A quinoline compound, preparation method and use and pharmaceutical composition thereof

Abstract

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

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical medicine, and particularly relates to a quinoline compound, a preparation method and use thereof and a pharmaceutical composition of the quinoline compound. BACKGROUND

[0002] DNA methylation, as an important epigenetic modification, mainly occurs at the C5 position of cytosine in DNA CpG island (5-methylcytosine, 5mC), which plays a key role in gene expression regulation, genomic imprinting maintenance, X chromosome inactivation and genome stability. DNMT1 is found to be a key enzyme for maintaining DNA methylation status in various diseases; DNMT1 accurately transmits the methylation pattern (maintains methylation) by recognizing hemimethylated DNA during DNA replication, ensuring the stability of epigenetic information transmission. From the molecular mechanism level, CpG methylation can inhibit gene expression in two ways: on the one hand, it directly hinders the binding of transcription factors and DNA through steric hindrance effect. For example, Yimeng Yin team found that embryonic development-related transcription factors (such as bHLH, bZIP and ETS family members) tend to bind to methylated CpG sites (this preference is due to the interaction between the hydrophobic methyl group of 5mC and the binding domain of transcription factors) by systematically analyzing 542 human methylation-sensitive SELEX transcription factors, but the methylation of CpG inhibits the binding of major transcription factors such as bHLH, bZIP and ETS due to steric hindrance effect. On the other hand, it forms a dense chromatin structure by recruiting methyl-binding proteins, for example, when tumor occurs, the non-methylation degree of CpG sequence outside the tumor suppressor CpG island increases, while the CpG in the CpG island is in a highly methylated state, so that the degree of chromosomal spiral increases and the expression of tumor suppressor genes is lost. In addition, gene knockout studies reveal the core position of DNMT1 in development and cell differentiation. Double allelic deletion of mouse DNMT1 leads to death at E8.5 in the embryonic period, and the embryonic genome presents more than 95% demethylation, accompanied by complete blockage of cell differentiation program. Similarly, when the expression level of DNMT1 in human differentiated cells is lower than the critical threshold (20%), it will trigger global demethylation, mitotic abnormalities and cell death. These findings not only confirm the indispensability of DNMT1 for maintaining epigenetic homeostasis, but also suggest that the expression level of DNMT1 needs to be precisely regulated to ensure normal cell function.

[0003] Currently, the DNMT1 inhibitors on the market are nucleoside drugs such as 5-azacytidine and decitabine, which inhibit the activity of DNMT1 by integrating themselves into DNA to form a covalent complex with DNMT1, leading to degradation of the protein as a misfolded protein recognized by the proteasome. With the degradation of the complex, the DNA is also damaged, so this kind of drug also has strong toxic side effects, including myelosuppression, nausea, vomiting and fatigue. In addition, natural products containing a large number of hydroxyl groups, such as epigallocatechin gallate (EGCG) and caffeic acid phenethyl ester (CAPE), inhibit the activity of DNMT1 through multiple mechanisms, but such molecules have serious off-target and poor activity. In addition to the above two types, in recent years, the development of DNMT1 targeted small molecule inhibitors has also made some progress. For example, carbazole, quinoline, deazapurine and dicyano pyridine small molecule inhibitors have been successfully obtained and shown certain antitumor activity in vitro and in vivo. Although a variety of DNMT1 inhibitors have been developed for the study of various diseases, these small molecule inhibitors still need to be further improved in activity and selectivity. For example, carbazole, although the IC 50 value of quinoline for DNMT1 reached 382 nM, but the IC 50 value for G9a was as low as 8 nM, indicating that its selectivity needs to be further improved. In summary, the development of DNMT1 selective inhibitors has important scientific significance and clinical application value, and is expected to provide new strategies and means for the treatment of various DNMT1 driven diseases. SUMMARY

[0004] In view of the problems in the prior art, the present application provides a quinoline compound, a preparation method and use thereof 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 isotopically labeled material thereof, or a crystal form thereof, or a prodrug thereof:

[0006]

[0007] Formula I

[0008] wherein R1 is selected from hydrogen, substituted or unsubstituted C1-C 10 alkoxy, wherein the substituent is selected from halogen, benzyl;

[0009] R2 is selected from hydrogen, -OL1R6, ;

[0010] or, R1, R2are linked to form a substituted or unsubstituted 5-10 membered cycloalkyl, substituted or unsubstituted 5-10 membered heterocycloalkyl, wherein the substituents are selected from C1-C 10 alkyl, C1-C 10 alkoxy, C1-C 10 amine, halogen, benzyl, -L1CO-R8;

[0011] L1is a covalent bond or -(CH2)1₋ 10 ;

[0012] R3is selected from substituted or unsubstituted 5-10 membered heterocycloalkyl, substituted or unsubstituted C3-C 10 cycloalkyl, substituted or unsubstituted C6-C 20 aryl, wherein the substituents are selected from C1-C 10 alkyl, C3- C 10 cycloalkyl, halogen, ;

[0013] R4is selected from hydrogen, substituted or unsubstituted C1-C 10 alkyl, substituted or unsubstituted C1-C 10 ester, wherein the substituents are selected from hydroxyl, C1-C 10 alkyl, halogen;

[0014] R5is selected from hydrogen, substituted or unsubstituted C1-C 10 alkyl, wherein the substituents are selected from hydroxyl, C1-C 10 alkyl, halogen;

[0015] or, R4, R5are linked to form a substituted or unsubstituted C6-C 10 aryl, wherein the substituents are selected from C1-C 10 alkyl, C1-C 10 alkoxy, halogen;

[0016] when R3is selected from substituted or unsubstituted C6-C 20 aryl, R1, R2, R4, R5are not simultaneously hydrogen;

[0017] R6is selected from substituted or unsubstituted 4-10 membered heterocycloalkyl, wherein the substituents are selected from C1-C 10 alkyl;

[0018] R7is selected from substituted or unsubstituted C1-C 10 alkyl, wherein the substituents are selected from halogen, C1-C 10 amine;

[0019] R8is selected from substituted or unsubstituted C1-C 10 amine, substituted or unsubstituted 5-10 membered heterocycloalkyl, wherein the substituents are selected from C1-C2alkyl, C3cycloalkyl, halogen, 10 alkyl, halogen;

[0020] R9is selected from hydrogen, amine protecting group;

[0021] R 10 selected from substituted or unsubstituted C1-C2alkyl, C3cycloalkyl, halogen, 10 alkyl, wherein the substituents are selected from halogen;

[0022] M is selected from carbon atom, nitrogen atom, sulfur atom;

[0023] w is selected from 1, 2;

[0024] x is selected from 1, 2;

[0025] y is selected from 0, 1, 2;

[0026] z is selected from 1, 2.

[0027] Preferably, R1is selected from hydrogen, methoxy;

[0028] R2is selected from hydrogen, -OCH2R6, ;

[0029] or, R1, R2are connected to form substituted or unsubstituted 5-6 membered cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl, wherein the substituents are selected from methyl, benzyl, -CH2CO-R8;

[0030] 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, ;

[0031] R4is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted C1ester, wherein the substituents are selected from hydroxyl;

[0032] R5is selected from hydrogen;

[0033] or, R4, R5are connected to form C6aryl;

[0034] when R3is selected from substituted or unsubstituted C6aryl, R1, R2, R4, R5are not simultaneously hydrogen;

[0035] R6is selected from substituted or unsubstituted 4-5 membered heterocycloalkyl, wherein the substituents are selected from methyl;

[0036] R7is selected from methyl;

[0037] R8is selected from substituted or unsubstituted amine, substituted or unsubstituted 5-9 membered heterocycloalkyl, wherein the substituent is selected from the group consisting of methyl, fluorine;

[0038] R9 is selected from the group consisting of hydrogen, Boc;

[0039] R 10 selected from the group consisting of C1-C3 alkyl;

[0040] M is selected from the group consisting of carbon atom, nitrogen atom;

[0041] w is selected from the group consisting of 1, 2;

[0042] x is selected from the group consisting of 1, 2;

[0043] y is selected from the group consisting of 0, 1, 2;

[0044] z is selected from the group consisting of 1, 2.

[0045] Preferably, R1 is selected from the group consisting of methoxy;

[0046] R2 is selected from the group consisting of -OCH2R6, ;

[0047] or, R1 and R2 are connected to form a 6-membered heterocycloalkyl, wherein the heteroatom is oxygen;

[0048] R3 is selected from the group consisting of substituted or unsubstituted 6-membered heterocycloalkyl, substituted or unsubstituted C6 aryl, wherein the substituent is selected from the group consisting of C1-C2 alkyl, N-methylpiperazinyl, and the heteroatom is nitrogen;

[0049] R4 is selected from the group consisting of hydrogen, substituted or unsubstituted methyl, wherein the substituent is selected from the group consisting of hydroxyl;

[0050] R5 is selected from the group consisting of hydrogen;

[0051] R6 is selected from the group consisting of substituted or unsubstituted 4-5 membered heterocycloalkyl, wherein the substituent is selected from the group consisting of methyl, and the heteroatom is nitrogen;

[0052] R7 is selected from the group consisting of methyl;

[0053] w is selected from the group consisting of 1;

[0054] x is selected from the group consisting of 1;

[0055] y is selected from the group consisting of 1;

[0056] z is selected from the group consisting of 1.

[0057] Preferably, the compound has a structure as shown in Formula II:

[0058]

[0059] Formula II

[0060] R3 is selected from substituted or unsubstituted 6-membered heterocycloalkyl, substituted or unsubstituted C4-C6 cycloalkyl, substituted or unsubstituted C6 aryl, wherein the substituent is selected from C1-C2 alkyl, C3 cycloalkyl, halogen, N-methyl piperazinyl, and the heteroatom is nitrogen, oxygen;

[0061] R4 is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted C1 ester, wherein the substituent is selected from hydroxyl;

[0062] R5 is selected from hydrogen;

[0063] or, R4 and R5 are connected to form a C6 aryl.

[0064] Preferably, R3 is selected from substituted or unsubstituted 6-membered heterocycloalkyl, substituted or unsubstituted C6 aryl, wherein the substituent is selected from C1-C2 alkyl, N-methyl piperazinyl, and the heteroatom is nitrogen;

[0065] R4 is selected from hydrogen, substituted or unsubstituted methyl, wherein the substituent is selected from hydroxyl;

[0066] R5 is selected from hydrogen.

[0067] Preferably, the compound of formula I is one of the following structures:

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074] .

[0075] The present application 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 isotopically labeled compound thereof, or a crystal form thereof, or a prodrug thereof, comprising the following steps:

[0076]

[0077] Step 1, reacting compound a with compound b to obtain compound c;

[0078] Step 2, deprotecting compound c to obtain compound d;

[0079] Step 3, reacting compound d with an aldehyde compound and a reducing agent to obtain compound e;

[0080] Step 4, reacting compound e with R-pinacol boronic acid to obtain compound f; the structure of R in the R-pinacol boronic acid is ;

[0081] Step 5, reacting compound f with H2N-R3 to obtain a compound shown in formula II.

[0082] Preferably, in step 1, the reaction is carried out under the action of a base, and the base is at least one selected from cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine and diisopropyl ethylamine;

[0083] And / or, in step 1, the solvent of the reaction is at least one selected from N , N dimethylformamide, dichloromethane, acetonitrile, tetrahydrofuran and dioxane;

[0084] And / or, in step 1, the temperature of the reaction is 40-80℃, and the reaction time is 3-8 h;

[0085] And / or, in step 2, the reaction is carried out under the action of an acid, and the acid is at least one selected from hydrochloric acid and trifluoroacetic acid;

[0086] And / or, in step 2, the solvent of the reaction is at least one selected from dichloromethane, acetonitrile, tetrahydrofuran, dioxane, methanol and ethanol;

[0087] And / or, in step 2, the temperature of the reaction is 20-25℃, and the reaction time is 2-6 h;

[0088] And / or, in step 3, the reducing agent is at least one selected from sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride;

[0089] And / or, in step 3, the solvent of the reaction is at least one selected from dichloromethane and methanol;

[0090] And / or, in step 3, the temperature of the reaction is 20-25℃, and the reaction time is 8-12 h;

[0091] And / or, in step 4, the reaction is carried out under the action of a base, and the base is sodium carbonate;

[0092] And / or, in step 4, the reaction is carried out under the action of a catalyst, and the catalyst is at least one selected from tetrakis(triphenylphosphine)palladium and 1,1'-bis(diphenylphosphino) palladium dichloride;

[0093] And / or, in step 4, the solvent of the reaction is at least one of 1,4-dioxane, water;

[0094] And / or, in step 4, the temperature of the reaction is 70-90℃, and the reaction time is 4-6 h;

[0095] And / or, in step 5, the catalyst of the reaction is selected from chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II), methanesulfonic acid(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II);

[0096] 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, diisopropylethylamine;

[0097] And / or, in step 5, the solvent of the reaction is at least one of 1,4-dioxane, toluene, dimethylformamide;

[0098] And / or, in step 5, the temperature of the reaction is 80-110℃, and the reaction time is 8-15 h.

[0099] The present application also provides a 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 isotopically labeled material thereof, or a crystal form thereof, or a prodrug thereof in the preparation of a DNA methyltransferase 1 inhibitor; the DNA methyltransferase 1 inhibitor is a drug for preventing and / or treating fibrosis, cancer, and a low-pressure and low-oxygen environment disease; the fibrosis is at least one of pulmonary fibrosis, liver fibrosis, and 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, and liver cancer; and 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, and brain edema.

[0100] The present application also provides a pharmaceutical composition which is a preparation obtained by adding a pharmaceutically acceptable excipient 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 isotopically labeled material thereof, or a crystal form thereof, or a prodrug thereof as an active ingredient.

[0101] The compounds and derivatives provided in the present application can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstract Service, Columbus, OH) nomenclature system.

[0102] Definitions of terms used in connection with the present invention: Unless otherwise indicated, the initial definition of a group or term provided herein applies to that group or term throughout the specification; for terms not specifically defined herein, the meaning attributable to them will be given to them in light of the disclosure and context, as would be given to one of ordinary skill in the art.

[0103] "Substitution" means replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0104] The minimum and maximum number of carbon atoms in a hydrocarbon group is indicated by a prefix, e.g., the prefix C a -C b Alkyl indicates any alkyl group of from "a" to "b" carbon atoms. Thus, for example, "C1-C6alkyl" refers to an alkyl group containing from 1 to 6 carbon atoms.

[0105] "Alkyl" refers to a saturated hydrocarbon chain having the specified number of members. For example, C1-C6alkyl refers to an alkyl group having from 1 to 6 members, e.g., from 1 to 4 members. The alkyl group can be straight or branched. Representative branched alkyl groups have one, two, or three branches. The alkyl group can be optionally substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and i-propyl), butyl (n-butyl, i-butyl, and t-butyl), pentyl (n-pentyl, i-pentyl, and neopentyl), and hexyl. The alkyl group can also be part of other groups, e.g., C1-C6alkoxy.

[0106] "Cycloalkyl" refers to a saturated or partially saturated cyclic group having from 3 to 10 carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, and spiro ring systems). For multiple ring systems having both aromatic and non-aromatic rings with no ring heteroatoms, the term "cycloalkyl" applies when the point of attachment is to a non-aromatic carbon atom (e.g., 5,6,7,8,- tetrahydronaphthalen-5-yl). The term "cycloalkyl" includes cycloalkenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, e.g., adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups that include multiple bicyclic ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like.

[0107] "Halogen" is fluorine (F), chlorine (Cl), bromine (Br), iodine (I).

[0108] "Haloalkyl" refers to an alkyl group in which the hydrogen atoms can be replaced by one or more halogen atoms. For example, C1-C6haloalkyl refers to an alkyl group containing from 1 to 6 carbon atoms in which the hydrogen atoms are replaced by one or more halogen atoms.

[0109] "Heterocycle," "heterocycloalkyl" means a saturated or unsaturated ring that is not aromatic, containing at least one heteroatom and having a single ring or multiple rings (including fused, bridged, and spiro ring systems); wherein the heteroatom is nitrogen, oxygen, or sulfur;

[0110] "Alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, for example, methoxy is -OCH3.

[0111] "Ester" means a group that is attached to the remainder of the molecule through a carbon chain, and which carbon chain contains at least one ester linkage (i.e., -COO-).

[0112] "Amino" means a group that is attached to the remainder of the molecule through a carbon chain or N, and which carbon chain contains at least one N.

[0113] "R a , R b are connected to form a ring" means that at least one atom from each of R a and R b are connected by a chemical bond, such that R a , R b and the molecular backbone structure in which they are located collectively form a ring structure.

[0114] The term "pharmaceutically acceptable" means that which is generally compatible with the other ingredients of a pharmaceutical formulation, and / or the salt formed is physiologically and pharmaceutically acceptable in vivo.

[0115] The terms "salt" and "pharmaceutically acceptable salt" refer to the acid and / or base salts of the foregoing compounds and stereoisomers thereof, and include two salt forms (inner salts) and quaternary salts, such as ammonium salts. These salts can be formed during the final isolation and purification of the compounds or stereoisomers, or by further treatment of the compounds or stereoisomers after isolation and purification. The salt can be recovered by filtration or by evaporation of the solvent from a solution of the salt. The salts of the present application can be hydrochloric, sulfuric, citric, benzenesulfonic, hydrobromic, hydrofluoric, phosphoric, acetic, propionic, succinic, oxalic, malic, succinic, fumaric, maleic, tartaric, or trifluoroacetic acid salts.

[0116] In certain embodiments, one or more compounds of the present application can be used in combination with one another. The compounds of the present application can also be used in combination with any other active agents useful in modulating cellular function or treating a disease. If a combination of compounds is used, the compounds can be administered simultaneously, separately or sequentially.

[0117] The present application provides quinoline compounds shown in formula I, which have excellent DNMT1 enzyme inhibitory activity and good selectivity, can be used as a new type of DNMT1 inhibitor, provide a new choice for treating diseases related to DNMT1 activity (for example, fibrosis, cancer, low pressure and low oxygen environment disease), and have wide application prospects.

[0118] Obviously, according to the above content of the present application, according to the ordinary technical knowledge and conventional means in the art, other various forms of modifications, substitutions or changes can be made without departing from the above basic technical idea of the present application.

[0119] The above content of the present application will be further described in detail through the specific embodiments in the form of examples. However, it should not be understood that the scope of the above subject matter of the present application is limited to the following examples. Any technology realized based on the above content of the present application belongs to the scope of the present application. DETAILED DESCRIPTION

[0120] In the following examples and experimental examples, the reagents and raw materials not specifically described are commercially available.

[0121] Example 1 Synthesis of compound A2

[0122] Step 1: Synthesis of intermediate A2-1 (5,6,7,8-tetrahydronaphthalen-2-amine)

[0123]

[0124] Take 6-amino-1,2,3,4-tetrahydro-1-naphthalenone (1 g, 1 eq) in a reaction bottle, add triethylsilane (5 mL, 5 eq) and trifluoroacetic acid (4.7 mL, 10 eq) to the reaction bottle, and react at room temperature for 5 h. After the reaction is completed, the obtained mixture is diluted with ethyl acetate (100 mL), extracted with water (40 mL x 2). The combined organic layer is 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 A2-1, which is directly used in the next step without purification. The yield is 100%.

[0125] Step 2: Synthesis of intermediate A2-2 (3-oxo-3-((5,6,7,8-tetrahydronaphthalen-2-yl)amino)propanoic acid)

[0126]

[0127] To a reaction flask containing intermediate A2-2 (1.7 g, 1 eq), methanesulfonic anhydride (2.55 g, 2 eq) was stirred at 70 °C for 2 h. The reaction was cooled to room temperature and filtered to give solid intermediate A2-3, which was used in the next step without further purification.

[0128] Step 3: Synthesis of intermediate A2-3 (6,7,8,9-tetrahydrobenzo[ g ]quinoline-2,4(l H ,3 H )-dione)

[0129]

[0130] To a reaction flask containing intermediate A2-2 (1.7 g, 1 eq), methanesulfonic anhydride (2.55 g, 2 eq) was stirred at 70 °C for 2 h. The reaction was cooled to room temperature and filtered to give solid intermediate A2-3, which was used in the next step without further purification.

[0131] Step 4: Synthesis of intermediate A2-4 (2,4-dichloro-6,7,8,9-tetrahydrobenzo[ g ]quinoline)

[0132]

[0133] To a reaction flask containing crude A2-3 from the previous step, phosphorus oxychloride (6 mL) was added and stirred at 110 °C for 12 h. The reaction was quenched by adding to ice water (100 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (PE / EA = 40% - 60%) to give intermediate A2-4 as a white solid, 1.3 g, 78% yield over 4 steps. MS (ESI) m / z 410.5 [M + H] + .

[0134] Step 5: Synthesis of intermediate A2-5 (4-chloro-2-(5-methylfuran-2-yl)-6,7,8,9- tetrahydrobenzo[ g ]quinoline)

[0135]

[0136] 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] + .

[0137] 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

[0138]

[0139] Take intermediate A2-5 (1 eq) and 5% potassium iodide in a 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%) was performed to give compound A2 in 47% yield.

[0140] HRMS (ESI) m / z : calcd forC 24 H 30 N3O + [M + H] + , 376.2383; found, 376.2384.

[0141] 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).

[0142] Example 2 Synthesis of Compound A1

[0143]

[0144] The synthesis method refers to Example 1, and the substituents are adjusted adaptively.

[0145] 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).

[0146] Example 3 Synthesis of Compound A3

[0147]

[0148] The synthesis method refers to steps 2-6 of Example 1, and the substituents are adjusted adaptively.

[0149] HRMS (ESI) m / z: calcd for C 23 H 28 N3O + [M + H]+ , 362.2227; found,362.2225.

[0150] 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).

[0151] Example 4 Synthesis of compound A4

[0152]

[0153] To a reaction flask was added compound A4-0 (1 eq), malonic acid (2 eq), and phosphorous oxychloride (15 mL) at 100 °C for 10 h. The phosphorous oxychloride was removed by distillation under reduced pressure, 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 x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by preparative plate to give intermediate A4-1. The subsequent synthesis was performed according to the procedures of Example 1, steps 5-6, with suitable adjustment of substituents.

[0154] HRMS (ESI) m / z: calcd for C 21 H 24 N3O3 + [M + H] + , 366.1812; found,366.1810.

[0155] 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).

[0156] Example 5 Synthesis of Compound A6

[0157] Step 1: Synthesis of intermediate A6-1 (1-methyl-1,2,3,4-tetrahydroquinoline-7-amine)

[0158]

[0159] 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%.

[0160] Step 2: Intermediate A6-2 (6,8-dichloro-1-methyl-1,2,3,4-tetrahydropyrido[3,2- g ]quinoline) synthesis

[0161]

[0162] 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).

[0163] Step 3: Intermediate A6-3 (6-chloro-1-methyl-8-(5-methylfuran-2-yl)-1,2,3,4-tetrahydropyrido[3,2- g ]quinoline) synthesis:

[0164]

[0165] 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%.

[0166] 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).

[0167] 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

[0168]

[0169] Take intermediate A6-3 (1 eq) and 5% potassium iodide into a sealing tube, and add... NMethylpyrrolidine (2 mL), finally to the reaction system added 4-amino-1- methylpiperidine (5 eq) and DIPEA (3 eq) at 180°C for 24 h. After the reaction was completed, direct flash column chromatography (dichloromethane / NH3·MeOH = 100% - 85%) to obtain 26 mg of white solid A6, yield 42%.

[0170] HRMS (ESI) m / z : calcd for C 24 H 31 N4O + [M + H] + , 391.2492; found,391.2492.

[0171] 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).

[0172] Example 6 Synthesis of compound A5

[0173]

[0174] Take compound A5-0 (1 eq) in a reaction bottle, add triethylsilane (5 eq), trifluoroacetic acid (10 eq) to the reaction bottle and react at room temperature for 5 h. After the reaction was completed, the mixture was concentrated under reduced pressure, diluted with ethyl acetate (100 mL), extracted with water (40 mL x 2). The combined organic layer was 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. The subsequent synthesis method refers to steps 1-4 of Example 5, and the substituent group is adjusted as appropriate.

[0175] HRMS (ESI) m / z : calcd for C23 H 28 N3O2 + [M + H] + , 378.2176; found, 378.2173.

[0176] 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).

[0177] Example 7 Synthesis of compound A7

[0178]

[0179] The synthesis method refers to steps 2-4 of Example 5, and the substituents are adjusted adaptively.

[0180] Example 8 Synthesis of compound A8

[0181] Step 1: Synthesis of intermediate A8-1 (6-nitro-3,4-dihydro-2 H -1,4-benzoxazine)

[0182]

[0183] Dissolve compound 2-amino-4-nitrophenol (50 g, 1 eq), 1,2-dibromoethane (64 g, 1.2 eq), potassium carbonate (79 g, 3 eq) in N , N- dimethylformamide (100 mL) and stirred at 125 °C for 6 h. The reaction mixture was quenched with water (1000 mL) and extracted with ethyl acetate (800 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (PE / EA = 5 / 1-1 / 1) to give intermediate A8-1. Yield 17 g of brown solid, 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).

[0184] Step 2: Synthesis of intermediate A8-2 (4-methyl-6-nitro-3,4-dihydro-2 H -1,4-benzoxazine)

[0185]

[0186] Intermediate A8-1 (660 mg, 1 eq) was dissolved in N , N dimethylformamide (7 mL) and stirred at 0 °C, then sodium hydride (296 mg, 2 eq) was added and stirred at this condition for 30 min. Then iodomethane (525 mg, 1 eq) was added to the reaction system, and stirred at room temperature for 5 min and 2 h. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was concentrated by distillation under reduced pressure to give intermediate A8-2, which was used directly in the next step without purification. Yield 650 mg of yellow solid, 90%.

[0187] Step 3: Synthesis of intermediate A8-3 (4-methyl-6-amino-3,4-dihydro-2 H -1,4-benzoxazine)

[0188]

[0189] To a solution of intermediate A8-2 (100 mg, 1 eq) in a mixture of methanol and formic acid 1 : 1 (6 mL) was added iron powder (145 mg, 5 eq) at 50 °C and stirred for 3 h. The reaction mixture was filtered through celite and concentrated under reduced pressure to give intermediate A8-3 as a grey oil in 100% yield, which was used directly in the next step without purification. 1 H NMR (400 MHz, Chloroform- d ) δ 7.58 (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).

[0190] Step 4: Synthesis of intermediate A8-4 (4-methyl-3,4-dihydro-2 H -[1,4]oxazepino[2,3- g ]quinoline-7,9(6 H ,8 H )-dione

[0191]

[0192] To a solution of intermediate A8-3 (85 mg, 1 eq) in malonic acid diethyl ester (2 mL) was heated at 100 °C for 30 min, then heated at 170 °C for 12 h. After the reaction was completed, the reaction mixture was cooled to room temperature as a brown solid. The solid was washed with ethyl acetate and filtered to give intermediate A8-4 as a brown solid in 50 mg, 42% yield.

[0193] Step 5: Synthesis of intermediate A8-5 (7,9-dichloro-4-methyl-3,4-dihydro-2 H -[1,4]oxazepino[2,3- g ]quinoline

[0194]

[0195] 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. 1 H 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).

[0196] 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

[0197]

[0198] 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] + .

[0199] 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

[0200]

[0201] Intermediate A8-6 (100 mg, 1 eq) was taken in a sealed tube with 5% potassium iodide and added N - methylpyrrolidinone (2 mL), finally to the reaction system added 4-amino-1- methylpiperidine (180 mg, 5 eq) and DIPEA (124 mg, 3 eq) and reacted at 180°C for 24 h. After the reaction was completed, direct flash column chromatography (dichloromethane / NH3·MeOH = 100% - 85%) gave 53 mg of yellow solid A8, yield 42%.

[0202] HRMS (ESI) m / z : calcd for C 23 H 29 N4O2 + [M + H] + , 393.2285; found, 393.2284.

[0203] 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).

[0204] Example 9 Synthesis of compound A9

[0205]

[0206] The synthesis method is referred to Example 8, and the substituent group is adjusted adaptively.

[0207] HRMS (ESI) m / z : calcd for C 29 H 33 N4O2 + [M + H] +, 469.2598; found,469.2598.

[0208] 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).

[0209] Example 10 Synthesis of Compound A10

[0210] Step 1: Intermediate 1 (methyl 2-(6-nitro-2,3-dihydro-4-methyl) H -benzo[ b Synthesis of [1,4]oxazazine-4-yl)acetate:

[0211]

[0212] 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).

[0213] Step 2: Synthesis of Intermediate 2 (methyl 2-(6-amino-2,3-dihydro-4 H -benzo[ b ][1,4]oxazepin-4-yl)acetate

[0214]

[0215] Intermediate 1 (1 g, 1 eq) was dissolved in methanol (15 mL) with 5% Pd / C and stirred at room temperature under hydrogen for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give Intermediate 2 as a gray oil. The product was used directly in the next step without purification. Yield was 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).

[0216]

[0217] Step 3: Synthesis of Intermediate 3 (methyl 2-(7,9-dihydroxy-2,3-dihydro-4 H -[1,4]oxazepino[2,3- g ]quinoline-4-yl)acetate

[0218] Intermediate 2 (500 mg, 1 eq) was added with diethyl malonate (721 mg, 3 eq) and stirred at 100 °C for 30 min, then the temperature was increased to 170 °C and stirred for 12 h. After the reaction was completed, the reaction system was cooled to room temperature and was a brown solid. The solid was washed with ethyl acetate and the filter cake was collected to give Intermediate 3 as a brown solid. Yield was 320 mg, 49%. MS (ESI)m / z 291.19 [M + H] + .

[0219] Step 4: Synthesis of Intermediate 4 (methyl 2-(7,9-dichloro-2,3-dihydro-4 H -[1,4]oxazepino[2,3- g ]quinoline-4-yl)acetate

[0220]

[0221] To a reaction flask was added dichlorophenyl phosphate (697 mg, 3 eq), then intermediate 3 (320 mg, 1 eq) was added to the reaction flask, the reaction was then warmed to 170 °C and stirred for 21 h. After the reaction was completed, it was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added to adjust the pH to about 7, and extracted with ethyl acetate (80 mL x 2). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (PE / EA = 100% - 60%) to give intermediate 4 as a yellow solid in 230 mg in 64% yield. 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).

[0222] Step 5: Synthesis of Intermediate 5 (methyl 2-(9-chloro-7-(5-methylfuran-2-yl)-2,3- dihydro-4 H -[1,4]oxazepino[2,3- g ]quinoline-4-yl)acetate

[0223]

[0224] To a reaction flask was added dichlorophenyl phosphate (697 mg, 3 eq), then intermediate 3 (320 mg, 1 eq) was added to the reaction flask, the reaction was then warmed to 170 °C and stirred for 21 h. After the reaction was completed, it was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added to adjust the pH to about 7, and extracted with ethyl acetate (80 mL x 2). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (PE / EA = 100% - 60%) to give intermediate 4 as a yellow solid in 230 mg in 64% yield. m / z373.23 [M + H] + .

[0225] Step 6: Intermediate 6 (methyl 2-[7-(5-methylfuran-2-yl)-9-((1-methylpiperidin-4- yl)amino)-2,3-dihydro-4 H -[1,4]oxazepino[2,3- g ]quinolin-4-yl]acetate) synthesis

[0226]

[0227] Intermediate 5 (50 mg, 1 eq), 10% RuPhos Pd G2 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) and reacted at 100 °C for 12 h under N2protection. The reaction was filtered to remove palladium upon completion and purified by prep plate to give Intermediate 6 as 38 mg white solid in 65% yield. 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).

[0228] Step 7: Intermediate 7 (2-[7-(5-methylfuran-2-yl)-9-((1-methylpiperidin-4-yl)amino)-2,3- dihydro-4 H -[1,4]oxazepino[2,3- gSynthesis of (S)-2-[(2-amino-5-quinolinyl)amino]-5-(2,3-dihydro-4-oxo-2-

[0229]

[0230] 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, and the reaction was allowed to proceed 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 distillation under reduced pressure to obtain intermediate 7, with a yield of 100%, which was used directly in the next step without purification.

[0231] Step 8: Synthesis of A10 N N - dimethyl-2-[7-(5-methylfuran-2-yl)-9-((1-methylpiperidin-4-yl)amino)-2,3-dihydro-4 H - [1,4]oxazepino[2,3- g ]quinolin-4-yl]acetamide

[0232]

[0233] Intermediate 7 (85 mg, 1 eq), dimethylamine hydrochloride (19 mg, 1.2 eq), and HATU (110 mg, 1.5 eq) were dissolved in dimethylformamide (5 mL), and diisopropylethylamine (74 mg, 3 eq) was finally added to the reaction system, and the reaction was allowed to proceed at room temperature overnight. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative plate to obtain compound A10. 30 mg of yellow solid was obtained, with a yield of 34%. N N - dimethyl-2-[7-(5-methylfuran-2-yl)-9-((1-methylpiperidin-4-yl)amino)-2,3-dihydro-4 N N - dimethyl-2-[7-(5-methylfuran-2-yl)-9-((1-methylpiperidin-4-yl)amino)-2,3-dihydro-4

[0234] HRMS (ESI) m / z : calcd for C 26 H 34 N5O3 + [M + H] + , 464.2656; found, 464.2654.

[0235] 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).

[0236] Example 11 Synthesis of compound A11

[0237]

[0238] The synthesis method of compound A11 was referred to Example 10, with suitable adjustment of substituents.

[0239] HRMS (ESI) m / z : calcd for C 29 H 38 N5O3 + [M + H] + , 504.2969; found, 504.2969.

[0240] 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).

[0241] Example 12 Synthesis of compound A12

[0242]

[0243] The synthesis method of compound A12 is referred to Example 10, with suitable adjustment of substituents.

[0244] HRMS (ESI) m / z : calcd for C 28 H 36 N5O3 + [M + H] + , 490.2813; found, 490.2816.

[0245] 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).

[0246] Example 13 Synthesis of compound A13

[0247]

[0248] The synthesis method of compound A13 is referred to Example 10, with suitable adjustment of substituents.

[0249] HRMS (ESI) m / z : calcd for C 29 H 36 N5O4 + [M + H] +, 518.2762; found,518.2767.

[0250] 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).

[0251] Example 14 Synthesis of compound A14

[0252]

[0253] The synthesis of compound A14 was performed according to the procedure of Example 10, with suitable adaptations of substituents.

[0254] HRMS (ESI) m / z : calcd for C 30 H 38 N5O4 + [M + H] + , 532.2918; found, 532.2924.

[0255] 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).

[0256] Example 15 Synthesis of compound A15

[0257]

[0258] The synthesis method of compound A15 was referred to Example 10, with suitable adjustment of substituents.

[0259] HRMS (ESI) m / z : calcd for C 30 H 40 N5O4 + [M + H] + , 534.3075; found, 534.3080.

[0260] 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).

[0261] Example 16 Synthesis of compound A16

[0262]

[0263] The synthesis of compound A16 was performed according to the procedure described in Example 10, with suitable adaptations of substituents.

[0264] HRMS (ESI) m / z : calcd for C 29 H 36 F2N5O3 + [M + H] + , 540.2781; found,540.2779.

[0265] 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).

[0266] Example 17 Synthesis of compound A17

[0267]

[0268] The synthesis method of compound A17 is referred to Example 10, and substituent groups are adapted accordingly.

[0269] 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, = 11.4Hz, 2H), 2.42 (s, 3H), 2.33 (s, 3H), 2.25 (t,

[0270]

[0271]

[0272] The synthesis method of compound A18 is referred to Example 10, and substituent groups are adapted accordingly.

[0273] 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).

[0274] Example 19 Synthesis of compound A19

[0275]

[0276] The synthesis of compound A19 was performed according to the procedure described in Example 10, with suitable adaptations of substituents.

[0277] HRMS (ESI) m / z : calcd for C 31 H 40 N5O3 + [M + H] + , 530.3126; found, 530.3121.

[0278] 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).

[0279] Example 20 Synthesis of compound A20

[0280]

[0281] The synthetic method of compound A20 is referred to Example 10, and the substituent groups are adapted accordingly.

[0282] HRMS (ESI) m / z : calcd for C 34 H 45 N6O5 + [M + H] + , 617.3446; found, 617.3435.

[0283] 1 H NMR (400 MHz, Chloroform- d ) δ 7.27 (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).

[0284] Example 21 Synthesis of compound A21

[0285] Step 1: Synthesis of intermediate 8 (2,4-dichloro-6-methoxyquinin-7-ol)

[0286]

[0287] To a reaction flask was added 2-methoxy-5-aminophenol (10 g, 1 eq), malonic acid (8.2 g, 1.1 eq), and phosphorus oxychloride (40 mL) was added to the reaction flask and reacted at 95 °C for 12 h. The phosphorus oxychloride was removed by distillation under reduced pressure and quenched with water (300 mL), extracted with ethyl acetate (200 mL x 3). The combined organic layer was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography (PE / EA = 100%-40%) to give intermediate 8 as a white solid, 3 g, in 17% yield. MS (ESI) m / z244.02 [M + H] + .

[0288] Step 2: Synthesis of Intermediate 9 (4-chloro-6-methoxy-2-(5-methylfuran-2-yl)quinoline-7-ol)

[0289]

[0290] 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] + .

[0291] 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)

[0292]

[0293] 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 , N Dimethylformamide (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] + .

[0294] Step 4: Synthesis of intermediate 3a (4-chloro-6-methoxy-7-((1-methylazacyclobutane-3-yl)methoxy)-2-(5-methylfuran-2-yl)quinoline):

[0295]

[0296] 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] + .

[0297] 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:

[0298]

[0299] 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%.

[0300] HRMS (ESI) m / z : calcd forC 26 H 35 N4O3 + [M + H] + , 451.2704; found, 451.2698.

[0301] 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).

[0302] Example 22 Synthesis of compound A22

[0303]

[0304] The synthesis method of compound A22 was referred to Example 21, with suitable adjustment of substituents.

[0305] HRMS (ESI) m / z : calcd for C 27 H 37 N4O3 + [M + H] + , 465.2860; found, 465.2856.

[0306] 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).

[0307] Example 23 Synthesis of Compound A24

[0308]

[0309] The synthesis method of compound A24 is as described in Example 21, with adaptive adjustments to the substituents.

[0310] HRMS (ESI) m / z : calcd for C 30 H 41 N4O3 + [M + H] + , 505.3173; found, 505.3169.

[0311] 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).

[0312] Example 24 Synthesis of compound A25

[0313]

[0314] The synthesis of compound A25 was performed according to the procedure described in Example 21, with suitable adaptations of substituents.

[0315] HRMS (ESI) m / z : calcd for C 32 H 45 N4O3 + [M + H] + , 533.3486; found, 533.3484.

[0316] 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).

[0317] Example 25 Synthesis of compound A26

[0318]

[0319] Step 1: Synthesis of Intermediate 10 (tert-butyl 6-(((4-nitrophenyl)sulfonyl)oxy)-2- azaspiro[3.3]heptane-2-carboxylate)

[0320] tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (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 reacted at room temperature for 3 h. The reaction was completed by concentration under reduced pressure, and the solid was filtered by washing with ethyl acetate to obtain Intermediate 10 as a white solid, 1.1 g, 92% yield. 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).

[0321] The subsequent steps refer to Example 21, with suitable adaptation of the substituents, to obtain compound A26.

[0322] 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).

[0323] Example 26 Synthesis of compound A27

[0324]

[0325] The synthesis method of compound A27 was referred to Example 25, with suitable adjustment of substituents.

[0326] HRMS (ESI) m / z : calcd for C 29 H 37 N4O5 + [M + H] + , 521.2758; found, 521.2756.

[0327] 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).

[0328] Example 27 Synthesis of compound A28

[0329]

[0330] The synthetic method of compound A28 was referred to Example 25 with adaption of substituents, to give the title compound.

[0331] HRMS (ESI) m / z : calcd for C 28 H 37 N4O4 + [M + H] + , 493.2809; found, 493.2804.

[0332] 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).

[0333] Example 28 Synthesis of compound A29

[0334]

[0335] The synthetic method of compound A29 was referred to Example 25 with adaption of substituents, to give the title compound.

[0336] HRMS (ESI) m / z : C 31 H 37 N4O3 + calcdfor[M + H] + , 513.2860; found, 513.2858.

[0337] 1H NMR (400 MHz, Methanol- d 4) 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).

[0338] Example 29 Synthesis of compound A30

[0339]

[0340] The synthesis method of compound A30 was referred to Example 25, with suitable adjustment of substituents.

[0341] HRMS (ESI) m / z : calcd for C 27 H 35 N4O3 + [M + H] + , 463.2704; found, 463.2698.

[0342] 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).

[0343] Example 30 Synthesis of compound A31

[0344]

[0345] The synthesis method of compound A31 was referred to Example 25, with suitable adjustment of substituents.

[0346] HRMS (ESI) m / z : calcd for C 29 H 38 N3O3 + [M + H] + , 476.2908; found, 476.2903.

[0347] 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).

[0348] Example 31 Synthesis of compound A32

[0349]

[0350] The synthetic method of compound A32 was referred to Example 25 with adaption of substituents, to give the target compound.

[0351] HRMS (ESI) m / z : calcd for C 29 H 38 N3O3 + [M + H] + , 476.2908; found, 476.2903.

[0352] 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).

[0353] Example 32 Synthesis of compound A33

[0354]

[0355] The synthetic method of compound A33 was referred to Example 25 with adaption of substituents, to give the target compound.

[0356] HRMS (ESI) m / z : calcd for C 29 H 39 N4O3 + [M + H] +, 491.3017; found, 491.3015.

[0357] 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).

[0358] Example 33 Synthesis of compound A34

[0359]

[0360] The synthesis method of compound A34 was referred to Example 25, with suitable adjustment of substituents.

[0361] HRMS (ESI) m / z : calcd for C 30 H 39 N4O3 + [M + H] + , 503.3017; found, 503.3015.

[0362] 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).

[0363] Example 34 Synthesis of compound A35

[0364]

[0365] The synthesis of compound A35 was performed according to the procedure described in Example 25, with appropriate adjustment of substituents.

[0366] HRMS (ESI) m / z : calcd for C 27 H 34 N3O4 + [M + H] + , 464.2544; found, 464.2539.

[0367] 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).

[0368] Example 35 Synthesis of compound A36

[0369]

[0370] The synthesis method of compound A36 was referred to Example 25, with suitable adjustment of substituents.

[0371] HRMS (ESI) m / z : calcd for C 26 H 30 F2N3O3 + [M + H] + , 470.2250; found,470.2245.

[0372] 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).

[0373] Example 36 Synthesis of compound A37

[0374]

[0375] The synthetic method of compound A37 was referred to example 25 with adaption of substituents.

[0376] HRMS (ESI) m / z : calcd for C 28 H 30 N3O3 + [M + H] + , 456.2282; found, 456.2275.

[0377] 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).

[0378] Example 37 Synthesis of compound A38

[0379]

[0380] The synthetic method of compound A38 was referred to example 25 with adaption of substituents.

[0381] HRMS (ESI) m / z : calcd for C 29 H 32 N3O3 + [M + H] + , 470.2438; found, 470.2433.

[0382] 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).

[0383] Example 38 Synthesis of compound A39

[0384]

[0385] The synthesis method of compound A39 was referred to Example 25, with suitable adjustment of substituents.

[0386] HRMS (ESI) ​ : calcd for C 28 H 29 FN3O3 + [M + H] + , 474.2187; found,474.2185.

[0387] 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).

[0388] Example 39 Synthesis of compound A40

[0389]

[0390] The synthetic method of compound A40 is referred to Example 25, with suitable adjustment of substituents.

[0391] HRMS (ESI) ​ : calcd for C 33 H 40 N5O3 + [M + H] + , 554.3126; found, 554.312.

[0392] 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).

[0393] The technical solutions of the present application are further described below through experiments.

[0394] Experimental Example 1: Testing of the enzyme activity of quinoline compounds on DNMT1 and G9a

[0395] I. Experimental methods

[0396] The enzyme activity test of DNMT1 was completed by Shanghai Ruizhi Chemical Research Co., Ltd. 1x assay buffer (modified Tris buffer) was prepared for subsequent experiments. The quinoline compounds dissolved in DMSO were transferred to the detection plate and serially diluted according to the set concentration. The final DMSO concentration was adjusted to 1%. Then, the enzyme solution was prepared in 1x assay buffer, and the substrate solution and 3H]-SAM solution. To the assay plate, 10 μL of enzyme solution (10 μL of 1x assay buffer for the vehicle control) was added and incubated at room temperature for 15 min. Then, 10 μL of substrate solution was added to each well, followed by 10 μL of [ 3 H]-SAM solution to initiate the reaction and incubated at 37°C for 180 min. After the reaction was completed, 10 μL of cold SAM solution was added to each well to stop 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 system was transferred to the filter plate and washed with ddH2O for 3 times (vacuum each time). Finally, the counts were read using the MicroBeta instrument.

[0397] The enzyme activity test of G9a was completed by Shanghai RuiZhi Chemical Research Co., Ltd. 1x assay buffer (modified Tris buffer) was prepared for subsequent experiments. The quinoline compounds dissolved in DMSO were transferred to the assay plate and serially diluted at the set concentration. Subsequently, the G9a enzyme solution was prepared in 1x assay buffer, and the substrate mixed solution was prepared in the same buffer. To the assay plate, 5 μL of enzyme solution (5 μL of 1x assay buffer for the vehicle control) was added and incubated at room temperature for 15 min. Then, 5 μL of substrate mixed solution was added to each well to initiate the reaction and incubate at room temperature for 60 min. Next, 1x Alphalisa buffer was prepared and the acceptor and donor microbead mixed solution was prepared therein. To the assay plate, 15 μL of acceptor and donor microbead mixed solution was added and incubated at room temperature for 60 min in the dark. Finally, the end point signal was read using the Alpha mode of Envision or EnSpire instrument.

[0398] II. Experimental results

[0399] The results are shown in Table 1, and it can be seen that the quinoline compounds prepared by the present application can inhibit the activity of DNA methyltransferase 1 (DNMT1) at 100 nM, 250 nM and 500 nM, and the inhibition rate of compounds A5, A21, A22, A26, A28, A30 and A40 on DNMT1 is higher.

[0400] As shown in Table 2, compounds A21, A22, A33 and A40 have better inhibition effect on DNMT1, and compound A40 has the strongest inhibition effect on DNMT1, with IC 50 value of 36 nM. Compounds A21 and A22 have better inhibition effect on G9a, and compound A22 has the strongest inhibition effect on G9a, with IC 50 value of 1.24 nM.

[0401] The above results show that the synthesized quinoline compounds of the application have significant inhibition effect on DNMT1, and can be used as DNMT1 inhibitors. Compound A40 has higher inhibition rate and selectivity on DNMT1.

[0402] Table 1 Single-concentration inhibition rate of quinoline compounds of the application on DNMT1

[0403]

[0404]

[0405] “-” means not tested

[0406] Table 2 IC of some compounds on DNMT1 and G9a 50

[0407]

[0408] Experimental Example 2 Pharmacokinetic study of compound A40

[0409] I. Experimental method

[0410] This experiment used 6 Balb / c mice (Chengdu Dasuo Experimental Animal Co., Ltd., license number: SCXK (Chuan) 2020-030). Each experiment was divided into 2 groups, 3 mice in each group. Sample preparation: weigh about 2.0 mg of compound A40, dissolve into a 50 mg / mL stock solution with 40.0 μL of DMSO, take 2 μL of the stock solution, 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, 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. After administration, collect blood samples at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h and 24 h, a total of 10 times, about 0.02 mL each time, and place the collected samples on ice.

[0411] Preparation of plasma samples: After thawing at room temperature, the collected plasma samples were vortexed to mix uniformly. Take 5 μL of plasma into each EP tube, add 100 μL of acetonitrile containing 20 ng / mL of internal standard SAHA to precipitate the protein, vortex for 10 s, centrifuge at 13000 rpm for 10 min, and take the supernatant into a sample bottle for testing.

[0412] Result analysis: the blood concentration data at different time points were processed by DAS 2.0 pharmacokinetic software to provide AUC (0-t) , AUC (0-∞) , C max (ng / mL), T max (h), T 1 / 2 (h) and F% and the average value and standard deviation.

[0413] II. Experimental results

[0414] The results are shown in Table 3, A40 has a long half-life after injection, in addition, the oral bioavailability of A40 is 17.93%, indicating that A40 has good drug property.

[0415] Table 3 Pharmacokinetic parameters of compound A40

[0416]

[0417] In conclusion, the quinoline compound provided by the application has excellent DNMT1 enzyme inhibition activity and good selectivity, can be used as a new type of DNMT1 inhibitor, and provides a new choice for the drug development and application of diseases driven by DNMT1.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized by: The compound is one of the following structures: 、 、 、 、 。 2. Use of the compound or pharmaceutically acceptable salt thereof according to claim 1 in the preparation 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.

3. A pharmaceutical composition, characterized by: It is a preparation prepared by adding a pharmaceutically acceptable adjuvant to the compound or pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.

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