered cycloalkyl group or a substituted or unsubstituted 5-10 membered heterocycloalkyl group, wherein the substituents are selected from C1-C2. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Amine, halogen, benzyl, -L1CO-R8; L1is a covalent bond or -(CH2) 1-10 ; R3 is selected from substituted or unsubstituted 5-10 membered heterocyclic alkyl groups, or substituted or unsubstituted C3-C groups. 10 cycloalkyl, substituted or unsubstituted C6-C 20 aryl, wherein the substituents are selected from C1-C 10 Alkyl, C3-C 10 cycloalkyl, halogen, ; R4is selected from hydrogen, substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted C1-C 10 ester, wherein the substituent is selected from the group consisting of hydroxy, C1-C 10 alkyl, halogen; R5is selected from hydrogen, substituted or unsubstituted C1-C 10 alkyl, wherein the substituents are selected from the group consisting of hydroxy, C1-C 10 alkyl, halogen; or R4, R5 are linked to form a substituted or unsubstituted C6-Ci0aryl; 10 aryl, wherein the substituents are selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, halogen; 10 alkyl, C1-C6alkoxy, halogen; 10 alkyl, C1-C6alkoxy, halogen; When R3 is selected from substituted or unsubstituted C6-C 20 In the aryl case, R1, R2, R4, and R5 are not all hydrogen atoms simultaneously; R6is selected from substituted or unsubstituted 4-10 membered heterocycloalkyl, wherein the substituents are selected from C1-C6alkyl; and 10 alkyl; R7is selected from substituted or unsubstituted C1-C 10 alkyl, wherein the substituents are selected from halogen, C1-C 10 amine groups; R8is selected from substituted or unsubstituted C1-C 10 an amine group, substituted or unsubstituted 5-10 membered heterocycloalkyl, wherein the substituents are selected from C1-C 10 alkyl, halogen; R9 is selected from hydrogen or an amino protecting group; R 10 selected from substituted or unsubstituted C1-C 10 alkyl, wherein the substituent is selected from halogen; M is selected from carbon, nitrogen, and sulfur atoms; w is selected from 1 and 2; x is selected from 1 and 2; y is selected from 0, 1, and 2; z is selected from 1 and 2.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopic label thereof, or a crystal form thereof, or a prodrug thereof, characterized in that: R1 is selected from hydrogen or methoxy groups; R2is selected from hydrogen, -OCH2R6, ; Alternatively, substituted or unsubstituted 5-6 membered cycloalkyl groups or substituted or unsubstituted 5-6 membered heterocycloalkyl groups formed by the connection of R1 and R2, wherein the substituents are selected from methyl, benzyl, and -CH2CO-R8; R3is selected from substituted or unsubstituted 5-6 membered heterocycloalkyl, substituted or unsubstituted C4-C6cycloalkyl, substituted or unsubstituted C6aryl, wherein the substituents are selected from C1-C2alkyl, C3cycloalkyl, halogen, ; R4 is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted C1 ester group, wherein the substituent is selected from hydroxyl; R5 is selected from hydrogen; Alternatively, a C6 aryl group formed by the connection of R4 and R5; When R3 is selected from substituted or unsubstituted C6 aryl groups, R1, R2, R4, and R5 are not all hydrogen at the same time; R6 is selected from substituted or unsubstituted 4-5 membered heterocyclic alkyl groups, wherein the substituent is selected from methyl; R7 is selected from methyl; R8is selected from substituted or unsubstituted aminyl, substituted or unsubstituted 5-9 membered heterocycloalkyl, wherein the substituents are selected from methyl, fluoro; R9 is selected from hydrogen and Boc; R 10 selected from C1-C3alkyl; M is selected from carbon atom and nitrogen atom; w is selected from 1 and 2; x is selected from 1 and 2; y is selected from 0, 1, and 2; z is selected from 1 and 2.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopic label thereof, or a crystal form thereof, or a prodrug thereof, characterized in that: R1 is selected from methoxy groups; R2is selected from -OCH2R6, ; Alternatively, a 6-membered heterocyclic alkyl group formed by connecting R1 and R2, wherein the heteroatom is oxygen; R3 is selected from substituted or unsubstituted 6-membered heterocyclic alkyl groups, substituted or unsubstituted C6 aryl groups, wherein the substituent is selected from C1-C2 alkyl groups, N-methylpiperazinyl groups, and the heteroatom is nitrogen; R4 is selected from hydrogen, substituted or unsubstituted methyl groups, wherein the substituent is selected from hydroxyl groups; R5 is selected from hydrogen; R6 is selected from substituted or unsubstituted 4-5 membered heterocyclic alkyl groups, wherein the substituent is selected from methyl and the heteroatom is nitrogen; R7 is selected from methyl; w is selected from 1; x is selected from 1; y is selected from 1; z is selected from 1.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopically-labeled version thereof, or a crystalline form thereof, or a prodrug thereof, wherein: The structural formula of the compound is shown in Formula II: Formula II R3 is selected from substituted or unsubstituted 6-membered heterocyclic alkyl, substituted or unsubstituted C4-C6 cycloalkyl, substituted or unsubstituted C6 aryl, wherein the substituent is selected from C1-C2 alkyl, C3 cycloalkyl, halogen, N-methylpiperazinyl, and the heteroatom is nitrogen or oxygen. R4 is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted C1 ester group, wherein the substituent is selected from hydroxyl; R5 is selected from hydrogen; Alternatively, a C6 aryl group formed by the connection of R4 and R5.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopically-labeled version thereof, or a crystalline form thereof, or a prodrug thereof, characterized in that: R3 is selected from substituted or unsubstituted 6-membered heterocyclic alkyl groups, substituted or unsubstituted C6 aryl groups, wherein the substituent is selected from C1-C2 alkyl groups, N-methylpiperazinyl groups, and the heteroatom is nitrogen. R4 is selected from hydrogen, substituted or unsubstituted methyl groups, wherein the substituent is selected from hydroxyl groups; R5 is selected from hydrogen.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopically-labeled version thereof, or a crystalline form thereof, or a prodrug thereof, wherein: The compound of formula I is one of the following structures: 。 7. A method of making a compound of claim 4 or 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopically-labeled form thereof, or a crystalline form thereof, or a prodrug thereof, characterized in that, The method comprises the following steps: Step 1, reacting compound a with compound b to obtain compound c; Step 2, compound c is subjected to a deprotection reaction to obtain compound d; Step 3, reacting compound d with an aldehyde compound and a reducing agent to obtain compound e; Step 4, reacting compound e with R-pinacolboronate, wherein R is ; Step 5, reacting compound f with H2N-R3 to obtain a compound of formula II; R3, R4, R5 are selected according to claims 4 or 5.

8. The production method according to claim 7, characterized by, In step 1, the reaction is carried out in the presence of a base selected from at least one of cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, diisopropyl ethylamine; and / or, in step 1, the solvent of the reaction is selected from N , N - at least one of dimethylformamide, dichloromethane, acetonitrile, tetrahydrofuran, dioxane; And / or, in step 1, the reaction temperature is 40-80℃, and the reaction time is 3-8 h; And / or, in step 2, the reaction is carried out in the presence of an acid selected from at least one of hydrochloric acid and trifluoroacetic acid; And / or, in step 2, the reaction solvent is at least one of dichloromethane, acetonitrile, tetrahydrofuran, dioxane, methanol, and ethanol; And / or, in step 2, the reaction temperature is 20-25℃, and the reaction time is 2-6 h; And / or, in step 3, the reducing agent is at least one of sodium triacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride; And / or, in step 3, the reaction solvent is at least one of dichloromethane and methanol; And / or, in step 3, the reaction temperature is 20-25℃, and the reaction time is 8-12 h; And / or, in step 4, the reaction is carried out in the presence of a base selected from sodium carbonate; And / or, in step 4, the reaction is carried out in the presence of a catalyst selected from at least one of tetrakis(triphenylphosphine)palladium and 1,1'-bis(diphenylphosphino) palladium dichloride; And / or, in step 4, the reaction solvent is at least one of 1,4-dioxane and water; And / or, in step 4, the reaction temperature is 70-90℃, and the reaction time is 4-6 h; And / or, in step 5, the catalyst is selected from chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) and methanesulfonic acid(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II); And / or, in step 5, the reaction is carried out in the presence of a base selected from at least one of cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, and diisopropyl ethylamine; And / or, in step 5, the reaction solvent is at least one of 1,4-dioxane, toluene, and dimethylformamide; And / or, in step 5, the reaction temperature is 80-110℃, and the reaction time is 8-15 h.

9. Use of the compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopically-labeled material thereof, or a crystal form thereof, or a prodrug thereof in the manufacture of a DNA methyltransferase 1 inhibitor; the DNA methyltransferase 1 inhibitor is a drug for preventing and / or treating fibrosis, cancer, low pressure and low oxygen environment disease; the fibrosis is at least one of pulmonary fibrosis, liver fibrosis, kidney fibrosis; the cancer is at least one of breast cancer, colorectal cancer, lung cancer, bladder cancer, blood cancer, prostate cancer, ovarian cancer, pancreatic cancer, gastric cancer, liver cancer; the low pressure and low oxygen environment disease is at least one of high altitude pulmonary hypertension, pulmonary edema, acute high altitude disease, chronic high altitude disease, brain edema.

10. A pharmaceutical composition, characterized by: It is a preparation in which the compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotopically-labeled material thereof, or a crystal form thereof, or a prodrug thereof is used as an active ingredient, and a pharmaceutically acceptable adjuvant is added.

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