WO2025113152A1 - 一种p-糖蛋白抑制剂及其制备方法和应用 - Google Patents

一种p-糖蛋白抑制剂及其制备方法和应用 Download PDF

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WO2025113152A1
WO2025113152A1 PCT/CN2024/131215 CN2024131215W WO2025113152A1 WO 2025113152 A1 WO2025113152 A1 WO 2025113152A1 CN 2024131215 W CN2024131215 W CN 2024131215W WO 2025113152 A1 WO2025113152 A1 WO 2025113152A1
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pyridin
phenyl
compound
dimethoxy
dihydrobenzofuran
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French (fr)
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崔孙良
钱海
周显晶
石炜
赖振成
张萍
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China Pharmaceutical University
Zhejiang University ZJU
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China Pharmaceutical University
Zhejiang University ZJU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • 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.
  • Multidrug resistance 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.
  • P-glycoprotein transmembrane protein
  • P-gp transmembrane protein
  • 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.
  • anticancer agents such as vinca alkaloids, anthracyclines, paclitaxel, doxorubicin, etc.
  • 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.
  • P-glycoprotein 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.
  • the present invention develops a class of P-glycoprotein inhibitors with novel structures and potent P-glycoprotein inhibitory activity.
  • 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.
  • 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;
  • n is selected from 0 to 4.
  • 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.
  • one end of the benzene ring in L is connected to an amide bond.
  • 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 ;
  • 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.
  • 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
  • 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.
  • 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).
  • any excipient known and widely used in the art can be used.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • an injection delivery fluid such as a glucose solution and an amino acid solution
  • 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.
  • drug-resistant tumor cells such as leukemia drug-resistant cells K562/A02, etc.
  • MDR multidrug resistance
  • XR9576 third-generation P-glycoprotein inhibitor Tariquidar
  • 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.
  • anticancer agents paclitaxel, docetaxel, doxorubicin, etc.
  • 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 ⁇ L RPMI 1640 medium was added to each well and incubated in a 37°C, 5% CO 2 incubator for 24 hours. 100 ⁇ L 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 ⁇ L of culture medium was added to each well of the test compound group and the positive control group, and 50 ⁇ L of the target compound (5 ⁇ M) and 50 ⁇ L 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.
  • 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.
  • 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 ⁇ L of RPMI 1640 medium per well, and placed in a 37°C, 5% CO 2 incubator for 24 hours.
  • 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.
  • 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.
  • SD rats 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.
  • 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.
  • 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.
  • 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°C 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.
  • 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.
  • 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°C for 3h.
  • 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.
  • 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%).

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Abstract

本发明公开了式(I)或(II)所示化合物或其可药用的盐及其制备方法和应用：该类化合物对P-糖蛋白高表达的耐药肿瘤细胞具有明显抑制活性，有较强的逆转肿瘤细胞多药耐药的作用，且部分化合物对P-糖蛋白抑制活性明显优于第三代P-糖蛋白抑制剂他立喹达，并且具有较小的细胞毒性。此外，该类化合物能够选择性抑制肠道上皮细胞P-糖蛋白，与由于肠道P-糖蛋白的抑制作用而不容易在消化道中吸收的抗癌剂联合口服给药时，提高抗癌剂的生物利用度。

Description

一种P-糖蛋白抑制剂及其制备方法和应用 技术领域
本发明涉及药物化学领域，具体涉及一种N-取代-1,2,3,4-四氢苯并呋喃[2,3-C]并吡啶类P-糖蛋白抑制剂及其制备方法和应用。
背景技术
多药耐药(multidrug resistance，MDR)是指肿瘤细胞对一种抗肿瘤药物产生耐药后，对其它结构和作用机制不同的抗肿瘤药物也产生交叉耐药的机制。
多药耐药的发生是目前肿瘤化学治疗失败的一个主要原因，同时也是肿瘤治疗中最常见、最棘手的问题。
因此，寻找逆转MDR药物以抑制多药耐药的产生已成为肿瘤治疗中亟需解决的问题。
肿瘤多药耐药现象产生的机制多样，涉及复杂的分子生物学基础目前尚未被完全解析，但其中肿瘤细胞跨膜蛋白——(P-糖蛋白，P-gp)的过度表达被认为是多药耐药产生的主要原因。过度表达的P-糖蛋白利用ATP水解释放的能量将进入肿瘤细胞内的抗癌剂(如长春生物碱、蒽环类药物、紫杉醇、多柔比星等)泵出细胞外，导致细胞内抗肿瘤药物的浓度低于有效浓度，使肿瘤细胞对多种化疗药物产生耐受，从而产生MDR。因此，P-糖蛋白抑制剂与抗癌剂联合给药治疗，有望能够解决肿瘤多药耐药问题。
自第一个多药耐药逆转剂维拉帕米被发现以来，多药耐药逆转剂的研究已历经三代。
第一代以维拉帕米和环孢霉素A为代表，此类抑制剂具有较大的心血管等副作用。第二代抑制剂活性增强，如Valspodar和Biricodard，但该类抑制剂明显影响与其联合应用抗癌药物的血浆药物动力学，限制了临床上的应用。第三代抑制剂是基于构效关系研究而设计开发的化合物，此类化合物抑制剂具有较好的活性和选择性，如Elacridar、他立喹达(Tariquidar)和WK-X-34等。
然而，由于各种副作用的出现，目前仍未有有效的逆转剂应用于临床治疗。
除癌症细胞外，还在包括肝、小肠、肾和血-脑内皮的许多正常人组织中发现P-糖蛋白。在所有这些组织中P-糖蛋白定位于细胞分泌区域。这种定位表明P-糖蛋白在限制外源毒性物质通过生物屏障的吸收起作用，比如紫杉醇等抗癌剂，由于自身理化 性质以及肠道上皮细胞P-糖蛋白外排等原因，导致这些药物临床上通常为静脉注射的方式给药。
因此，临床上亟需新一代安全、有效的P-糖蛋白抑制剂，解决肿瘤多药耐药以及提高抗癌剂生物利用度等问题。
针对上述问题，本发明开发了一类结构新颖的P-糖蛋白抑制剂，并且具有强效的P-糖蛋白抑制活性。
发明内容
本发明提供了具有P-糖蛋白抑制活性的式(I)或(II)所示化合物或其可药用的盐，均未表现出明显细胞毒性作用，且部分化合物或其可药用盐的P-糖蛋白抑制活性明显优于第三代P-糖蛋白抑制剂他立喹达，式(Ⅰ)或(Ⅱ)所示化合物或其可药用的盐具有潜在的预防和治疗肿瘤多药耐药发生的作用，可提高抗癌剂口服生物利用度，具备潜在抗肿瘤价值。
式(I)或(II)所示化合物或其可药用的盐：
R1、R2、R3、R4、R6、R7相同或不相同，分别独立选自H、卤素、C1～C5烷基或C1～C5烷氧基；
R5、R8相同或不相同，分别独立选自取代或未取代的苯基、吡啶基、吡嗪基、喹啉基、异喹啉基、色酮基、喹诺酮基或喹喔啉基；所述苯基、吡啶基、吡嗪基、喹啉基、异喹啉基、色酮基、喹诺酮基或喹喔啉基上的取代基分别独立选自氰基或卤素；
m选自0～4；
X选自-NHC(＝O)-或-NHS(＝O)2-；
L选自n分别独立选自0～4。
本发明所述的可药用的盐可包括与下列酸形成的加成盐：盐酸、硫酸、磷酸、氢溴酸、醋酸、三氟乙酸、丙酮酸、柠檬酸、酒石酸、乳酸、马来酸、苯磺酸、琥珀酸以及与类似的已知可以接受的酸形成的盐。
进一步的，所述的式(I)或(II)所示化合物或其可药用的盐，L中苯环一端与酰胺键连接。
更进一步的，所述的式(I)或(II)所示化合物或其可药用的盐，所述化合物选自以下任一：
N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-3-基)喹唑啉-4-胺，可记为化合物10a；
N-(4-((6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)-2-(吡啶-3-基)喹唑啉-4-胺，可记为化合物10b；
N-(4-(2-(7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-3-基)喹唑啉-4-胺，可记为化合物10c；
N-(4-((7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)-2-(吡啶-3-基)喹唑啉-4-胺，可记为化合物10d；
N-(4-(2-(3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-3-基)喹唑啉-4-胺，可记为化合物10e；
N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-4-基)喹唑啉-4-胺，可记为化合物10f；
N-(4-((6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)-2-(吡啶-4-基)喹唑啉-4-胺，可记为化合物10g；
N-(4-(2-(7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-4-基)喹唑啉-4-胺，可记为化合物10h；
N-(4-((7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)-2-(吡啶-4-基)喹唑啉-4-胺，可记为化合物10i；
N-(4-(2-(3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-4-基)喹唑啉-4-胺，可记为化合物10j；
N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺，可记为化合物13a；
N-(2-((4-((6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺，可记为化合物13b；
N-(2-((4-(2-(7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺，可记为化合物13c；
N-(2-((4-((7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺，可记为化合物13d；
N-(2-((4-(2-(3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺，可记为化合物13e；
2-(3-氰基苯甲酰胺基)-N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-4,5-二甲氧化苯甲酰胺，可记为化合物13f；
N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)烟酰胺，可记为化合物13g；
N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(3-氟苯甲酰胺基)-4,5-二甲氧基苯甲酰胺，可记为化合物13h；
N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-4,5-二甲氧基-2-(吡啶-3-磺胺基)苯甲酰胺，可记为化合物13i；
N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-2-甲酰胺，可记为化合物13j；
N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-2-氧乙基)苯基)氨甲酰基)-4,5-二甲氧基苯基)喹啉-3-甲酰胺，可记为化合物13k；
N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二氟苯基)喹啉-3-甲酰胺，可记为化合物13l；
N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)苯基)喹啉-3-甲酰胺，可记为化合物13m；
N-(2-((4-(3-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-3-氧丙基)苯基)氨甲酰基)-4,5-二甲氧基苯基)喹啉-3-甲酰胺，可记为化合物13n；
(E)-N-(2-((4-(3-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-3-氧丙-1-烯-1-基)苯基)氨甲酰基)-4,5-二甲氧基苯基)喹啉-3-甲酰胺，可记为化合物13o；
(E)-N-(2-((4-(3-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-3-氧丙-1-烯-1-基) 苯基)氨甲酰基)苯基)喹啉-3-甲酰胺，可记为化合物13p；
N-(4-(4,5-二甲氧基-2-(喹啉-3-甲酰胺基)苯甲酰胺基)苯基)-6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-甲酰胺，可记为化合物13q。
上述罗列的具体化合物的化学结构为：
本发明还提供了所述的式(I)或(II)所示化合物的制备方法，合成路线：
化合物10即为式(I)所示化合物，其中Y为
化合物13即为式(II)所示化合物，其中Y为 -NH-Z为-X-R8；
化合物1在乙酸/三氟化硼乙醚条件下发生邻位傅克酰基化得到化合物2，化合物2与溴乙酸乙酯在碳酸铯作碱下生成化合物3，化合物3发生水解反应得到化合物4，化合物4发生环化反应得到化合物5，化合物5在乙酸溶剂中与苄胺、甲醛水溶液发生多组分反应得到化合物6，化合物6脱苄基得到化合物7，化合物7与卤代物发生亲核取代反应或者经酰胺缩合反应得到化合物8，化合物8经硝基还原反应得到化合物9；化合物9与化合物14发生亲核取代反应得到化合物10；或者，化合物9与化合物15进行酰胺缩合反应得到化合物11，化合物11经硝基还原反应得到化合物12，化合物12经酰胺缩合反应或磺胺缩合反应得到化合物13。
本发明还提供了所述的式(I)或(II)所示化合物或其可药用的盐在制备P-糖蛋白抑制剂中的应用。所述P-糖蛋白抑制剂可为口服制剂。
所述的式(I)或(II)所示化合物或其可药用的盐能够改进或增加抗癌剂的效力，增加肿瘤对抗癌剂的敏感性，降低肿瘤对抗癌剂的MDR，具体的，可通过增强化疗药 物的细胞毒性，或增加治疗药物的净吸收、分布、代谢或消除的特征来提高癌症治疗效果。
因此，本发明还提供了所述的式(I)或(II)所示化合物或其可药用的盐在制备用于提高抗癌症药物癌症治疗效果的抗药性调节剂中的应用。所述抗药性调节剂可为口服制剂。
所述抗癌症药物可为由于肠道P-糖蛋白的抑制作用而不容易在消化道中吸收的药物，可包括紫杉烷类、长春生物碱、蒽环类药、喜树碱、鬼臼毒素、米托蒽酯、放线菌素、秋水仙碱等。所述紫杉烷类包括紫杉醇、多西他赛。所述长春生物碱包括长春新碱、长春碱。所述蒽环类药包括柔红霉素、多柔比星。所述喜树碱包括托泊替康、伊立替康。
所述癌症可为实体瘤或血液系统恶性肿瘤，可选自白血病、多发性骨髓瘤、淋巴瘤。所述白血病可为急性淋巴细胞白血病、急性髓性白血病、慢性淋巴细胞白血病、慢性髓性白血病。所述淋巴瘤可为霍奇金淋巴瘤、非霍奇金淋巴瘤、套细胞淋巴瘤、滤泡型淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、弥散性大B细胞淋巴瘤。
本发明还提供了一种药物组合物，包含所述的式(Ⅰ)或(Ⅱ)所示化合物或其可药用的盐，以及一种或多种可药用载体、稀释剂、赋形剂。可药用载体是指能与组合物中的活性成分相容(在一些实施方案中，能稳定活性成分)并且对所治疗的个体无害的载体。药用载剂和/或赋形剂可选自稀释剂、填充剂、盐、崩解剂、黏合剂、润滑剂、助流剂、润湿剂、控制释放基质、着色剂、调味剂、缓冲剂、稳定剂、增溶剂及其组合。包含本文所述的式(Ⅰ)或(Ⅱ)的化合物或其药学上可接受的盐的药物组合物可以以各种已知的方式、例如口服、局部、直肠、肠胃外、吸入或植入等方式施用。根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体制剂、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等。为了使片剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，竣甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯毗咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净 的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。为了使丸剂形式的药物组合物成形，可使用本领域任何己知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石粉等；粘合剂，如阿拉伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。为了使栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋性剂,例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油等)，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体，例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。本发明中，所述药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状，选择各种剂型的制剂给药。例如，片剂、丸剂、溶液、悬浮液、乳液、颗粒剂或胶囊口服给药；针剂可以单独给药，或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射；栓剂为给药到直肠。
本发明与现有技术相比，有益效果有：式(I)或(II)所示化合物或其可药用的盐能够有效地抑制P-糖蛋白。该类化合物对P-糖蛋白高表达的耐药肿瘤细胞(如白血病耐药细胞K562/A02等)具有明显抑制活性，有较强的逆转肿瘤细胞多药耐药(MDR)的作用，且部分化合物对P-糖蛋白抑制活性明显优于第三代P-糖蛋白抑制剂他立喹达(Tariquidar，XR9576)，并且具有较小的细胞毒性。此外，该类化合物能够选择性抑制肠道上皮细胞P-糖蛋白，与由于肠道P-糖蛋白的抑制作用而不容易在消化道中吸收的抗癌剂(紫杉醇、多西他赛、多柔比星等)联合口服给药时，提高抗癌剂的生物利用度。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。
生物实验实施例一：化合物的细胞毒作用
本实验测试了27个化合物对K562/A02细胞的细胞毒作用。耐阿霉素的人白血病细胞株K562/A02细胞在含10％ FBS，1％青链霉素的RPMI 1640培养液中培养。将处于对数生长期的细胞以每孔6000个细胞的密度铺板于96孔板中，每孔100μL RPMI 1640培养基，放置于37℃，5％ CO2孵箱中孵育24h。阿霉素对照组每孔加入100μL 的一系列浓度梯度的阿霉素，空白对照组加入100μL培养液，受试化合物组和阳性对照组分别每孔加入50μL目标化合物(5μM)和50μL一系列浓度梯度的阿霉素，每个浓度下设置三个复孔。加药完毕后孵育48h，弃去溶液。加入1mg/mL的MTT溶液继续孵育4h,弃去溶液，加入DMSO后摇床振摇5min。在酶标仪490nm波长处读数，计算细胞抑制率，并用Graghpad 5.0软件中量效曲线计算化合物IC50值。
试验结果如表1所示，从测试结果可以看出，所有化合物对K562/A02细胞均没有明显细胞毒性。
表1化合物对K562/A02细胞的细胞毒作用
生物实验实施例二：化合物对耐阿霉素人白血病细胞(K562/A02)的逆转作用
以Tariquidar为阳性对照，K562/A02细胞在含10％ FBS，1％青链霉素的RPMI 1640培养液中培养。将处于对数生长期的细胞以每孔6000个细胞的密度铺板于96孔板中，每孔100μL RPMI 1640培养基，放置于37℃，5％ CO2孵箱中孵育24h。阿霉素对照组每孔加入100μL的一系列浓度梯度的阿霉素，空白对照组加入100μL培养液，受试化合物组和阳性对照组分别每孔加入50μL目标化合物(5μM)和50μL一系列浓度梯度的阿霉素，每个浓度下设置三个复孔。加药完毕后孵育48h，弃去溶液。加入1mg/mL的MTT溶液继续孵育4h,弃去溶液，加入DMSO后摇床振摇5min。在酶标仪490nm波长处读数，计算细胞抑制率，并用Graghpad 5.0软件中量效曲线计算化合物IC50值，并求得逆转倍数(RF)，逆转倍数以IC50(ADM)/IC50(ADM+逆转剂)表示。
本实验分批测定了27个化合物在5μM浓度下对耐阿霉素的白血病细胞抗药性的逆转活性，如表2所示，试验结果表明，27个化合物中绝大部分化合物具有逆转MDR 活性，且部分化合物的逆转活性超过阳性对照品Tariquidar。
表2化合物(5μM浓度)对耐阿霉素人白血病细胞耐药性的逆转作用
生物实验实施例三：化合物13o与抗癌剂口服联合给药，提高抗癌剂生物利用度
紫杉醇(PTX)、多西他赛(DTX)、多柔比星(DOX)等抗肿瘤药物，由于其理化性质以及肠道上皮细胞P-糖蛋白外排等原因，导致这些药物临床上通常为静脉注射的方式给药。本发明中的化合物13o及其药用盐对肠道P-gp具有一定抑制作用，能够提高抗癌剂的口服生物利用度。
紫杉醇是一种重要的抗肿瘤药物，通过与细胞内微管蛋白结合，阻碍肿瘤细胞的正常分裂和增殖。主要用于进展期卵巢癌一线以及后继治疗；淋巴结阳性乳腺癌患者在含阿霉素标准方案联合化疗后的辅助治疗；6个月内复发的乳腺癌；非小细胞肺癌患者；卡波氏肉瘤的治疗。临床上紫杉醇使用剂型通常为溶液型，静脉注射用，容易导致一系列不良反应，包括周围神经性病变、骨髓抑制以及皮肤毒性等。因此化合物 13o及其药用盐与紫杉醇联合口服给药，能够提高紫杉醇生物利用度，改变紫杉醇传统静脉给药方式，减轻紫杉醇的不良副作用以及提高患者医从性。
随机将6只14-15周龄大的Sprague-Dawley(SD)大鼠禁食超过12h同时允许它们饮水，然后随机分为2组。第一组灌胃给予20mg/kg紫杉醇；第二组灌胃同时给予20mg/kg紫杉醇和10mg/kg化合物13o，分别于0.5h、1h、2h、4h、6h、8h、10h、12h、24h时间点采集血样以及测定紫杉醇血药浓度。
试验结果如表3所示，从AUCLast_plasma结果上看化合物13o能够明显提高自身不容易在消化道中吸收的紫杉醇的口服生物利用度。
表3PTX在大鼠体内药动学参数

注：AUCLast_plasma表示药时曲线下面积；Cmax表示药物的峰值浓度；Tmax表示药物
峰值浓度达峰时间；T1/2表示药物消除半衰期；VZ/F表示药物表观分布容积；CLZ/F表示药物清除率。
制备实施例1
3,4-二甲氧基-2-羟基苯乙酮制备：将20g 3,4-二甲氧基苯酚加入到250mL二口瓶中，氩气保护，在0℃下加入80mL 48％三氟化硼乙醚溶液以及12mL醋酸，继续在此温度下反应30min，随后移至80℃油浴反应3h。反应结束后，0℃下加水淬灭，大量黄绿色固体析出，过滤，滤饼进行甲醇重结晶，减压干燥得到灰色固体18.3g(产率：72％)。1H NMR(400MHz,CDCl3)δ12.64(s,1H),7.04(s,1H),6.44(s,1H),3.90(s,3H),3.86(s,3H),2.55(s,3H)。13C NMR(101MHz,CDCl3)δ202.09,160.14,156.83,141.91,111.74,111.69,100.57,56.71,56.20,26.39。
制备实施例2
2,4-二羟基苯乙酮制备：将15g间苯二酚加入到250mL二口瓶中，氩气保护，在0℃下加入80mL 48％三氟化硼乙醚溶液以及12mL醋酸，继续在此温度下反应30min， 随后移至80℃油浴反应3h。反应结束后，0℃下加水淬灭，二氯甲烷萃取三次(100mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物用少量混合有机溶液(V乙酸乙酯：V石油醚＝1:3)打浆，过滤，减压干燥得到白色固体16.5g(产率：80％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ202.77,165.12,162.72,133.09,114.33,107.78,103.51,26.22。
制备实施例3
4-苄氧基-2-羟基苯乙酮制备：称量7.6g 2,4-二羟基苯乙酮和7.9g碳酸钾加入到100mL二口瓶中，氩气保护，加入50mL乙腈，室温缓慢滴加6.5mL溴化苄，随后加热回流6h。反应结束后，减压除去乙腈，二氯甲烷萃取三次(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物用少量混合有机溶液(V乙酸乙酯：V石油醚＝1：5)打浆，过滤，减压干燥得到白色固体10.5g(产率：87％)。1H NMR(400MHz,CDCl3)δ12.74(s,1H),7.64(d,J＝9.0Hz,1H),7.45–7.32(m,5H),6.55–6.49(m,2H),5.09(s,2H),2.55(s,3H)。13C NMR(101MHz,CDCl3)δ202.62,165.23,135.93,132.40,128.74,128.34,127.56,114.14,108.14,101.94,70.24,26.24。
制备实施例4
3,4-二甲氧基-2-羟基苯乙酮制备：称量10g原料2,3,4-三羟基苯乙酮和17g碳酸钾加入到100mL单口瓶中，加入50mL DMF，室温下缓慢滴加8mL碘甲烷，室温继续反应24h。反应结束后，反应液加入适量水，乙酸乙酯萃取三次(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物用少量混合有机溶液(V乙酸乙酯：V石油醚＝1：3)打浆，过滤，减压干燥得到白色固体8.7g(产率：75％)。1H NMR(400MHz,CDCl3)δ12.54(s,1H),7.47(d,J＝9.0Hz,1H),6.47(d,J＝9.0Hz,1H),3.90(s,3H),3.86(s,3H),2.54(s,3H)。13C NMR(101MHz,CDCl3)δ203.27,158.53,157.04,136.50,127.05,115.33,102.92,60.66,56.13,26.39。
制备实施例5
2-(2-乙酰基-4,5-二甲氧基苯氧基)乙酸乙酯制备：11g 3,4-二甲氧基-2-羟基苯乙酮、20g碳酸铯加入到250mL二口瓶中，氩气保护，注射器加入100mL丙酮和7.5mL溴乙酸乙酯，60℃反应3h。反应结束后，将反应液减压除去，加入100mL水，二氯甲烷萃取三次(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为乙酸乙酯：石油醚＝1：5，减压干燥得白色固体10.4g(产率：66％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ197.31,168.27,153.64,153.33,143.84,120.05,112.54,97.50,66.67,61.59,56.23,56.15,32.18,14.17。
制备实施例6
2-(6-乙酰基-2,3-二甲氧基苯氧基)乙酸乙酯制备：称量原料8.7g和15g碳酸铯加入到250mL二口瓶中，氩气保护，注射器加入100mL丙酮和7.5mL溴乙酸乙酯，60℃反应3h。反应结束后，将反应液减压除去，二氯甲烷萃取三次(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为乙酸乙酯：石油醚＝1：3，减压干燥得白色液体11g(产率：88％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ198.05,168.91,157.21,151.75,141.20,126.16,125.51,107.26,69.89,61.05,56.07,31.24,14.10。
制备实施例7
2-(2-乙酰基-5-(苄氧基)苯氧基)乙酸乙酯制备:称量原料10g和13.5g碳酸铯加入到250mL二口瓶中，氩气保护，加入100mL丙酮，在室温下经注射器滴加5.0mL溴乙酸乙酯，随后60℃反应3h。反应结束后，将反应液减压除去，二氯甲烷萃取三次(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为乙酸乙酯：石油醚＝1：3，室温 减压干燥得白色固体12.5g(产率：92％)。1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.7Hz,1H),7.44–7.30(m,5H),6.63(dd,J＝8.7,2.0Hz,1H),6.40(d,J＝2.2Hz,1H),5.08(s,2H),4.66(s,2H),4.26(q,J＝7.1Hz,2H),2.67(s,3H),1.30(t,J＝7.1Hz,3H)。13CNMR(101MHz,CDCl3)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。
制备实施例8
2-(2-乙酰基-4,5-二甲氧基苯氧基)乙酸制备：称量10g 2-(2-乙酰基-4,5-二甲氧基苯氧基)乙酸乙酯加入到100mL单口瓶中，加入30mL甲醇，冰浴下滴加25mL 2N NaOH水溶液，滴加结束后移至室温反应6h。反应结束后，减压除去反应液中的甲醇，冰浴下向反应液中加入2M HCl水溶液，反应液pH调至2～3，继续冰浴条件下搅拌30min，大量白色固体析出，过滤，减压干燥得到白色固体产物8.1g(产率：90％)。
制备实施例9
2-(6-乙酰基-2,3-二甲氧基苯氧基)乙酸制备：称量10g原料加入到100mL单口瓶中，加入30mL甲醇，冰浴下滴加25mL 2N NaOH水溶液，滴加结束后移至室温反应6h。反应结束后，减压除去反应液中的甲醇，冰浴下向反应液中加入2M HCl水溶液，反应液pH调至2～3，继续冰浴条件下搅拌30min，大量白色固体析出，过滤，减压干燥得到白色固体产物7.5g(产率：83％)。
制备实施例10
2-(2-乙酰基-5-(苄氧基)苯氧基)乙酸制备：称量12g原料加入到100mL单口瓶中，加入30mL甲醇，冰浴下滴加25mL 2N NaOH水溶液，滴加结束后移至室温反应6h。反应结束后，减压除去反应液中的甲醇，冰浴下向反应液中加入2M HCl水溶液，反应液pH调至2～3，继续冰浴条件下搅拌30min，大量白色固体析出，过滤，减压干燥得到白色固体产物10.2g(产率：93％)。
制备实施例11
5,6-二甲氧基-3-甲基苯并呋喃制备：将11g 2-(2-乙酰基-4,5-二甲氧基苯氧基)乙酸和25g无水乙酸钠加入到250mL二口瓶中，加入100mL乙酸酐，氩气保护，110℃反应12h。反应结束后，在冰浴下加饱和碳酸氢钠水溶液淬灭，直至无气泡产生，乙酸乙酯萃取(100mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相乙酸乙酯：石油醚＝1：10，减压干燥得到白色固体6.3g(产率：76％)。1H NMR(400MHz,CDCl3)δ7.31(s,1H),7.01(s,1H),6.93(s,1H),3.94(s,3H),3.91(s,3H),2.21(s,3H)。13C NMR(101MHz,CDCl3)δ149.84,147.90,146.31,140.51,120.85,115.67,100.88,95.48,56.47,56.26,8.05。
制备实施例12
6,7-二甲氧基-3-甲基苯并呋喃制备：将15g原料和34g无水乙酸钠加入到250mL二口瓶中，加入100mL乙酸酐，氩气保护，110℃反应12h。反应结束后，在冰浴下加饱和碳酸氢钠水溶液淬灭，直至无气泡产生，乙酸乙酯萃取(100mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相乙酸乙酯：石油醚＝1：10，减压干燥得到白色液体9.5g(产率：84％)。1H NMR(400MHz,CDCl3)δ7.32(d,J＝1.2Hz,1H),7.07(d,J＝8.4Hz,1H),6.90(d,J＝8.4Hz,1H),4.14(s,3H),3.90(s,3H),2.18(d,J＝1.1Hz,3H)。13C NMR(101MHz,CDCl3)δ148.77,147.24,141.02,134.76,125.40,115.60,112.39,109.42,60.85,57.36 7.83。
制备实施例13
6-(苄氧基)-3-甲基苯并呋喃制备：将15g原料和30g无水乙酸钠加入到250mL二口瓶中，加入100mL乙酸酐，氩气保护，110℃反应12h。反应结束后，冰浴条件下加饱和碳酸氢钠水溶液淬灭，直至无气泡产生，乙酸乙酯萃取(100mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相乙酸乙酯：石油醚＝1：10，减压干燥得到白色 固体9.7g(产率：82％)。1H NMR(400MHz,CDCl3)δ7.50–7.31(m,7H),7.07(d,J＝1.7Hz,1H),6.97(dd,J＝8.5,1.8Hz,1H),5.11(s,2H),2.22(s,3H)。13C NMR(101MHz,CDCl3)δ157.09,156.12,140.62,137.06,128.62,127.99,127.53,122.80,119.52,115.52,112.00,97.36,70.66,7.95。
制备实施例14
2-苄基-6,7-二甲氧基-1,2,3,4-四氢苯并呋喃[2,3-c]吡啶制备：称量3.84g 5,6-二甲氧基-3-甲基苯并呋喃加入到100mL单口瓶中，加入40mL乙酸、32mL 36-38％甲醛水溶液以及8.5g苄胺，氩气保护，60℃反应3h。反应结束后，冷却至室温，加入饱和碳酸氢钠水溶液淬灭，直至无气泡产生，乙酸乙酯萃取(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为乙酸乙酯：石油醚＝1：3，室温减压干燥得白色固体5.5g(产率：85％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ150.41,149.15,147.04,146.24,138.26,129.11,128.43,127.32,120.11,111.35,100.63,95.74,61.88,56.49,56.33,50.34,50.15,20.98。
制备实施例15
2-苄基-7-(苄氧基)-1,2,3,4-四氢苯并呋喃[2,3-c]吡啶制备：称量7.15g 6-(苄氧基)-3-甲基苯并呋喃加入到250mL单口瓶中，加入60mL乙酸、48mL 36-38％甲醛水溶液以及13g苄胺，氩气保护，60℃反应3h。反应结束后，冷却至室温，加入饱和碳酸氢钠水溶液淬灭，直至无气泡产生，乙酸乙酯萃取(100mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为乙酸乙酯：石油醚＝1：10，减压干燥得白色固体5.6g(产率：51％)。1H NMR(400MHz,CDCl3)δ7.48–7.28(m,11H),7.04(d,J＝2.1Hz,1H),6.93(dd,J＝8.5,2.2Hz,1H),5.09(s,2H),3.87(s,2H),3.73(s,2H),2.96(t,J＝5.2Hz,2H),2.83–2.72(m,2H)。13C NMR(101MHz,CDCl3)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。
制备实施例16
2-苄基-7,8-二甲氧基-1,2,3,4-四氢苯并呋喃[2,3-c]吡啶制备：称量1.92g 6,7-二甲氧基-3-甲基苯并呋喃加入到100mL单口瓶中，加10mL乙腈、10mL 36-38％甲醛水溶液以及5.7g苄胺盐酸盐，90℃反应3h。反应结束后，冷却至室温，加入饱和碳酸氢钠水溶液淬灭，直至无气泡产生，乙酸乙酯萃取(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为乙酸乙酯：石油醚＝1：20，减压干燥得白色固体1.7g(产率：53％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)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。
制备实施例17
6,7-二甲氧基-1,2,3,4-四氢苯并呋喃[2,3-c]吡啶制备：称量3.2g 2-苄基-6,7-二甲氧基-1,2,3,4-四氢苯并呋喃[2,3-c]吡啶加入到100mL二口瓶中，加入640mg 10wt％Pd/C，20mL THF和20mL甲醇，氢气置换三次，室温反应12-24h。反应结束，过滤(加入硅藻土助滤)，二氯甲烷/甲醇混合溶剂洗涤滤饼，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为甲醇：二氯甲烷＝1：10，减压干燥得白色固体2.1g(产率：90％)。1H 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),3.32(bs,2H),2.95(s,2H),2.53(s,2H)。13C NMR(101MHz,CDCl3)δ151.24,148.64,147.11,146.21,120.25,111.69,100.52,95.67,56.46,56.31,43.33,43.24,22.68。
制备实施例18
1,2,3,4-四氢苯并呋喃[2,3-c]吡啶-7-醇制备：称量6.0g原料加入到100mL二口瓶中， 加入1.2g 10wt％Pd/C，50mL乙酸乙酯，氢气置换三次，60℃反应6h。反应结束，过滤(加入硅藻土助滤)，二氯甲烷/甲醇混合溶剂洗涤滤饼，减压除去溶剂得到粗产物。粗产物用少量乙酸乙酯打浆、过滤，减压干燥得灰白色固体2.5g(产率：81％)。1H 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)。13C NMR(101MHz,DMSO)δ155.25,155.05,151.25,120.68,118.97,111.78,111.71,98.32,42.97,42.68,22.43。
制备实施例19
7-羟基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-羧酸叔丁酯制备：称量原料3.8g加入到100mL单口瓶中，加入30mL甲醇，在0℃下缓慢加入4.8g Boc2O，随后缓慢滴加2.8mL三乙胺，继续0℃反应1h。反应结束后，减压除去溶剂，乙酸乙酯萃取(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为乙酸乙酯：石油醚＝1：3，减压干燥得白色固体4.5g(产率：77％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ155.68,155.36,153.81,121.09,118.77,111.56,98.61,80.81,42.48,40.93,28.49,20.78。
制备实施例20
7-((三氟甲基磺酰基)氧基)-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-羧酸叔丁基酯制备：称量原料2.9g加入到50mL二口瓶中，加入25mL无水二氯甲烷，-5℃条件下分别滴加2.5mL三氟甲磺酸酐和2.0mL三乙胺，继续反应3h。反应结束后，加少量水淬灭，乙酸乙酯萃取(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为乙酸乙酯：石油醚＝1：5，室温减压干燥得白色固体3.5g(产率：83％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ154.85,154.04,146.02,128.02,120.40,119.22,117.20,116.30,105.46,80.64,28.40。
制备实施例21
3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-羧酸叔丁酯:称量1.26g原料、33mg Pd(OAc)2和80mg三苯基膦加入到25mL二口瓶中,加入15mL DMF，氩气置换气体三次，经注射器加入0.24mL甲酸以及1.2mL三乙胺，100℃反应3h。反应结束后，冷却至室温，乙酸乙酯萃取(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为乙酸乙酯：石油醚＝1：10，室温减压干燥得白色固体650mg(产率：79％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ154.99,154.77,127.83,123.71,122.65,118.69,111.18,80.35,42.47,40.82,28.47,20.83。
制备实施例22
1,2,3,4-四氢苯并呋喃[2,3-c]吡啶盐酸盐制备：称量2.7g原料加入到耐压管中，加入10mL氯化氢乙酸乙酯溶液，50℃反应6h。反应结束后，减压除去溶剂，残留固体用少量乙酸乙酯打浆，过滤，减压干燥得白色固体1.6g(产率：77％)。1H 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)。13C NMR(101MHz,DMSO)δ154.58,146.07,127.09,125.09,123.66,119.86,111.74,111.68,41.14,40.08,18.01。
制备实施例23
6,7-二甲氧基-2-(4-硝基苯乙基)-1,2,3,4-四氢苯并呋喃[2,3-c]吡啶制备：称量1.2g 6,7-二甲氧基-1,2,3,4-四氢苯并呋喃[2,3-c]吡啶、4-硝基苯乙基溴2.3g、83mg KI以及1.0g三乙胺加入到25mL二口瓶中，加入10mL DMF，氩气保护，100℃反应2h。反应结束后，冷却至室温，加入适量水，乙酸乙酯萃取(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为乙酸乙酯：石油醚＝1：3，室温减压干燥得黄色固体1.1g(产率：58％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ149.86,149.15,148.10,147.15,146.57,146.30,129.56,123.66,119.91,111.41,100.63,95.72,58.30,56.48,56.33,50.54,50.25,34.08,20.95。
制备实施例24
(E)-1-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-3-(4-硝基苯基)丙-2-烯-1-酮制备：称量690mg 6,7-二甲氧基-1,2,3,4-四氢苯并呋喃[2,3-c]吡啶、700mg肉桂酸和1.35g HATU到二口瓶中，氩气保护，0℃条件下经注射器分别加入5mL DMF以及450mg三乙胺到反应体系中，滴加结束后继续反应30min，随后移至室温反应1h。反应结束后，加入适量的水，DCM萃取(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为二氯甲烷：甲醇＝50：1，室温减压干燥得黄色固体1.0g(产率：82％)。1H NMR(400MHz,CDCl3，构象异构体)δ8.22(d,J＝8.5Hz,2H),7.78–7.63(m,3H),7.14–6.96(m,2H),6.87(d,J＝8.5Hz,1H),4.82(d,J＝16.1Hz,2H),4.12–3.84(m,8H),2.80(d,J＝18.9Hz,2H)。13C NMR(101MHz,CDCl3，构象异构体)δ165.39,149.40,148.19,148.11,147.71,147.59,146.76,146.59,146.52,141.34,140.50,128.42,124.17,121.83,121.57,119.26,113.28,111.36,100.62,100.48,95.78,95.65,56.50,56.34,44.13,44.00,41.50,40.37,22.07,20.60。
制备实施例25
(4-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基甲基)苯基)氨基甲酸叔丁基酯制备：称量1.2g 6,7-二甲氧基-1,2,3,4-四氢苯并呋喃[2,3-c]吡啶和1.3g(4-(氯甲基)苯基)氨基甲酸叔丁酯加入到25mL二口瓶中，氩气保护，加入10mL DMF，缓慢滴加1mL三乙胺，随后移至60℃反应2h。反应结束后，冷却至室温，乙酸乙酯萃取(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为乙酸乙酯：石油醚＝1：3，室温减压干燥得黄色固体1.7g(产率：77％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ152.90,149.78,149.17,147.07,146.22,137.78,131.96,129.93,119.93,118.62,111.31,100.61,95.71,80.52,61.06,56.45,56.30,50.02,49.86,28.37,20.67。
制备实施例26
4-((6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯胺制备：称量1.5g原料加入到50mL单口瓶中，加入10mL乙醇以及5mL 6N HCl，60℃反应1h。反应结束后，冷却至室温，用2N NaOH(aq.)调至pH＝8～9,二氯甲烷萃取(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为乙酸乙酯：石油醚＝1：1，室温减压干燥得黄色固体950mg(产率：83％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ150.55,149.12,146.96,146.17,145.71,130.35,127.84,120.13,115.04,111.37,100.62,95.73,61.45,56.47,56.31,50.13,49.92,20.96。
制备实施例27
4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯胺制备：称量1.0g6,7-二甲氧基-2-(4-硝基苯乙基)-1,2,3,4-四氢苯并呋喃[2,3-c]吡啶加入到25mL二口瓶中，加入100mg 10wt％Pd/C，10mL甲醇，室温反应2h。反应结束，过滤，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为乙酸乙酯：石油醚＝1:1，室温减压干燥得黄色固体810mg(产率：88％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ150.29,149.16,147.04,146.22,144.64,129.98,129.52,120.06,115.33,111.41,100.65,95.75,59.89,56.48,56.33,50.63,50.34,33.39,21.03。
制备实施例28
(E)-3-(4-氨基苯基)-1-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丙-2-烯-1-酮:称量610mg(E)-1-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-3-(4-硝基苯基)丙-2-烯-1-酮和900mg氯化亚锡加入到耐压管中，加入6mL乙醇和6mL 6N HCl，90℃反应3h。反应结束后，DCM萃取(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为二氯甲烷：甲醇＝50：1，室温减压干燥得黄色固体450mg(产率：79％)。1H NMR(400MHz,CDCl3)δ7.65(d,J＝15.3Hz,1H),7.37(d,J＝8.3Hz,2H),7.02(s,1H),6.88(s,1H),6.76(d,J＝14.6Hz,1H),6.65(d,J＝8.4Hz,2H),4.82(s,2H),4.06–3.88(m,10H),2.77(s,2H)。13C NMR(101MHz,CDCl3)δ167.03,149.34,148.31,147.45,146.44,143.75,129.61,125.45,119.52,114.89,100.56,95.74,56.49,56.34。
制备实施例29
(E)-N-(4-(3-(7,8-二甲氧基-1,2,3,4-四氢二苯并[b,d]呋喃-3-基)-3-氧代丙-1-烯-1-基)苯基)-4,5-二甲氧氧基-2-硝基苯甲酰胺制备：称量340mg 4,5-二甲氧基-2-硝基苯甲酸加入到二口瓶中，氩气保护，经注射器加入5mL无水二氯甲烷和1滴DMF，0℃条件下将0.4mL草酰氯经注射器缓慢加入到反应体系当中，继续反应30min，后移至室温反应3h。反应结束后，减压除去溶剂以及过量的草酰氯，残留固体溶于3mL无水二氯甲烷中，缓慢加入到预先准备好的380mg(E)-3-(4-氨基苯基)-1-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)丙-2-烯-1-酮/5mL DCM反应体系当中，随后加入200mg三乙胺，继续室温反应1h。反应结束后，加入适量水，二氯甲烷萃取(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为二氯甲烷：甲醇＝50：1，室温减压干燥得淡黄色固体440mg(产率：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)。
制备实施例30
N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-4,5-二甲氧基-2-硝基苯甲酰胺制备：称量340mg 4,5-二甲氧基-2-硝基苯甲酸加入到二口瓶中，氩气保护，经注射器加入5mL无水二氯甲烷和1滴DMF，0℃条件下将0.4mL草酰氯经注射器缓慢加入到反应体系当中，继续反应30min，后移至室温反应3h。反应结束后，减压除去溶剂以及过量的草酰氯，残留固体溶于3mL无水二氯甲烷中，缓慢加入到预先准备好的350mg 4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯胺/5mL DCM反应体系当中，随后加入200mg三乙胺，继续室温反应1h。反应结束后，加入适量水，二氯甲烷萃取(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为二氯甲烷：甲醇＝50：1，室温减压干燥得黄色固体410mg(产率：73％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ164.85,153.51,150.03,149.33,149.13,147.01,146.16,138.34,136.70,135.87,129.26,127.28,120.61,119.96,111.41,110.11,107.05,100.64,95.70,59.34,56.68,56.45,56.44,56.28,50.62,50.26,33.61,20.95。
制备实施例31
(E)-2-氨基-N-(4-(3-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-3-氧丙-1-烯-1-基)苯基)-4,5-二甲氧基苯甲酰胺制备：称量590mg原料和300mg氯化亚锡，加入3mL EtOH和3mL 6N HCl，90℃反应3h。反应结束后，DCM萃取(50mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为二氯甲烷：甲醇＝50：1，室温减压干燥得黄色固体410mg(产率：74％)。1H NMR(400MHz,CDCl3+CD3OD，构象异构体)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)。13CNMR(101MHz,CDCl3+CD3OD，构象异构体)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。
制备实施例32
2-氨基-N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-4,5-二甲氧基苯甲酰胺制备：称量400mg 2-氨基-N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-4,5-二甲氧基苯甲酰胺加入到25mL二口瓶中，加入80mg 10wt％Pd/C，5mL甲醇和5mL四氢呋喃，室温反应2h。反应结束，过滤，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为二氯甲烷：甲醇＝50：1，室温减压干燥得黄色固体320mg(产率：85％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ167.20,153.64,150.00,149.17,147.06,146.22,144.98,141.08,136.25,135.99,129.23,120.94,119.97,111.40,111.27,107.64,101.04,100.62,95.72,59.33,57.11,56.45,56.31,55.81,50.56,50.21,33.59,20.91。
制备实施例33
N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺制备:称量70mg喹啉-3-羧酸加入到10mL单口瓶中，加入5mL无水四氢呋喃以及0.15mL氯化亚砜，氩气保护，60℃反应12h。反应结束后减压除去溶剂以及过量的氯化亚砜，得到灰色固体。称量106mg 2-氨基-N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-4,5-二甲氧基苯甲酰胺加入到10mL单口瓶中，加入5mL无水二氯甲烷，将现制备酰氯加入到反应体系当中，随后加入40mg三乙胺，室温继续反应1h。反应结束后，加入适量1N NaOH溶液，室温搅拌30min，二氯甲烷萃取(50mL×3)，合并有机相，水洗三 次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为二氯甲烷：甲醇＝50：1，室温减压干燥得黄色固体85mg化合物13a(产率：62％)。1H NMR(400MHz,CDCl3+CD3OD)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)。13C NMR(101MHz,CDCl3+CD3OD)δ167.90,163.69,152.36,149.41,149.17,148.72,148.56,147.05,146.12,144.51,136.31,136.01,135.85,135.11,131.72,129.19,129.05,128.50,127.63,127.29,126.96,121.84,119.75,112.59,111.27,110.75,104.79,100.70,95.70,59.14,56.33,56.29,56.16,55.97,50.42,50.05,33.18,20.52。
制备实施例34
N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-3-基)喹唑啉-4-胺制备：称量105mg 4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯胺和72mg 4-氯-2-(吡啶-3-基)喹唑啉加入到Schlenk管中，氩气保护，加入3mL无水乙醇以及3μL甲磺酸，70℃反应5h。反应结束后，DCM萃取(30mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为二氯甲烷：甲醇＝50：1，室温减压干燥得黄色固体110mg化合物10a(产率：66％)。1H NMR(500MHz,CDCl3)δ9.73(d,J＝1.6Hz,1H),8.79(dt,J＝7.9,1.8Hz,1H),8.69(dd,J＝4.7,1.5Hz,1H),7.99(d,J＝8.3Hz,1H),7.91(d,J＝8.2Hz,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)。13C NMR(126MHz,CDCl3)δ158.51,157.49,150.83,150.30,150.11,149.15,147.04,146.21,136.46,136.24,135.75,134.18,133.10,129.31,126.52,123.27,121.69,120.36,120.00,114.02,111.41,100.62,95.72,59.36,56.46,56.31,50.63,50.33,33.73,20.99。
制备实施例35
N-(4-((6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)-2-(吡啶-3-基)喹唑啉-4-胺制备：称量100mg 4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯胺和72mg 4-氯-2-(吡啶-3-基)喹唑啉加入到Schlenk管中，氩气保护，加入3mL无水乙醇以及3μL甲磺酸，70℃反应5h。反应结束后，DCM萃取(30mL×3)，合并有机相，水洗三次，饱和食盐水水洗一次，无水硫酸钠干燥，减压除去溶剂得到粗产物。粗产物进行柱色谱分离，流动相为二氯甲烷：甲醇＝50：1，室温减压干燥得黄色固体95mg化合物10b(产率：58％)。1H NMR(500MHz,CDCl3)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)。13C NMR(126MHz,CDCl3)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。
制备实施例36
N-(4-(2-(7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-3-基)喹唑啉-4-胺制备：
参照制备实施例34中制备方法，制备得到黄色固体化合物10c(产率：68％)。1H NMR(500MHz,CDCl3)δ9.74–9.71(m,1H),8.78(d,J＝7.9Hz,1H),8.71–8.66(m,1H),7.97(dd,J＝8.3,1.4Hz,1H),7.93(d,J＝8.3Hz,1H),7.83–7.76(m,3H),7.74–7.63(m,1H),7.53(dd,J＝11.8,7.4Hz,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＝8.3Hz,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)。13C NMR(126MHz,CDCl3)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。
制备实施例37
N-(4-((7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)-2-(吡啶-3-基)喹唑啉-4-胺制备：参照制备实施例35中制备方法，制备得到黄色固体化合物10d(产率： 63％)。1H NMR(500MHz,CDCl3)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)。13C NMR(126MHz,CDCl3)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.
制备实施例38
N-(4-(2-(3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-3-基)喹唑啉-4-胺制备；参照制备实施例34中制备方法，制备得到黄色固体化合物10e(产率：61％)。1H NMR(500MHz,CDCl3)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)。13C NMR(126MHz,CDCl3)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。
制备实施例39
N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-4-基)喹唑啉-4-胺制备：
参照制备实施例34中制备方法，制备得到黄色固体化合物10f(产率：63％)。1H NMR(500MHz,CDCl3)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)。13C NMR(126MHz,CDCl3)δ158.32,157.64,150.77,150.24,150.08,149.17,147.09,146.25,146.14,136.45,136.35,133.19,129.60,129.32,127.01,122.40,121.68,120.37,119.98,114.29,111.42,100.62,95.73,59.34,56.47,56.32,50.67,50.33,33.74,20.99。
制备实施例40
N-(4-((6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)-2-(吡啶-4-基)喹 唑啉-4-胺制备：
参照制备实施例35中制备方法，制备得到黄色固体化合物10g(产率：65％)。1H NMR(500MHz,CDCl3)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),3.90(s,3H),3.83(s,2H),3.69(s,2H),2.93(t,J＝5.5Hz,2H),2.74(s,2H)。13C NMR(126MHz,CDCl3)δ158.32,157.62,150.79,150.27,149.15,147.06,146.24,146.09,137.48,134.40,133.24,129.77,129.64,127.07,122.39,121.41,120.36,120.04,114.30,111.37,100.60,95.71,61.36,56.47,56.31,50.32,50.23,20.98。
制备实施例41
N-(4-(2-(7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-4-基)喹唑啉-4-胺制备：参照制备实施例34中制备方法，制备得到黄色固体化合物10h(产率：63％)。1H NMR(500MHz,CDCl3)δ8.77(d,J＝5.6Hz,2H),8.37(dd,J＝4.7,1.3Hz,2H),8.02(d,J＝8.1Hz,1H),7.93(d,J＝8.2Hz,1H),7.86–7.82(m,1H),7.80(d,J＝8.4Hz,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)。13C NMR(126MHz,CDCl3)δ158.32,157.65,150.86,150.76,150.24,148.55,146.73,146.15,136.46,136.33,134.80,133.19,129.59,129.31,127.01,124.29,122.40,121.67,120.38,114.30,111.72,111.37,109.26,61.01,59.25,57.31,50.52,50.22,33.76,20.87。
制备实施例42
N-(4-((7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)-2-(吡啶-4-基)喹唑啉-4-胺制备：参照制备实施例35中制备方法，制备得到黄色固体化合物10i(产率：59％)。1H NMR(500MHz,CDCl3)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),7.51(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)。13C NMR(126MHz,CDCl3)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。
制备实施例43
N-(4-(2-(3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-4-基)喹唑啉-4-胺制备：参照制备实施例34中制备方法，制备得到黄色固体化合物10j(产率：71％)。1H NMR(500MHz,CDCl3)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)。
13C NMR(126MHz,CDCl3)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。
制备实施例44
N-(2-((4-((6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13b(产率：53％)。1H NMR(500MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ167.49,163.96,152.92,150.19,149.42,149.15,148.82,147.05,146.22,144.68,136.54,135.85,135.80,131.50,129.90,129.41,129.24,127.52,127.25,126.95,121.01,120.02,112.14,111.36,109.66,105.06,100.58,95.71,61.25,56.46,56.31,56.19,50.27,50.10,20.94。
制备实施例45
N-(2-((4-(2-(7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13c(产率：49％)。1H NMR(500MHz,CDCl3)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＝8.4Hz,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)。13C NMR(126MHz,CDCl3)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。
制备实施例46
N-(2-((4-((7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13d(产率：43％)。1H NMR(500MHz,CDCl3)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)。13C NMR(101MHz,CDCl3+CD3OD)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。
制备实施例47
N-(2-((4-(2-(3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13e(产率：47％)。1H NMR(500MHz,CDCl3)δ12.47(s,1H),9.54(d,J＝2.3Hz,1H),8.77(d,J＝2.1Hz,1H),8.61(s,1H),8.17(d,J＝8.6Hz,1H),8.00(d,J＝7.7Hz,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)。13C NMR(101MHz,CDCl3)δ167.46,163.92,154.74,152.84,151.13,149.38,148.81,144.65,137.06,135.83,135.74,135.51,131.49,129.44,129.38,129.22,128.04,127.50,127.25,126.94,123.38,122.47,121.29,118.63,112.19,111.41,111.09,109.71,105.06,59.26,56.47,56.18,50.54,50.17,33.67,20.83。
制备实施例48
2-(3-氰基苯甲酰胺基)-N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-4,5-二甲氧化苯甲酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13f(产率：42％)。1H NMR(500MHz,DMSO)δ12.09(s,1H),10.47(s,1H),8.29(s,1H),8.19(d,J＝8.0Hz,1H),8.15(s,1H),8.09(d,J＝7.7Hz,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)δ167.46,163.14,151.92,149.49,148.30,146.95,144.92,137.67,136.28,135.76,133.88,131.97,131.30,130.77,129.40,122.36,118.71,118.58,115.00,112.53,112.48,111.68,105.79,101.97,96.57,56.51,56.49,56.46,56.12,49.95,48.08,29.64,18.26。
制备实施例49
N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)烟酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13g(产率：45％)。1H NMR(400MHz,CDCl3)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＝7.8,4.9Hz,1H),7.29(d,J＝8.3Hz,2H),7.05(s,1H),7.01(s,1H),6.88(s,1H),3.92(s,6H),3.90(s,3H),3.81(s,3H),3.74(s,2H),2.97–2.84(m,6H),2.76–2.70(m,2H)。13C NMR(101MHz,CDCl3)δ167.43,163.83,152.81,152.58,150.10,149.14,147.01,146.18,144.63,137.22,135.59,135.38,134.81,130.25,129.49,123.57,121.32,119.95,112.13,111.42,109.51,104.97,100.51,95.65,59.37,56.43,56.31,56.19,50.66,50.34,33.77,21.04。
制备实施例50
N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(3-氟苯甲酰胺基)-4,5-二甲氧基苯甲酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13h(产率：43％)。1H NMR(500MHz,CDCl3)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,3H),3.84(s,3H),3.76–3.72(m,5H),2.97–2.85(m,6H),2.77–2.71(m,2H)。
13C NMR(101MHz,CDCl3)δ167.41,164.35,152.74,149.15,147.05,146.21,144.55,135.58,135.50,130.58,130.50,129.48,122.72,122.69,121.29,119.94,119.07,118.86,114.96,114.73,112.32,111.42,109.57,105.01,100.54,95.67,59.35,56.45,56.42,56.32,56.15,50.66,50.32,33.74,21.01。
制备实施例51
N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-4,5-二甲氧基 -2-(吡啶-3-磺胺基)苯甲酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13i(产率：45％)。1H NMR(500MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)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。
制备实施例52
N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹喔啉-2-甲酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13j(产率：43％)。1H NMR(400MHz,CDCl3+CD3OD)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)。13C NMR(101MHz,CDCl3+CD3OD)δ171.45,165.96,155.85,153.26,153.12,151.13,150.16,148.69,148.08,147.23,144.53,140.35,139.83,137.44,136.07,135.01,134.37,132.97,132.61,125.68,123.73,118.61,115.27,115.10,108.88,104.81,99.76,63.07,60.29,60.09,59.85,54.38,53.95,36.99,24.35。
制备实施例53
N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-2-氧乙基)苯基)氨甲酰基)-4,5-二甲氧基苯基)喹啉-3-甲酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13k(产率：44％)。1H NMR(500MHz,CDCl3,构象异构体)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,4H),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)。13C NMR(126MHz,CDCl3,构象异构体)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。
制备实施例54
N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二氟苯基)喹啉-3-甲酰胺制备:参照制备实施例33中制备方法，制备得到淡黄色固体化合物13l(产率：39％)。1H NMR(400MHz,CDCl3)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)。13C NMR(101MHz,CDCl3)δ166.05,163.94,150.04,149.53,149.15,148.59,147.06,146.22,137.48,136.16,135.22,131.70,129.42,129.23,127.61,126.90,126.77,121.50,119.97,116.83,116.13,111.43,111.32,111.09,100.58,95.69,59.30,56.46,56.32,50.63,50.33,33.75,21.00。
制备实施例55
N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)苯基)喹啉-3-甲酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13m(产率：43％)。1H NMR(400MHz,CDCl3)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＝7.5Hz,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)。13C NMR(101MHz,CDCl3)δ167.47,164.18,150.08,149.48,149.15,148.70,147.04,146.20,139.08,137.01,136.05,135.77,132.59,131.62,129.47,129.21,127.59,127.28,127.14,126.95,123.38,121.95,121.55,120.92,119.98,111.42,100.58,95.70,59.37,56.44,56.31,50.63,50.33,33.76,21.01。
制备实施例56
N-(2-((4-(3-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-3-氧丙基)苯基)氨甲酰基)-4,5-二甲氧基苯基)喹啉-3-甲酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13n(产率：46％)。
1H NMR(500MHz,CDCl3,构象异构体)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＝8.4Hz,1H),7.98(d,J＝8.1Hz,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,1H),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)。13C NMR(126MHz,CDCl3,构象异构体)δ171.47,171.32,167.51,167.42,163.85,152.83,149.35,149.29,148.79,148.73,148.53,147.57,147.44,147.04,146.50,146.41,144.61,138.08,137.95,135.92,135.85,135.80,135.57,131.47,129.35,129.20,129.09,127.49,127.30,126.95,121.46,121.32,119.37,119.31,113.09,112.08,111.29,109.79,105.00,100.56,100.42,95.75,95.58,56.45,56.41,56.28,56.25,56.16,43.68,43.35,40.78,39.71,35.78,35.33,30.80,30.78,21.74,20.60。
制备实施例57
(E)-N-(2-((4-(3-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-3-氧丙-1-烯-1-基)苯基)氨甲酰基)-4,5-二甲氧基苯基)喹啉-3-甲酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13o(产率：38％)。1H NMR(400MHz,CDCl3+CD3OD,构象异构体)δ9.40(s,1H),8.70(s,1H),8.43(s,1H),8.07(d,J＝8.4Hz,1H),7.94(d,J＝8.1Hz,1H),7.76(t,J＝7.6Hz,1H),7.68(d,J＝8.3Hz,2H),7.63–7.51(m,2H),7.47(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)。13C NMR(101MHz,CDCl3+CD3OD,构象异构体)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。
制备实施例58
(E)-N-(2-((4-(3-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-3-氧丙-1-烯-1-基)苯基)氨甲酰基)苯基)喹啉-3-甲酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13p(产率：46％)。1H NMR(400MHz,CDCl3+CD3OD,构象异构体)δ9.45(s,1H),8.84(s,1H),8.71(d,J＝8.3Hz,1H),8.14(d,J＝8.4Hz,1H),8.07(d,J＝8.1Hz,1H),7.95–7.85(m,2H),7.80(d,J＝8.3Hz,2H),7.73–7.59(m,5H),7.27(t,J＝7.6Hz,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)。13C NMR(101MHz,CDCl3+CD3OD,构象异构体)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。
制备实施例59
N-(4-(4,5-二甲氧基-2-(喹啉-3-甲酰胺基)苯甲酰胺基)苯基)-6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-甲酰胺制备：参照制备实施例33中制备方法，制备得到淡黄色固体化合物13q(产率：43％)。1H NMR(400MHz,CDCl3+CD3OD)δ9.35(s,1H),8.70(s,1H),8.42(s,1H),8.03(d,J＝8.4Hz,1H),7.92(d,J＝8.0Hz,1H),7.74(t,J＝7.5Hz,1H),7.54(t,J＝7.4Hz,1H),7.46(d,J＝8.2Hz,2H),7.29(s,1H),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)。13C NMR(101MHz,CDCl3+CD3OD)δ168.01,163.58,158.22,152.39,149.22,148.72,148.46,148.12,147.26,146.24,144.48,136.56,136.13,135.24,131.74,129.18,128.54,128.01,127.65,127.30,126.97,121.98,119.51,112.26,110.64,104.66,100.58,95.65,56.35,56.27,56.19,56.01,44.29,42.26,41.61,20.96。
此外应理解，在阅读了本发明的上述描述内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 式(I)或(II)所示化合物或其可药用的盐：
    R1、R2、R3、R4、R6、R7相同或不相同，分别独立选自H、卤素、C1～C5烷基或C1～C5烷氧基；
    R5、R8相同或不相同，分别独立选自取代或未取代的苯基、吡啶基、吡嗪基、喹啉基、异喹啉基、色酮基、喹诺酮基或喹喔啉基；所述苯基、吡啶基、吡嗪基、喹啉基、异喹啉基、色酮基、喹诺酮基或喹喔啉基上的取代基分别独立选自氰基或卤素；
    m选自0～4；
    X选自-NHC(＝O)-或-NHS(＝O)2-；
    L选自n分别独立选自0～4。
  2. 根据权利要求1所述的式(I)或(II)所示化合物或其可药用的盐，其特征在于，L中苯环一端与酰胺键连接。
  3. 根据权利要求2所述的式(I)或(II)所示化合物或其可药用的盐，其特征在于，所述化合物选自以下任一：
    N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-3-基)喹唑啉-4-胺；
    N-(4-((6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)-2-(吡啶-3-基)喹 唑啉-4-胺；
    N-(4-(2-(7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-3-基)喹唑啉-4-胺；
    N-(4-((7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)-2-(吡啶-3-基)喹唑啉-4-胺；
    N-(4-(2-(3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-3-基)喹唑啉-4-胺；
    N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-4-基)喹唑啉-4-胺；
    N-(4-((6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)-2-(吡啶-4-基)喹唑啉-4-胺；
    N-(4-(2-(7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-4-基)喹唑啉-4-胺；
    N-(4-((7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)-2-(吡啶-4-基)喹唑啉-4-胺；
    N-(4-(2-(3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(吡啶-4-基)喹唑啉-4-胺；
    N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺；
    N-(2-((4-((6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺；
    N-(2-((4-(2-(7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺；
    N-(2-((4-((7,8-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)甲基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺；
    N-(2-((4-(2-(3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-3-甲酰胺；
    2-(3-氰基苯甲酰胺基)-N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-4,5-二甲氧化苯甲酰胺；
    N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)烟酰胺；
    N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-2-(3-氟苯甲酰胺基)-4,5-二甲氧基苯甲酰胺；
    N-(4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)-4,5-二甲氧基-2-(吡啶-3-磺胺基)苯甲酰胺；
    N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二甲氧基苯基)喹啉-2-甲酰胺；
    N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-2-氧乙基)苯基)氨甲酰基)-4,5-二甲氧基苯基)喹啉-3-甲酰胺；
    N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)-4,5-二氟苯基)喹啉-3-甲酰胺；
    N-(2-((4-(2-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)乙基)苯基)氨甲酰)苯基)喹啉-3-甲酰胺；
    N-(2-((4-(3-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-3-氧丙基)苯基)氨甲酰基)-4,5-二甲氧基苯基)喹啉-3-甲酰胺；
    (E)-N-(2-((4-(3-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-3-氧丙-1-烯-1-基)苯基)氨甲酰基)-4,5-二甲氧基苯基)喹啉-3-甲酰胺；
    (E)-N-(2-((4-(3-(6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-基)-3-氧丙-1-烯-1-基)苯基)氨甲酰基)苯基)喹啉-3-甲酰胺；
    N-(4-(4,5-二甲氧基-2-(喹啉-3-甲酰胺基)苯甲酰胺基)苯基)-6,7-二甲氧基-3,4-二氢苯并呋喃[2,3-c]吡啶-2(1H)-甲酰胺。
  4. 一种根据权利要求1～3任一项所述的式(I)或(II)所示化合物的制备方法，其特征在于，合成路线：
    化合物10即为式(I)所示化合物，其中Y为
    化合物13即为式(II)所示化合物，其中Y为 -NH-Z为-X-R8；
    化合物1在乙酸/三氟化硼乙醚条件下发生邻位傅克酰基化得到化合物2，化合物2与溴乙酸乙酯在碳酸铯作碱下生成化合物3，化合物3发生水解反应得到化合物4，化合物4发生环化反应得到化合物5，化合物5在乙酸溶剂中与苄胺、甲醛水溶液发生多组分反应得到化合物6，化合物6脱苄基得到化合物7，化合物7与卤代物发生亲核取代反应或者经酰胺缩合反应得到化合物8，化合物8经硝基还原反应得到化合物9；化合物9与化合物14发生亲核取代反应得到化合物10；或者，化合物9与化合物15进行酰胺缩合反应得到化合物11，化合物11经硝基还原反应得到化合物12，化合物12经酰胺缩合反应或磺胺缩合反应得到化合物13。
  5. 根据权利要求1～3任一项所述的式(I)或(II)所示化合物或其可药用的盐在制备P-糖蛋白抑制剂中的应用。
  6. 根据权利要求5所述的应用，其特征在于，所述P-糖蛋白抑制剂为口服制剂。
  7. 根据权利要求1～3任一项所述的式(I)或(II)所示化合物或其可药用的盐在制备用于提高抗癌症药物癌症治疗效果的抗药性调节剂中的应用。
  8. 根据权利要求7所述的应用，其特征在于，所述抗癌症药物为由于肠道P-糖蛋白的抑制作用而不容易在消化道中吸收的药物，包括紫杉烷类、长春生物碱、蒽环类药、喜树碱、鬼臼毒素、米托蒽酯、放线菌素、秋水仙碱；
    所述紫杉烷类包括紫杉醇、多西他赛；
    所述长春生物碱包括长春新碱、长春碱；
    所述蒽环类药包括柔红霉素、多柔比星；
    所述喜树碱包括托泊替康、伊立替康。
  9. 根据权利要求7所述的应用，其特征在于，所述癌症为实体瘤或血液系统恶性肿瘤，选自白血病、多发性骨髓瘤、淋巴瘤；
    所述白血病为急性淋巴细胞白血病、急性髓性白血病、慢性淋巴细胞白血病、慢性髓性白血病；
    所述淋巴瘤为霍奇金淋巴瘤、非霍奇金淋巴瘤、套细胞淋巴瘤、滤泡型淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、弥散性大B细胞淋巴瘤。
  10. 根据权利要求7所述的应用，其特征在于，所述抗药性调节剂为口服制剂。
PCT/CN2024/131215 2023-11-29 2024-11-11 一种p-糖蛋白抑制剂及其制备方法和应用 Pending WO2025113152A1 (zh)

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