WO2025113152A1 - P-glycoprotein inhibitor, preparation method therefor, and use thereof - Google Patents

Abstract

Disclosed in the present invention are a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, a preparation method therefor, and a use thereof. The compounds have significant inhibitory activity on drug-resistant tumor cells having high expression of P-glycoprotein, and have a relatively strong effect of reversing multidrug resistance of tumor cells, and some of the compounds have significantly superior inhibitory activity on P-glycoprotein than Tariquidar, a third-generation P-glycoprotein inhibitor, and have relatively small cytotoxicity. In addition, the compounds can selectively inhibit P-glycoprotein on intestinal epithelial cells, and when orally administered in combination with an anticancer agent that is not easily absorbed in the digestive tract due to the inhibitory effect of intestinal P-glycoprotein, the compounds can improve the bioavailability of the anticancer agent.

Description

A P-glycoprotein inhibitor and its preparation method and application Technical Field

The present invention relates to the field of pharmaceutical chemistry, and in particular to an N-substituted-1,2,3,4-tetrahydrobenzofuran[2,3-C]pyridine P-glycoprotein inhibitor, and a preparation method and application thereof.

Background Art

Multidrug resistance (MDR) refers to a mechanism in which tumor cells, after becoming resistant to one anticancer drug, also develop cross-resistance to other anticancer drugs with different structures and mechanisms of action.

The occurrence of multidrug resistance is a major reason for the failure of current tumor chemotherapy, and it is also the most common and difficult problem in tumor treatment.

Therefore, finding drugs that reverse MDR to inhibit the development of multidrug resistance has become an urgent problem to be solved in tumor treatment.

The mechanism of multidrug resistance in tumors is diverse, involving complex molecular biological foundations that have not yet been fully resolved. However, the overexpression of the transmembrane protein (P-glycoprotein, P-gp) in tumor cells is considered to be the main cause of multidrug resistance. Overexpressed P-glycoprotein uses the energy released by ATP hydrolysis to pump anticancer agents (such as vinca alkaloids, anthracyclines, paclitaxel, doxorubicin, etc.) that enter tumor cells out of the cells, causing the concentration of anticancer drugs in the cells to be lower than the effective concentration, making tumor cells tolerant to a variety of chemotherapy drugs, thereby producing MDR. Therefore, the combined administration of P-glycoprotein inhibitors and anticancer agents is expected to solve the problem of multidrug resistance in tumors.

Since the discovery of the first multidrug resistance reversal agent, verapamil, the research on multidrug resistance reversal agents has gone through three generations.

The first generation is represented by Verapamil and Cyclosporine A, which have significant cardiovascular and other side effects. The second generation of inhibitors has enhanced activity, such as Valspodar and Biricodard, but this type of inhibitor significantly affects the plasma pharmacokinetics of anticancer drugs used in combination with them, limiting their clinical application. The third generation of inhibitors are compounds designed and developed based on structure-activity relationship studies. This type of compound inhibitor has good activity and selectivity, such as Elacridar, Tariquidar, and WK-X-34.

However, due to the emergence of various side effects, there is still no effective reversal agent used in clinical treatment.

In addition to cancer cells, P-glycoprotein is also found in many normal human tissues including the liver, small intestine, kidney and blood-brain endothelium. In all these tissues, P-glycoprotein is localized to the cell secretory region. This localization suggests that P-glycoprotein plays a role in limiting the absorption of exogenous toxic substances through biological barriers, such as anticancer agents such as paclitaxel, which are absorbed by the body due to their physical and chemical properties. Due to the properties of intestinal epithelial cells and the excretion of P-glycoprotein, these drugs are usually administered intravenously in clinical practice.

Therefore, a new generation of safe and effective P-glycoprotein inhibitors is urgently needed in clinical practice to solve problems such as tumor multidrug resistance and improve the bioavailability of anticancer agents.

In view of the above problems, the present invention develops a class of P-glycoprotein inhibitors with novel structures and potent P-glycoprotein inhibitory activity.

Summary of the invention

The present invention provides compounds represented by formula (I) or (II) or pharmaceutically acceptable salts thereof having P-glycoprotein inhibitory activity, none of which exhibits obvious cytotoxic effects, and some compounds or pharmaceutically acceptable salts thereof have P-glycoprotein inhibitory activities significantly superior to those of the third-generation P-glycoprotein inhibitor taliciquidat. The compounds represented by formula (I) or (II) or pharmaceutically acceptable salts thereof have potential effects in preventing and treating the occurrence of multidrug resistance in tumors, can improve the oral bioavailability of anticancer agents, and have potential anti-tumor value.

The compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof:

R ¹ , R ² , R ³ , R ⁴ , R ⁶ , and R ⁷ are the same or different and are independently selected from H, halogen, C ₁ ～C ₅ alkyl or C ₁ ～C ₅ alkoxy;

R ⁵ and R ⁸ are the same or different and are independently selected from substituted or unsubstituted phenyl, pyridyl, pyrazinyl, quinolyl, isoquinolyl, chromonyl, quinolone or quinoxalinyl; the substituents on the phenyl, pyridyl, pyrazinyl, quinolyl, isoquinolyl, chromonyl, quinolone or quinoxalinyl are independently selected from cyano or halogen;

m is selected from 0 to 4;

X is selected from -NHC(=O)- or -NHS(=O) ₂ -;

L is selected from n is independently selected from 0 to 4.

The pharmaceutically acceptable salts of the present invention may include addition salts formed with the following acids: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid, succinic acid and salts formed with similar known acceptable acids.

Furthermore, in the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof, one end of the benzene ring in L is connected to an amide bond.

Furthermore, the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof is selected from any one of the following:

N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine, which can be referred to as compound 10a;

N-(4-((6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine, which can be referred to as compound 10b;

N-(4-(2-(7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine, which can be referred to as compound 10c;

N-(4-((7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine, which can be referred to as compound 10d;

N-(4-(2-(3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine, which can be referred to as compound 10e;

N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-4-yl)quinazolin-4-amine, which can be referred to as compound 10f;

N-(4-((6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)-2-(pyridin-4-yl)quinazolin-4-amine, which can be referred to as compound 10g;

N-(4-(2-(7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-4-yl)quinazolin-4-amine, which can be referred to as compound 10h;

N-(4-((7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)-2-(pyridin-4-yl)quinazolin-4-amine, which can be referred to as compound 10i;

N-(4-(2-(3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-4-yl)quinazolin-4-amine, which can be referred to as compound 10j;

N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide, which can be referred to as compound 13a;

N-(2-((4-((6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide, which can be referred to as compound 13b;

N-(2-((4-(2-(7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide, which can be referred to as compound 13c;

N-(2-((4-((7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide, which can be referred to as compound 13d;

N-(2-((4-(2-(3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide, which can be referred to as compound 13e;

2-(3-cyanobenzamido)-N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-4,5-dimethoxybenzamide, which can be referred to as compound 13f;

N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)nicotinamide, which can be referred to as compound 13g;

N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(3-fluorobenzamido)-4,5-dimethoxybenzamide, which can be referred to as compound 13h;

N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-4,5-dimethoxy-2-(pyridine-3-sulfonyl)benzamide, which can be referred to as compound 13i;

N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-2-carboxamide, which can be referred to as compound 13j;

N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)-2-oxoethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide, which can be referred to as compound 13k;

N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-difluorophenyl)quinoline-3-carboxamide, which can be referred to as compound 131;

N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)phenyl)quinoline-3-carboxamide, which can be referred to as compound 13m;

N-(2-((4-(3-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)-3-oxopropyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide, which can be referred to as compound 13n;

(E)-N-(2-((4-(3-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)-3-oxoprop-1-en-1-yl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide, which can be referred to as compound 13o;

(E)-N-(2-((4-(3-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)-3-oxoprop-1-en-1-yl) phenyl)carbamoyl)phenyl)quinoline-3-carboxamide, which can be referred to as compound 13p;

N-(4-(4,5-dimethoxy-2-(quinoline-3-carboxamido)benzamido)phenyl)-6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridine-2(1H)-carboxamide can be referred to as compound 13q.

The chemical structures of the specific compounds listed above are:

The present invention also provides a method for preparing the compound represented by formula (I) or (II), and the synthetic route is:

Compound 10 is a compound represented by formula (I), wherein Y is

Compound 13 is a compound represented by formula (II), wherein Y is -NH-Z is -XR ⁸ ;

Compound 1 undergoes ortho-Friedel-Crafts acylation under acetic acid/boron trifluoride ether conditions to obtain compound 2, compound 2 reacts with ethyl bromoacetate in the presence of cesium carbonate as a base to generate compound 3, compound 3 undergoes hydrolysis reaction to obtain compound 4, compound 4 undergoes cyclization reaction to obtain compound 5, compound 5 undergoes multi-component reaction with benzylamine and formaldehyde aqueous solution in acetic acid solvent to obtain compound 6, compound 6 is debenzylated to obtain compound 7, compound 7 undergoes nucleophilic substitution reaction with a halide or undergoes amide condensation reaction to obtain compound 8, compound 8 undergoes nitro reduction reaction to obtain compound 9; compound 9 undergoes nucleophilic substitution reaction with compound 14 to obtain compound 10; or, compound 9 undergoes amide condensation reaction with compound 15 to obtain compound 11, compound 11 undergoes nitro reduction reaction to obtain compound 12, and compound 12 undergoes amide condensation reaction or sulfonamide condensation reaction to obtain compound 13.

The present invention also provides the use of the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof in the preparation of a P-glycoprotein inhibitor. The P-glycoprotein inhibitor may be an oral preparation.

The compound represented by formula (I) or (II) or its pharmaceutically acceptable salt can improve or increase the efficacy of anticancer agents, increase the sensitivity of tumors to anticancer agents, and reduce the MDR of tumors to anticancer agents. Specifically, it can enhance the efficacy of chemotherapy drugs. The goal is to improve the efficacy of cancer treatment by reducing the cytotoxicity of a drug or by increasing the net absorption, distribution, metabolism, or elimination characteristics of a therapeutic drug.

Therefore, the present invention also provides the use of the compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof in the preparation of a drug resistance regulator for improving the cancer treatment effect of an anti-cancer drug. The drug resistance regulator can be an oral preparation.

The anticancer drug may be a drug that is not easily absorbed in the digestive tract due to the inhibitory effect of intestinal P-glycoprotein, and may include taxanes, vinca alkaloids, anthracyclines, camptothecins, podophyllotoxin, mitoxantrone, actinomycin, colchicine, etc. The taxanes include paclitaxel and docetaxel. The vinca alkaloids include vincristine and vinblastine. The anthracyclines include daunorubicin and doxorubicin. The camptothecins include topotecan and irinotecan.

The cancer may be a solid tumor or a hematological malignancy, which may be selected from leukemia, multiple myeloma, and lymphoma. The leukemia may be acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and chronic myeloid leukemia. The lymphoma may be Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, B cell lymphoma, T cell lymphoma, and diffuse large B cell lymphoma.

The present invention also provides a pharmaceutical composition comprising the compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, and excipients. A pharmaceutically acceptable carrier refers to a carrier that is compatible with the active ingredient in the composition (in some embodiments, can stabilize the active ingredient) and is harmless to the individual being treated. Pharmaceutical carriers and/or excipients may be selected from diluents, fillers, salts, disintegrants, adhesives, lubricants, glidants, wetting agents, controlled release matrices, colorants, flavoring agents, buffers, stabilizers, solubilizers, and combinations thereof. The pharmaceutical composition comprising the compound of formula (I) or (II) described herein or a pharmaceutically acceptable salt thereof may be administered in various known ways, such as oral, topical, rectal, parenteral, inhalation, or implantation. Depending on the purpose of treatment, the pharmaceutical composition may be prepared into various types of dosage unit forms, such as tablets, pills, powders, liquid preparations, suspensions, emulsions, granules, capsules, suppositories, and injections (solutions and suspensions). In order to shape the pharmaceutical composition in tablet form, any excipient known and widely used in the art can be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, etc.; binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrants such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride of stearic acid, starch and lactose, etc.; disintegration inhibitors such as white sugar, tristearate, coconut oil and hydrogenated oil; adsorption promoters such as quaternary ammonium base and sodium lauryl sulfate, etc.; wetting agents such as glycerol, starch, etc.; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, etc.; and lubricants such as purified Talc, stearate, boric acid powder and polyethylene glycol, etc. It is also possible to select common coating materials to make sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layer film tablets and multi-layer tablets as needed. In order to shape the pharmaceutical composition in the form of pills, any known and widely used excipients in the art can be used, for example, carriers, such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talcum powder, etc.; adhesives, such as gum arabic powder, tragacanth powder, gelatin and ethanol, etc.; disintegrants, such as agar and kelp powder, etc. In order to shape the pharmaceutical composition in the form of suppositories, any known and widely used excipients in the art can be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides, etc. In order to prepare the pharmaceutical composition in the form of injections, the solution or suspension can be sterilized (preferably adding an appropriate amount of sodium chloride, glucose or glycerol, etc.) to make an injection with isotonicity equal to that of blood. When preparing injections, any commonly used carriers in the art may also be used, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and fatty acid esters of polyethylene sorbitan, etc. In addition, common solvents, buffers and analgesics may be added. In the present invention, there is no particular restriction on the method of administration of the pharmaceutical composition. Various dosage forms of preparations may be selected for administration according to the patient's age, sex and other conditions and symptoms. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules may be administered orally; injections may be administered alone or mixed with an injection delivery fluid (such as a glucose solution and an amino acid solution) for intravenous injection; suppositories are administered to the rectum.

Compared with the prior art, the present invention has the following beneficial effects: the compound represented by formula (I) or (II) or its pharmaceutically acceptable salt can effectively inhibit P-glycoprotein. The compound has obvious inhibitory activity on drug-resistant tumor cells (such as leukemia drug-resistant cells K562/A02, etc.) with high expression of P-glycoprotein, has a strong effect of reversing multidrug resistance (MDR) of tumor cells, and some compounds have significantly better inhibitory activity on P-glycoprotein than the third-generation P-glycoprotein inhibitor Tariquidar (XR9576), and have less cytotoxicity. In addition, the compound can selectively inhibit intestinal epithelial cell P-glycoprotein, and when it is combined with anticancer agents (paclitaxel, docetaxel, doxorubicin, etc.) that are not easily absorbed in the digestive tract due to the inhibitory effect of intestinal P-glycoprotein for oral administration, the bioavailability of the anticancer agent is improved.

DETAILED DESCRIPTION

The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

Biological Experiment Example 1: Cytotoxic Effects of Compounds

This experiment tested the cytotoxic effects of 27 compounds on K562/A02 cells. The human leukemia cell line K562/A02 cells resistant to doxorubicin were cultured in RPMI 1640 medium containing 10% FBS and 1% penicillin-streptomycin. The cells in the logarithmic growth phase were plated in a 96-well plate at a density of 6000 cells per well, and 100 μL RPMI 1640 medium was added to each well and incubated in a 37°C, 5% CO ₂ incubator for 24 hours. 100 μL of doxorubicin was added to each well of the doxorubicin control group. A series of concentration gradients of doxorubicin were added to the blank control group, 100 μL of culture medium was added to each well of the test compound group and the positive control group, and 50 μL of the target compound (5 μM) and 50 μL of a series of concentration gradients of doxorubicin were added to each well, respectively. Three replicate wells were set at each concentration. After the addition of the drug, incubate for 48 hours and discard the solution. Add 1 mg/mL MTT solution and continue incubation for 4 hours, discard the solution, add DMSO and shake on a shaker for 5 minutes. Read the reading at a wavelength of 490 nm on the microplate reader, calculate the cell inhibition rate, and calculate the compound IC ₅₀ value using the dose-effect curve in Graphicpad 5.0 software.

The test results are shown in Table 1. It can be seen from the test results that all compounds have no obvious cytotoxicity to K562/A02 cells.

Table 1 Cytotoxic effects of compounds on K562/A02 cells

Biological Experiment Example 2: Reversal Effect of Compounds on Adriamycin-Resistant Human Leukemia Cells (K562/A02)

With Tariquidar as the positive control, K562/A02 cells were cultured in RPMI 1640 medium containing 10% FBS and 1% penicillin-streptomycin. Cells in the logarithmic growth phase were plated in a 96-well plate at a density of 6,000 cells per well, 100 μL of RPMI 1640 medium per well, and placed in a 37°C, 5% CO ₂ incubator for 24 hours. 100 μL of a series of concentration gradients of doxorubicin were added to each well of the doxorubicin control group, 100 μL of culture medium was added to the blank control group, 50 μL of the target compound (5 μM) and 50 μL of a series of concentration gradients of doxorubicin were added to each well of the test compound group and the positive control group, respectively, and three replicate wells were set at each concentration. After the addition of the drug, incubate for 48 hours and discard the solution. Add 1 mg/mL of MTT solution and continue incubation for 4 hours, discard the solution, add DMSO and shake on a shaker for 5 minutes. The reading was taken at 490 nm on a microplate reader to calculate the cell inhibition rate. The compound _IC50 value was calculated using the dose-effect curve in Graphicpad 5.0 software, and the reversal factor (RF) was obtained. The reversal factor was expressed as _IC50 (ADM)/ _IC50 (ADM+reversal agent).

In this experiment, 27 compounds were tested in batches for their reversal activity on doxorubicin-resistant leukemia cells at a concentration of 5 μM. As shown in Table 2, the test results showed that most of the 27 compounds had the ability to reverse MDR. The reversal activity of some compounds exceeded that of the positive control Tariquidar.

Table 2 Reversal effect of compounds (5 μM concentration) on drug resistance of doxorubicin-resistant human leukemia cells

Biological Experiment Example 3: Oral administration of compound 13o in combination with an anticancer agent to improve the bioavailability of the anticancer agent

Anti-tumor drugs such as paclitaxel (PTX), docetaxel (DTX), and doxorubicin (DOX) are usually administered by intravenous injection in clinical practice due to their physical and chemical properties and the excretion of P-glycoprotein in intestinal epithelial cells. Compound 13o and its pharmaceutically acceptable salt in the present invention have a certain inhibitory effect on intestinal P-gp and can improve the oral bioavailability of anti-cancer agents.

Paclitaxel is an important anti-tumor drug that binds to intracellular microtubules to inhibit the normal division and proliferation of tumor cells. It is mainly used for the first-line and follow-up treatment of advanced ovarian cancer; adjuvant treatment of patients with lymph node-positive breast cancer after standard chemotherapy with doxorubicin; breast cancer recurring within 6 months; patients with non-small cell lung cancer; and treatment of Kaposi's sarcoma. Paclitaxel is usually used in the form of a solution for intravenous injection in clinical practice, which can easily lead to a series of adverse reactions, including peripheral neuropathy, bone marrow suppression, and skin toxicity. Therefore, the compound The oral administration of 13o and its pharmaceutical salts in combination with paclitaxel can improve the bioavailability of paclitaxel, change the traditional intravenous administration of paclitaxel, reduce the adverse side effects of paclitaxel and improve patient compliance.

Six 14-15 week old Sprague-Dawley (SD) rats were randomly divided into two groups after being fasted for more than 12 hours and allowed to drink water. The first group was given 20 mg/kg paclitaxel by gavage; the second group was given 20 mg/kg paclitaxel and 10 mg/kg compound 13o by gavage at the same time. Blood samples were collected at 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 12h, and 24h to measure the blood concentration of paclitaxel.

The test results are shown in Table 3. From the AUC _{Last_plasma} results, it can be seen that compound 13o can significantly improve the oral bioavailability of paclitaxel, which is not easily absorbed in the digestive tract.

Table 3 Pharmacokinetic parameters of PTX in rats

Note: AUC _{Last_plasma} represents the area under the drug-time curve; C _max represents the peak concentration of the drug; T _max represents the time when the drug reaches its peak concentration; T _1/2 represents the elimination half-life of the drug; V _Z /F represents the apparent distribution volume of the drug; CL _Z /F represents the drug clearance rate.

Preparation Example 1

Preparation of 3,4-dimethoxy-2-hydroxyacetophenone: Add 20g of 3,4-dimethoxyphenol to a 250mL two-necked bottle, under argon protection, add 80mL of 48% boron trifluoride ether solution and 12mL of acetic acid at 0℃, continue to react at this temperature for 30min, then move to 80℃ oil bath for 3h. After the reaction is completed, add water to quench at 0℃, a large amount of yellow-green solid precipitates, filter, recrystallize the filter cake with methanol, and dry under reduced pressure to obtain 18.3g of gray solid (yield: 72%). ¹ H NMR (400MHz, CDCl ₃ )δ12.64(s,1H),7.04(s,1H),6.44(s,1H),3.90(s,3H),3.86(s,3H),2.55(s,3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 202.09, 160.14, 156.83, 141.91, 111.74, 111.69, 100.57, 56.71, 56.20, 26.39.

Preparation Example 2

Preparation of 2,4-dihydroxyacetophenone: Add 15g of resorcinol into a 250mL two-necked bottle, under argon protection, add 80mL of 48% boron trifluoride ether solution and 12mL of acetic acid at 0°C, and continue to react at this temperature for 30min. Then move to 80℃ oil bath to react for 3h. After the reaction, add water to quench at 0℃, extract with dichloromethane three times (100mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product was slurried with a small amount of mixed organic solution (V _{ethyl acetate} : V _{petroleum ether} = 1:3), filtered, and dried under reduced pressure to obtain 16.5g of a white solid (yield: 80%). ¹ H NMR (400MHz, CDCl ₃ )δ12.68(s,1H),7.64(d,J＝8.5Hz,1H),6.46–6.34(m,2H),5.91(s,1H),2.56(s,3H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 202.77, 165.12, 162.72, 133.09, 114.33, 107.78, 103.51, 26.22.

Preparation Example 3

Preparation of 4-benzyloxy-2-hydroxyacetophenone: Weigh 7.6g of 2,4-dihydroxyacetophenone and 7.9g of potassium carbonate into a 100mL two-necked flask, protect with argon, add 50mL of acetonitrile, slowly add 6.5mL of benzyl bromide at room temperature, and then heat and reflux for 6h. After the reaction is completed, remove acetonitrile under reduced pressure, extract with dichloromethane three times (50mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product is slurried with a small amount of mixed organic solution (V _{ethyl acetate} : V _{petroleum ether} = 1:5), filtered, and dried under reduced pressure to obtain 10.5g of a white solid (yield: 87%). ¹ H NMR (400MHz, CDCl ₃ ) δ 12.74 (s, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.45–7.32 (m, 5H), 6.55–6.49 (m, 2H), 5.09 (s, 2H), 2.55 (s, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 202.62, 165.23, 135.93, 132.40, 128.74, 128.34, 127.56, 114.14, 108.14, 101.94, 70.24, 26.24.

Preparation Example 4

Preparation of 3,4-dimethoxy-2-hydroxyacetophenone: Weigh 10g of raw material 2,3,4-trihydroxyacetophenone and 17g of potassium carbonate into a 100mL single-mouth bottle, add 50mL of DMF, slowly drop 8mL of iodomethane at room temperature, and continue to react at room temperature for 24h. After the reaction is completed, add appropriate amount of water to the reaction solution, extract three times with ethyl acetate (50mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product is slurried with a small amount of mixed organic solution (V _{ethyl acetate} : V _{petroleum ether} = 1:3), filtered, and dried under reduced pressure to obtain 8.7g of white solid (yield: 75%). ¹ H NMR (400MHz, CDCl ₃ ) δ 12.54 (s, 1H), 7.47 (d, J = 9.0 Hz, 1H), 6.47 (d, J = 9.0 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 2.54 (s, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 203.27, 158.53, 157.04, 136.50, 127.05, 115.33, 102.92, 60.66, 56.13, 26.39.

Preparation Example 5

Preparation of ethyl 2-(2-acetyl-4,5-dimethoxyphenoxy)acetate: 11g 3,4-dimethoxy-2-hydroxyacetophenone and 20g cesium carbonate were added to a 250mL two-necked bottle, argon protection, 100mL acetone and 7.5mL ethyl bromoacetate were added by syringe, and the reaction was carried out at 60°C for 3h. After the reaction, the reaction solution was removed under reduced pressure, 100mL water was added, and dichloromethane was extracted three times (50mL×3), the organic phases were combined, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography, the mobile phase was ethyl acetate: petroleum ether = 1:5, and dried under reduced pressure to obtain 10.4g of a white solid (yield: 66%). ¹ H NMR (400MHz, CDCl ₃ )δ7.40(s,1H),6.39(s,1H),4.68(s,2H),4.26(q,J＝7.1Hz,2H),3.89(s,3H),3.85(s,3H),2.68(s,3H),1.28(t,J＝7.1Hz,3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 197.31, 168.27, 153.64, 153.33, 143.84, 120.05, 112.54, 97.50, 66.67, 61.59, 56.23, 56.15, 32.18, 14.17.

Preparation Example 6

Preparation of ethyl 2-(6-acetyl-2,3-dimethoxyphenoxy)acetate: weigh 8.7g of raw materials and 15g of cesium carbonate and add them to a 250mL two-necked bottle, protect with argon, add 100mL of acetone and 7.5mL of ethyl bromoacetate with a syringe, and react at 60℃ for 3h. After the reaction, remove the reaction solution under reduced pressure, extract with dichloromethane three times (50mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, the mobile phase is ethyl acetate: petroleum ether = 1:3, and dried under reduced pressure to obtain 11g of white liquid (yield: 88%). ¹ H NMR (400MHz, CDCl ₃ )δ7.50–7.42(m,1H),6.72–6.65(m,1H),4.78–4.71(m,2H),4.24–4.14(m,2H) ,3.90–3.83(m,3H),3.82–3.75(m,3H),2.66–2.55(m,3H),1.30–1.16(m,3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 198.05, 168.91, 157.21, 151.75, 141.20, 126.16, 125.51, 107.26, 69.89, 61.05, 56.07, 31.24, 14.10.

Preparation Example 7

Preparation of ethyl 2-(2-acetyl-5-(benzyloxy)phenoxy)acetate: weigh 10g of the raw material and 13.5g of cesium carbonate and add them to a 250mL two-necked flask, protect with argon, add 100mL of acetone, add 5.0mL of ethyl bromoacetate dropwise via a syringe at room temperature, and then react at 60°C for 3h. After the reaction is completed, the reaction solution is removed under reduced pressure, extracted with dichloromethane three times (50mL×3), the organic phases are combined, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, the mobile phase is ethyl acetate: petroleum ether = 1:3, room temperature Drying under reduced pressure gave 12.5 g of a white solid (yield: 92%). ¹ H NMR (400 MHz, CDCl ₃ ) δ7.84 (d, J=8.7 Hz, 1H), 7.44-7.30 (m, 5H), 6.63 (dd, J=8.7, 2.0 Hz, 1H), 6.40 (d, J=2.2 Hz, 1H), 5.08 (s, 2H), 4.66 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 2.67 (s, 3H), 1.30 (t, J=7.1 Hz, 3H). ¹³ CNMR (101MHz, CDCl ₃ )δ197.66,167.97,163.42,158.97,136.08,132.93,128.74,128.34,127.57,121.85,106.91,99.98,70.35,65.55,61.58,32.06,14.16.

Preparation Example 8

Preparation of 2-(2-acetyl-4,5-dimethoxyphenoxy)acetic acid: Weigh 10g of ethyl 2-(2-acetyl-4,5-dimethoxyphenoxy)acetic acid and add it to a 100mL single-mouth bottle, add 30mL of methanol, and drop 25mL of 2N NaOH aqueous solution under ice bath. After the dropwise addition, move to room temperature to react for 6h. After the reaction is completed, remove the methanol in the reaction solution under reduced pressure, add 2M HCl aqueous solution to the reaction solution under ice bath, adjust the pH of the reaction solution to 2-3, continue stirring under ice bath conditions for 30min, a large amount of white solid precipitates, filter, and dry under reduced pressure to obtain 8.1g of white solid product (yield: 90%).

Preparation Example 9

Preparation of 2-(6-acetyl-2,3-dimethoxyphenoxy)acetic acid: Weigh 10g of the raw material and add it to a 100mL single-mouth bottle, add 30mL of methanol, and drop 25mL of 2N NaOH aqueous solution under ice bath. After the dropwise addition, move to room temperature to react for 6h. After the reaction is completed, remove the methanol in the reaction solution under reduced pressure, add 2M HCl aqueous solution to the reaction solution under ice bath, adjust the pH of the reaction solution to 2-3, continue stirring under ice bath conditions for 30min, a large amount of white solid precipitates, filter, and dry under reduced pressure to obtain 7.5g of white solid product (yield: 83%).

Preparation Example 10

Preparation of 2-(2-acetyl-5-(benzyloxy)phenoxy)acetic acid: weigh 12g of the raw material and add it to a 100mL single-mouth bottle, add 30mL of methanol, and drop 25mL of 2N NaOH aqueous solution under ice bath. After the dropwise addition, move to room temperature to react for 6h. After the reaction is completed, remove the methanol in the reaction solution under reduced pressure, add 2M HCl aqueous solution to the reaction solution under ice bath, adjust the pH of the reaction solution to 2-3, continue stirring under ice bath conditions for 30min, a large amount of white solid precipitates, filter, and dry under reduced pressure to obtain 10.2g of white solid product (yield: 93%).

Preparation Example 11

Preparation of 5,6-dimethoxy-3-methylbenzofuran: Add 11g of 2-(2-acetyl-4,5-dimethoxyphenoxy)acetic acid and 25g of anhydrous sodium acetate to a 250mL two-necked flask, add 100mL of acetic anhydride, protect with argon, and react at 110°C for 12h. After the reaction is completed, add saturated sodium bicarbonate aqueous solution to quench in an ice bath until no bubbles are generated, extract with ethyl acetate (100mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, with the mobile phase of ethyl acetate: petroleum ether = 1:10, and dried under reduced pressure to obtain 6.3g of a white solid (yield: 76%). ¹ H NMR (400MHz, CDCl ₃ ) δ7.31(s,1H),7.01(s,1H),6.93(s,1H),3.94(s,3H),3.91(s,3H),2.21(s,3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 149.84, 147.90, 146.31, 140.51, 120.85, 115.67, 100.88, 95.48, 56.47, 56.26, 8.05.

Preparation Example 12

Preparation of 6,7-dimethoxy-3-methylbenzofuran: 15g of raw material and 34g of anhydrous sodium acetate were added to a 250mL two-necked flask, 100mL of acetic anhydride was added, argon protection was applied, and the reaction was carried out at 110°C for 12h. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added to quench the mixture under an ice bath until no bubbles were generated, and ethyl acetate was extracted (100mL×3), the organic phases were combined, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography, with the mobile phase of ethyl acetate: petroleum ether = 1:10, and dried under reduced pressure to obtain 9.5g of a white liquid (yield: 84%). ¹ H NMR (400MHz, CDCl ₃ ) δ7.32 (d, J = 1.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 4.14 (s, 3H), 3.90 (s, 3H), 2.18 (d, J = 1.1 Hz, 3H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 148.77, 147.24, 141.02, 134.76, 125.40, 115.60, 112.39, 109.42, 60.85, 57.36 7.83.

Preparation Example 13

Preparation of 6-(Benzyloxy)-3-methylbenzofuran: Add 15g of raw materials and 30g of anhydrous sodium acetate to a 250mL two-necked flask, add 100mL of acetic anhydride, protect with argon, and react at 110°C for 12h. After the reaction is completed, add saturated sodium bicarbonate aqueous solution to quench under ice bath conditions until no bubbles are generated, extract with ethyl acetate (100mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, with the mobile phase of ethyl acetate: petroleum ether = 1:10, and dried under reduced pressure to obtain a white Solid 9.7 g (yield: 82%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.50-7.31 (m, 7H), 7.07 (d, J=1.7 Hz, 1H), 6.97 (dd, J=8.5, 1.8 Hz, 1H), 5.11 (s, 2H), 2.22 (s, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 157.09, 156.12, 140.62, 137.06, 128.62, 127.99, 127.53, 122.80, 119.52, 115.52, 112.00, 97.36, 70.66, 7.95.

Preparation Example 14

Preparation of 2-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydrobenzofuran[2,3-c]pyridine: Weigh 3.84g of 5,6-dimethoxy-3-methylbenzofuran into a 100mL single-mouth bottle, add 40mL of acetic acid, 32mL of 36-38% formaldehyde aqueous solution and 8.5g of benzylamine, protect with argon, and react at 60℃ for 3h. After the reaction is completed, cool to room temperature, add saturated sodium bicarbonate aqueous solution to quench until no bubbles are generated, extract with ethyl acetate (50mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, the mobile phase is ethyl acetate: petroleum ether = 1:3, and dried under reduced pressure at room temperature to obtain 5.5g of white solid (yield: 85%). ¹ H NMR (400MHz, CDCl ₃ )δ7.48–7.29(m,5H),7.03(s,1H),6.92(s,1H),3.96(s,3H),3.94(s,3H),3.81(s,2H),3.68(s,2H),2.90(t,J＝5.5Hz,2H),2.77–2.71(m,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ150.41,149.15,147.04,146.24,138.26,129.11,128.43,127.32,12 0.11,111.35,100.63,95.74,61.88,56.49,56.33,50.34,50.15,20.98.

Preparation Example 15

Preparation of 2-benzyl-7-(benzyloxy)-1,2,3,4-tetrahydrobenzofuran[2,3-c]pyridine: Weigh 7.15g of 6-(benzyloxy)-3-methylbenzofuran into a 250mL single-mouth bottle, add 60mL of acetic acid, 48mL of 36-38% formaldehyde aqueous solution and 13g of benzylamine, protect with argon, and react at 60℃ for 3h. After the reaction is completed, cool to room temperature, add saturated sodium bicarbonate aqueous solution to quench until no bubbles are generated, extract with ethyl acetate (100mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, the mobile phase is ethyl acetate: petroleum ether = 1:10, and dried under reduced pressure to obtain 5.6g of white solid (yield: 51%). ¹ H NMR (400MHz, CDCl ₃ )δ7.48–7.28(m,11H),7.04(d,J＝2.1Hz,1H),6.93(dd,J＝8.5,2.2Hz,1H),5.0 9(s,2H),3.87(s,2H),3.73(s,2H),2.96(t,J＝5.2Hz,2H),2.83–2.72(m,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ156.60,155.65,137.02,129.44,128.60,127.98,127.82,127.53,121.64,118.72,111.85,111.05,97.77,70.72,61.26,49.87,49.66, 20.28.

Preparation Example 16

Preparation of 2-benzyl-7,8-dimethoxy-1,2,3,4-tetrahydrobenzofuran[2,3-c]pyridine: Weigh 1.92g of 6,7-dimethoxy-3-methylbenzofuran into a 100mL single-mouth bottle, add 10mL of acetonitrile, 10mL of 36-38% formaldehyde aqueous solution and 5.7g of benzylamine hydrochloride, and react at 90℃ for 3h. After the reaction is completed, cool to room temperature, add saturated sodium bicarbonate aqueous solution to quench until no bubbles are generated, extract with ethyl acetate (50mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, the mobile phase is ethyl acetate: petroleum ether = 1:20, and dried under reduced pressure to obtain 1.7g of white solid (yield: 53%). ¹ H NMR (400MHz, CDCl ₃ )δ7.42–7.26(m,5H),7.00(d,J＝8.4Hz,1H),6.87(d,J＝8.4Hz,1H),4.11(s,3H),3.91 (s,3H),3.78(s,2H),3.67–3.63(m,2H),2.87(t,J＝5.6Hz,2H),2.69(t,J＝5.6Hz,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ151.13,148.43,146.63,138.17,134.81,129.11,128.43,127.34,124 .43,111.61,111.27,109.20,61.83,60.96,57.33,50.19,50.06,20.86.

Preparation Example 17

Preparation of 6,7-dimethoxy-1,2,3,4-tetrahydrobenzofuran[2,3-c]pyridine: Weigh 3.2g of 2-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydrobenzofuran[2,3-c]pyridine into a 100mL two-necked bottle, add 640mg 10wt% Pd/C, 20mL THF and 20mL methanol, replace with hydrogen three times, and react at room temperature for 12-24h. After the reaction is completed, filter (add diatomaceous earth to assist filtering), wash the filter cake with a mixed solvent of dichloromethane/methanol, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, with the mobile phase being methanol: dichloromethane = 1:10, and dried under reduced pressure to obtain 2.1g of a white solid (yield: 90%). ¹ H NMR (400MHz, DMSO) δ7.24 (d, J = 8.3 Hz, 1H), 6.87 (s, 1H), 6.71 (dd, J = 8.2, 1.4 Hz, 1H), 3.79 (s, 2H), 3.32 (bs, 2H), 2.95 (s, 2H), 2.53 (s, 2H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 151.24, 148.64, 147.11, 146.21, 120.25, 111.69, 100.52, 95.67, 56.46, 56.31, 43.33, 43.24, 22.68.

Preparation Example 18

Preparation of 1,2,3,4-tetrahydrobenzofuran[2,3-c]pyridin-7-ol: weigh 6.0 g of the raw material and add it into a 100 mL two-necked bottle. Add 1.2g 10wt% Pd/C, 50mL ethyl acetate, replace with hydrogen three times, and react at 60℃ for 6h. After the reaction is completed, filter (add diatomaceous earth to assist filtering), wash the filter cake with a mixed solvent of dichloromethane/methanol, and remove the solvent under reduced pressure to obtain a crude product. The crude product is slurried with a small amount of ethyl acetate, filtered, and dried under reduced pressure to obtain 2.5g of off-white solid (yield: 81%). ¹ H NMR (400MHz, DMSO) δ7.24 (d, J＝8.3Hz, 1H), 6.87 (s, 1H), 6.71 (dd, J＝8.2, 1.4Hz, 1H), 3.79 (s, 2H), 2.95 (s, 2H), 2.53 (s, 2H). ¹³ C NMR (101 MHz, DMSO) δ 155.25, 155.05, 151.25, 120.68, 118.97, 111.78, 111.71, 98.32, 42.97, 42.68, 22.43.

Preparation Example 19

Preparation of tert-butyl 7-hydroxy-3,4-dihydrobenzofuran[2,3-c]pyridine-2(1H)-carboxylate: Weigh 3.8g of the raw material and add it to a 100mL single-mouth bottle, add 30mL of methanol, slowly add 4.8g of Boc ₂ O at 0°C, then slowly drop 2.8mL of triethylamine, and continue to react at 0°C for 1h. After the reaction is completed, remove the solvent under reduced pressure, extract with ethyl acetate (50mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, the mobile phase is ethyl acetate: petroleum ether = 1:3, and dried under reduced pressure to obtain 4.5g of a white solid (yield: 77%). ¹ H NMR (400MHz, CDCl ₃ )δ7.22(d,J＝8.3Hz,1H),6.95(s,1H),6.80(dd,J＝8.3,2.1Hz,1H),6.54(s,1H),4.55(s,2H),3.73(s,2H),2.66(t,J＝5.6Hz,2H),1.51(s,9H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 155.68, 155.36, 153.81, 121.09, 118.77, 111.56, 98.61, 80.81, 42.48, 40.93, 28.49, 20.78.

Preparation Example 20

Preparation of tert-butyl 7-((trifluoromethylsulfonyl)oxy)-3,4-dihydrobenzofuran[2,3-c]pyridine-2(1H)-carboxylate: Weigh 2.9g of the raw material and add it to a 50mL two-necked bottle, add 25mL of anhydrous dichloromethane, add 2.5mL of trifluoromethanesulfonic anhydride and 2.0mL of triethylamine dropwise at -5°C, and continue the reaction for 3h. After the reaction is completed, add a small amount of water to quench, extract with ethyl acetate (50mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, the mobile phase is ethyl acetate: petroleum ether = 1:5, and dried under reduced pressure at room temperature to obtain 3.5g of white solid (yield: 83%). ¹ H NMR (400MHz, CDCl ₃ )δ7.46(d,J＝8.5Hz,1H),7.40(d,J＝2.2Hz,1H),7.17(dd,J＝8.5,2.2Hz,1H),4.61(s,2H),3.76(s,2H),2.73(s,2H),1.50(s,9H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 154.85, 154.04, 146.02, 128.02, 120.40, 119.22, 117.20, 116.30, 105.46, 80.64, 28.40.

Preparation Example 21

3,4-Dihydrobenzofuran[2,3-c]pyridine-2(1H)-carboxylic acid tert-butyl ester: Weigh 1.26g of raw material, 33mg of Pd(OAc) ₂ and 80mg of triphenylphosphine into a 25mL two-necked bottle, add 15mL of DMF, replace the gas with argon three times, add 0.24mL of formic acid and 1.2mL of triethylamine via a syringe, and react at 100℃ for 3h. After the reaction is completed, cool to room temperature, extract with ethyl acetate (50mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, the mobile phase is ethyl acetate: petroleum ether = 1:10, and dried under reduced pressure at room temperature to obtain 650mg of a white solid (yield: 79%). ¹ H NMR (400MHz, CDCl ₃ ) δ7.45–7.38(m,2H),7.26–7.18(m,2H),4.59(s,2H),3.74(s,2H),2.71(s,2H),1.50(s,9H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 154.99, 154.77, 127.83, 123.71, 122.65, 118.69, 111.18, 80.35, 42.47, 40.82, 28.47, 20.83.

Preparation Example 22

Preparation of 1,2,3,4-tetrahydrobenzofuran[2,3-c]pyridine hydrochloride: Weigh 2.7g of raw materials into a pressure tube, add 10mL of hydrogen chloride ethyl acetate solution, and react at 50℃ for 6h. After the reaction, remove the solvent under reduced pressure, slurry the residual solid with a small amount of ethyl acetate, filter, and dry under reduced pressure to obtain 1.6g of white solid (yield: 77%). ¹ H NMR (400MHz, DMSO) δ10.24 (s, 2H), 7.68–7.55 (m, 2H), 7.40–7.26 (m, 2H), 4.39 (s, 2H), 3.53 (s, 2H), 2.96 (s, 2H). ¹³ C NMR (101 MHz, DMSO) δ 154.58, 146.07, 127.09, 125.09, 123.66, 119.86, 111.74, 111.68, 41.14, 40.08, 18.01.

Preparation Example 23

Preparation of 6,7-dimethoxy-2-(4-nitrophenylethyl)-1,2,3,4-tetrahydrobenzofuran[2,3-c]pyridine: Weigh 1.2g 6,7-dimethoxy-1,2,3,4-tetrahydrobenzofuran[2,3-c]pyridine, 2.3g 4-nitrophenylethyl bromide, 83mg KI and 1.0g triethylamine into a 25mL two-necked bottle, add 10mL DMF, argon protection, and react at 100℃ for 2h. After the reaction is completed, cool to room temperature, add appropriate amount of water, extract with ethyl acetate (50mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, the mobile phase is ethyl acetate: petroleum ether = 1:3, and dried under reduced pressure at room temperature to obtain 1.1g of yellow solid (yield: 58%). ¹ H NMR (400MHz, CDCl ₃ )δ8.16(d,J＝8.5Hz,2H),7.41(d,J＝8.4Hz,2H),7.03(s,1H),6.90(s,1H),3.94(s,3H),3.92(s,3H),3.73(s,2H),3.06–2.98(m,2H), 2.95–2.87(m,4H),2.73(s,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ149.86,149.15,148.10,147.15,146.57,146.30,129.56,123.66,119.9 1,111.41,100.63,95.72,58.30,56.48,56.33,50.54,50.25,34.08,20.95.

Preparation Example 24

Preparation of (E)-1-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)-3-(4-nitrophenyl)prop-2-en-1-one: Weigh 690 mg of 6,7-dimethoxy-1,2,3,4-tetrahydrobenzofuran[2,3-c]pyridine, 700 mg of cinnamic acid and 1.35 g of HATU into a two-necked bottle, under argon protection, add 5 mL of DMF and 450 mg of triethylamine to the reaction system via a syringe at 0°C, continue to react for 30 minutes after the addition is completed, and then move to room temperature to react for 1 hour. After the reaction is completed, add an appropriate amount of water, extract with DCM (50 mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a mobile phase of dichloromethane:methanol=50:1, and dried under reduced pressure at room temperature to obtain 1.0 g of a yellow solid (yield: 82%). ¹ H NMR (400 MHz, CDCl ₃ , conformational isomer) δ8.22 (d, J=8.5 Hz, 2H), 7.78–7.63 (m, 3H), 7.14–6.96 (m, 2H), 6.87 (d, J=8.5 Hz, 1H), 4.82 (d, J=16.1 Hz, 2H), 4.12–3.84 (m, 8H), 2.80 (d, J=18.9 Hz, 2H). ¹³ C NMR (101 MHz, CDCl ₃ , conformer) δ 165.39, 149.40, 148.19, 148.11, 147.71, 147.59, 146.76, 146.59, 146.52, 141.34, 140.50, 128.42, 124.17, 121.83, 121.57, 119.26, 113.28, 111.36, 100.62, 100.48, 95.78, 95.65, 56.50, 56.34, 44.13, 44.00, 41.50, 40.37, 22.07, 20.60.

Preparation Example 25

Preparation of tert-butyl (4-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-ylmethyl)phenyl)carbamate: Weigh 1.2g of 6,7-dimethoxy-1,2,3,4-tetrahydrobenzofuran[2,3-c]pyridine and 1.3g of tert-butyl (4-(chloromethyl)phenyl)carbamate and add them to a 25mL two-necked bottle, under argon protection, add 10mL of DMF, slowly drop 1mL of triethylamine, and then move to 60°C to react for 2h. After the reaction is completed, cool to room temperature, extract with ethyl acetate (50mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, the mobile phase is ethyl acetate: petroleum ether = 1:3, and dried under reduced pressure at room temperature to obtain 1.7g of yellow solid (yield: 77%). ¹ H NMR (400MHz, CDCl ₃ ) δ7.39–7.27(m,4H),6.97(s,1H),6.85(s,1H),6.70(s,1H),3.89(s,3H),3.87(s,3H),3.72(s,2H),3.63(s,2H),2.89 –2.80(m,2H),2.68(s,2H),1.50(s,9H). ¹³ C NMR (101MHz, CDCl ₃ )δ152.90,149.78,149.17,147.07,146.22,137.78,131.96,129.93,119.93,118.6 2,111.31,100.61,95.71,80.52,61.06,56.45,56.30,50.02,49.86,28.37,20.67.

Preparation Example 26

Preparation of 4-((6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)aniline: Weigh 1.5g of the raw material into a 50mL single-mouth bottle, add 10mL of ethanol and 5mL of 6N HCl, and react at 60℃ for 1h. After the reaction is completed, cool to room temperature, adjust pH to 8-9 with 2N NaOH (aq.), extract with dichloromethane (50mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, the mobile phase is ethyl acetate: petroleum ether = 1:1, and dried under reduced pressure at room temperature to obtain 950mg of a yellow solid (yield: 83%). ¹ H NMR (400MHz, CDCl ₃ )δ7.15(d,J＝8.2Hz,2H),6.98(s,1H),6.86(s,1H),6.65(d,J＝8.2Hz,2H),3.90(s, 3H), 3.88 (s, 3H), 3.78–3.49 (m, 6H), 2.82 (t, J = 5.6Hz, 2H), 2.67 (t, J = 5.3Hz, 2H). ¹³ C NMR (101MHz, CDCl ₃ )δ150.55,149.12,146.96,146.17,145.71,130.35,127.84,120.13,11 5.04,111.37,100.62,95.73,61.45,56.47,56.31,50.13,49.92,20.96.

Preparation Example 27

Preparation of 4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)aniline: Weigh 1.0g of 6,7-dimethoxy-2-(4-nitrophenylethyl)-1,2,3,4-tetrahydrobenzofuran[2,3-c]pyridine into a 25mL two-necked bottle, add 100mg of 10wt% Pd/C, 10mL of methanol, and react at room temperature for 2h. After the reaction is completed, filter, remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography, the mobile phase is ethyl acetate: petroleum ether = 1:1, and dried under reduced pressure at room temperature to obtain 810mg of a yellow solid (yield: 88%). ¹ H NMR (400MHz, CDCl ₃ )δ7.05–6.99(m,3H),6.88(s,1H),6.62(d,J＝8.3Hz,2H),3.92(s,3H),3.90(s,3H), 3.71(s,2H),3.57(s,2H),2.89(t,J＝5.6Hz,2H),2.81(s,4H),2.72(t,J＝5.4Hz,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ150.29,149.16,147.04,146.22,144.64,129.98,129.52,120.06,115.3 3,111.41,100.65,95.75,59.89,56.48,56.33,50.63,50.34,33.39,21.03.

Preparation Example 28

(E)-3-(4-aminophenyl)-1-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)prop-2-en-1-one: 610 mg (E)-1-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)-3-(4-nitrophenyl)prop-2-en-1-one and 900 mg stannous chloride were weighed and added to a pressure tube, 6 mL ethanol and 6 mL 6N HCl were added, and the mixture was reacted at 90°C for 3 h. After the reaction was completed, DCM was extracted (50 mL×3), the organic phases were combined, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a mobile phase of dichloromethane:methanol=50:1, and dried under reduced pressure at room temperature to obtain 450 mg of a yellow solid (yield: 79%). ¹ H NMR (400 MHz, CDCl ₃ )δ7.65(d,J＝15.3 Hz,1H),7.37(d,J＝8.3 Hz,2H),7.02(s,1H),6.88(s,1H),6.76(d,J＝14.6 Hz,1H),6.65(d,J＝8.4 Hz,2H),4.82(s,2H),4.06–3.88(m,10H),2.77(s,2H). ¹³ C NMR (101MHz, CDCl ₃ ) δ 167.03, 149.34, 148.31, 147.45, 146.44, 143.75, 129.61, 125.45, 119.52, 114.89, 100.56, 95.74, 56.49, 56.34.

Preparation Example 29

Preparation of (E)-N-(4-(3-(7,8-dimethoxy-1,2,3,4-tetrahydrodibenzo[b,d]furan-3-yl)-3-oxoprop-1-en-1-yl)phenyl)-4,5-dimethoxy-2-nitrobenzamide: Weigh 340 mg of 4,5-dimethoxy-2-nitrobenzoic acid and add it into a two-necked flask. Under argon protection, add 5 mL of anhydrous dichloromethane and 1 drop of DMF via syringe. At 0°C, slowly add 0.4 mL of oxalyl chloride into the reaction system via syringe. Continue the reaction for 30 min, then move to room temperature for 3 h. After the reaction, the solvent and excess oxalyl chloride were removed under reduced pressure, and the residual solid was dissolved in 3 mL of anhydrous dichloromethane and slowly added to the pre-prepared 380 mg (E)-3-(4-aminophenyl)-1-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)prop-2-en-1-one/5 mL DCM reaction system, followed by the addition of 200 mg of triethylamine, and the reaction was continued at room temperature for 1 h. After the reaction, an appropriate amount of water was added, and dichloromethane was extracted (50 mL×3). The organic phases were combined, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography, with the mobile phase being dichloromethane:methanol=50:1, and dried under reduced pressure at room temperature to obtain 440 mg of a light yellow solid (yield: 75%). 1H NMR(400MHz, CDCl3)δ8.95–8.49(m,1H),7.63(d,J＝7.1Hz,2H),7.59–7.38(m,4H),7.01(s,1H), 6.95(d,J＝9.2Hz,1H),6.91–6.75(m,2H),4.81–4.68(m,2H),4.00–3.82(m,14H),2.65-2.85(m,2H).

Preparation Example 30

Preparation of N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-4,5-dimethoxy-2-nitrobenzamide: Weigh 340 mg of 4,5-dimethoxy-2-nitrobenzoic acid and add it into a two-necked flask. Under argon protection, add 5 mL of anhydrous dichloromethane and 1 drop of DMF via syringe. At 0°C, slowly add 0.4 mL of oxalyl chloride into the reaction system via syringe. Continue the reaction for 30 minutes, then move to room temperature for 3 hours. After the reaction, the solvent and excess oxalyl chloride were removed under reduced pressure, and the residual solid was dissolved in 3 mL of anhydrous dichloromethane and slowly added to the pre-prepared 350 mg 4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)aniline/5 mL DCM reaction system, followed by the addition of 200 mg of triethylamine, and the reaction was continued at room temperature for 1 h. After the reaction, an appropriate amount of water was added, and dichloromethane was extracted (50 mL×3). The organic phases were combined, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated by column chromatography, with the mobile phase being dichloromethane:methanol=50:1, and dried under reduced pressure at room temperature to obtain 410 mg of a yellow solid (yield: 73%). ¹ H NMR (400MHz, CDCl ₃ )δ8.18(s,1H),7.50–7.42(m,3H),7.17(d,J＝8.3Hz,2H),6.96(s,1H),6.90(s,1H ),6.84(s,1H),3.93–3.83(m,12H),3.70(s,2H),2.95–2.80(m,6H),2.70(s,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ164.85,153.51,150.03,149.33,149.13,147.01,146.16,138.34,136.70,135.87,129.26,127.28,120.61,1 19.96,111.41,110.11,107.05,100.64,95.70,59.34,56.68,56.45,56.44,56.28,50.62,50.26,33.61,20.95.

Preparation Example 31

Preparation of (E)-2-amino-N-(4-(3-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)-3-oxoprop-1-en-1-yl)phenyl)-4,5-dimethoxybenzamide: Weigh 590 mg of raw material and 300 mg of stannous chloride, add 3 mL of EtOH and 3 mL of 6N HCl, and react at 90°C for 3 h. After the reaction, extract with DCM (50 mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a mobile phase of dichloromethane:methanol=50:1, and dried under reduced pressure at room temperature to obtain 410 mg of a yellow solid (yield: 74%). ¹ H NMR (400MHz, CDCl ₃ +CD ₃ OD, conformer) δ7.63–7.52 (m, 3H), 7.51–7.42 (m, 2H), 7.10–7.01 (m, 1H), 6.96 (s, 1H), 6.90–6.74 (m, 2H), 6.22–6.15 (m, 1H), 4.74 (s, 2H), 4.02–3.67 (m, 14H), 2.81–2.61 (m, 2H). ¹³ CNMR (101MHz, CDCl ₃ +CD ₃ OD, conformer) δ167.71, 167.03, 153.67, 149.35, 147.38, 146.34,145.17,143.21,140.82,140.17,130.40,128.63,120.64,119.39,115.35,111.87,107.54,100.89,100.61,95.75,57.00,56.41,56.23,55.68,43.94,41.38,40.26,21.88,20.54.

Preparation Example 32

Preparation of 2-amino-N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-4,5-dimethoxybenzamide: Weigh 400 mg of 2-amino-N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-4,5-dimethoxybenzamide and add it to a 25 mL two-necked bottle, add 80 mg of 10 wt% Pd/C, 5 mL of methanol and 5 mL of tetrahydrofuran, and react at room temperature for 2 h. After the reaction is completed, filter and remove the solvent under reduced pressure to obtain a crude product. The crude product is separated by column chromatography with a mobile phase of dichloromethane:methanol=50:1, and dried under reduced pressure at room temperature to obtain 320 mg of a yellow solid (yield: 85%). ¹ H NMR (400MHz, CDCl ₃ )δ7.91(s,1H),7.46(d,J＝8.4Hz,2H),7.20(d,J＝8.4Hz,2H),7.00(s,1H),6.98(s,1H),6.87(s,1H),6.20(s,1H), 3.92–3.89(m,5H),3.89(s,3H),3.84(s,3H),3.80(s,3H),3.73(s,2H),2.93–2.83(m,6H),2.72(t,J＝5.3Hz,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ167.20,153.64,150.00,149.17,147.06,146.22,144.98,141.08,136.25,135.99,129.23,120.94,119.97,1 11.40,111.27,107.64,101.04,100.62,95.72,59.33,57.11,56.45,56.31,55.81,50.56,50.21,33.59,20.91.

Preparation Example 33

Preparation of N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide: Weigh 70 mg of quinoline-3-carboxylic acid and add it to a 10 mL single-necked bottle, add 5 mL of anhydrous tetrahydrofuran and 0.15 mL of thionyl chloride, protect with argon, and react at 60°C for 12 h. After the reaction, remove the solvent and excess thionyl chloride under reduced pressure to obtain a gray solid. Weigh 106 mg of 2-amino-N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-4,5-dimethoxybenzamide into a 10 mL single-mouth bottle, add 5 mL of anhydrous dichloromethane, add the prepared acyl chloride into the reaction system, then add 40 mg of triethylamine, and continue the reaction at room temperature for 1 hour. After the reaction is completed, add an appropriate amount of 1N NaOH solution, stir at room temperature for 30 minutes, extract with dichloromethane (50 mL×3), combine the organic phases, wash the three The crude product was separated by column chromatography with a mobile phase of dichloromethane:methanol=50:1 and dried under reduced pressure at room temperature to obtain 85 mg of yellow solid compound 13a (yield: 62%). ¹ H NMR (400MHz, CDCl ₃ +CD ₃ OD)δ9.47(s,1H),8.82(s,1H),8.52(s,1H),8.14(d,J＝8.3Hz,1H),8.05(d,J＝8 .1Hz,1H),7.85(t,J＝7.4Hz,1H),7.67(t,J＝7.4Hz,1H),7.59(d,J＝7.9Hz,2H),7 .39(s,1H),7.27(d,J＝8.0Hz,2H),7.03(s,1H),6.91(s,1H),4.02(s,3H),3.96 (s,3H),3.92(s,3H),3.91(s,3H),3.76(s,2H),3.00–2.85(m,6H),2.77(s,2H). ¹³ C NMR (101MHz, CDCl ₃ +CD ₃ OD)δ167.90,163.69,152.36,149.41,149.17,148.72,148.56,147.05,146.1 2,144.51,136.31,136.01,135.85,135.11,131.72,129.19,129.05,128.50, 127.63,127.29,126.96,121.84,119.75,112.59,111.27,110.75,104.79,100.70,95.70,59.14,56.33,56.29,56.16,55.97,50.42,50.05,33.18,20.52.

Preparation Example 34

Preparation of N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine: Weigh 105 mg of 4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)aniline and 72 mg of 4-chloro-2-(pyridin-3-yl)quinazoline into a Schlenk tube, protect with argon, add 3 mL of anhydrous ethanol and 3 μL of methanesulfonic acid, and react at 70°C for 5 h. After the reaction, extract with DCM (30 mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a mobile phase of dichloromethane:methanol=50:1, and dried under reduced pressure at room temperature to obtain 110 mg of yellow solid compound 10a (yield: 66%). ¹ H NMR (500 MHz, CDCl ₃ ) δ9.73 (d, J=1.6 Hz, 1H), 8.79 (dt, J=7.9, 1.8 Hz, 1H), 8.69 (dd, J=4.7, 1.5 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.85-7.77 (m, 3H), 7.60 (s, 1H), 7.55 (t, J= 7.3Hz,1H),7.41(dd,J＝7.8,4.8Hz,1H),7.34(d,J＝8.3Hz,2H),7.02(s,1H),6.89(s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.77 (s, 2H), 3.00–2.89 (m, 6H), 2.75 (t, J = 5.2Hz, 2H). ¹³ C NMR (126MHz, CDCl ₃ )δ158.51,157.49,150.83,150.30,150.11,149.15,147.04,146.21,136.46,136.24,135.75,134.18,133.10,129.31,12 6.52,123.27,121.69,120.36,120.00,114.02,111.41,100.62,95.72,59.36,56.46,56.31,50.63,50.33,33.73,20.99.

Preparation Example 35

Preparation of N-(4-((6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine: Weigh 100 mg of 4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)aniline and 72 mg of 4-chloro-2-(pyridin-3-yl)quinazoline into a Schlenk tube, protect with argon, add 3 mL of anhydrous ethanol and 3 μL of methanesulfonic acid, and react at 70°C for 5 h. After the reaction, extract with DCM (30 mL×3), combine the organic phases, wash three times with water, wash once with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain a crude product. The crude product was separated by column chromatography with a mobile phase of dichloromethane:methanol=50:1, and dried under reduced pressure at room temperature to obtain 95 mg of yellow solid compound 10b (yield: 58%). ¹ H NMR (500 MHz, CDCl ₃ )δ9.74(s,1H),8.79(s,1H),8.69(s,1H),8.11–7.75(m,5H),7.73–7.33(m,5H),7.00(s,1H),6.88(s,1H),3.92(s,3H),3.90(s,3H),3.81(s,2H),3.69(s,2H),2.92(s,2H),2.73(s,2H). ¹³ C NMR (126MHz, CDCl ₃ )δ158.52,157.46,150.87,150.29,149.14,147.02,146.21,137.52,135.77,134.25,134.16,133.16,129.80,129.38 ,126.60,123.30,121.36,120.35,120.06,114.04,111.37,100.60,95.71,61.33,56.46,56.31,50.32,50.14,20.96.

Preparation Example 36

Preparation of N-(4-(2-(7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine:

Referring to the preparation method in Preparation Example 34, a yellow solid compound 10c was prepared (yield: 68%). ¹ H NMR (500 MHz, CDCl ₃ ) δ9.74-9.71 (m, 1H), 8.78 (d, J=7.9 Hz, 1H), 8.71-8.66 (m, 1H), 7.97 (dd, J=8.3, 1.4 Hz, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.83-7.76 (m, 3H), 7.74-7.63 (m, 1H), 7.53 (dd, J=11.8, 7.4 Hz, 1H),7.42–7.38(m,1H),7.32(dd,J＝8.2,2.7Hz,2H),7.01(d,J＝8.3Hz,1H),6.87(d,J＝8.3 Hz, 1H), 4.13 (s, 3H), 3.91 (s, 3H), 3.77 (d, J = 1.1Hz, 2H), 2.98–2.88 (m, 6H), 2.73 (s, 2H). ¹³ C NMR (126MHz, CDCl ₃ )δ158.50,157.53,150.90,150.84,150.83,150.31,148.50,146.71,136.51,136.20,135.76,134.79,134.21,133.08,129.28 ,126.51,124.33,123.28,121.73,120.48,114.05,111.71,111.37,109.23,61.01,59.29,57.31,50.49,50.23,33.73,20.88.

Preparation Example 37

Preparation of N-(4-((7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine: Referring to the preparation method in Preparation Example 35, a yellow solid compound 10d was prepared (yield: 63%). ¹ H NMR (500MHz, CDCl ₃ )δ9.75(s,1H),8.79(dt,J＝7.9,1.8Hz,1H),8.70(d,J＝3.8Hz,1H),8.00(d,J＝8.3Hz,1H),7. 93(d,J＝8.1Hz,1H),7.89–7.80(m,3H),7.64(d,J＝3.9Hz,1H),7.56(t,J＝7.6Hz,1H),7.49(d, J＝8.3Hz,2H),7.42(dd,J＝7.8,4.8Hz,1H),7.01(d,J＝8.4Hz,1H),6.87(d,J＝8.4Hz,1H),4.11 (s,3H),3.91(s,3H),3.81(s,2H),3.70(s,2H),2.91(t,J＝5.6Hz,2H),2.72(t,J＝5.4Hz,2H). ¹³ C NMR (126MHz, CDCl ₃ )δ158.54,157.46,151.06,150.89,150.88,150.30,148.42,146.64,137.52,135.77,134.80,134.24,134.16,133.16,129.78 ,129.39,126.60,124.41,123.30,121.37,120.33,114.03,111.64,111.31,109.21,61.32,60.95,57.32,50.21,50.06,20.88.

Preparation Example 38

Prepared by N-(4-(2-(3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine; referring to the preparation method in Preparation Example 34, a yellow solid compound 10e was obtained (yield: 61%). ¹ H NMR (500MHz, CDCl ₃ )δ9.73(s,1H),8.79(d,J＝7.9Hz,1H),8.69(d,J＝3.4Hz,1H),7.99(d,J＝8.3Hz,1H),7.91(d,J＝8.1Hz,1H),7.85–7.77(m,3H),7.56 (t,J＝7.2Hz,2H),7.47–7.39(m,3H),7.35(d,J＝8.2Hz,2H),7.25–7.17(m,2H),3.80(s,2H),3.02–2.90(m,6H),2.83–2.76(m,2H). ¹³ C NMR (126MHz, CDCl ₃ )δ158.55,157.49,154.75,151.26,150.87,150.34,136.45,136.28,135.75,134.17,133.12,129.37,129.34,128.09, 126.54,123.33,123.27,122.43,121.70,120.33,118.62,114.01,111.43,111.08,59.37,50.58,50.24,33.72,20.88.

Preparation Example 39

Preparation of N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-4-yl)quinazolin-4-amine:

Referring to the preparation method in Preparation Example 34, a yellow solid compound 10f was prepared (yield: 63%). ¹ H NMR (500MHz, CDCl ₃ )δ8.76(d,J＝4.0Hz,2H),8.37(d,J＝4.6Hz,2H),8.01(d,J＝8.2Hz,1H),7. 93(d,J＝8.1Hz,1H),7.84(t,J＝7.6Hz,1H),7.79(d,J＝7.9Hz,2H),7.62(s, 1H),7.58(t,J＝7.4Hz,1H),7.36(d,J＝7.9Hz,2H),7.02(s,1H),6.89(s,1H ),3.92(s,3H),3.91(s,3H),3.77(s,2H),3.03–2.91(m,6H),2.75(s,2H). ¹³ C NMR (126MHz, CDCl ₃ )δ158.32,157.64,150.77,150.24,150.08,149.17,147.09,146.25,146.14,136.45,136.35,133.19,129.60,129.32,12 7.01,122.40,121.68,120.37,119.98,114.29,111.42,100.62,95.73,59.34,56.47,56.32,50.67,50.33,33.74,20.99.

Preparation Example 40

N-(4-((6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)-2-(pyridin-4-yl)quinoline Preparation of oxazoline-4-amine:

Referring to the preparation method in Preparation Example 35, 10 g of a yellow solid compound was obtained (yield: 65%). ¹ H NMR (500MHz, CDCl ₃ )δ8.77(d,J＝5.6Hz,2H),8.37(d,J＝5.9Hz,2H),8.02(d,J＝8.2Hz,1H),7.95(d,J＝8.2Hz,1H),7.90–7.82(m,3H),7.67(s,1H),7.59(t,J＝7.4Hz ,1H),7.52(d,J＝8.3Hz,2H),7.00(s,1H),6.88(s,1H),3.92(s,3H),3.9 0(s,3H),3.83(s,2H),3.69(s,2H),2.93(t,J＝5.5Hz,2H),2.74(s,2H). ¹³ C NMR (126MHz, CDCl ₃ )δ158.32,157.62,150.79,150.27,149.15,147.06,146.24,146.09,137.48,134.40,133.24,129.77,129.64,12 7.07,122.39,121.41,120.36,120.04,114.30,111.37,100.60,95.71,61.36,56.47,56.31,50.32,50.23,20.98.

Preparation Example 41

Preparation of N-(4-(2-(7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-4-yl)quinazolin-4-amine: Referring to the preparation method in Preparation Example 34, a yellow solid compound 10h was obtained (yield: 63%). ¹ H NMR (500 MHz, CDCl ₃ ) δ8.77 (d, J=5.6 Hz, 2H), 8.37 (dd, J=4.7, 1.3 Hz, 2H), 8.02 (d, J=8.1 Hz, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.86-7.82 (m, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.63 (s, 1H), 7.58 (t, J＝7.2Hz,1H),7.36(d,J＝8.4Hz,2H),7.02(d,J＝8.4Hz,1H),6.88(d,J＝8.4Hz,1H) ,4.13(s,3H),3.91(s,3H),3.79(s,2H),3.01–2.92(m,6H),2.74(t,J=5.4Hz,2H). ¹³ C NMR (126MHz, CDCl ₃ )δ158.32,157.65,150.86,150.76,150.24,148.55,146.73,146.15,136.46,136.33,134.80,133.19,129.59,129.31,12 7.01,124.29,122.40,121.67,120.38,114.30,111.72,111.37,109.26,61.01,59.25,57.31,50.52,50.22,33.76,20.87.

Preparation Example 42

Preparation of N-(4-((7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)-2-(pyridin-4-yl)quinazolin-4-amine: Referring to the preparation method in Preparation Example 35, a yellow solid compound 10i was prepared (yield: 59%). ¹ H NMR (500MHz, CDCl ₃ )δ8.77(d,J＝5.6Hz,2H),8.38(d,J＝5.8Hz,2H),8.02(d,J＝8.3Hz,1H),7.95 (d,J＝8.2Hz,1H),7.91–7.81(m,3H),7.70(s,1H),7.59(t,J＝7.5Hz,1H),7.5 1(d,J＝8.2Hz,2H),7.01(d,J＝8.4Hz,1H),6.87(d,J＝8.4Hz,1H),4.11(s,3H) ,3.91(s,3H),3.83(s,2H),3.71(s,2H),2.93(t,J=5.5Hz,2H),2.73(s,2H). ¹³ C NMR (126MHz, CDCl ₃ )δ158.31,157.61,151.01,150.78,150.26,148.48,146.67,146.11,137.52,134.79,134.32,133.23,129.76,129.62 ,127.07,124.36,122.40,121.37,120.38,114.31,111.68,111.31,109.24,61.30,60.96,57.30,50.20,50.11,20.87.

Preparation Example 43

Preparation of N-(4-(2-(3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-4-yl)quinazolin-4-amine: Referring to the preparation method in Preparation Example 34, a yellow solid compound 10j was prepared (yield: 71%). ¹ H NMR (500MHz, CDCl ₃ )δ8.77(dd,J＝4.5,1.6Hz,2H),8.37(dd,J＝4.5,1.6Hz,2H),8.02(dd,J＝8.4,0.7Hz,1H),7.92(d,J＝8.0Hz,1H),7.87–7.82(m,1H),7.82–7.77( m,2H),7.61–7.56(m,2H),7.47–7.41(m,2H),7.37(d,J＝8.4Hz,2H),7. 25–7.19(m,2H),3.81(s,2H),3.12–2.89(m,6H),2.79(t,J＝5.6Hz,2H).

¹³ C NMR (126MHz, CDCl ₃ )δ158.33,157.61,154.73,151.22,150.76,150.24,146.11,136.42,136.36,133.18,129.61,129.32,128.06,127 .01,123.35,122.45,122.38,121.65,120.32,118.60,114.27,111.42,111.07,59.32,50.60,50.22,33.74,20.87.

Preparation Example 44

Preparation of N-(2-((4-((6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide: Referring to the preparation method in Preparation Example 33, a pale yellow solid compound 13b was obtained (yield: 53%). ¹ H NMR (500 MHz, CDCl ₃ )δ12.45(s,1H),9.54(d,J＝2.2Hz,1H),8.77(d,J＝1.9Hz,1H),8.60(s,1H),8.17(d,J＝8. 4Hz,1H),8.08(s,1H),8.00(d,J＝7.9Hz,1H),7.86–7.80(m,1H),7.67–7.61(m,3H),7.45 (d,J＝8.3Hz,2H),7.10(s,1H),6.99(s,1H),6.87(s,1H),3.98(s,3H),3.92(s,3H),3.90 (s,3H),3.85(s,3H),3.79(s,2H),3.65(s,2H),2.88(t,J＝5.5Hz,2H),2.73–2.69(m,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ167.49,163.96,152.92,150.19,149.42,149.15,148.82,147.05,1 46.22,144.68,136.54,135.85,135.80,131.50,129.90,129.41,129.2 4,127.52,127.25,126.95,121.01,120.02,112.14,111.36,109.66,10 5.06,100.58,95.71,61.25,56.46,56.31,56.19,50.27,50.10,20.94.

Preparation Example 45

Preparation of N-(2-((4-(2-(7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide: Referring to the preparation method in Preparation Example 33, a pale yellow solid compound 13c was obtained (yield: 49%). ¹ H NMR (500 MHz, CDCl ₃ )δ12.45(s,1H),9.53(d,J＝2.2Hz,1H),8.76(d,J＝1.9Hz,1H),8.58(s,1H),8.17(d,J＝8.4Hz,1H ),8.08(s,1H),8.00(d,J＝8.0Hz,1H),7.87–7.79(m,1H),7.63(t,J＝7.4Hz,1H),7.58(d,J＝8.4H z,2H),7.29(d,J＝8.3Hz,2H),7.09(s,1H),7.01(d,J＝8.4Hz,1H),6.88(d,J＝8.4Hz,1H),4.13(s ,3H),3.97(s,3H),3.91(s,3H),3.84(s,3H),3.76(s,2H),2.96–2.86(m,6H),2.75–2.70(m,2H). ¹³ C NMR (126MHz, CDCl ₃ )δ167.43,163.92,152.90,150.84,149.40,148.81,148.53,146.71,144.67,137.14,135.81,135.80,135.43,134.78,131.47,129.44, 129.39,129.20,127.48,127.26,126.94,124.28,121.27,112.13,111.71,111.35,109.64,109.24,105.08,61.00,59.21,57.30,56.50,56.18,50.48,50.19,33.73,20.87.

Preparation Example 46

Preparation of N-(2-((4-((7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide: Referring to the preparation method in Preparation Example 33, a pale yellow solid compound 13d was obtained (yield: 43%). ¹ H NMR (500 MHz, CDCl ₃ )δ12.46(s,1H),9.54(d,J＝1.8Hz,1H),8.78(s,1H),8.62(s,1H),8.17(d,J＝8.4Hz,1H ),8.04–7.97(m,2H),7.83(t,J＝7.4Hz,1H),7.67–7.60(m,3H),7.45(d,J＝8.2Hz,2H), 7.10(s,1H),7.00(d,J＝8.4Hz,1H),6.87(d,J＝8.4Hz,1H),4.10(s,3H),4.00(s,3H),3 .91(s,3H),3.88(s,3H),3.79(s,2H),3.67(s,2H),2.88(t,J＝5.3Hz,2H),2.70(s,2H). ¹³ C NMR (101MHz, CDCl ₃ +CD ₃ OD)δ167.80,163.76,152.56,150.61,148.95,148.67,148.42,146.60,144 .55,136.95,136.01,135.31,134.66,134.17,131.70,129.89,129.23,128. 82,127.63,127.28,126.98,124.21,121.35,112.50,111.76,111.25,110.53,109.25,104.88,61.20,60.89,57.25,56.41,56.10,49.98,49.89,20.58.

Preparation Example 47

Preparation of N-(2-((4-(2-(3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide: Referring to the preparation method in Preparation Example 33, a pale yellow solid compound 13e was obtained (yield: 47%). ¹ H NMR (500 MHz, CDCl ₃ ) δ12.47 (s, 1H), 9.54 (d, J=2.3 Hz, 1H), 8.77 (d, J=2.1 Hz, 1H), 8.61 (s, 1H), 8.17 (d, J=8.6 Hz, 1H), 8.00 (d, J=7.7 Hz, 1H), 7.94 (s, 1H), 7.85-7.80 (m, 1H), 7.65-7.61 (m, 1H), 7. 56(d,J＝8.4Hz,2H),7.45–7.40(m,2H),7.30(d,J＝8.4Hz,2H),7.25–7.19(m,2H),7.09( s,1H),4.00(s,3H),3.89(s,3H),3.77(s,2H),2.98–2.87(m,6H),2.77(t,J＝5.6Hz,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ167.46,163.92,154.74,152.84,151.13,149.38,148.81,144.65,137 .06,135.83,135.74,135.51,131.49,129.44,129.38,129.22,128.04,12 7.50,127.25,126.94,123.38,122.47,121.29,118.63,112.19,111.41,111.09,109.71,105.06,59.26,56.47,56.18,50.54,50.17,33.67,20.83.

Preparation Example 48

Preparation of 2-(3-cyanobenzamido)-N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-4,5-dimethoxybenzamide: Referring to the preparation method in Preparation Example 33, a pale yellow solid compound 13f was obtained (yield: 42%). ¹ H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 10.47 (s, 1H), 8.29 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.15 (s, 1H), 8.09 (d, J = 7.7 Hz, 1H), 7.80 (t, J ＝7.8Hz,1H),7.67(d,J＝8.3Hz,2H),7.53(s,1H),7.33(d,J＝8.4Hz,2H),7.30(s,1H),7.17(s,1H),4.76–4. 40(m,2H),3.90(s,3H),3.87(s,3H),3.81(s,6H),3.57–3.39(m,4H),3.24–3.13(m,2H),3.12–2.93(m,2H). ^13C NMR (126MHz, DMSO) δ167.46,163.14,151.92,149.49,148.30,146.95,144.92,137.67,136.28,135.76,133.88,131.97,131.30,130.77,129. 40,122.36,118.71,118.58,115.00,112.53,112.48,111.68,105.79,1 01.97,96.57,56.51,56.49,56.46,56.12,49.95,48.08,29.64,18.26.

Preparation Example 49

Preparation of N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)nicotinamide: Referring to the preparation method in Preparation Example 33, 13 g of a pale yellow solid compound was obtained (yield: 45%). ¹ H NMR (400 MHz, CDCl ₃ )δ12.26(s,1H),9.27(d,J＝1.7Hz,1H),8.76(dd,J＝4.7,1.2Hz,1H),8.51(s,1H) ,8.25(d,J＝8.0Hz,1H),8.09(s,1H),7.55(d,J＝8.3Hz,2H),7.43(dd,J＝7.8,4.9 Hz,1H),7.29(d,J＝8.3Hz,2H),7.05(s,1H),7.01(s,1H),6.88(s,1H),3.92(s,6 H),3.90(s,3H),3.81(s,3H),3.74(s,2H),2.97–2.84(m,6H),2.76–2.70(m,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ167.43,163.83,152.81,152.58,150.10,149.14,147.01,146.18,144.63,137.22,135.59,135.38,134.81,130.25,129.49,1 23.57,121.32,119.95,112.13,111.42,109.51,104.97,100.51,95.65,59.37,56.43,56.31,56.19,50.66,50.34,33.77,21.04.

Preparation Example 50

Preparation of N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridine-2(1H)-yl)ethyl)phenyl)-2-(3-fluorobenzamide)-4,5-dimethoxybenzamide: Referring to the preparation method in Preparation Example 33, a light yellow solid compound 13h was obtained (yield: 43%). ¹ H NMR (500MHz, CDCl ₃ )δ12.05(s,1H),8.43(s,1H),8.29(s,1H),7.73(t,J＝6.4Hz,2H),7.60(d ,J＝8.1Hz,2H),7.47(dd,J＝13.6,7.9Hz,1H),7.29(d,J＝8.1Hz,2H),7.25 –7.21(m,1H),7.02(d,J＝2.1Hz,2H),6.88(s,1H),3.92(s,3H),3.91(s,3 H),3.84(s,3H),3.76–3.72(m,5H),2.97–2.85(m,6H),2.77–2.71(m,2H).

¹³ C NMR (101 MHz, CDCl ₃ )δ167.41,164.35,152.74,149.15,147.05,146.21,144.55,135.58,1 35.50,130.58,130.50,129.48,122.72,122.69,121.29,119.94,119. 07,118.86,114.96,114.73,112.32,111.42,109.57,105.01,100.54, 95.67,59.35,56.45,56.42,56.32,56.15,50.66,50.32,33.74,21.01.

Preparation Example 51

N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-4,5-dimethoxy -2-(pyridine-3-sulfonylamino)benzamide preparation: Referring to the preparation method in Preparation Example 33, a light yellow solid compound 13i was prepared (yield: 45%). ¹ H NMR (500MHz, CDCl ₃ )δ8.76(d,J＝1.5Hz,1H),8.60(d,J＝3.8Hz,1H),8.06(d,J＝8.0Hz,1H),7.70(s,1H),7.33(d,J＝7.8Hz,2H),7.30–7.17(m,5H),7.01(s, 1H),6.91(s,1H),6.87(s,1H),3.93(s,3H),3.91(s,3H),3.90(s,3H),3.84(s,3H),3.74(s,2H),2.96–2.85(m,6H),2.76–2.71(m,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ166.11,153.31,152.70,149.95,149.14,147.93,147.05,146.37,146.20,137.22,135.58,135.13,134.98,132.48,129.39,123. 77,121.06,119.92,115.95,111.42,109.23,107.62,100.53,95.67,59.21,56.47,56.42,56.35,56.30,50.62,50.30,33.65,20.97.

Preparation Example 52

Preparation of N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoxaline-2-carboxamide: Referring to the preparation method in Preparation Example 33, a light yellow solid compound 13j was obtained (yield: 43%). ¹ H NMR (400MHz, CDCl ₃ +CD ₃ OD)δ9.42(s,1H),8.32(s,1H),8.14–8.08(m,1H),7.94(d,J＝8.1Hz,1H),7.73–7.63(m,2H),7.43(d,J＝7.4Hz,2H),7.18(s,1H),7.06(d,J =7.9Hz,2H),6.82(s,1H),6.70(s,1H),3.81(s,3H),3.75(s,3H),3.70(s,3H),3.69(s,3H),3.57(s,2H),2.83–2.65(m,6H),2.57(s,2H). ¹³ C NMR (101 MHz, CDCl ₃ +CD ₃ OD)δ171.45,165.96,155.85,153.26,153.12,151.13,150.16,148.69, 148.08,147.23,144.53,140.35,139.83,137.44,136.07,135.01,134. 37,132.97,132.61,125.68,123.73,118.61,115.27,115.10,108.88,1 04.81,99.76,63.07,60.29,60.09,59.85,54.38,53.95,36.99,24.35.

Preparation Example 53

Preparation of N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)-2-oxoethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide: Referring to the preparation method in Preparation Example 33, a pale yellow solid compound 13k was obtained (yield: 44%). ¹ H NMR (500 MHz, CDCl ₃ , conformational isomers) δ12.58–12.50 (m, 1H), 9.53–9.49 (m, 1H), 8.76–8.72 (m, 1H), 8.68–8.60 (m, 1H), 8.53–8.50 (m, 1H), 8.16–8.12 (m, 1H), 7.98–7.94 (m, 1H), 7.83–7.77 (m, 1H), 7.63–7.59 (m, 1H), 7.59–7.52 (m ,2H),7.23–7.16(m,3H),7.01–6.95(m,1H),6.87–6.79(m,1H),4.80–4.56(m,2H),3.96–3.92(m,4 H),3.91–3.88(m,3H),3.88–3.85(m,3H),3.83–3.80(m,4H),3.79–3.75(m,2H),2.71–2.56(m,2H). ¹³ C NMR (126MHz, CDCl ₃ , conformational isomers)δ170.50,170.44,167.54,167.52,163.89,163.85,152.70,152.66,149.34,149.31,148.75,148.66,148.20,147.62,147.49,146.81,146.54,146.42,144.55,136.50,136.45,135.97,135.84,135.73,135.68,131.47,131.45,131.15,130.92,129.36,129.33,129.26,129.21, 129.18,127.48,127.46,127.29,127.26,126.95,126.92,121.52,119.30,119.23,113.06,112.16,112.10,111.32,110.01,104.93,100.59,100.44,95.74,95.63,56.43,56.39,56.29,56.13,44.23,44.03,40.93,40.85,40.55,39.94,21.67,20.60.

Preparation Example 54

Preparation of N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-difluorophenyl)quinoline-3-carboxamide: Referring to the preparation method in Preparation Example 33, a light yellow solid compound 131 was obtained (yield: 39%). ¹ H NMR (400MHz, CDCl ₃ )δ12.49(s,1H),9.50(s,1H),8.97–8.65(m,3H),8.16(d,J＝6.9Hz,1H),7.99(d,J＝6.6Hz,1H),7.90–7.77(m,1H) ,7.74–7.54(m,4H),7.27(s,2H),7.01(s,1H),6.88(s,1H),3.92(s,6H),3.74(s,2H),2.92(bs,6H),2.73(s,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ166.05,163.94,150.04,149.53,149.15,148.59,147.06,146.22,137.48,136.16,135.22,131.70,129.42,129.23,127.61,126.9 0,126.77,121.50,119.97,116.83,116.13,111.43,111.32,111.09,100.58,95.69,59.30,56.46,56.32,50.63,50.33,33.75,21.00.

Preparation Example 55

Preparation of N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)phenyl)quinoline-3-carboxamide: Referring to the preparation method in Preparation Example 33, a pale yellow solid compound 13m was obtained (yield: 43%). ¹ H NMR (400 MHz, CDCl ₃ )δ12.08(s,1H),9.51(d,J＝1.3Hz,1H),8.87(s,1H),8.76(s,1H),8.60(d,J＝8.3Hz,1H),8.18(d, J＝8.4Hz,1H),8.00(d,J＝8.1Hz,1H),7.83(t,J＝7.5Hz,1H),7.70(d,J＝8.1Hz,2H),7.64(t,J＝7.5H z,1H),7.59(d,J＝7.6Hz,1H),7.37(t,J＝7.8Hz,1H),7.29(d,J＝8.1Hz,2H),7.00(s,1H),6.90(t,J =7.6Hz,1H),6.87(s,1H),3.90(s,3H),3.89(s,3H),3.74(s,2H),2.99–2.85(m,6H),2.73(s,2H). ¹³ C NMR (101MHz, CDCl ₃ )δ167.47,164.18,150.08,149.48,149.15,148.70,147.04,146.20,1 39.08,137.01,136.05,135.77,132.59,131.62,129.47,129.21,127.5 9,127.28,127.14,126.95,123.38,121.95,121.55,120.92,119.98,11 1.42,100.58,95.70,59.37,56.44,56.31,50.63,50.33,33.76,21.01.

Preparation Example 56

Preparation of N-(2-((4-(3-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)-3-oxopropyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide: Referring to the preparation method in Preparation Example 33, a light yellow solid compound 13n was obtained (yield: 46%).

¹ H NMR (500 MHz, CDCl ₃ , conformer) δ12.51 (s, 1H), 9.52 (s, 1H), 8.75 (s, 1H), 8.56 (s, 1H), 8.38–8.22 (m, 1H), 8.15 (d, J＝8.4 Hz, 1H), 7.98 (d, J＝8.1 Hz, 1H), 7.84–7.79 (m,1H),7.62(t,J＝7.5Hz,1H),7.55(d,J＝8.3Hz,1H),7.52(d,J＝8.3Hz,1H), 7.24(t,J＝8.2Hz,2H),7.15–7.07(m,1H),7.05–6.95(m,1H),6.89–6.80(m,1 H),4.62(m,2H),3.95(s,3H),3.94–3.91(m,1H),3.91–3.84(m,6H),3.81(s, 3H), 3.72(t,J＝5.4Hz,1H), 3.00(dd,J＝15.8,8.0Hz,2H), 2.79–2.65(m,4H). ¹³ C NMR (126 MHz, CDCl ₃ , conformational isomers) δ 171.47, 171.32, 167.51, 167.42, 163.85, 152.83, 149.35, 149.29, 148.79, 148.73, 148.53, 147.57, 147.44, 147.04, 146.50, 146.41, 144.61, 138.08, 137.95, 135.92, 135.85, 135.80, 135.57, 131.47, 129.35, 129.20, 129.09, 1 ,27.49,127.30,126.95,121.46,121.32,119.37,119.31,113.09,112.08,111.29,109.79,105.00,100.56,100.42,95.75,95.58,56.45,56.41,56.28,56.25,56.16,43.68,43.35,40.78,39.71,35.78,35.33,30.80,30.78,21.74,20.60.

Preparation Example 57

(E)-N-(2-((4-(3-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)-3-oxoprop-1-en-1-yl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide Preparation: Referring to the preparation method in Preparation Example 33, a pale yellow solid compound 13o was obtained (yield: 38%). ¹ H NMR (400 MHz, CDCl ₃ +CD ₃ OD, conformer) δ9.40 (s, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.76 (t, J = 7.6 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.63–7.51 (m, 2H), 7.4 7(d,J＝8.2Hz,2H),7.25–7.22(m,1H),7.01–6.93(m,1H),6.89–6.75(m,2H),4.75( s,2H),3.90(s,3H),3.85(s,6H),3.82(s,3H),2.82(s,2H),2.73(d,J＝21.9Hz,2H). ¹³ C NMR (101MHz, CDCl ₃ +CD ₃ OD, conformer)δ167.82,166.87,163.60,152.60,149.33,148.91,148.51,148.17,147.51,146.97,146.40,144.45,142.92,139.51,136.09,135.37,131.72,131.15,129.22,128.80,128 .65,127.65,127.17,126.95,121.14,119.33,116.21,115.89,112.17,110.56,104.67,100.58,100.49,95.72,95.62,56.40,56.30,56.25,56.06,44.05,43.95,41.41,21.91,20.56.

Preparation Example 58

Preparation of (E)-N-(2-((4-(3-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridine-2(1H)-yl)-3-oxoprop-1-en-1-yl)phenyl)carbamoyl)phenyl)quinoline-3-carboxamide: Referring to the preparation method in Preparation Example 33, a light yellow solid compound 13p was obtained (yield: 46%). ¹ H NMR (400 MHz, CDCl ₃ +CD ₃ OD, conformer) δ9.45 (s, 1H), 8.84 (s, 1H), 8.71 (d, J=8.3 Hz, 1H), 8.14 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.95–7.85 (m, 2H), 7.80 (d, J=8.3 Hz, 2H), 7.73–7.59 (m, 5H), 7.27 (t, J=7.6 Hz, 1H), 7.12–6.86 (m, 3H), 4.83 (s, 2H), 4.08–3.97 (m, 2H), 3.92 (s, 6H), 2.98–2.68 (m, 2H). ¹³ C NMR (101MHz, CDCl ₃ +CD ₃ OD, conformational isomer) δ165.64,164.48, 161.12,146.69,145.95,145.71,145.34,144.67,144.32,143.60,140.39,136.91,136.33,133.68,130.18,129.29,128.60,126.57,125.94,125.61,125.45 ,125.16,124.55,124.34,120.99,118.87,118.80,118.58,116.72,113.20,110.31,108.89,97.98,93.06,53.60,53.41,41.28,38.66,37.67,19.10,17.78.

Preparation Example 59

Preparation of N-(4-(4,5-dimethoxy-2-(quinoline-3-carboxamido)benzamido)phenyl)-6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridine-2(1H)-carboxamide: Referring to the preparation method in Preparation Example 33, a pale yellow solid compound 13q was obtained (yield: 43%). ¹ H NMR (400 MHz, CDCl ₃ +CD ₃ OD) δ9.35 (s, 1H), 8.70 (s, 1H), 8.42 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.74 (t, J=7.5 Hz, 1H), 7.54 (t, J=7.4 Hz, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.29 (s, 1 H),7.20(d,J＝8.2Hz,2H),6.91(s,1H),6.79(s,1H),4.47(s,2H),4.31(s,2H),3.91 (s,3H),3.84(s,3H),3.81(s,3H),3.80(s,3H),3.66(t,J=5.1Hz,2H),2.63(s,2H). ¹³ C NMR (101MHz, CDCl ₃ +CD ₃ OD)δ168.01,163.58,158.22,152.39,149.22,148.72,148.46,148.12,1 47.26,146.24,144.48,136.56,136.13,135.24,131.74,129.18,128.54, 128.01,127.65,127.30,126.97,121.98,119.51,112.26,110.64,104.66,100.58,95.65,56.35,56.27,56.19,56.01,44.29,42.26,41.61,20.96.

In addition, it should be understood that after reading the above description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (10)

The compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof:
R ¹ , R ² , R ³ , R ⁴ , R ⁶ , and R ⁷ are the same or different and are independently selected from H, halogen, C ₁ ～C ₅ alkyl or C ₁ ～C ₅ alkoxy; R ⁵ and R ⁸ are the same or different and are independently selected from substituted or unsubstituted phenyl, pyridyl, pyrazinyl, quinolyl, isoquinolyl, chromonyl, quinolone or quinoxalinyl; the substituents on the phenyl, pyridyl, pyrazinyl, quinolyl, isoquinolyl, chromonyl, quinolone or quinoxalinyl are independently selected from cyano or halogen; m is selected from 0 to 4; X is selected from -NHC(=O)- or -NHS(=O) ₂ -; L is selected from n is independently selected from 0 to 4. The compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that one end of the benzene ring in L is connected to an amide bond. The compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that the compound is selected from any one of the following: N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine; N-(4-((6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)-2-(pyridin-3-yl)quinoline Oxazoline-4-amine; N-(4-(2-(7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine; N-(4-((7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine; N-(4-(2-(3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-3-yl)quinazolin-4-amine; N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-4-yl)quinazolin-4-amine; N-(4-((6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)-2-(pyridin-4-yl)quinazolin-4-amine; N-(4-(2-(7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-4-yl)quinazolin-4-amine; N-(4-((7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)-2-(pyridin-4-yl)quinazolin-4-amine; N-(4-(2-(3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(pyridin-4-yl)quinazolin-4-amine; N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide; N-(2-((4-((6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide; N-(2-((4-(2-(7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide; N-(2-((4-((7,8-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)methyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide; N-(2-((4-(2-(3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide; 2-(3-cyanobenzamido)-N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-4,5-dimethoxybenzamide; N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)nicotinamide; N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-2-(3-fluorobenzamido)-4,5-dimethoxybenzamide; N-(4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)-4,5-dimethoxy-2-(pyridine-3-sulfonyl)benzamide; N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-2-carboxamide; N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)-2-oxoethyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide; N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)-4,5-difluorophenyl)quinoline-3-carboxamide; N-(2-((4-(2-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)phenyl)carbamoyl)phenyl)quinoline-3-carboxamide; N-(2-((4-(3-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)-3-oxopropyl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide; (E)-N-(2-((4-(3-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)-3-oxoprop-1-en-1-yl)phenyl)carbamoyl)-4,5-dimethoxyphenyl)quinoline-3-carboxamide; (E)-N-(2-((4-(3-(6,7-dimethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)-3-oxoprop-1-en-1-yl)phenyl)carbamoyl)phenyl)quinoline-3-carboxamide; N-(4-(4,5-dimethoxy-2-(quinoline-3-carboxamido)benzamido)phenyl)-6,7-dimethoxy-3,4-dihydrobenzofurano[2,3-c]pyridine-2(1H)-carboxamide. A method for preparing a compound of formula (I) or (II) according to any one of claims 1 to 3, characterized in that the synthetic route is:
Compound 10 is a compound represented by formula (I), wherein Y is Compound 13 is a compound represented by formula (II), wherein Y is -NH-Z is -XR ⁸ ; Compound 1 undergoes ortho-Friedel-Crafts acylation under acetic acid/boron trifluoride ether conditions to obtain compound 2, compound 2 reacts with ethyl bromoacetate in the presence of cesium carbonate as a base to generate compound 3, compound 3 undergoes hydrolysis reaction to obtain compound 4, compound 4 undergoes cyclization reaction to obtain compound 5, compound 5 undergoes multi-component reaction with benzylamine and formaldehyde aqueous solution in acetic acid solvent to obtain compound 6, compound 6 is debenzylated to obtain compound 7, compound 7 undergoes nucleophilic substitution reaction with a halide or undergoes amide condensation reaction to obtain compound 8, compound 8 undergoes nitro reduction reaction to obtain compound 9; compound 9 undergoes nucleophilic substitution reaction with compound 14 to obtain compound 10; or, compound 9 undergoes amide condensation reaction with compound 15 to obtain compound 11, compound 11 undergoes nitro reduction reaction to obtain compound 12, and compound 12 undergoes amide condensation reaction or sulfonamide condensation reaction to obtain compound 13. Use of a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a P-glycoprotein inhibitor. The use according to claim 5, characterized in that the P-glycoprotein inhibitor is an oral preparation. Use of a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a drug resistance regulator for improving the cancer treatment effect of an anti-cancer drug. The use according to claim 7, characterized in that the anticancer drug is a drug that is not easily absorbed in the digestive tract due to the inhibitory effect of intestinal P-glycoprotein, including taxanes, vinca alkaloids, anthracyclines, camptothecin, podophyllotoxin, mitoxantrone, actinomycin, and colchicine; The taxanes include paclitaxel and docetaxel; Said vinca alkaloids include vincristine and vinblastine; The anthracyclines include daunorubicin and doxorubicin; The camptothecins include topotecan and irinotecan. The use according to claim 7, characterized in that the cancer is a solid tumor or a hematological malignancy selected from leukemia, multiple myeloma, and lymphoma; The leukemia is acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia; The lymphoma is Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, follicular lymphoma, B cell lymphoma, T cell lymphoma, diffuse large B cell lymphoma. The use according to claim 7 is characterized in that the drug resistance regulator is an oral preparation.