Preparation of tricyclic heterocyclic derivative and application of tricyclic heterocyclic derivative as antitumor drug

Abstract

The invention belongs to the field of pharmaceutical chemicals, and discloses preparation of a tricyclic heterocyclic derivative and application of the tricyclic heterocyclic derivative as an antitumor drug. The structure of the tricyclic heterocyclic derivative is # imgabs0 #. The invention provides a pharmaceutical composition containing the tricyclic heterocyclic derivative and a pharmaceutically acceptable salt, a solvate, an isotope derivative or a prodrug thereof. The invention aims to provide a preparation containing the tricyclic heterocyclic derivative, and a pharmaceutically acceptable salt, a solvate, an isotope derivative or a prodrug of the tricyclic heterocyclic derivative. Various in-vitro tumor cell line tests prove that the compounds have remarkable anti-tumor cell proliferation activity.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a pharmaceutical composition of tricyclic heterocyclic compounds, and also relates to its use in the prevention and / or treatment of tumors and other diseases. Background Art

[0002] Given that tumors show a high incidence and mortality rate and remain an important factor endangering human health globally, the research and development of anti-tumor drugs have always attracted much attention.

[0003] In recent years, tricyclic heterocyclic derivatives have been reported to have potential anti-tumor activities. For example, usnic acid derived from lichen plants can inhibit the growth of leukemia, lung cancer, prostate cancer, and breast cancer. Harmine has potential tumor suppression properties and inflammation regulation effects. Chlorpromazine is clinically applied to the treatment of glioblastoma multiforme. Although there have been reports on the anti-tumor activities of tricyclic heterocyclic derivatives, most of these compounds are derived from natural products, with complex structures, difficult synthesis, and limited effects. They are mostly used in the material field and central nervous system diseases, and the research on the anti-tumor activities of such compounds has not been further developed. Therefore, it is necessary to develop new tricyclic heterocyclic derivatives with simple synthesis operations and potential research value for anti-tumor drugs. Summary of the Invention

[0004] Aiming at the deficiencies of the existing technology, one of the purposes of the present invention is to provide tricyclic heterocyclic derivatives and their pharmaceutically acceptable salts (pharmaceutically acceptable salts), solvates, isotope derivatives or prodrugs; the second purpose of the present invention is to provide a preparation method of tricyclic heterocyclic derivatives and their pharmaceutically acceptable salts, solvates, isotope derivatives or prodrugs; the third purpose of the present invention is to provide the application of tricyclic heterocyclic derivatives and their pharmaceutically acceptable salts, solvates, isotope derivatives or prodrugs in the preparation of drugs for treating hematological tumors or solid tumors; the fourth purpose of the present invention is to provide a pharmaceutical composition containing the tricyclic heterocyclic derivatives and their pharmaceutically acceptable salts, solvates, isotope derivatives or prodrugs; the fifth purpose of the present invention is to provide a preparation containing the tricyclic heterocyclic derivatives and their pharmaceutically acceptable salts, solvates, isotope derivatives or prodrugs.

[0005] To achieve the above purposes, the present invention provides the following technical solutions:

[0006] A tricyclic heterocyclic derivative or its pharmaceutically acceptable salt, solvate, isotope derivative or prodrug, wherein the structure of the tricyclic heterocyclic derivative is shown as general formula I:

[0007]

[0008] In the formula:

[0009] X is selected from the group consisting of: NH, O, S;

[0010] Y is CH or N;

[0011] (R1) m The hydrogen on the pyridine ring is replaced by m R1, n is 0, 1, 2 or 3; each R1 is independently selected from: deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, carboxyl, sulfonamide, alkylamino, dialkylamino, acetylamino, cyclic amine, heterocyclic group, -C1-C8 alkyl, -C 1-8 Alkoxy, -S(O)2C 1-8 Alkyl, -S(O)2NHC 1-8 Alkyl, -S(O)C 1-8 Alkyl, -C(O)OC 1-8 Alkyl, -C(O)NHC 1-8 alkyl,

[0012] wherein the group is unsubstituted or optionally substituted with one, two or more substituents, each of which is independently selected from deuterium, halogen, hydroxyl, thiol, amino, nitro, cyano, carboxyl, sulfonamide, alkylamino, dialkylamino, acetylamino, cyclic amine, -C1-C3 alkyl, halo-C1-C3 alkyl, heterocyclic, -C1-C3 alkoxy, -C1-C3 fluoroalkoxy, -C(O)OC 1-3 Alkyl, -S(O)2C 1-3 Alkyl, -S(O)2NHC 1-3 Alkyl, -S(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -C(O)NHC 1-3 alkyl;

[0013] R2 is independently selected from:

[0014] a) aryl or heteroaryl, which is unsubstituted or optionally substituted with 1, 2 or more substituents, each of which is independently selected from deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, sulfonamido, alkylamino, dialkylamino, acetylamino, cyclic amine, heterocyclic group, -C1-C8 alkyl, -C 1-8 Alkoxy, -C(O)R a 、-C(O)NHR a 、-C(O)NHR a 、-C(S)NHR a 、-C(S)NHR a 、-S(O)R a 、-S(O)2R a 、-S(O)2NHR a 、-C(O)OR a, -CH2R a , wherein R a is selected from deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, sulfonyl, sulfonamido, alkylamino, dialkylamino, acetylamino, cycloamine, heterocyclic group, -C1-C8 alkyl, -C 1-8 alkoxy, -C3-C8 cycloalkyl, -C4-C8 heterocyclic group;

[0015] b) a fused 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle, or a fused 3- to 7-membered saturated or partially unsaturated monocyclic ring; the fused 3- to 7-membered saturated or partially unsaturated monocyclic heterocycle or the fused 3- to 7-membered saturated or partially unsaturated monocyclic ring is unsubstituted or substituted with one, two or more substituents, and each of the substituents is independently selected from deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, sulfonamido, alkylamino, dialkylamino, acetylamino, cycloamine, heterocyclic group, -C1-C8 alkyl, -C 1-8 alkoxy, -S(O)2C 1-8 alkyl, -S(O)2NHC 1-8 alkyl, -S(O)C 1-8 alkyl, -C(O)OC 1-8 alkyl, -C(O)NHC 1-8 alkyl;

[0016] c) a heterocyclic group, which is unsubstituted or optionally substituted with one, two or more substituents, and each of the substituents is independently selected from deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, sulfonamido, alkylamino, dialkylamino, acetylamino, cycloamine, heterocyclic group, -C1-C8 alkyl, -C 1-8 alkoxy, -S(O)2C 1-8 alkyl, -S(O)2NHC 1-8 alkyl, -S(O)C 1-8 alkyl, -C(O)OC 1-8 alkyl, -C(O)NHC 1-8 alkyl;

[0017] d) -C3-C8 cycloalkyl, -C5-C8 cycloalkenyl, -C7-C 10 fused cycloalkyl, -C7-C[[ID= 42]] 10 bridged cycloalkyl, -C7-C 10 spirocycloalkyl, -C4-C8 heterocyclic group, -C5-C8 heterocycloalkenyl, -C7-C 10 fused heterocycloalkyl, -C7-C 10 bridged heterocycloalkyl, -C7-C 10A spiroheterocycloalkyl group, which is unsubstituted or optionally substituted with one, two or more substituents, each of which is independently selected from deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, sulfonamido, alkylamino, dialkylamino, acetylamino, cycloamine, heterocyclic group, -C1-C8 alkyl, -C 1-8 alkoxy, -S(O)2C 1-8 alkyl, -S(O)2NHC 1-8 alkyl, -S(O)C 1-8 alkyl, -C(O)OC 1-8 alkyl, -C(O)NHC 1-8 alkyl;

[0018] Preferably,

[0019] X is selected from: NH, O, S;

[0020] Y is CH or N;

[0021] (R1) m is that the hydrogen on the pyridine ring is substituted by m R1s, n is 0, 1, 2 or 3; each R1 is independently selected from: deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, sulfonamido, alkylamino, dialkylamino, acetylamino, cycloamine, heterocyclic group, -C1-C8 alkyl, -C 1-6 alkoxy, -S(O)2C 1-6 alkyl, -S(O)2NHC 1-6 alkyl, -S(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -C(O)NHC 1-6 alkyl,

[0022] wherein the group is unsubstituted or optionally substituted with one or two substituents, each of which is independently selected from deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, alkylamino, dialkylamino, acetylamino, cycloamine, -C1-C3 alkyl, halo-C1-C3 alkyl, heterocyclic group, -C1-C3 alkoxy, -C1-C3 fluoroalkoxy, -C(O)OC 1-8 alkyl, -S(O)2C 1-3 alkyl, -S(O)C 1-3 alkyl;

[0023] R2 is independently selected from:

[0024] a) aryl or heteroaryl, which is unsubstituted or optionally substituted with 1, 2 or more substituents, each of which is independently selected from deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, sulfonamido, alkylamino, dialkylamino, acetylamino, cyclic amine, heterocyclic group, -C1-C8 alkyl, -C 1-8 Alkoxy, -C(O)R a 、-C(O)NHR a 、-C(O)NHR a 、-C(S)NHR a 、-C(S)NHR a 、-S(O)R a 、-S(O)2R a 、-S(O)2NHR a 、-C(O)OR a 、-CH2R a , where R a Selected from deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, sulfonyl, sulfonamido, alkylamino, dialkylamino, acetylamino, cyclic amine, heterocyclic group, -C1-C8 alkyl, -C 1-8 Alkoxy, -C3-C8 cycloalkyl, -C4-C8 heterocyclyl;

[0025] b) a fused 3- to 7-membered saturated or partially unsaturated monocyclic ring, or a fused 3- to 7-membered saturated or partially unsaturated monocyclic ring; the fused 3- to 7-membered saturated or partially unsaturated monocyclic ring or the fused 3- to 7-membered saturated or partially unsaturated monocyclic ring is unsubstituted or substituted with one, two or more substituents, each of which is independently selected from deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, sulfonamide, alkylamino, dialkylamino, acetylamino, cycloamine, heterocyclyl, -C1-C8 alkyl, -C 1-6 Alkoxy, -S(O)2C 1-6 Alkyl, -S(O)2NHC 1-6 Alkyl, -S(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -C(O)NHC 1-6 alkyl;

[0026] c) heterocyclic group, which is unsubstituted or optionally substituted by 1, 2 or more substituents, each of which is independently selected from deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, sulfonamido, alkylamino, dialkylamino, acetylamino, cyclic amine, heterocyclic group, -C1-C8 alkyl, C 1-8 Alkoxy, -S(O)2C 1-8 Alkyl, -S(O)2NHC 1-8 Alkyl, -S(O)C1-8 alkyl, -C(O)OC 1-8 alkyl, -C(O)NHC 1-8 alkyl;

[0027] d) -C3-C8 cycloalkyl, -C5-C8 cycloalkenyl, -C7-C 10 fused cycloalkyl, -C7-C 10 bridged cycloalkyl, -C7-C 10 spirocycloalkyl, -C4-C8 heterocyclic group, -C5-C8 heterocycloalkenyl, -C7-C 10 fused heterocycloalkyl, -C7-C 10 bridged heterocycloalkyl, -C7-C 10 spiroheterocycloalkyl, which is unsubstituted or optionally substituted by one, two or more substituents, and each of the substituents is independently selected from deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, sulfonamide, alkylamino, dialkylamino, acetylamino, cyclic amine, heterocyclic group, -C1-C8 alkyl, -C 1-8 alkoxy, -S(O)2C 1-8 alkyl, -S(O)2NHC 1-8 alkyl, -S(O)C 1-8 alkyl, -C(O)OC 1-8 alkyl, -C(O)NHC 1-8 alkyl;

[0028] Preferably, the pharmaceutically acceptable salt is formed by reacting the tricyclic heterocyclic derivative with an acid; the acid includes inorganic acids and organic acids; the acid is hydrochloric acid, nitric acid, acetic acid, hydrobromic acid, sulfuric acid, phosphoric acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, lactic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid.

[0029] Preferably, the structure of the tricyclic heterocyclic derivative is as follows:

[0030]

[0031] The preparation method of the above-mentioned tricyclic heterocyclic derivative or its pharmaceutically acceptable salt, isotope derivative or prodrug is selected from one of the following three schemes:

[0032] 1) Scheme 1

[0033]

[0034] Step 1: Under high-temperature alkaline conditions and in the presence of a catalyst, the corresponding boric acid or pinacol borate compound is subjected to a Suzuki reaction to obtain compound Ia. The preferred alkaline reagent is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium acetate, or sodium tert-butoxide. The preferred catalyst is palladium acetate, tetrakis(triphenylphosphine)palladium, or dichloro[bis(triphenylphosphine)]palladium. The preferred temperature is 60-100 °C;

[0035] Step 2: In a dichloromethane solution of compound Ia, the methyl group is removed with boron tribromide solution to obtain intermediate Ib. The reaction temperature is preferably 0-25 °C, and the reaction time is preferably 4-24 hours.

[0036] Step 3: Under high-temperature alkaline conditions, intermediate Ib undergoes an intramolecular nucleophilic substitution reaction to obtain intermediate Ic. The preferred alkaline reagent is potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide, or n-butyllithium. The preferred solvent is N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide. The preferred temperature is 80-140 °C.

[0037] Step 4: Under high-temperature alkaline conditions and in the presence of a catalyst and a ligand, compound Ic is reacted with the corresponding amine to obtain the tricyclic heterocyclic derivative shown in general formula I. The preferred temperature is 80-140 °C. The preferred alkaline reagent is potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, potassium acetate, or sodium tert-butoxide. The preferred catalyst is dichloro[bis(triphenylphosphine)]palladium, tris(dibenzylideneacetone)dipalladium, or dichloromethane complex of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II). The preferred ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 1,1'-binaphthalene-2,2'-bis(diphenylphosphine), or 2-bis(cyclohexylphosphino)-2',4',6'-triisopropylbiphenyl.

[0038] 2) Scheme 2

[0039]

[0040] Step 1: Under high-temperature alkaline conditions and in the presence of a catalyst, the corresponding boric acid or pinacol borate compound is subjected to a Suzuki reaction to obtain compound IIa. The preferred alkaline reagent is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium acetate, or sodium tert-butoxide. The preferred catalyst is palladium acetate, tetrakis(triphenylphosphine)palladium, or dichloro[bis(triphenylphosphine)]palladium. The preferred temperature is 60-100 °C;

[0041] Step 2: Under acidic and sodium nitrite conditions, IIa undergoes a diazotization reaction to obtain a diazonium salt, which then undergoes a halogenation reaction to obtain intermediate IIb. The preferred acid is hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid. The halogenating reagent is preferably potassium iodide or sodium iodide.

[0042] Step 3: Under the conditions of m-chloroperbenzoic acid and trifluoromethanesulfonic acid, IIb is converted into the corresponding salt IIc.

[0043] Step 4: Under high-temperature alkaline conditions, IId is obtained. The alkaline conditions preferably include potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide, and n-butyllithium. The solvent preferably includes N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. The temperature preferably ranges from 80°C to 140°C.

[0044] Step 5: Under high-temperature alkaline conditions, in the presence of a catalyst and a ligand, compound IId reacts with the corresponding amine to obtain the tricyclic heterocyclic derivative represented by general formula I. The temperature preferably ranges from 80°C to 140°C. The alkaline reagent preferably includes potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, potassium acetate, or sodium tert-butoxide. The catalyst preferably includes dichlorobis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex. The ligand preferably includes 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 1,1'-binaphthalene-2,2'-bis(diphenylphosphine), or 2-bis(cyclohexylphosphino)-2',4',6'-triisopropylbiphenyl.

[0045] 3) Scheme 3

[0046]

[0047] Step 1: Under high-temperature alkaline conditions, in the presence of a catalyst, the corresponding boric acid or pinacol borate compound undergoes a Suzuki reaction to obtain compound IIIa. The alkaline reagent preferably includes potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium acetate, and sodium tert-butoxide. The catalyst preferably includes palladium acetate, tetrakis(triphenylphosphine)palladium, or dichlorobis(triphenylphosphine)palladium. The temperature preferably ranges from 60°C to 100°C.

[0048] Step 2: Under high-temperature alkaline conditions, intermediate IIIa undergoes an intramolecular nucleophilic substitution reaction to obtain intermediate IIIb. The alkaline reagent preferably includes potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide, and n-butyllithium. The solvent preferably includes N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. The temperature preferably ranges from 80°C to 140°C.

[0049] Step 3: Under high-temperature and alkaline conditions, in the presence of a catalyst and a ligand, react compound IIIb with the corresponding amine to obtain the tricyclic heterocyclic derivative shown in General Formula I. The temperature is preferably 80-140 °C. The alkaline reagent is preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, potassium acetate or sodium tert-butoxide. The catalyst is preferably dichlorobis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex. The ligand is preferably 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) or 2-bis(cyclohexylphosphino)-2',4',6'-triisopropylbiphenyl.

[0050] wherein X is NH, O, S; Y is CH or N; (R1) m and R2 are as defined in claim 1.

[0051] The compound prepared by the present invention was tested by high-resolution mass spectrometry, nuclear magnetic resonance, etc., and it was proved that the prepared compound is the compound shown in General Formula I.

[0052] A pharmaceutical composition containing the above tricyclic heterocyclic derivative or a pharmaceutically acceptable salt, solvate, isotope derivative or prodrug thereof.

[0053] Preferably, the active ingredient of the pharmaceutical composition is a single compound containing General Formula I, a mixture of several compounds, or a combination of at least one compound of General Formula I and at least one other active ingredient; the weight percentage content of the active component in the pharmaceutical composition is 0.01-99.99%;

[0054] Preferably, the pharmaceutical composition further includes a carrier; the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, glidants, preservatives, taste masking agents or solubilizing agents in the pharmaceutical field;

[0055] Preferably, the pharmaceutical composition is a preparation; the preparation is an injection, tablet, powder, granule, capsule, oral liquid, ointment, cream.

[0056] Use of the above tricyclic heterocyclic derivative or a pharmaceutically acceptable salt, solvate, isotope derivative or prodrug thereof in the preparation of anti-tumor drugs for prevention and / or treatment.

[0057] Preferably, the tumors include hematological cancers such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, follicular lymphoma, and breast cancer, cervical cancer, colorectal cancer, liver cancer, ovarian cancer, pancreatic cancer, kidney cancer, gastric cancer, lung cancer, non-small cell lung cancer, oral cancer, prostate cancer, bladder cancer, skin cancer, fallopian tube tumors, melanoma, glioma, myeloma.

[0058] The beneficial effects of the present invention are as follows:

[0059] (1) The present invention provides tricyclic heterocyclic derivatives, their preparation methods and applications. These compounds have been tested on various in vitro tumor cell lines and have significant anti-tumor cell proliferation activity. These results indicate that general formula I is a promising anti-tumor small molecule.

[0060] (2) The compounds provided by the present invention are easy to obtain raw materials, simple to operate, have a short synthesis route, and have good application prospects for the prevention and / or treatment of tumors. Detailed implementation manners

[0061] The present invention is illustrated below through specific examples. It should be noted that these examples make the present invention easier to understand without limiting the scope of the present invention. Unless otherwise specifically marked in the following examples, they are usually carried out according to the routine.

[0062] Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific implementation manners, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0063] Compounds for which the synthesis method is not described in the experiment are all commercially purchased, or the compounds are known compounds or can be synthesized by those skilled in the art through the synthesis methods of similar compounds.

[0064] Example 1: Preparation of 7-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)benzofuro[2,3-c]pyridin-3-amine

[0065]

[0066] Step 1: Synthesis of intermediate 1a

[0067] Dissolve 6.22 g of anhydrous potassium carbonate in 22.5 mL of water to prepare a 2 M potassium carbonate solution. Dissolve 2-chloro-5-fluoro-4-iodopyridine (3.86 g, 15 mmol), 4-fluoro-2-methoxyphenylboronic acid (3.06 g, 18 mmol), and tetrakis(triphenylphosphine)palladium (1.73 g, 1.5 mmol) in ethylene glycol dimethyl ether (37.5 mL), displace with nitrogen three times, and add the potassium carbonate solution dropwise under a nitrogen atmosphere. Heat the reaction to 100 °C and react for 12 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Separate the layers, extract the aqueous phase with ethyl acetate (30 mL * 3), combine the organic phases, wash with saturated sodium chloride aqueous solution (100 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, mix with silica gel, and purify by column chromatography (petroleum ether:dichloromethane = 4:1 - 1:1) to obtain white powder 1a (3.54 g, yield 92%). LCMS m / z (ESI): 256.0[M+H], 1 H NMR (500 MHz, CDCl3) δ 8.27 (s, 1H), 7.36–7.28 (m, 3H), 7.25–7.22 (m, 1H), 6.81–6.70 (m, 2H), 3.82 (s, 3H).

[0068] Step 2: Synthesis of intermediate 1b

[0069] Place compound 1a (51.1 mg, 0.2 mmol) in a reaction tube, evacuate, displace with nitrogen three times, and dissolve in anhydrous dichloromethane (2 mL) under a nitrogen atmosphere. Cool the temperature to 0 °C and slowly add boron tribromide solution (1 M / L, 0.4 mL) dropwise to the reaction system. After the addition, gradually warm to room temperature and react for 20 hours. Monitor the reaction by TLC until completion. Quench by adding 5 mL of water under ice bath conditions, extract the aqueous phase with dichloromethane (the organic phase is combined, washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, mixed with silica gel, and purified by column chromatography (petroleum ether:ethyl acetate = 10:0 - 4:1) to obtain 1b (white solid, 24.8 mg, yield 51%), LCMS m / z (ESI): 241.9[M+H] + 。 1 H NMR (500 MHz, CDCl3) δ 11.77 (s, 1H), 11.00 (d, J = 5.2 Hz, 1H), 10.89 (s, 1H), 10.75 (t, J = 7.4 Hz, 1H), 10.20 (dd, J = 14.7, 9.2 Hz, 2H).

[0070] Step 3: Synthesis of intermediate 1c

[0071] Weigh successively compound 1b (108.3 mg, 4.5 mmol) and potassium carbonate (1865.8 mg, 13.5 mmol) into a reaction flask. Replace the air with nitrogen three times, and then add ultra-dry N-methylpyrrolidone (10 mL) to dissolve them under a nitrogen atmosphere. Place it in an oil bath at 140 °C and stir for 4 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Add water (100 mL) to the reaction solution, continue to stir for 30 minutes, then filter out the solid, wash it with water and dry it to obtain intermediate 1c (white powder, 554.0 mg, yield 56%). LCMS m / z (ESI): 221.3 [M+H] + 。 1 H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 7.95 (dd, J = 8.6, 5.3 Hz, 1H), 7.84 (s, 1H), 7.35 (dd, J = 8.6, 2.1 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H).

[0072] Step 4: Synthesis of final product 1

[0073] Weigh successively 2-bis(cyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (13.3 mg, 0.028 mmol), tris(dibenzylideneacetone)dipalladium(0) (18.3 mg, 0.02 mmol), intermediate 1c (44.3 mg, 0.2 mmol), 1-methyl-4-(6-aminopyridin-3-yl)piperazine (38.5 mg, 0.2 mmol), and anhydrous potassium phosphate powder (129.2 mg, 0.6 mmol) into a dry reaction tube. Replace the air with nitrogen three times, and then add ultra-dry N,N-dimethylformamide (1.0 mL) under a nitrogen atmosphere. Heat the reaction to 120 °C and react for 12 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Filter through diatomaceous earth and wash with ethyl acetate. Concentrate the obtained filtrate under reduced pressure, mix with silica gel, and then separate and purify by column chromatography (dichloromethane:methanol = 10:1 to 9:1) to obtain final product 1 (white powder, 47.9 mg, yield 63%). 1 H NMR (500 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.64 (s, 1H), 8.42 (s, 1H), 8.20 (dd, J = 8.6, 5.6 Hz, 1H), 7.94 (d, J = 2.6 Hz, 1H), 7.69 (dd, J = 9.3, 2.2 Hz, 1H), 7.41 (dt, J = 9.1, 5.9 Hz, 2H), 7.30 (td, J = 9.3, 2.3 Hz, 1H), 3.10–3.04 (m, 4H), 2.49–2.45 (m, 4H), 2.23 (s, 3H). 19 FNMR (471 MHz, DMSO-d6) δ -109.08.13 C NMR(151 MHz, DMSO-d6) δ 164.08, 162.45, 157.51 (d, J = 14.5 Hz), 150.52, 148.17, 148.04, 141.15, 134.36, 131.95, 128.69 (d, J = 532.2 Hz), 123.85 (d, J = 10.8 Hz), 118.93, 111.90, 111.42 (d, J = 24.1 Hz), 100.71, 100.28 (d, J = 27.2 Hz), 54.54, 48.96, 45.73.

[0074] Example 2: Preparation of 7-Fluoro-N-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzofuro[2,3-c]pyridin-3-amine

[0075] The preparation method was the same as that of Example 1, except that 6-(4-methylpiperazin-1-yl)pyridin-3-amine was used in Step 4 to obtain the title compound. Yellow powder, 0.2 mmol, 28.5 mg, yield 38%. 1 H NMR(500 MHz, DMSO-d6) δ 8.72 (d, J = 11.5 Hz, 1H), 8.54 (s, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.24 (dd, J = 8.5, 5.8 Hz, 1H), 7.83 (dd, J = 9.0, 2.3 Hz, 1H), 7.66 (dd, J = 9.3, 1.5 Hz, 1H), 7.32 (s, 1H), 7.30–7.26 (m, 1H), 6.84 (d, J = 9.0 Hz, 1H), 3.40 (d, J = 4.3 Hz, 4H), 2.44 (d, J = 4.2 Hz, 4H), 2.25 (s, 3H). 13 C NMR(151 MHz, DMSO-d6) δ 164.18, 162.55, 157.61 (d, J = 14.0 Hz), 154.77, 152.77, 147.67, 139.10, 132.52, 130.06 (d, J = 5.5 Hz), 129.97, 124.22 (d, J = 10.8 Hz), 118.74, 111.25 (d, J = 24.0 Hz), 107.29, 100.19 (d, J = 27.2 Hz), 98.83, 54.39, 45.72, 45.33.

[0076] Example 3: Preparation of 7-Fluoro-N-(4-(4-methylpiperazin-1-yl)phenyl)benzofuro[2,3-c]pyridin-3-amine

[0077] The preparation method was the same as that of Example 1, except that 4-(4-methylpiperazin-1-yl)aniline was used in Step 4 to obtain the title compound. 0.2 mmol, yellow powder, 21.1 mg, 28%. 1 H NMR(500MHz,DMSO-d6)δ8.71(s,1H),8.54(s,1H),8.20(dd,J=8.6,5.7Hz,1H),7.64(dd,J=9.4,2.2Hz,1H),7.44(d,J=8.9Hz,2H),7.35(s,1H),7.27(td,J=9.3,2.3Hz,1H),6.89(d,J=9.0Hz,2H),3.09–3.00(m,4H),2.48–2.42(m,4H),2.22(s,3H). 13 C NMR(151MHz,DMSO-d6)δ164.15,162.52,157.57(d,J=14.1Hz),152.74,147.54,145.71,134.46,132.37,130.05,124.12(d,J=10.9Hz),119.82,118.80,116.38,111.21(d,J=23.9Hz),100.18(d,J=27.2Hz),98.85,54.77,49.10,45.79.

[0078] Example 4: Preparation of 7-fluoro-N-(5-morpholinopyridin-2-yl)benzofuro[2,3-c]pyridin-3-amine

[0079] The preparation method was the same as that of Example 1, except that 5-morpholinopyridin-2-amine was used in Step 4 to obtain the title compound. 0.2 mmol, yellow powder, 26.5 mg, 36%. 1 H NMR(500MHz,DMSO-d6)δ9.50(s,1H),8.64(s,1H),8.43(s,1H),8.20(dd,J=8.6,5.6Hz,1H),7.95(d,J=2.7Hz,1H),7.69(dd,J=9.3,2.2Hz,1H),7.46–7.40(m,2H),7.30(td,J=9.2,2.2Hz,1H),3.77–3.73(m,4H),3.07–3.03(m,4H). 1313C NMR(151MHz,DMSO-d6)δ164.11,162.48,157.54(d,J=14.0Hz),149.48(d,J=309.6Hz),148.09,141.18,134.27,131.99,130.50,126.74,123.90(d,J=10.6Hz),118.96,111.95,111.47(d,J=24.2Hz),100.80,100.31(d,J=27.2Hz),66.11,49.40.

[0080] Example 5: Preparation of 7-Fluoro-N-(5-(piperazin-1-yl)pyridin-2-yl)benzofuro[2,3-c]pyridin-3-amine

[0081] The preparation method was the same as that of Example 1, except that 5-(piperazin-1-yl)pyridin-2-amine was used in Step 4 to obtain the title compound. 0.2 mmol, yellow powder, 21.5 mg, yield 30%. 1 1H NMR(500MHz,DMSO-d6)δ10.91(s,1H),8.94(s,2H),8.78(s,1H),8.34(dd,J=8.6,5.6Hz,1H),8.11(s,1H),7.92(d,J=2.7Hz,1H),7.87(d,J=8.2Hz,1H),7.79(dd,J=9.2,2.1Hz,1H),7.46(d,J=9.4Hz,1H),7.39(td,J=9.3,2.2Hz,1H),3.34(d,J=5.7Hz,4H),3.30(s,4H).

[0082] Example 6: Preparation of 7-Fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)benzofuro[3,2-d]pyrimidin-2-amine

[0083] The preparation method was the same as that of Example 1, except that 2,4-dichloro-5-fluoropyrimidine was used instead of 2-chloro-5-fluoro-4-iodopyridine in Step 1 to obtain the title compound. 0.2 mmol, yellow powder, 24.4 mg, 32%. 11H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.98 (s, 1H), 8.22 (d, J = 9.1 Hz, 1H), 8.19 (dd, J = 8.7, 5.7 Hz, 1H), 8.00 (d, J = 2.9 Hz, 1H), 7.82 (dd, J = 9.3, 2.1 Hz, 1H), 7.44 (dd, J = 9.1, 3.0 Hz, 1H), 7.40 (td, J = 9.2, 2.2 Hz, 1H), 3.15–3.09 (m, 4H), 2.48 (d, J = 5.2 Hz, 4H), 2.23 (s, 3H).

[0084] Example 7: Preparation of 8-Fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)benzofuro[2,3-c]pyridin-3-amine

[0085] The preparation method was the same as that of Example 1, except that (3-fluoro-2-methoxyphenyl)boronic acid was used instead of (4-fluoro-2-methoxyphenyl)boronic acid in Step 1, to obtain the title compound. 0.2 mmol, yellow powder, 48.5 mg, 64%. 1 1H NMR (500 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.74 (d, J = 0.9 Hz, 1H), 8.49 (d, J = 0.9 Hz, 1H), 7.99 (dd, J = 7.8, 0.8 Hz, 1H), 7.95 (t, J = 1.8 Hz, 1H), 7.63–7.55 (m, 1H), 7.46–7.40 (m, 3H), 3.11–3.05 (m, 4H), 2.49–2.46 (m, 4H), 2.23 (s, 3H). 19 19F NMR (565 MHz, DMSO-d6) δ -136.50. 13 13C NMR (151 MHz, DMSO-d6) δ 150.66, 148.47, 147.83 (d, J = 74.3 Hz), 146.83, 143.57 (d, J = 11.6 Hz), 141.23, 134.32, 132.13, 131.22, 126.96, 125.89, 124.29 (d, J = 5.7 Hz), 118.56, 116.28 (d, J = 15.9 Hz), 111.97, 100.98, 54.55, 48.94, 45.75.

[0086] Example 8: Preparation of 6-Fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)benzofuro[2,3-c]pyridin-3-amine

[0087] The preparation method was the same as that of Example 1, except that (5-fluoro-2-methoxyphenyl)boronic acid was used instead of (4-fluoro-2-methoxyphenyl)boronic acid in Step 1 to obtain the title compound. 0.2 mmol, yellow powder, 32.7 mg, 43%. 1 H NMR(500MHz,DMSO-d6)δ9.49(s,1H),8.68(s,1H),8.47(s,1H),8.06(dd,J=8.3,2.5Hz,1H),7.94(d,J=1.5Hz,1H),7.76(dd,J=9.0,3.9Hz,1H),7.51(td,J=9.1,2.7Hz,1H),7.45–7.35(m,2H),3.12–3.01(m,4H),2.48(d,J=4.6Hz,4H),2.23(s,3H). 19 FNMR(565MHz,DMSO-d6)δ-119.44. 13 C NMR(151MHz,DMSO-d6)δ159.11,157.54,153.14,150.21,148.19(d,J=3.7Hz),141.16,134.29,132.26,131.00,126.99,123.28(d,J=10.7Hz),117.62(d,J=26.0Hz),113.59(d,J=9.3Hz),111.90,108.65(d,J=25.3Hz),101.11,54.56,49.00,45.77.

[0088] Example 9: Preparation of 5-fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)benzofuro[2,3-c]pyridin-3-amine

[0089] The preparation method was the same as that of Example 1, except that (2-fluoro-6-methoxyphenyl)boronic acid was used instead of (4-fluoro-2-methoxyphenyl)boronic acid in Step 1 to obtain the title compound. 0.2 mmol, yellow powder, 54.8 mg, 80%. 11H NMR (500 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.69 (d, J = 0.5 Hz, 1H), 8.45 (s, 1H), 7.94 (d, J = 2.9 Hz, 1H), 7.67 (dd, J = 8.2, 5.7 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 9.0 Hz, 1H), 7.40 (dd, J = 9.1, 3.0 Hz, 1H), 7.30–7.25 (m, 1H), 3.11–3.05 (m, 4H), 2.49–2.44 (m, 4H), 2.22 (s, 3H). 19 19F NMR (565 MHz, DMSO-d6) δ -116.24. 13 13C NMR (151 MHz, DMSO-d6) δ 158.22 (d, J = 20.3 Hz), 157.36 (d, J = 222.8 Hz), 150.63, 148.02, 146.68, 141.23, 134.36, 131.39 (d, J = 8.4 Hz), 130.66, 129.56, 126.82, 111.92, 111.16 (d, J = 20.6 Hz), 109.43 (d, J = 18.4 Hz), 108.81 (d, J = 3.4 Hz), 101.94, 54.55, 48.90, 45.74.

[0090] Example 10: Preparation of 7-Fluoro-N-(3-(4-methylpiperazin-1-yl)phenyl)benzofuro[2,3-c]pyridin-3-amine

[0091] Prepared in the same manner as in Example 1, except that 3-(4-methylpiperazin-1-yl)aniline was used in Step 4 to obtain the title compound. 0.2 mmol, yellow powder, 46.6 mg, yield 62%. 1 1H NMR (500 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.62 (s, 1H), 8.24 (dd, J = 8.5, 5.7 Hz, 1H), 7.68 (dd, J = 9.3, 2.1 Hz, 1H), 7.47 (s, 1H), 7.32–7.26 (m, 1H), 7.19 (s, 1H), 7.10 (dt, J = 15.8, 8.0 Hz, 2H), 6.50 (d, J = 7.2 Hz, 1H), 3.12 (s, 4H), 2.48 (s, 4H), 2.23 (s, 3H). 19 19F NMR (471 MHz, DMSO-d6) δ -108.90. 1313C NMR (151 MHz, DMSO-d6) δ 164.19, 162.56, 157.61, 157.52, 151.84 (d, J = 57.5 Hz), 147.80, 142.92, 132.35, 129.55 (d, J = 158.9 Hz), 124.20 (d, J = 10.9 Hz), 118.73, 111.30 (d, J = 24.0 Hz), 108.51 (d, J = 99.0 Hz), 105.06, 100.31, 100.18, 100.13, 54.64, 48.24, 45.70.

[0092] Example 11: Preparation of 7-Fluoro-N-(3-fluoro-5-(methylsulfonyl)phenyl)benzofuro[2,3-c]pyridin-3-amine

[0093] The preparation method was the same as that of Example 1, except that 3-fluoro-5-(methylsulfonyl)aniline was used in Step 4 to obtain the title compound. 0.2 mmol, yellow powder, 44.7 mg, 60%. 1 1H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.75 (s, 1H), 8.31 (dd, J = 8.6, 5.7 Hz, 1H), 8.15 (dd, J = 12.1, 1.9 Hz, 1H), 7.92 (s, 1H), 7.72 (dd, J = 9.3, 2.2 Hz, 1H), 7.54 (s, 1H), 7.33 (td, J = 9.2, 2.2 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 3.26 (s, 3H). 19 19F NMR (471 MHz, DMSO-d6) δ -108.28, -109.36. 13 13C NMR (126 MHz, DMSO-d6) δ 163.94 (d, J = 152.2 Hz), 161.99 (d, J = 150.0 Hz), 157.68 (d, J = 14.2 Hz), 150.42, 148.55, 144.85 (d, J = 11.4 Hz), 142.69 (d, J = 9.0 Hz), 132.70, 130.02, 124.48 (d, J = 10.8 Hz), 118.43, 111.58 (d, J = 24.0 Hz), 111.28, 107.18 (d, J = 27.1 Hz), 104.05 (d, J = 25.1 Hz), 102.06, 100.34 (d, J = 27.4 Hz), 43.30.

[0094] Example 12: Preparation of 7-Fluoro-N-(3-methyl-5-(methylsulfonyl)phenyl)benzofuro[2,3-c]pyridin-3-amine

[0095] The preparation method was the same as that of Example 1, except that 3-methyl-5-(methylsulfonyl)aniline was used in Step 4 to obtain the title compound. 0.2 mmol, yellow powder, 66.5 mg, 90%. 1 H NMR (500 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.71 (s, 1H), 8.28 (dd, J = 8.6, 5.7 Hz, 1H), 8.10 (s, 1H), 7.81 (s, 1H), 7.71 (dd, J = 9.3, 2.2 Hz, 1H), 7.51 (s, 1H), 7.32 (td, J = 9.3, 2.3 Hz, 1H), 7.22 (s, 1H), 3.18 (s, 3H), 2.39 (s, 3H). 19 F NMR (471 MHz, DMSO-d6) δ -108.51. 13 C NMR (126 MHz, DMSO-d6) δ 164.48, 162.52, 157.65 (d, J = 14.3 Hz), 151.07, 148.29, 142.13 (d, J = 234.5 Hz), 139.51, 132.58, 130.01, 124.36 (d, J = 10.9 Hz), 121.76, 118.54, 118.27, 112.15, 111.59, 101.47, 100.43, 43.71, 21.25.

[0096] Example 13: Preparation of 7-Fluoro-N-(3-methoxy-5-(methylsulfonyl)phenyl)benzofuro[2,3-c]pyridin-3-amine

[0097] The preparation method was the same as that of Example 1, except that 3-methoxy-5-(methylsulfonyl)aniline was used in Step 4 to obtain the title compound. 0.2 mmol, yellow powder, 34.1 mg, 44%. 1 H NMR (500 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.72 (s, 1H), 8.29 (dd, J = 8.6, 5.7 Hz, 1H), 7.79 (t, J = 1.6 Hz, 1H), 7.76 (t, J = 2.1 Hz, 1H), 7.71 (dd, J = 9.3, 2.2 Hz, 1H), 7.52 (s, 1H), 7.33 (td, J = 9.3, 2.3 Hz, 1H), 6.95–6.91 (m, 1H), 3.85 (s, 3H), 3.21 (s, 3H). 1919F NMR (471 MHz, DMSO-d6) δ -108.46. 13 13C NMR (126 MHz, DMSO-d6) δ 164.49, 162.53, 160.20, 157.65 (d, J = 14.2 Hz), 150.93, 148.33, 144.17, 142.14, 132.59, 129.99, 124.39 (d, J = 11.0 Hz), 118.52, 111.50 (d, J = 23.8 Hz), 107.96, 107.01, 102.58, 101.64, 100.32 (d, J = 27.1 Hz), 55.56, 43.56.

[0098] Example 14: Preparation of 7-Fluoro-N-(3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)benzofuro[2,3-c]pyridin-3-amine

[0099] Prepared in the same manner as in Example 1, except that 3-Trifluoromethyl-5-(methylsulfonyl)aniline was used in Step 4, to give the title compound. 0.2 mmol, yellow powder, 16.0 mg, 25%. 1 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.78 (s, 1H), 8.53 (s, 1H), 8.49 (s, 1H), 8.33 (dd, J = 8.6, 5.6 Hz, 1H), 7.73 (dd, J = 9.3, 2.2 Hz, 1H), 7.66 (s, 1H), 7.56 (s, 1H), 7.34 (td, J = 9.4, 2.3 Hz, 1H), 3.32 (s, 3H). 19 19F NMR (471 MHz, DMSO-d6) δ -61.47, -108.20. 13 13C NMR (151 MHz, DMSO-d6) δ 164.42, 162.79, 157.73 (d, J = 14.5 Hz), 150.32, 148.67, 144.06, 142.54, 132.80, 130.09, 124.56 (d, J = 10.5 Hz), 118.40, 118.09, 116.63, 113.50, 111.64 (d, J = 24.4 Hz), 102.26, 100.38 (d, J = 27.2 Hz), 43.30.

[0100] Example 15: Preparation of 7-Fluoro-N-(4-(methylsulfonyl)phenyl)benzofuro[2,3-c]pyridin-3-amine

[0101] The preparation method was the same as that of Example 1, except that 4-(methylsulfonyl)aniline was used in Step 4 to obtain the title compound. Yellow powder, 0.2 mmol, 7.4 mg, 10%. 1 H NMR (500 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.74 (s, 1H), 8.30 (dd, J = 8.5, 5.7 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.7 Hz, 2H), 7.75–7.71 (m, 1H), 7.62 (s, 1H), 7.38–7.30 (m, 1H), 3.13 (s, 3H). 19 F NMR (471 MHz, DMSO-d6) δ -108.36. 13 C NMR (151 MHz, DMSO-d6) δ 184.91, 168.25, 165.10, 163.46, 158.32 (d, J = 10.8 Hz), 156.21, 149.56, 143.12, 130.60 (d, J = 10.9 Hz), 129.90, 129.68, 124.36, 116.92, 106.93 (d, J = 21.7 Hz), 100.57 (d, J = 26.0 Hz), 56.16.

[0102] Example 16: Preparation of 7-Fluoro-N-(3-(methylsulfonyl)phenyl)benzofuro[2,3-c]pyridin-3-amine

[0103] The preparation method was the same as that of Example 1, except that 4-(methylsulfonyl)aniline was used in Step 4 to obtain the title compound. Yellow powder, 0.2 mmol, 28.5 mg, 40%. 1 H NMR (500 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.70 (s, 1H), 8.30–8.25 (m, 2H), 8.00 (dd, J = 8.2, 1.3 Hz, 1H), 7.71 (dd, J = 9.3, 2.2 Hz, 1H), 7.55–7.51 (m, 2H), 7.41–7.36 (m, 1H), 7.32 (td, J = 9.4, 2.2 Hz, 1H), 3.20 (s, 3H). 1313C NMR (151 MHz, DMSO-d6) δ 164.33, 162.70, 157.67 (d, J = 14.5 Hz), 150.99, 148.35, 143.16, 141.27, 132.62, 129.91 (d, J = 25.8 Hz), 124.37 (d, J = 10.7 Hz), 121.41, 118.53, 117.72, 114.63, 111.52 (d, J = 23.9 Hz), 101.51, 100.33 (d, J = 27.2 Hz), 43.71.

[0104] Example 17: Preparation of 7-Fluoro-N-(3-(methylsulfonyl)methyl)phenyl)benzofuro[2,3-c]pyridin-3-amine

[0105] The preparation method was the same as that of Example 1, except that 3-(methylsulfonyl)methyl)aniline was used in Step 4 to obtain the title compound. 0.2 mmol, yellow powder, 33.1 mg, 45%. 1 1H NMR (500 MHz, DMSO-d6) δ 9.20 (s, 1H), 8.63 (s, 1H), 8.22 (dd, J = 8.6, 5.7 Hz, 1H), 7.72–7.65 (m, 2H), 7.61 (s, 1H), 7.53 (s, 1H), 7.35–7.26 (m, 2H), 6.93 (d, J = 7.5 Hz, 1H), 4.45 (s, 2H), 2.95 (s, 3H). 19 19F NMR (471 MHz, DMSO-d6) δ -108.75. 13 13C NMR (126 MHz, DMSO-d6) δ 164.40, 162.44, 157.60 (d, J = 14.4 Hz), 151.65, 148.02, 142.35, 132.44, 129.73 (d, J = 90.9 Hz), 128.85, 124.15 (d, J = 10.8 Hz), 122.77, 119.94, 118.68, 117.64, 111.40 (d, J = 24.0 Hz), 100.37, 100.18, 59.74, 40.11.

[0106] Example 18: Preparation of 4-((7-Fluorobenzofuro[2,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide

[0107] The preparation method was the same as that of Example 1, except that 4-amino-N,N-dimethylbenzenesulfonamide was used in Step 4 to obtain the title compound. White powder, 0.2 mmol, 75.0 mg, yield 97%. 11H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.73 (s, 1H), 8.29 (dd, J = 8.6, 5.7 Hz, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.72 (dd, J = 9.3, 2.2 Hz, 1H), 7.66–7.59 (m, 3H), 7.37–7.33 (m, 1H), 2.58 (s, 6H).

[0108] Example 19: Preparation of 7-Fluoro-N-(5-(piperazine-1-sulfonyl)pyridin-2-yl)benzofuro[2,3-c]pyridin-3-amine

[0109] The preparation method was the same as that of Example 1, except that 5-(piperazine-1-sulfonyl)pyridin-2-amine was used in Step 4 to obtain the title compound. White powder, 0.2 mmol, 22.8 mg, yield 53%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.82 (s, 1H), 8.68–8.57 (m, 4H), 8.31 (dd, J = 8.5, 5.6 Hz, 1H), 7.99 (dd, J = 8.9, 2.4 Hz, 1H), 7.78 (dd, J = 9.2, 1.9 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.37 (td, J = 9.4, 2.0 Hz, 1H), 3.22 (s, 4H), 3.14 (s, 4H).

[0110] Example 20: Preparation of 7-Fluoro-N-(4-(piperidine-1-sulfonyl)phenyl)benzofuro[2,3-c]pyridin-3-amine

[0111] The preparation method was the same as that of Example 1, except that 4-(piperidine-1-sulfonyl)aniline was used in Step 4 to obtain the title compound. 1 1H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.73 (d, J = 5.2 Hz, 1H), 8.33–8.23 (m, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.73 (dd, J = 8.7, 6.4 Hz, 1H), I 7.60 (d, J = 8.7 Hz, 3H), 7.35–7.30 (m, 1H), 2.85 (s, 4H), 1.54 (s, 4H), 1.35 (s, 2H).

[0112] Example 21: Preparation of 7-Fluoro-N-(4-(4-methylpiperazin-1-yl)quinazolin-7-yl)benzofuro[2,3-c]pyridin-3-amine

[0113] The preparation method was the same as that of Example 1, except that 4-(4-methylpiperazin-1-yl)quinazolin-7-amine was used in Step 4 to obtain the title compound. 0.2 mmol, yellow powder, 35.8 mg, 42%. 1 H NMR (500 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 8.33 (d, J = 1.6 Hz, 1H), 8.29 (dd, J = 8.5, 5.6 Hz, 1H), 7.87 (d, J = 9.1 Hz, 1H), 7.73 (dd, J = 9.3, 2.0 Hz, 1H), 7.64 (s, 1H), 7.62 (dd, J = 9.1, 1.6 Hz, 1H), 7.34 (td, J = 9.4, 2.1 Hz, 1H), 3.67 (s, 4H), 2.56 (s, 4H), 2.28 (s, 3H). 19 F NMR (471 MHz, DMSO-d6) δ -108.42. 13 C NMR (151 MHz, DMSO-d6) δ 164.33, 163.31, 162.70, 157.69, 157.60, 153.96, 151.91 (d, J = 369.2 Hz), 148.54, 145.77, 132.52, 130.15, 125.71, 124.34 (d, J = 11.1 Hz), 118.53, 111.56 (d, J = 24.0 Hz), 111.48, 109.90 (d, J = 68.9 Hz), 102.26, 100.35 (d, J = 27.3 Hz), 54.42, 48.98, 45.55.

[0114] Example 22: Preparation of 7-fluoro-N-(6-methoxyquinolin-8-yl)benzofuro[2,3-c]pyridin-3-amine

[0115] The preparation method was the same as that of Example 1, except that 6-methoxyquinolin-8-amine was used in Step 4 to obtain the title compound. 0.2 mmol, yellow powder, 25.2 mg, 35%. 1 H NMR (500 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.79 (s, 1H), 8.75–8.71 (m, 1H), 8.55 (d, J = 2.5 Hz, 1H), 8.23 (dd, J = 13.3, 6.9 Hz, 2H), 8.07 (s, 1H), 7.72 (d, J = 9.3 Hz, 1H), 7.56 (dd, J = 8.2, 4.2 Hz, 1H), 7.34 (t, J = 9.0 Hz, 1H), 6.86 (s, 1H), 3.90 (s, 3H). 1919F NMR (565 MHz, DMSO-d6) δ -108.49. 13 13C NMR (151 MHz, DMSO-d6) δ 164.31, 162.68, 158.28, 157.67 (d, J = 14.1 Hz), 150.63, 148.42, 145.17, 136.73 (d, J = 424.7 Hz), 134.65, 132.60, 129.86, 129.13, 124.16 (d, J = 10.7 Hz), 122.32, 118.66, 111.61 (d, J = 24.1 Hz), 104.17, 102.98, 100.38 (d, J = 27.2 Hz), 95.97, 55.30.

[0116] Example 23: Preparation of 7-Methoxy-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)benzofuro[2,3-c]pyridin-3-amine

[0117]

[0118] Step 1: Synthesis of Intermediate 23a

[0119] The preparation method was the same as that of Intermediate 1a, except that 2,4-dimethoxyphenylboronic acid was used instead of (4-fluoro-2-methoxyphenyl)boronic acid in Step 1 to obtain the title compound. White powder, 1.5 mmol, 364.9 mg, yield: 91%. 1 1H NMR (500 MHz, CDCl3) δ 8.24 (d, J = 1.5 Hz, 1H), 7.35 (d, J = 5.2 Hz, 1H), 7.21 (dd, J = 8.4, 1.1 Hz, 1H), 6.62–6.55 (m, 2H), 3.87 (s, 3H), 3.82 (s, 3H).

[0120] Step 2: Synthesis of Intermediate 23b

[0121] The preparation method was the same as that of Intermediate 1b. White solid, 3 mmol, 723.6 mg, crude product. LCMS m / z (ESI): 240.0 [M+H] + . 1 1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.72 (s, 1H), 8.40 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 5.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 6.34 (dd, J = 8.4, 2.3 Hz, 1H).

[0122] Step 3: Synthesis of Intermediate 23c

[0123] The preparation method is the same as that of Intermediate 1c. White solid, 3 mmol, 329.4 mg, yield 50%. LCMS m / z (ESI): 220.0 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.15 (d, J = 3.3 Hz, 1H), 8.05 (dd, J = 8.5, 1.6 Hz, 1H), 7.08 (s, 1H), 6.95 (dd, J = 8.6, 1.9 Hz, 1H).

[0124] Step 4: Synthesis of Intermediate 23d

[0125] Weigh anhydrous potassium carbonate powder and Intermediate 23c into a 10 mL reaction tube, displace with nitrogen three times, and add ultra-dry N,N-dimethylformamide (2 mL) to dissolve under a nitrogen atmosphere. Stir at room temperature for 19 hours, and TLC detects that the raw materials have completely reacted. Filter with diatomaceous earth, wash with ethyl acetate, concentrate the obtained filtrate under reduced pressure, mix with silica gel, and then separate and purify by column chromatography (petroleum ether: ethyl acetate = 9:1 to 4:1) to obtain Intermediate 23d. White solid, 0.5 mmol, 73.6 mg, yield 63%. 1 HNMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.23 (s, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 7.11 (dd, J = 8.7, 2.2 Hz, 1H), 3.90 (s, 3H).

[0126] Step 5: Synthesis of Final Product 23

[0127] The preparation method is the same as that of Example 1. Using Intermediate 23d and 1-methyl-4-(6-aminopyridin-3-yl)piperazine, according to the general operation of Step 4 in Example 1, the title compound is obtained. Yellow powder, 0.2 mmol, 23.4 mg, yield 30%. 11H NMR (500 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.56 (s, 1H), 8.31 (d, J = 3.8 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.39 (dd, J = 9.0, 2.6 Hz, 1H), 7.30 (d, J = 1.4 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 3.89 (s, 3H), 3.07 (s, 4H), 2.49–2.45 (m, 4H), 2.23 (s, 3H).

[0128] Example 24: Preparation of 3 - ((5 - (4 - methylpiperazin - 1 - yl)pyridin - 2 - yl)amino)benzofuro[2,3 - c]pyridin - 7 - ol

[0129] In the same preparation method as in Example 1, using intermediate 23c and 1 - methyl - 4 - (6 - aminopyridin - 3 - yl)piperazine, according to the general operation of Step 4 in Example 1, the title compound was obtained. Brown powder, 0.2 mmol, 20.7 mg, yield 28%. 1 1H NMR (500 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 7.91 (dd, J = 12.5, 5.5 Hz, 2H), 7.46 (d, J = 9.0 Hz, 1H), 7.37 (dd, J = 9.0, 2.7 Hz, 1H), 7.00 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 3.06 (s, 4H), 2.47 (s, 4H), 2.22 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 160.24, 158.89, 150.33, 148.43, 147.66, 141.11, 134.56, 133.12, 129.61, 127.00, 123.12, 113.84, 112.53, 111.87, 100.10, 98.33, 54.60, 49.06, 45.78.

[0130] Example 25: Preparation of 3 - ((4 - (4 - methylpiperazin - 1 - yl)phenyl)amino)benzofuro[2,3 - c]pyridin - 7 - ol

[0131] In the same preparation method as in Example 1, using intermediate 23c and 4 - (4 - methylpiperazin - 1 - yl)aniline, according to the general operation of Step 4 in Example 1, the title compound was obtained. Yellow solid, 0.2 mmol, 19.4 mg, yield 26%. 11H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.60 (s, 1H), 8.41 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.20 (s, 1H), 6.97 (s, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.4 Hz, 1H), 3.03 (s, 4H), 2.45 (s, 4H), 2.21 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 160.21, 158.83, 152.43, 147.10, 145.49, 134.80, 133.40, 129.12, 123.25, 119.54, 116.40, 113.60, 112.20, 98.18, 98.14, 54.79, 49.17, 45.81.

[0132] Example 26: Preparation of 3-((5-Morpholinopyridin-2-yl)amino)benzofuro[2,3-c]pyridin-7-ol

[0133] Using the same preparation method as in Example 1, with intermediate 23c and 5-morpholinopyridin-2-amine, according to the general procedure of Step 4 in Example 1, the title compound was obtained. Yellow solid, 0.2 mmol, 14.5 mg, yield 20%. 1 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.38 (s, 1H), 8.50 (s, 1H), 8.24 (s, 1H), 7.94 (d, J = 2.9 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 9.0 Hz, 1H), 7.40 (dd, J = 9.1, 3.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 8.5, 2.0 Hz, 1H). 13 13C NMR (151 MHz, DMSO-d6) δ 160.18, 158.82, 150.23, 148.64, 147.60, 141.04, 134.33, 133.05, 129.56, 126.74, 123.06, 113.77, 112.46, 111.82, 100.07, 98.27, 66.12, 49.44.

[0134] Example 27: Preparation of 3-((5-(Piperazin-1-yl)pyridin-2-yl)amino)benzofuro[2,3-c]pyridin-7-ol

[0135] The preparation method was the same as that of Example 1. Using intermediate 23c and 5-(piperazin-1-yl)pyridin-2-amine, according to the general operation of Step 4 in Example 1, the title compound was obtained. 0.2 mmol, 31.2 mg, yield 43%. 1 H NMR(600MHz,DMSO-d6)δ11.28(s,1H),10.71(s,1H),9.07(s,2H),8.65(s,1H),8.05(d,J=8.5Hz,1H),7.90(s,2H),7.82(s,1H),7.39(d,J=9.8Hz,1H),7.07(s,1H),6.95(d,J=8.6Hz,1H),3.35(d,J=4.5Hz,4H),3.30(s,4H).

[0136] Example 28: Preparation of 3-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)benzofuro[2,3-c]pyridin-8-ol

[0137] The preparation method was the same as that of Example 1, except that (2,3-dimethoxyphenyl)boronic acid was used instead of (4-fluoro-2-methoxyphenyl)boronic acid in Step 1, to obtain the title compound. 0.2 mmol, yellow powder, 22.2 mg, 30%. 1 H NMR(500MHz,DMSO-d6)δ10.33(s,1H),9.44(s,1H),8.65(d,J=0.6Hz,1H),8.40(s,1H),7.94(d,J=2.6Hz,1H),7.53(d,J=7.1Hz,1H),7.41(dt,J=9.1,5.9Hz,2H),7.22(t,J=7.8Hz,1H),7.08(d,J=7.8Hz,1H),3.11–3.05(m,4H),2.50(d,J=1.7Hz,4H),2.25(s,3H). 13 C NMR(151MHz,DMSO-d6)δ150.12,148.33,147.31,145.75,143.47,141.02,134.41,133.03,130.68,126.98,124.01,123.83,116.06,112.35,111.81,100.85,54.50,48.94,45.66.

[0138] Example 29: Preparation of 3-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)benzofuro[2,3-c]pyridin-6-ol

[0139] The preparation method was the same as that of Example 1, except that (2,5-dimethoxyphenyl)boronic acid was used instead of (4-fluoro-2-methoxyphenyl)boronic acid in Step 1 to obtain the title compound. 0.18 mmol, yellow powder, 15.4 mg, 20%. 1 H NMR (500 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.39 (s, 1H), 8.58 (d, J = 0.7 Hz, 1H), 8.33 (d, J = 0.6 Hz, 1H), 7.94 (d, J = 2.8 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.46–7.36 (m, 2H), 7.07 (dd, J = 8.9, 2.5 Hz, 1H), 3.11–3.03 (m, 1H), 3.11–3.03 (m, 1H), 2.48 (d, J = 4.8 Hz, 1H), 2.23 (s, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 153.57, 150.76, 149.88, 148.34, 147.99, 141.06, 134.46, 132.73, 130.49, 126.97, 122.76, 118.63, 112.75, 111.77, 106.59, 100.74, 54.57, 49.02, 45.76.

[0140] Example 30: Preparation of 3-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)benzofuro[2,3-c]pyridin-5-ol

[0141] The preparation method was the same as that of Example 1, except that (2,6-dimethoxyphenyl)boronic acid was used instead of (4-fluoro-2-methoxyphenyl)boronic acid in Step 1 to obtain the title compound. 0.2 mmol, yellow powder, 5.8 mg, 8%. 1 H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.37 (s, 1H), 8.54 (d, J = 0.8 Hz, 1H), 8.31 (d, J = 0.8 Hz, 1H), 7.91 (d, J = 2.9 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.40 (dt, J = 9.1, 5.6 Hz, 2H), 7.09 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 3.09–3.05 (m, 4H), 2.48–2.46 (m, 4H), 2.23 (s, 3H). 1313C NMR (151 MHz, DMSO-d6) δ 158.43, 154.89, 150.29, 148.29, 146.71, 141.10, 134.52, 132.15, 130.99, 129.26, 126.76, 111.77, 110.78, 108.78, 102.66, 102.50, 54.58, 49.01, 45.77.

[0142] Example 31: Preparation of N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)benzofuro[2,3-c]pyridin-3-amine

[0143] The preparation method was the same as that of Example 1, except that 2-methoxyphenylboronic acid was used instead of (4-fluoro-2-methoxyphenyl)boronic acid in Step 1 to obtain the title compound. 0.2 mmol, yellow powder, 21.6 mg, 30%. 1 1H NMR (500 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.66 (s, 1H), 8.45 (s, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.95 (d, J = 2.7 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.46–7.38 (m, 3H), 3.11–3.04 (m, 4H), 2.49–2.44 (m, 4H), 2.22 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 156.95, 150.29, 148.26, 147.31, 141.14, 134.39, 132.49, 130.62, 130.22, 126.97, 123.33, 122.53, 122.22, 112.33, 111.87, 100.86, 54.59, 49.03, 45.79.

[0144] Example 32: Preparation of 8-fluoro-3-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)benzofuro[2,3-c]pyridin-7-ol

[0145] The preparation method was the same as that of Example 1, except that 3-fluoro-2,4-dimethoxyphenylboronic acid was used instead of (4-fluoro-2-methoxyphenyl)boronic acid in Step 1 to obtain the title compound. Yellow solid, 0.2 mmol, 13.2 mg, yield 17%. 11H NMR (600 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.60 (s, 1H), 8.30 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.42–7.38 (m, 1H), 7.04 (t, J = 7.9 Hz, 1H), 3.08 (s, 4H), 2.50–2.47 (m, 4H), 2.24 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 150.63, 148.21, 147.99, 147.08, 145.50, 141.14, 137.02 (d, J = 244.0 Hz), 134.41, 132.78, 130.21, 126.94, 117.66, 116.09, 114.05, 111.90, 100.36, 54.53, 48.95, 45.71.

[0146] Example 33: Preparation of N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-7-(trifluoromethyl)benzofuro[2,3-c]pyridin-3-amine

[0147] The preparation method was the same as that of Example 1, except that (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid was used instead of (4-fluoro-2-methoxyphenyl)boronic acid in Step 1 to obtain the title compound. Yellow powder, 0.15 mmol, 29.0 mg, yield 45%. 1 1H NMR (500 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.77 (s, 1H), 8.58 (s, 1H), 8.41 (d, J = 8.1 Hz, 1H), 8.21 (s, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.45–7.37 (m, ²H), 3.09 (d, J = 4.1 Hz, 4H), 2.48 (d, J = 4.5 Hz, 4H), 2.23 (s, 3H). 19 19F NMR (565 MHz, DMSO-d6) δ -60.10. 13 13C NMR (151 MHz, DMSO-d6) δ 156.23, 150.62, 148.07, 141.26, 134.29, 131.35, 131.29, 130.00 (d, J = 32.3 Hz), 126.98, 125.99, 124.95, 123.83, 120.02, 111.99, 110.04, 101.23, 54.58, 48.97, 45.79.

[0148] Example 34: Preparation of 7-Methyl-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)benzofuro[2,3-c]pyridin-3-amine

[0149] The preparation method was the same as that of Example 1, except that (2-methoxy-4-methylphenyl)boronic acid was used instead of (4-fluoro-2-methoxyphenyl)boronic acid in Step 1, to obtain the title compound. Yellow powder, 0.2 mmol, 26.7 mg, yield 36%. 1 HNMR(500MHz,DMSO-d6)δ9.42(s,1H),8.60(s,1H),8.38(s,1H),8.01(d,J=7.9Hz,1H),7.94(d,J=2.6Hz,1H),7.53(s,1H),7.41(dt,J=9.1,5.9Hz,2H),7.26(d,J=7.9Hz,1H),3.09–3.04(m,4H),2.48–2.44(m,4H),2.22(s,3H). 13 C NMR(151MHz,DMSO-d6)δ157.41,150.23,148.29,147.37,141.09,140.72,134.38,132.57,130.33,126.95,124.59,122.02,119.66,112.31,111.81,100.62,54.58,49.03,45.79,21.62.

[0150] Example 35: Preparation of 3-((3-(4-methylpiperazin-1-yl)phenyl)amino)benzofuro[2,3-c]pyridin-7-ol

[0151] The preparation method was the same as that of Example 1, using Intermediate 23c and 3-(4-methylpiperazin-1-yl)aniline, and according to the general operation of Step 4 in Example 1, the title compound was obtained. Yellow powder, 0.2 mmol, 26.2 mg, yield 35%. 1 H NMR(500MHz,CDCl3)δ8.48(s,1H),7.78(d,J=8.6Hz,1H),7.35(d,J=2.5Hz,2H),7.24(t,J=8.1Hz,1H),7.10(dd,J=8.6,2.0Hz,1H),6.88–6.83(m,2H),6.67–6.63(m,2H),5.90(s,1H),3.26–3.22(m,4H),2.59–2.56(m,4H),2.34(s,3H). 13CNMR(126MHz,CDCl3)δ159.10,158.80,152.58,152.01,148.80,142.40,133.78,131.13,130.07,122.92,117.55,113.07,111.50,110.68,107.95,100.04,98.28,55.18,49.05,46.22.

[0152] Example 36: Preparation of 3-((3-Fluoro-5-(methylsulfonyl)phenyl)amino)benzofuro[2,3-c]pyridin-7-ol

[0153] Using the same preparation method as in Example 1, with intermediate 23c and 3-fluoro-5-(methylsulfonyl)aniline, according to the general procedure of Step 4 in Example 1, the title compound was obtained. Yellow powder, 0.2 mmol, 22.3 mg, yield 30%. 1 H NMR(500MHz,DMSO-d6)δ10.34(s,1H),9.80(s,1H),8.61(s,1H),8.16(dt,J=12.2,2.1Hz,1H),8.00(d,J=8.5Hz,1H),7.91(d,J=1.5Hz,1H),7.38(s,1H),7.20–7.14(m,1H),7.02(d,J=2.0Hz,1H),6.89(dd,J=8.5,2.0Hz,1H),3.25(s,3H). 19 F NMR(471MHz,DMSO-d6)δ-109.43. 13 C NMR(126MHz,DMSO-d6)δ161.43,160.68,159.01,150.20,148.11,145.11,142.70,133.77,129.11,123.62,113.17,112.62,111.16,107.02(d,J=27.1Hz),103.81(d,J=25.1Hz),101.14,98.25,43.33.

[0154] Example 37: Preparation of 3-((3-Methoxy-5-(methylsulfonyl)phenyl)amino)benzofuro[2,3-c]pyridin-7-ol

[0155] Using the same preparation method as in Example 1, with intermediate 23c and 3-methoxy-5-(methylsulfonyl)aniline, according to the general procedure of Step 4 in Example 1, the title compound was obtained. Yellow powder, 0.2 mmol, 21.8 mg, yield 28%. 1HNMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.50 (s, 1H), 8.57 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.81–7.73 (m, 2H), 7.36 (s, 1H), 7.01 (d, J = 2.0 Hz, 1H), 6.92–6.90 (m, 1H), 6.88 (dd, J = 8.5, 2.0 Hz, 1H), 3.84 (s, 3H), 3.20 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 160.53, 160.20, 158.94, 150.69, 147.88, 144.37, 142.10, 133.64, 129.07, 123.53, 113.28, 112.50, 107.83, 106.84, 102.32, 100.75, 98.24, 55.56, 43.58.

[0156] Example 38: Preparation of 3 - ((2 - methoxy - 4 - (methylsulfonyl)phenyl)amino)benzofuro[2,3 - c]pyridin - 7 - ol

[0157] Using the same preparation method as in Example 1, with intermediate 23c and 2 - methoxy - 4 - (methylsulfonyl)aniline, according to the general procedure of Step 4 in Example 1, the title compound was obtained. Yellow powder, 0.2 mmol, 19.2 mg, yield 25%. 1 HNMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.62–8.55 (m, 3H), 7.89 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 0.6 Hz, 1H), 7.45 (dd, J = 8.6, 2.0 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.90 (dd, J = 8.5, 2.1 Hz, 1H), 4.00 (s, 3H), 3.17 (s, 3H).

[0158] Example 39: Preparation of 3 - ((3 - (methylsulfonyl)-5 - (trifluoromethyl)phenyl)amino)benzofuro[2,3 - c]pyridin - 7 - ol

[0159] Using the same preparation method as in Example 1, with intermediate 23c and 3 - (trifluoromethyl)-5 - (methylsulfonyl)aniline, according to the general procedure of Step 4 in Example 1, the title compound was obtained. Yellow powder, 0.2 mmol, 30.9 mg, yield 36%. 11H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.94 (s, 1H), 8.64 (s, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.40 (s, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.90 (dd, J = 8.5, 2.0 Hz, 1H), 3.32 (s, 3H). 19 19F NMR (471 MHz, DMSO-d6) δ -61.46. 13 13C NMR (126 MHz, DMSO-d6) δ 160.64, 159.00, 150.06, 148.20, 144.23, 142.50, 133.82, 130.57 (d, J = 31.9 Hz), 129.12, 124.69, 123.63, 122.52, 117.93, 116.48, 113.15, 112.60, 101.26, 98.23, 43.31.

[0160] Example 40: Preparation of 3-((4-(methylsulfonyl)phenyl)amino)benzofuro[2,3-c]pyridin-7-ol

[0161] Using the same preparation method as in Example 1, with intermediate 23c and 4-(methylsulfonyl)aniline, according to the general procedure of Step 4 in Example 1, the title compound was obtained. Yellow powder, 0.2 mmol, 42.2 mg, yield 59%. 1 1H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.66 (s, 1H), 8.59 (s, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.87 (s, 1H), 7.85 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.45 (s, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 8.5, 2.0 Hz, 1H), 3.12 (s, 3H). 13 13C NMR (126 MHz, DMSO-d6) δ 160.53, 158.93, 150.11, 148.15, 147.11, 133.64, 130.17, 129.23, 128.28, 123.49, 115.96, 113.26, 112.57, 101.45, 98.23, 44.22.

[0162] Example 41: Preparation of 3-((3-(methylsulfonyl)phenyl)amino)benzofuro[2,3-c]pyridin-7-ol

[0163] The preparation method was the same as that of Example 1. Using intermediate 23c and 3-(methylsulfonyl)aniline, according to the general operation of Step 4 in Example 1, the title compound was obtained. Yellow powder, 0.2 mmol, 40.2 mg, yield 56%. 1 H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.50 (s, 1H), 8.56 (s, 1H), 8.29 (s, 1H), 7.98 (dd, J = 12.7, 8.4 Hz, 2H), 7.51 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 6.9 Hz, 2H), 7.01 (d, J = 1.4 Hz, 1H), 6.88 (dd, J = 8.5, 1.7 Hz, 1H), 3.19 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 160.51, 158.95, 150.73, 147.89, 143.37, 141.24, 133.66, 129.78, 129.05, 123.47, 121.26, 117.45, 114.44, 113.32, 112.50, 100.62, 98.25, 43.73.

[0164] Example 42: Preparation of 3-((3-((methylsulfonyl)methyl)phenyl)amino)benzofuro[2,3-c]pyridin-7-ol

[0165] The preparation method was the same as that of Example 1. Using intermediate 23c and 3-(methylsulfonyl)methyl)aniline, according to the general operation of Step 4 in Example 1, the title compound was obtained. Yellow powder, 0.2 mmol, 47.3 mg, yield 61%. 1 H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.09 (s, 1H), 8.49 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.61 (s, 1H), 7.38 (s, 1H), 7.27 (t, J = 7.9 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.0 Hz, 1H), 4.44 (s, 2H), 2.95 (s, 3H). 1313C NMR (126 MHz, DMSO-d6) δ 160.36, 158.88, 151.33, 147.56, 142.57, 133.52, 129.32, 129.10, 128.81, 123.30, 122.52, 119.76, 117.48, 113.45, 112.38, 99.61, 98.22, 59.78.

[0166] Example 43: Preparation of 4-((7-Hydroxybenzo[2,3-c]pyridin-3-yl)amino)-N,N-dimethylbenzenesulfonamide

[0167] The preparation method was the same as that of Example 1. Using intermediate 23c and 4-amino-N,N-dimethylbenzenesulfonamide, according to the general operation of Step 4 in Example 1, the title compound was obtained. Yellow powder, 0.2 mmol, 19.7 mg, yield 26%. 1 1H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.64 (s, 1H), 8.58 (s, 1H), 7.97 (t, J = 6.7 Hz, 1H), 7.87 (d, J = 8.9 Hz, 2H), 7.61 (d, J = 8.9 Hz, 2H), 7.45 (s, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 8.5, 2.0 Hz, 1H), 2.57 (s, 6H). 13 13C NMR (151 MHz, DMSO-d6) δ 160.56, 158.95, 150.19, 148.12, 146.72, 133.66, 129.19, 128.96, 123.69, 123.50, 115.94, 113.27, 112.59, 101.40, 98.25, 37.72.

[0168] Example 44: Preparation of 3-((4-(Piperazine-1-ylsulfonyl)phenyl)amino)benzofuro[2,3-c]pyridin-7-ol

[0169] The preparation method was the same as that of Example 1. Using intermediate 23c and 4-(piperazine-1-ylsulfonyl)aniline, according to the general operation of Step 4 in Example 1, the title compound was obtained. Yellow powder, 0.2 mmol, 14.8 mg, yield 17%. 11H NMR (600 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.58 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.45 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.05 (s, 1H), 2.75 (d, J = 3.3 Hz, 4H), 2.71 (d, J = 4.1 Hz, 4H). 13 13C NMR (151 MHz, DMSO-d6) δ 160.56, 158.95, 153.17, 150.17, 148.13, 146.79, 133.66, 129.60, 129.20, 129.00, 123.50, 115.92, 112.66, 101.42, 98.25, 46.79, 46.73, 44.69.

[0170] Example 45: Preparation of 3-((4-(piperidine-1-ylsulfonyl)phenyl)amino)benzofuro[2,3-c]pyridin-7-ol

[0171] Using the same preparation method as in Example 1, with intermediate 23c and 4-(piperidine-1-ylsulfonyl)aniline, according to the general procedure of Step 4 in Example 1, the title compound was obtained. Yellow powder, 0.2 mmol, 14.6 mg, yield 17%. 1 1H NMR (600 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.63 (s, 1H), 8.58 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.44 (s, 1H), 7.02 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 2.85 (s, 4H), 1.54 (s, 4H), 1.35 (s, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 160.54, 158.94, 150.19, 148.11, 146.65, 133.64, 129.18, 128.81, 124.53, 123.50, 115.92, 113.27, 112.57, 101.38, 98.24, 46.64, 24.70, 22.96.

[0172] Example 46: Preparation of 7-Fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)benzo[4,5]thieno[2,3-c]pyridin-3-amine

[0173]

[0174] Step 1: Synthesis of Intermediate 46a

[0175] According to the general procedure of Step 1 in Example 1, 4-fluorobenzeneboronic acid and 6-chloro-4-iodopyridin-3-amine were used to obtain the title compound. White powder, 5 mmol, 954.6 mg, yield 80%. LCMS m / z (ESI): 223.1 [M+H] + .

[0176] Step 2: Synthesis of Intermediate 46b

[0177] Weigh Intermediate 46a (954.6 mg, 4 mmol) and dissolve it in tetrahydrofuran (12 mL). Add dropwise 4M hydrochloric acid aqueous solution (9.6 mL), and the temperature of the reaction solution drops to 0 °C. Weigh sodium nitrite (414.0 mg, 6 mmol) and dissolve it in 0.8 mL of water. Add it dropwise to the reaction solution and stir at 0 °C for 20 minutes. Weigh potassium iodide (1593.6 mg, 9.6 mmol) and dissolve it in 0.8 mL of water. Add it dropwise to the reaction solution and continue the reaction in an ice bath for 10 minutes, then gradually raise the temperature to room temperature. After 3 hours, TLC detected that the raw materials had completely reacted. Add saturated aqueous solution of sodium thiosulfate under stirring until the reaction solution turned light yellow and there was no further color change. Extract the aqueous phase with ethyl acetate (100 mL * 3), combine the organic phases, wash with saturated sodium chloride aqueous solution (200 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, mix with silica gel and separate and purify by column chromatography (petroleum ether: ethyl acetate = 9:1 - 4:1) to obtain 46b (white solid, 922.4 mg, yield 69%), LCMS m / z (ESI): 334.2 [M+H] + . 1 1H NMR (500 MHz, CDCl3) δ 8.80 (s, 1H), 7.36–7.31 (m, 2H), 7.29 (s, 1H), 7.20–7.14 (m, 2H).

[0178] Step 3: Synthesis of Intermediate 46c

[0179] Weigh the intermediate 46b (922.4 mg, 2.7 mmol), dissolve it in 6 mL of dichloromethane. Under ice-bath conditions, successively add m-chloroperbenzoic acid (698.9 mg, 4.05 mmol) and trifluoromethanesulfonic acid (1215.6 mg, 8.1 mmol). Transfer to room temperature and react overnight. TLC detection shows that the raw materials have completely reacted. After removing the solvent using a rotary evaporator, add diethyl ether (5 mL), stir at room temperature for 20 minutes, then filter to remove the diethyl ether, obtaining 1546.4 mg of a white powder.

[0180] Step 4: Synthesis of intermediate 46d

[0181] Weigh successively compound 46c (967.2 mg, 2 mmol), cesium carbonate (2606.6 mg, 8 mmol), and sulfur powder (256.6 mg, 8 mmol) into a reaction flask, displace with nitrogen three times, and under a nitrogen atmosphere, add ultra-dry dimethyl sulfoxide (10 mL) to dissolve. Place it in an oil bath at 100 °C and stir for 3 h. TLC detection shows that the raw materials have completely reacted. After cooling to room temperature, add water (100 mL) to the reaction solution, extract the aqueous phase with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated sodium chloride aqueous solution (200 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, mix with silica gel, and then separate and purify by column chromatography (petroleum ether: ethyl acetate = 9:1 - 4:1) to obtain 46d (white solid, 179.2 mg, yield 38%). LCMS m / z (ESI): 238.1 [M+H] + 。 1 H NMR (500 MHz, CDCl3) δ 8.84 (d, J = 0.6 Hz, 1H), 8.12 (dd, J = 8.8, 5.1 Hz, 1H), 7.93 (d, J = 0.6 Hz, 1H), 7.57 (dd, J = 8.4, 2.3 Hz, 1H), 7.26 (td, J = 8.6, 2.3 Hz, 1H).

[0182] Step 5: Synthesis of the final product 46

[0183] Using the same preparation method as in Example 1, using intermediate 46d and 1-methyl-4-(6-aminopyridin-3-yl)piperazine, according to the general operation in Step 4 of Example 1, the title compound is obtained. Brown powder, 0.2 mmol, 20.2 mg, yield 26%. 11H NMR (500 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.84 (s, 1H), 8.63 (s, 1H), 8.32–8.26 (m, 1H), 7.99 (dd, J = 11.4, 2.3 Hz, 2H), 7.46–7.38 (m, 3H), 3.11–3.07 (m, 4H), 2.49–2.46 (m, 4H). 19 19F NMR (565 MHz, DMSO-d6) δ -110.97. 13 13C NMR (151 MHz, DMSO) δ 163.33, 161.70, 151.99, 148.00, 143.04 (d, J = 10.8 Hz), 142.49 (d, J = 19.0 Hz), 141.28, 134.45, 130.21, 126.89, 125.89, 124.66 (d, J = 10.0 Hz), 113.44 (d, J = 24.2 Hz), 112.23, 110.14 (d, J = 26.0 Hz), 101.45, 54.57, 48.94, 45.78.

[0184] Example 47: Preparation of 7-Fluoro-N-(3-((methylsulfonyl)methyl)phenyl)benzo[4,5]thieno[2,3-c]pyridin-3-amine

[0185] Prepared in the same manner as in Example 1, using Intermediate 46d and 3-((methylsulfonyl)methyl)aniline, and according to the general procedure of Step 4 in Example 1, the title compound was obtained. Yellow powder, 0.3 mmol, 6.5 mg, yield 6%. 1 1H NMR (500 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.84 (s, 1H), 8.33 (dd, J = 8.2, 4.9 Hz, 1H), 7.99 (d, J = 9.5 Hz, 1H), 7.66 (dd, J = 19.1, 10.5 Hz, 3H), 7.40 (t, J = 8.8 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 6.95 (d, J = 7.4 Hz, 1H), 4.46 (s, 2H), 2.96 (s, 3H).

[0186] Example 48: Preparation of 7-Fluoro-N-(3-methyl-5-(methylsulfonyl)phenyl)benzo[4,5]thieno[2,3-c]pyridin-3-amine

[0187] Prepared in the same manner as in Example 1, using Intermediate 46d and 3-methyl-5-(methylsulfonyl)aniline, and according to the general procedure of Step 4 in Example 1, the title compound was obtained. Yellow powder, 0.2 mmol, 7.0 mg, yield 9%.1 1H NMR (500 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.91 (s, 1H), 8.36 (dd, J = 8.7, 5.3 Hz, 1H), 8.10 (s, 1H), 8.03–7.97 (m, 1H), 7.80 (s, 1H), 7.65 (s, 1H), 7.43–7.38 (m, 1H), 7.24 (s, 1H), 3.18 (s, 3H), 2.40 (s, 3H). 19 19F NMR (471 MHz, DMSO-d6) δ -110.48. 13 13C NMR (126 MHz, DMSO-d6) δ 163.65, 161.69, 152.57, 143.16 (d, J = 11.1 Hz), 142.85, 142.30, 141.23, 139.58, 129.82, 126.45, 125.08, 122.14, 118.48, 113.49 (d, J = 24.0 Hz), 112.49, 110.13 (d, J = 26.0 Hz), 102.09, 43.71, 21.25.

[0188] Example 49: Preparation of 7-Fluoro-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-9H-pyrrolo[2,3-b]indol-3-amine

[0189]

[0190] Step 1: Synthesis of Intermediate 49a

[0191] According to the general procedure of Step 1 in Example 1, 2-chloro-4-fluorobenzeneboronic acid and 6-chloro-4-iodopyridin-3-amine were used to obtain the title compound. Yellow solid, 5 mmol, 876.3 mg, yield 45%. 1 1H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.28 (td, J = 8.3, 2.1 Hz, 2H), 7.12 (td, J = 8.3, 2.4 Hz, 1H), 7.00 (s, 1H), 3.63 (s, 2H).

[0192] Step 2: Synthesis of Intermediate 49b

[0193] Weigh compound 49a (771.3 mg, 3 mmol) and potassium tert-butoxide (1698.3 mg, 15 mmol) into a reaction flask in sequence. Replace the air with nitrogen three times, and add ultradry DMSO (10 mL) to dissolve them under a nitrogen atmosphere. Place it in an oil bath at 130 °C and stir for 4 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Add water (30 mL) to the reaction solution, continue to stir for 30 minutes, then filter out the solid, wash it with water and dry it to obtain intermediate 49b (yellow solid, 139.0 mg, yield 21%). LCMS m / z (ESI): 221.1 [M+H] + 。

[0194] Step 3: Synthesis of the final product 49

[0195] Using the same preparation method as in Example 1, with intermediate 49b and 1-methyl-4-(6-aminopyridin-3-yl)piperazine, according to the general operation in Step 4 of Example 1, the title compound was obtained. Yellow powder, 0.6 mmol, 27.6 mg, yield 13%. 1 H NMR (500 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.11 (dd, J = 8.6, 5.6 Hz, 1H), 7.91 (s, 1H), 7.37 (s, 2H), 7.26 (dd, J = 10.1, 2.2 Hz, 1H), 6.99 (td, J = 9.6, 2.3 Hz, 1H), 3.08–3.03 (m, 4H), 2.49–2.44 (m, 4H), 2.23 (s, 3H).

[0196] Example 50: Preparation of 7-methoxy-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-9H-pyrrolo[2,3-b]indol-3-amine

[0197] Using the same preparation method as in Example 49, except that 2-chloro-4-methoxyphenylboronic acid was used instead of 2-chloro-4-fluorophenylboronic acid in Step 1, the title compound was obtained. Yellow powder, 0.6 mmol, 18.3 mg, yield 8%. 1 H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.03 (s, 1H), 8.42 (s, 1H), 8.29 (s, 1H), 7.91 (dd, J = 18.4, 5.7 Hz, 2H), 7.37 (dt, J = 9.1, 6.0 Hz, 2H), 6.95 (d, J = 2.0 Hz, 1H), 6.77 (dd, J = 8.6, 2.1 Hz, 1H), 3.85 (s, 3H), 3.09–3.00 (m, 4H), 2.49–2.44 (m, 4H), 2.23 (s, 3H).

[0198] Test Example 1: Anti-tumor Activity Test at the Cellular Level

[0199] Cells in the logarithmic growth phase were incubated overnight in a 96-well plate (15,000 - 20,000 cells / well), different concentrations of the compound were added, and then the plate was placed in an incubator at 37°C with 5% CO2 and cultured for another 72 hours. Then, CCK8 detection reagent was added and cultured at 37°C for 2 - 4 hours. After that, the OD values were measured at 450 and 650 nm. The formula for calculating the cell survival rate (V%) per well is: V(%) = (As - Ac) / (Ab - Ac) × 100. (A: OD 450 - OD 650 , s: sample, b: blank, c: control). The anti-proliferative IC of the compound was calculated using GraphPad Prism 9.5 software 50 .

[0200] Table 1. Anti-proliferative Activity of the Compound against Leukemia Cell Lines

[0201]

[0202]

[0203] a NT: Not tested.

[0204] Table 2. Anti-proliferative Activity of the Compound against Multiple Tumor Cell Lines

[0205]

[0206]

[0207] a NT: Not tested.

[0208] Tables 1 and 2 show that such compounds exhibit significant in vitro anti-proliferative activity against multiple tumor cell lines, including hematological cancers such as leukemia and breast cancer, cervical cancer, colorectal cancer, liver cancer, ovarian cancer, pancreatic cancer, kidney cancer, gastric cancer, non-small cell lung cancer, lung cancer, oral cancer, prostate cancer, bladder cancer, skin cancer, fallopian tube tumors, melanoma, glioma, and myeloma. In addition, we used the MV4-11 cell line resistant to Venetoxlax (MV4-11-VR) and found that such compounds can overcome the resistance of Venetoxlax and have excellent anti-tumor activity against MV4-11-VR cells.

[0209] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the purpose and scope of the present technical solution, and they should all be covered within the scope of the claims of the present invention.

Claims

1. A tricyclic heterocyclic derivative, characterized in that, The structure of the tricyclic heterocyclic derivatives is shown in General Formula I: In the formula: X is selected from: NH, O or S; Y is CH or N; (R1) m The hydrogen on the pyridine ring is substituted by m R1s, n is 0, 1, 2 or 3; each R1 is independently selected from: deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, sulfonamide, alkylamino, dialkylamino, acetylamino, cyclic amine, heterocyclic group, -C1-C8 alkyl, -C 1-8 alkoxy, -S(O)2C 1-8 alkyl, -S(O)2NHC 1-8 alkyl, -S(O)C 1-8 alkyl, -C(O)OC 1-8 alkyl or -C(O)NHC 1-8 alkyl; wherein the group is unsubstituted or optionally substituted by one, two or more substituents, and the substituents are independently selected from deuterium, halogen, hydroxyl, mercapto, amino, nitro, cyano, carboxyl, sulfonamide, alkylamino, dialkylamino, acetylamino, cyclic amine, -C1-C3 alkyl, halo-C1-C3 alkyl, heterocyclic group, -C1-C3 alkoxy, -C1-C3 fluoroalkoxy, -C(O)OC 1-3 alkyl, -S(O)2C 1-3 alkyl, -S(O)2NHC 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)OC 1-3 alkyl or -C(O)NHC 1-3 alkyl.

2. The tricyclic heterocyclic derivative according to claim 1, wherein R2 is independently selected from one of the following structures a), b), c) or d): a) an aryl or heteroaryl group, which is unsubstituted or optionally substituted with one, two or more substituents, each substituent independently selected from deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, carboxy, sulfonamido, alkylamino, dialkylamino, acetylamino, cyclic amine, heterocyclic group, -C1-C8 alkyl, -C 1-8 alkoxy, -C(O)R a -, -C(O)NHR a -, -C(O)NHR a -, -C(S)NHR a -, -C(S)NHR a -, -S(O)R a -, -S(O)2R a -, -S(O)2NHR a -, -C(O)OR a or -CH2R a , wherein R a is selected from deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, sulfonyl, sulfonamido, alkylamino, dialkylamino, acetylamino, cyclic amine, heterocyclic group, -C1-C8 alkyl, -C 1-8 alkoxy, -C3-C8 cycloalkyl or -C4-C8 heterocyclic group; b) fused 3- to 7-membered saturated or partially unsaturated monocyclic heterocycles, or fused 3- to 7-membered saturated or partially unsaturated monocycles; said fused 3- to 7-membered saturated or partially unsaturated monocyclic heterocycles or fused 3- to 7-membered saturated or partially unsaturated monocycles are unsubstituted or substituted with one, two or more substituents, said substituents being independently selected from deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, carboxy, sulfonamido, alkylamino, dialkylamino, acetylamino, cyclic amine, heterocyclic group, -C1-C8 alkyl, -C 1-8 alkoxy, -S(O)2C 1-8 alkyl, -S(O)2NHC 1-8 alkyl, -S(O)C 1-8 alkyl, -C(O)OC 1-8 alkyl or -C(O)NHC 1-8 alkyl; c) a heterocyclic group, which is unsubstituted or optionally substituted by one, two or more substituents, each of said substituents being independently selected from deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, carboxy, sulfonamido, alkylamino, dialkylamino, acetylamino, cyclic amine, heterocyclic group, -C1-C8 alkyl, -C 1-8 alkoxy, -S(O)2C 1-8 alkyl, -S(O)2NHC 1-8 alkyl, -S(O)C 1-8 alkyl, -C(O)OC 1-8 alkyl or -C(O)NHC 1-8 alkyl; d)-C3-C8 cycloalkyl, -C5-C8 cycloalkenyl, -C7-C 10 fused cycloalkyl, -C7-C 10 bridged cycloalkyl, -C7-C 10 spirocycloalkyl, -C4-C8 heterocyclic group, -C5-C8 heteroalkenyl, -C7-C 10 fused heterocycloalkyl, -C7-C 10 bridged heterocycloalkyl or -C7-C 10 spiroheterocycloalkyl, which is unsubstituted or optionally substituted with one, two or more substituents, each substituent independently selected from deuterium, halogen, hydroxy, mercapto, amino, nitro, cyano, carboxy, sulfonamido, alkylamino, dialkylamino, acetylamino, cyclic amine, heterocyclic group, C1-C8 alkyl, C 1-8 alkoxy, S(O)2C 1-8 alkyl, S(O)2NHC 1-8 alkyl, S(O)C 1-8 alkyl, C(O)OC 1-8 alkyl or C(O)NHC 1-8 alkyl.

3. The tricyclic heterocyclic derivative according to claim 1, characterized in that, The structure of the tricyclic heterocyclic derivatives is shown as follows:

4. A pharmaceutical composition comprising a pharmaceutically acceptable salt, solvate, isotope derivative or prodrug of the tricyclic heterocyclic derivative according to any one of claims 1 to 3.

5. The pharmaceutically acceptable salt, solvate, isotope derivative or prodrug of the tricyclic heterocyclic derivative according to claim 4, characterized in that, The pharmaceutically acceptable salt is formed by reacting the tricyclic heterocyclic derivative with an acid; the acid includes inorganic acids and organic acids; the acid is hydrochloric acid, nitric acid, acetic acid, hydrobromic acid, sulfuric acid, phosphoric acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, lactic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid or benzoic acid.

6. The pharmaceutically acceptable salt, solvate, isotope derivative or prodrug of the tricyclic heterocyclic derivative according to claim 4, characterized in that, The active ingredient of the pharmaceutical composition is a single compound containing General Formula I, a mixture of several compounds, or a combination of at least one compound of General Formula I and at least one other active ingredient; the weight percentage content of the active component in the pharmaceutical composition is 0.01 - 99.99%; The pharmaceutical composition is a preparation; the preparation is an injection, tablet, powder, granule, capsule, oral liquid, ointment or cream.

7. The pharmaceutically acceptable salt, solvate, isotope derivative or prodrug of the tricyclic heterocyclic derivative according to claim 6, characterized in that, The pharmaceutical composition further comprises a carrier; the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, glidants, preservatives, taste masking agents or solubilizing agents in the pharmaceutical field.

8. A method for preparing a tricyclic heterocyclic derivative according to any one of claims 1 to 3, characterized in that, Selected from one of the following three schemes: 1) Scheme One The first step: Under high-temperature alkaline conditions and in the presence of a catalyst, boric acid or a pinacol borate compound is subjected to a Suzuki reaction to obtain Compound Ia, and the alkaline reagent is selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium acetate or sodium tert-butoxide; the catalyst is selected from palladium acetate, tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride; the temperature is 60 - 100 °C; The second step: In a dichloromethane solution of Compound Ia, the methyl group is removed with a boron tribromide solution, the reaction temperature is 0 - 25 °C, and the reaction time is 4 - 24 hours; ​ Step 4: Under high-temperature alkaline conditions and in the presence of a catalyst and a ligand, react compound Ic with the corresponding amine to obtain the tricyclic heterocyclic derivative shown in general formula I; the temperature is 80 - 140 °C, the basic reagent is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, potassium acetate or sodium tert-butoxide; the catalyst is selected from bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium or [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex, and the ligand is selected from 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) or 2-bis(cyclohexylphosphino)-2',4',6'-triisopropylbiphenyl; 2) Scheme 2 Step 1: Under high-temperature alkaline conditions and in the presence of a catalyst, react the corresponding boric acid or bis(pinacolato)diboron compound through a Suzuki reaction to obtain compound IIa; the alkaline conditions are selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium acetate or sodium tert-butoxide; the catalyst is selected from palladium acetate, tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride; the temperature is 60 - 100 °C; Step 2: Under acidic and sodium nitrite conditions, IIa undergoes a diazotization reaction to obtain a diazonium salt, and then undergoes a halogenation reaction to obtain intermediate IIb; the acid is selected from hydrochloric acid, nitric acid, sulfuric acid or phosphoric acid, and the halogenating reagent is selected from potassium iodide or sodium iodide; Step 3: Under m-chloroperbenzoic acid and trifluoromethanesulfonic acid conditions, IIb forms the corresponding salt IIc; Step 4: Under high-temperature alkaline conditions, obtain IId; the alkaline conditions are selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide or n-butyllithium; the solvent is selected from N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; the temperature is 80 - 140 °C; Step 5: Under high-temperature alkaline conditions and in the presence of a catalyst and a ligand, react compound IId with the corresponding amine to obtain the tricyclic heterocyclic derivative shown in general formula I; the temperature is 80 - 140 °C; the alkaline conditions are preferably potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, potassium acetate or sodium tert-butoxide, the catalyst is preferably bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium or [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex, and the ligand is preferably 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) or 2-bis(cyclohexylphosphino)-2',4',6'-triisopropylbiphenyl; 3) Scheme 3 Step 1: Under high-temperature alkaline conditions and in the presence of a catalyst, react the corresponding boric acid or bis(pinacolato)diboron compound through a Suzuki reaction to obtain compound IIIa; the alkaline conditions are selected from potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium acetate or sodium tert-butoxide; the catalyst is selected from palladium acetate, tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride, and the temperature is 60 - 100 °C; Step 2: Under high-temperature and alkaline conditions, intermediate IIIa undergoes an intramolecular nucleophilic substitution reaction to obtain intermediate IIIb; the alkaline conditions are selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium tert-butoxide or n-butyllithium, and the solvent is preferably N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; the temperature is 80-140°C; Step 3: Under high-temperature and alkaline conditions, in the presence of a catalyst and a ligand, compound IIIb is reacted with the corresponding amine to obtain the tricyclic heterocyclic derivative represented by the general formula I, and the temperature is 80-140°C; the alkaline conditions are selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, potassium acetate or sodium tert-butoxide; the catalyst is selected from bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium or [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex, and the ligand is selected from 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) or 2-bis(cyclohexylphosphino)-2',4',6'-triisopropylbiphenyl.

9. Use of a pharmaceutical composition of the tricyclic heterocyclic derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, solvate, isotope derivative or prodrug of the tricyclic heterocyclic derivative according to any one of claims 3 to 6 in the preparation of an anti-tumor drug for prevention and / or treatment.

10. The application according to claim 9, wherein The tumors include hematological cancers such as acute myeloid leukemia, multiple myeloma, chronic lymphocytic leukemia, follicular lymphoma, and breast cancer, cervical cancer, colorectal cancer, liver cancer, ovarian cancer, pancreatic cancer, kidney cancer, gastric cancer, non-small cell lung cancer, lung cancer, oral cancer, prostate cancer, bladder cancer, skin cancer, fallopian tube tumor, melanoma, glioma or myeloma.

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