WO2022121317A1 - 1,1'-biphenyl-2,6-diphenolic compound and use thereof - Google Patents

1,1'-biphenyl-2,6-diphenolic compound and use thereof Download PDF

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WO2022121317A1
WO2022121317A1 PCT/CN2021/107218 CN2021107218W WO2022121317A1 WO 2022121317 A1 WO2022121317 A1 WO 2022121317A1 CN 2021107218 W CN2021107218 W CN 2021107218W WO 2022121317 A1 WO2022121317 A1 WO 2022121317A1
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biphenyl
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张婷
林祖铭
张靖
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福建省中科生物股份有限公司
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Definitions

  • the invention belongs to the field of medicinal chemistry, in particular to a class of 1,1'-biphenyl-2,6-diphenol compounds with broad-spectrum antitumor activity and applications thereof.
  • Cancer also known as malignant tumor, is a malignant and common disease that seriously threatens human health, and has become the "second killer” after cardiovascular disease.
  • malignant tumor deaths accounted for 23.91% of all deaths among residents, and its morbidity and mortality rates have continued to rise in the past decade.
  • the present invention aims to develop a compound with broad-spectrum antitumor activity with high efficiency and low toxicity.
  • the present invention obtains a series of 1,1'-biphenyl-2,6-diphenol compounds through screening, design and synthesis, the compounds have the activity of inhibiting the proliferation of tumor cells.
  • One object of the present invention is to provide a 1,1'-biphenyl-2,6-diphenol compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, the chemical structural formula of the compound is as shown in formula (I) Show:
  • R1, R2, R3, R4 are each independently selected from:
  • the heteroaryl group is a 3-10-membered heteroaryl group containing 1-3 kinds of heteroatoms in N, S, and O.
  • R1, R2, R3, R4 are respectively preferably selected from:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the 1,1'-biphenyl-2,6-diphenol compound represented by formula (I).
  • the present invention provides 1,1'-biphenyl-2,6-diphenol compounds represented by formula (I), pharmaceutically acceptable salts or stereoisomers thereof, and compounds comprising 1,1'-biphenyl-
  • formula (I) 1,1'-biphenyl-2,6-diphenol compounds represented by formula (I)
  • pharmaceutically acceptable salts or stereoisomers thereof and compounds comprising 1,1'-biphenyl-
  • compounds comprising 1,1'-biphenyl- The use of the pharmaceutical composition of 2,6-diphenol compounds in the preparation of antitumor drugs.
  • the specific use is for inhibiting tumor cell proliferation.
  • the present invention provides a new compound with good biological activity. Through the method of in vitro tumor cell activity test, it is found that it has inhibitory activity on tumor cell proliferation, and has the potential to develop anti-tumor drugs.
  • Electrospray (ESI) mass spectra were acquired on a Finnigan LCQ ion trap.
  • DCM dichloromethane
  • HPLC high performance liquid chromatography
  • TFA trifluoroacetic acid
  • DIPEA N,N-diisopropylethylamine
  • EDCI 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • HOBt 1-hydroxybenzotriazole
  • rt room temperature
  • EA ethyl acetate
  • DMAP 4-dimethylaminopyridine
  • DMP 2,2-dimethoxypropane
  • HATU 2-(7-azabenzotriazole)-N,NN,N'-tetramethylurea hexafluorophosphate
  • THF tetrahydrofluorofuran
  • Boc 2 O di-tert-butyl dicarbonate
  • DMF N,N-dimethylformamide
  • DME ethylene glycol dimethyl ether
  • PPTS pyridinium p-toluenesulf
  • the preparation method of compound 3 take 25ml reaction tube, add compound 2 (0.22mmol), compound 1 (0.18mmol), Cs 2 CO 3 (0.36 mmol), Pd(PPh 3 ) 4 (0.02 mmol), 1,4- Dioxane (2ml) replaced Ar gas and then placed in an oil bath at 80°C to react for 12h, and the reaction was completed by TLC detection. Filter through celite, remove the solvent under reduced pressure, and separate and purify compound 3 by column chromatography.
  • Preparation method of compound I-1 ⁇ I-6 take a 25ml reaction tube, add compound 3 (0.18mmol), 2mL of DCM, put it in an ice-ethanol bath (-15°C), slowly add 0.9ml of BBr3 (1.0M) dropwise in DCM), the reaction was naturally heated up for 12h, and the reaction was completed by TLC detection. The system was placed in an ice-water bath and quenched by adding 0.2 ml of MeOH. Then water and dichloromethane were added, followed by liquid separation extraction, drying over anhydrous sodium sulfate, concentration under reduced pressure, and separation and purification by column chromatography to obtain compounds I-1 to I-6.
  • Preparation of compound 7 take a 25ml reaction tube, add compound 6 (25mg, 0.07mmol), DMAP (1.3mg, 0.01mmol), EDCI (20mg, 0.10mmol), DIPEA (36ul, 0.21mmol) at room temperature and stir for 30min at room temperature, then add N-acetyl-L-isoleucine (0.08mmol), the reaction was carried out for 12h, and the completion of the reaction was detected by TLC. Saturated NaHCO 3 was added, extracted with dichloromethane, the organic phases were combined, washed with saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain amide intermediate 7.
  • HepG2 and human lung cancer cells A549 were cultured in a petri dish with DMEM complete medium (containing 10% fetal bovine serum and 1X penicillin-streptomycin double antibody solution), and cells in logarithmic growth phase were taken. At 70%-80% confluence, after trypsinization, resuspend the cells in culture medium and count them, prepare a cell suspension with a density of about 7 ⁇ 104 cells/mL, and inoculate the cells in a 96-well plate with 100 ⁇ L of cell suspension per well. Incubate in a 37°C incubator until cells adhere.
  • DMEM complete medium containing 10% fetal bovine serum and 1X penicillin-streptomycin double antibody solution
  • DMSO methyl methoxysulfoxide
  • the culture medium was used to dilute to the required working concentration during the experiment. After discarding the culture medium in the 96-well plate, 100 ⁇ L of compound solutions with different working concentrations were added to the experimental group, 100 ⁇ L of culture medium was added to the blank control group, and 100 ⁇ L of antitumor drug cisplatin and gemcitabine solutions of different concentrations were added to the positive control group. Place in an incubator for culture.
  • the inhibitory effect of other compounds on HepG2 cells was better than that of the positive drug cisplatin, and the inhibitory effect of compound I-4 on HepG2 cells was Equivalent to the positive drug gemcitabine; the above compounds also have inhibitory effect on lung cancer A549 cells, but the inhibitory activity is slightly inferior to the positive drugs cisplatin and gemcitabine.
  • the biologically active 1,1'-biphenyl-2,6-diphenol compounds provided by the present invention have the activity of inhibiting the proliferation of tumor cells, have great potential for drug research and development, and can be used as lead compounds. in the development of anticancer drugs.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

Disclosed is a 1,1'-biphenyl-2,6-diphenolic compound and the use thereof. The 1,1'-biphenyl-2,6-diphenolic compound is a new compound, and has good biological activity. By means of in vitro tumor cell activity experiments, it was found that the compound has inhibitory activity on tumor cell proliferation, and has the potential of developing an anti-tumor medicament.

Description

1,1′-联苯-2，6-二酚类化合物及其应用1,1'-biphenyl-2,6-diphenol compound and its application 技术领域technical field
本发明属于药物化学领域，具体涉及一类具有广谱抗肿瘤活性的1,1'-联苯-2，6-二酚类化合物及其应用。The invention belongs to the field of medicinal chemistry, in particular to a class of 1,1'-biphenyl-2,6-diphenol compounds with broad-spectrum antitumor activity and applications thereof.
背景技术Background technique
癌症又称为恶性肿瘤，是一种严重威胁人类健康的恶性和常见疾病，已成为继心血管疾病后威胁人类健康的“第二大杀手”。2019年，国家癌症中心发布的数据显示：恶性肿瘤死亡占居民全部死因的23.91％，且近十几年来其发病死亡率呈持续上升态势。Cancer, also known as malignant tumor, is a malignant and common disease that seriously threatens human health, and has become the "second killer" after cardiovascular disease. In 2019, data released by the National Cancer Center showed that malignant tumor deaths accounted for 23.91% of all deaths among residents, and its morbidity and mortality rates have continued to rise in the past decade.
尽管抗肿瘤药物的发展取得了重要进步，但现有的标准治疗手段仍然是手术切除、化疗和放疗。传统的化疗药物在临床上虽疗效明显，但选择性差、靶向性低导致毒副作用明显且易出现多药耐药现象，从而降低患者的生存质量。故本发明旨在开发高效、低毒的具有广谱抗肿瘤活性的化合物。Despite important advances in the development of antitumor drugs, the current standard of care is still surgical resection, chemotherapy, and radiotherapy. Although traditional chemotherapeutic drugs are clinically effective, their poor selectivity and low targeting result in obvious toxic and side effects and prone to multidrug resistance, thus reducing the quality of life of patients. Therefore, the present invention aims to develop a compound with broad-spectrum antitumor activity with high efficiency and low toxicity.
发明内容SUMMARY OF THE INVENTION
有鉴于此，本发明经过筛选、设计并合成得到了一系列1,1'-联苯-2，6-二酚类化合物，该化合物具抑制肿瘤细胞增殖的活性。In view of this, the present invention obtains a series of 1,1'-biphenyl-2,6-diphenol compounds through screening, design and synthesis, the compounds have the activity of inhibiting the proliferation of tumor cells.
本发明采取的具体技术方案是：The concrete technical scheme that the present invention takes is:
本发明的一个目的是提供一种1,1'-联苯-2，6-二酚类化合物、其药学上可接受的盐或其立体异构体，化合物的化学结构式如式(I)所示：One object of the present invention is to provide a 1,1'-biphenyl-2,6-diphenol compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, the chemical structural formula of the compound is as shown in formula (I) Show:
Figure PCTCN2021107218-appb-000001
Figure PCTCN2021107218-appb-000001
R1，R2，R3，R4各自独立地选自：R1, R2, R3, R4 are each independently selected from:
氢，卤素，硝基，氰基，氨基或取代氨基，C1-3的醛基，C1-6烷基或取代烷基，羧基或取代羧基，羟基或取代羟基，芳基或被0～5个基团取代的芳基，杂芳基或0～5个基团取代的杂芳基；Hydrogen, halogen, nitro, cyano, amino or substituted amino, C1-3 aldehyde group, C1-6 alkyl or substituted alkyl, carboxyl or substituted carboxyl, hydroxyl or substituted hydroxyl, aryl or by 0 to 5 group-substituted aryl group, heteroaryl group or 0-5 group-substituted heteroaryl group;
所述杂芳基为包含N、S、O中的1～3种杂原子的3～10元杂芳基。The heteroaryl group is a 3-10-membered heteroaryl group containing 1-3 kinds of heteroatoms in N, S, and O.
其中，R1，R2，R3，R4分别优选自：Among them, R1, R2, R3, R4 are respectively preferably selected from:
Figure PCTCN2021107218-appb-000002
Figure PCTCN2021107218-appb-000002
本发明还提供了一种药物组合物，包含式(I)所示的1,1'-联苯-2，6-二酚类化合物。The present invention also provides a pharmaceutical composition comprising the 1,1'-biphenyl-2,6-diphenol compound represented by formula (I).
本发明提供了式(I)所示1,1'-联苯-2，6-二酚类化合物、其药学上可接受的盐或其立体异构体及包含1,1'-联苯-2，6-二酚类化合物的药物组合物在制备抗肿瘤药物中的用途。The present invention provides 1,1'-biphenyl-2,6-diphenol compounds represented by formula (I), pharmaceutically acceptable salts or stereoisomers thereof, and compounds comprising 1,1'-biphenyl- The use of the pharmaceutical composition of 2,6-diphenol compounds in the preparation of antitumor drugs.
进一步地，具体用途是用于抑制肿瘤细胞增殖。Further, the specific use is for inhibiting tumor cell proliferation.
本发明的有益效果是：本发明提供了一种新的化合物，该化合物具备良好的生物活性。通过体外肿瘤细胞活性实验的方法，发现其对肿瘤细胞增殖具有抑制活性，具备开发抗肿瘤药物的潜力。The beneficial effects of the present invention are as follows: the present invention provides a new compound with good biological activity. Through the method of in vitro tumor cell activity test, it is found that it has inhibitory activity on tumor cell proliferation, and has the potential to develop anti-tumor drugs.
具体实施方式Detailed ways
下面结合实施例对本发明作进一步地详细说明，但本发明的实施方式不 限于此，在不脱离本发明上述技术思想情况下，根据本领域普通技术知识和惯用手段，做出各种替换和变更，均应包括在本发明的范围内。The present invention will be described in further detail below in conjunction with the examples, but the embodiments of the present invention are not limited to this. Without departing from the above-mentioned technical idea of the present invention, various replacements and changes are made according to common technical knowledge and conventional means in the field. , should be included in the scope of the present invention.
具体实施例化合物结构汇总表(表1)：Specific embodiment compound structure summary table (table 1):
Table 1Table 1
Figure PCTCN2021107218-appb-000003
Figure PCTCN2021107218-appb-000003
Table 1(continued)Table 1(continued)
Figure PCTCN2021107218-appb-000004
Figure PCTCN2021107218-appb-000004
Table 1(continued)Table 1(continued)
Figure PCTCN2021107218-appb-000005
Figure PCTCN2021107218-appb-000005
合成实验部分Synthetic experiment part
就如下涉及的实施例而言，使用本文所述的方法或本领域众所周知的其他方法合成本发明的化合物。For the examples referred to below, the compounds of the invention were synthesized using the methods described herein or other methods well known in the art.
通用纯化和分析方法：General purification and analysis methods:
在硅胶GF254预涂覆板(merck)上进行薄层色谱。在中压下经硅胶(300-400 目，Greagent)进行柱色谱分离。成分通过UV光(254nm)和通过碘蒸气、碱性KMnO 4溶液(KMnO 4：K 2CO 3：NaOH：H 2O＝1.5g：10g：0.125g：200ml)磷钼酸溶液(10g磷钼酸+200ml乙醇)显影。必要时，将化合物通过HPLC纳谱分析(Chromcore 8-120 C18,8um,10X250mm)柱纯化，流动相为乙腈/H 2O(70％～100％),流速：10ml/min。 Thin layer chromatography was performed on silica gel GF254 precoated plates (merck). Column chromatography was performed on silica gel (300-400 mesh, Greagent) at medium pressure. Composition by UV light (254nm) and by iodine vapor, alkaline KMnO4 solution ( KMnO4 :K2CO3: NaOH : H2O = 1.5g: 10g: 0.125g: 200ml) phosphomolybdic acid solution (10g phosphomolybdate acid + 200 ml ethanol) for development. If necessary, compounds were purified by HPLC nanospectroscopy (Chromcore 8-120 C18, 8um, 10X250mm) column, mobile phase was acetonitrile/ H2O (70%-100%), flow rate: 10ml/min.
将1H-NMR谱在400MHz操作的Bruker Avance 400谱仪(对于1H而言)进行记录。将四甲基硅烷信号用作参比。化学位移以百万分率(ppm)进行报道且偶合常数(J)以Hz计。以下缩写用于峰裂分:s＝单；br.s.＝宽信号；d＝双；t＝三；m＝多重；dd＝双双。1H-NMR spectra were recorded on a Bruker Avance 400 spectrometer (for 1H) operating at 400 MHz. The tetramethylsilane signal was used as a reference. Chemical shifts are reported in parts per million (ppm) and coupling constants (J) are in Hz. The following abbreviations are used for peak splitting: s = single; br.s. = broad signal; d = double; t = triple; m = multiple; dd = double double.
电喷雾(ESI)质谱经Finnigan LCQ离子阱获得。Electrospray (ESI) mass spectra were acquired on a Finnigan LCQ ion trap.
试剂纯化参考Purification of Laboratory Chemicals(Perrin,D.D.,Armarego,W.L.F.and Perrins Eds,D.R.；Pergamon Press:Oxford,1980)一书进行。石油醚是60-90℃馏分、乙酸乙酯、甲醇、二氯甲烷均为分析纯。Reagent purification was carried out with reference to the book Purification of Laboratory Chemicals (Perrin, D.D., Armarego, W.L.F. and Perrins Eds, D.R.; Pergamon Press: Oxford, 1980). Petroleum ether is a 60-90°C fraction, and ethyl acetate, methanol, and dichloromethane are all analytically pure.
下文中的缩写具有以下含义：Abbreviations below have the following meanings:
DCM：二氯甲烷；HPLC：高效液相色谱法；TFA：三氟乙酸；DIPEA：N,N-二异丙基乙胺；EDCI：1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐；HOBt：1-羟基苯并三唑；rt：室温；EA:乙酸乙酯；DMAP：4-二甲氨基吡啶；DMP：2,2-二甲氧基丙烷；HATU：2-(7-氮杂苯并三氮唑)-N，N-N,N’-四甲基脲六氟磷酸酯；THF:四氢氟喃；Boc 2O：二碳酸二叔丁酯；DMF：N,N-二甲基甲酰胺；DME：乙二醇二甲醚；PPTS：对甲苯磺酸吡啶盐；NIS：N-碘代丁二酰亚胺 DCM: dichloromethane; HPLC: high performance liquid chromatography; TFA: trifluoroacetic acid; DIPEA: N,N-diisopropylethylamine; EDCI: 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride; HOBt: 1-hydroxybenzotriazole; rt: room temperature; EA: ethyl acetate; DMAP: 4-dimethylaminopyridine; DMP: 2,2-dimethoxypropane; HATU: 2-(7-azabenzotriazole)-N,NN,N'-tetramethylurea hexafluorophosphate; THF: tetrahydrofluorofuran; Boc 2 O: di-tert-butyl dicarbonate; DMF: N,N-dimethylformamide; DME: ethylene glycol dimethyl ether; PPTS: pyridinium p-toluenesulfonate; NIS: N-iodosuccinimide
具体合成实验Specific synthesis experiments
下面通过具体实施例详细描述本发明的实施方式，但是无论如何它们不 能解释为对本发明的限制。Embodiments of the present invention will be described in detail below by way of specific examples, but they should not be construed as limiting the present invention in any way.
Figure PCTCN2021107218-appb-000006
Figure PCTCN2021107218-appb-000006
1.化合物I-1～I-6的合成通式如下：1. The synthetic general formula of compounds I-1～I-6 is as follows:
Figure PCTCN2021107218-appb-000007
Figure PCTCN2021107218-appb-000007
化合物2制备：取100ml单口瓶，加入5-(1,1-二甲基庚基)间苯二酚(1.02g，8.06mmol)，乙腈(16ml)置于冰水浴中，分两次加入NIS(1.86g，8.06mmol)加完后自然升温，反应2h，TLC检测反应完毕，加入饱和NaHCO3，减压除去大部分乙腈，乙醚分液萃取，合并有机相，减压浓缩，柱层析分离纯化(Hexanes/EA＝1:8)，得二酚碘代物(1.88g,93％)。Preparation of compound 2: take a 100ml single-neck bottle, add 5-(1,1-dimethylheptyl)resorcinol (1.02g, 8.06mmol), acetonitrile (16ml) is placed in an ice-water bath, and NIS is added twice After adding (1.86g, 8.06mmol), the temperature was naturally raised, the reaction was completed for 2h, and the reaction was detected by TLC. Saturated NaHCO was added, most of the acetonitrile was removed under reduced pressure, and the organic phases were separated and extracted with ether. The organic phases were combined, concentrated under reduced pressure, and separated and purified by column chromatography. (Hexanes/EA=1:8) to obtain diphenol iodide (1.88 g, 93%).
取25ml单口瓶，加入上述二酚碘代物(0.5g,2mmol)，丙酮(10ml)，K2CO3(0.83g，6mmol),硫酸二甲酯(0.47ml,5mmol)室温反应24h,TLC检测反应完毕。往体系加入10ml水，搅拌10min,减压除去丙酮，加入乙醚分液萃取，饱和食盐水洗，无水硫酸钠干燥，减压浓缩，柱层析分离纯化 (Hexanes/EA＝1:20)，得到油状化合物2(0.53g，95％)。Take a 25ml single-neck bottle, add the above-mentioned diphenol iodide (0.5g, 2mmol), acetone (10ml), K2CO3 (0.83g, 6mmol), dimethyl sulfate (0.47ml, 5mmol) and react at room temperature for 24h, and TLC detects the completion of the reaction. Add 10 ml of water to the system, stir for 10 min, remove acetone under reduced pressure, add ether for liquid separation, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify by column chromatography (Hexanes/EA=1:20) to obtain Compound 2 as an oil (0.53 g, 95%).
化合物3的制备方法：取25ml反应管，加入化合物2(0.22mmol),化合物1(0.18mmol)，Cs 2CO 3(0.36mmol)，Pd(PPh 3) 4(0.02mmol)，1，4-二氧六环(2ml)置换Ar气后置于80℃油浴反应12h，TLC检测反应完毕。硅藻土过滤，减压除去溶剂，柱层析分离纯化得化合物3。 The preparation method of compound 3: take 25ml reaction tube, add compound 2 (0.22mmol), compound 1 (0.18mmol), Cs 2 CO 3 (0.36 mmol), Pd(PPh 3 ) 4 (0.02 mmol), 1,4- Dioxane (2ml) replaced Ar gas and then placed in an oil bath at 80°C to react for 12h, and the reaction was completed by TLC detection. Filter through celite, remove the solvent under reduced pressure, and separate and purify compound 3 by column chromatography.
化合物I-1～I-6的制备方法：取25ml反应管，加入化合物3(0.18mmol)，DCM 2mL，置于冰乙醇浴中(-15℃)，缓慢滴加0.9ml BBr 3(1.0M in DCM)，自然升温反应12h，TLC检测反应完毕。体系置于冰水浴中，加入0.2ml MeOH淬灭。再加入水，二氯甲烷，分液萃取，无水硫酸钠干燥，减压浓缩，柱层析分离纯化得化合物I-1～I-6。 Preparation method of compound I-1～I-6: take a 25ml reaction tube, add compound 3 (0.18mmol), 2mL of DCM, put it in an ice-ethanol bath (-15°C), slowly add 0.9ml of BBr3 (1.0M) dropwise in DCM), the reaction was naturally heated up for 12h, and the reaction was completed by TLC detection. The system was placed in an ice-water bath and quenched by adding 0.2 ml of MeOH. Then water and dichloromethane were added, followed by liquid separation extraction, drying over anhydrous sodium sulfate, concentration under reduced pressure, and separation and purification by column chromatography to obtain compounds I-1 to I-6.
下面具体描述实施例化合物I-1～I-6的合成:Describe the synthesis of embodiment compound I-1～I-6 in detail below:
实施例1Example 1
化合物I-1：
Figure PCTCN2021107218-appb-000008
Compound I-1:
Figure PCTCN2021107218-appb-000008
化合物1硼酸制备：取250ml三口瓶，加入3-溴-4-甲基苯甲酸甲酯(2.0g，8.77mmol)、频哪醇联硼酸酯(4.46g，17.54mmol)、PdCl 2(dppf).DCM(143mg,0.175mmol),KOAc(3.44g,35.08mmol)先置换Ar气，加入1,4-二氧六环(60ml),除氧(隔膜泵抽体系，置换Ar气)，置于80℃油浴反应12h,TLC检测反应完毕。硅藻土过滤，减压除去溶剂，加入乙醚、水，分液萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，减压浓缩，柱层析分离纯化(Hexanes/EA＝20:1)得到较纯硼酸酯化合物,在重结晶除去过量的硼试剂 (Hexanes/EA)得白色固体化合物1硼酸酯(1.81g,75％)。将上述硼酸酯，加入甲醇20ml,12N浓硫酸2.7ml,加热回流12h，TLC检测反应完毕，减压浓缩，乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩得到硼酸化合物1(1.26g，95％)。 Preparation of compound 1 boronic acid: take a 250ml there-necked flask, add 3-bromo-4-methylbenzoic acid methyl ester (2.0g, 8.77mmol), pinacol boronate (4.46g, 17.54mmol), PdCl 2 (dppf ).DCM (143mg, 0.175mmol), KOAc (3.44g, 35.08mmol) first replace Ar gas, add 1,4-dioxane (60ml), remove oxygen (diaphragm pumping system, replace Ar gas), set The reaction was carried out in an oil bath at 80 °C for 12 h, and the reaction was completed by TLC detection. Filter through celite, remove the solvent under reduced pressure, add ether and water, extract by liquid separation, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify by column chromatography (Hexanes/EA=20:1 ) to obtain a relatively pure boronate compound, and the excess boron reagent (Hexanes/EA) was removed by recrystallization to obtain a white solid compound 1 boronate ester (1.81g, 75%). The above boric acid ester was added with 20 ml of methanol and 2.7 ml of 12N concentrated sulfuric acid, heated to reflux for 12 h, TLC detected the completion of the reaction, concentrated under reduced pressure, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain boronic acid compound 1 (1.26 g , 95%).
化合物3制备：取25ml反应管，加入化合物2(274mg,0.70mmol),化合物1硼酸(150mg,0.77mmol)，Cs 2CO 3(458mg,1.40mmol)，Pd(PPh 3) 4(0.07mmol,81mg)，1,4-二氧六环(3ml)。置换Ar气后置于80℃油浴反应12h，TLC检测反应完毕。硅藻土过滤，减压除去溶剂，柱层析分离纯化(Hexanes/EA＝8:1)得中间体3(220mg,76％)。 Preparation of compound 3: take a 25ml reaction tube, add compound 2 (274mg, 0.70mmol), compound 1 boronic acid (150mg, 0.77mmol), Cs 2 CO 3 (458mg, 1.40mmol), Pd(PPh 3 ) 4 (0.07mmol, 81 mg), 1,4-dioxane (3 ml). After replacing Ar gas, it was placed in an oil bath at 80 °C for 12 h, and the reaction was completed by TLC detection. Filter through celite, remove the solvent under reduced pressure, and separate and purify by column chromatography (Hexanes/EA=8:1) to obtain Intermediate 3 (220 mg, 76%).
化合物I-1制备：取25ml反应管，加入中间体(100mg,0.24mmol)，DCM 2.4mL，置于冰乙醇浴中(-15℃)，缓慢滴加0.72ml BBr 3(1.0M in DCM)，自然升温反应3h，TLC检测反应完毕。体系置于冰水浴中，加入0.2ml MeOH淬灭，加入饱和碳酸氢钠，二氯甲烷，分液萃取，无水硫酸钠干燥，减压浓缩，柱层析分离纯化(Hexanes/EA＝1:3)得化合物I-1(23mg,25％)。 1H NMR(400MHz,CDCl 3)δ:8.04(dd,J＝8.0,1.7Hz,1H),7.99(s,1H),7.48(d,J＝8.0Hz,1H),6.56(s,2H),4.51(s,2H),3.90(s,3H),2.24(s,3H),1.61–1.54(m,2H),1.28(s,6H),1.26–1.19(m,6H),1.16–1.07(m,2H),0.86(t,J＝6.8Hz,3H).MS(ESI)m/z:385[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 24H 33O 4 +385.2373；Found 385.2368. Preparation of compound I-1: take a 25ml reaction tube, add intermediate (100mg, 0.24mmol), DCM 2.4mL, put it in an ice-ethanol bath (-15°C), slowly add 0.72ml BBr3 (1.0M in DCM) dropwise , the reaction was naturally heated for 3h, and the reaction was completed by TLC detection. The system was placed in an ice-water bath, quenched by adding 0.2 ml of MeOH, added with saturated sodium bicarbonate, dichloromethane, liquid-separated extraction, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography (Hexanes/EA=1: 3) Compound I-1 (23 mg, 25%) was obtained. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.04 (dd, J=8.0, 1.7 Hz, 1H), 7.99 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 6.56 (s, 2H) ,4.51(s,2H),3.90(s,3H),2.24(s,3H),1.61–1.54(m,2H),1.28(s,6H),1.26–1.19(m,6H),1.16–1.07 (m,2H),0.86(t,J＝6.8Hz,3H).MS(ESI)m/z:385[M+H] + .HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 33 O 4 + 385.2373; Found 385.2368.
实施例2Example 2
化合物I-2Compound I-2
Figure PCTCN2021107218-appb-000009
Figure PCTCN2021107218-appb-000009
以化合物2、相应的硼酸1为原料，参照化合物I-1的方法来获得I-2(72mg,63％)。 1H NMR(400MHz,MeOD)δ:6.84(d,J＝1.7Hz,1H),6.81(d,J＝8.1Hz,1H),6.71(dd,J＝8.1,1.8Hz,1H),6.41(s,2H),1.61–1.53(m,2H),1.32–1.19(m,6H),1.26(s,6H)1.17–1.05(m,2H),0.87(t,J＝6.2Hz,3H). Using compound 2 and the corresponding boronic acid 1 as raw materials, referring to the method of compound I-1, I-2 (72 mg, 63%) was obtained. 1 H NMR (400 MHz, MeOD) δ: 6.84 (d, J=1.7 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 6.71 (dd, J=8.1, 1.8 Hz, 1H), 6.41 ( s, 2H), 1.61–1.53 (m, 2H), 1.32–1.19 (m, 6H), 1.26 (s, 6H), 1.17–1.05 (m, 2H), 0.87 (t, J=6.2Hz, 3H).
实施例3Example 3
化合物I-3
Figure PCTCN2021107218-appb-000010
Compound I-3
Figure PCTCN2021107218-appb-000010
以化合物2、相应的硼酸1为原料，参照化合物I-1的方法来获得I-3(72mg,44％)。 1H NMR(400MHz,CDCl3)δ:7.33(t,J＝7.8Hz,1H),6.79–6.73(m,2H),6.72–6.68(m,1H),6.56(s,2H),4.98(brs,2H),3.76(brs,2H),1.58–1.55(m,2H),1.26(s,6H),1.25–1.17(m,6H),1.16–1.07(m,2H),0.86(t,J＝6.8Hz,3H).MS(ESI)m/z:328[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 21H 30NO 2 +328.2271；Found 328.2264. Using compound 2 and the corresponding boronic acid 1 as raw materials, according to the method of compound I-1, I-3 (72 mg, 44%) was obtained. 1 H NMR (400MHz, CDCl3)δ: 7.33(t, J=7.8Hz, 1H), 6.79-6.73(m, 2H), 6.72-6.68(m, 1H), 6.56(s, 2H), 4.98(brs ,2H),3.76(brs,2H),1.58–1.55(m,2H),1.26(s,6H),1.25–1.17(m,6H),1.16–1.07(m,2H),0.86(t,J =6.8Hz,3H).MS(ESI)m/z: 328[M+H] + .HRMS(ESI)m/z:[M+H] + Calcd for C 21 H 30 NO 2 + 328.2271; Found 328.2264 .
实施例4Example 4
化合物I-4Compound I-4
Figure PCTCN2021107218-appb-000011
Figure PCTCN2021107218-appb-000011
以化合物2、相应的硼酸1为原料，参照化合物I-1的方法来获得I-4(100mg,70％)。 1H NMR(400MHz,CDCl 3)δ7.46–7.38(m,2H),7.38–7.28(m,2H),6.57(s,2H),4.82(s,2H),3.04–2.91(m,1H),1.63–1.55(m,2H),1.31(d,J＝6.9Hz,6H),1.26(s,6H),1.25–1.19(m,6H),1.19–1.04(m,2H),0.86(t,J＝6.8Hz,3H).GC-MS(EI)m/z:[M] +354.24. Using compound 2 and the corresponding boronic acid 1 as raw materials, referring to the method of compound I-1, I-4 (100 mg, 70%) was obtained. 1 H NMR (400MHz, CDCl 3 )δ7.46-7.38(m,2H),7.38-7.28(m,2H),6.57(s,2H),4.82(s,2H),3.04-2.91(m,1H) ),1.63–1.55(m,2H),1.31(d,J=6.9Hz,6H),1.26(s,6H),1.25–1.19(m,6H),1.19–1.04(m,2H),0.86( t,J=6.8Hz,3H).GC-MS(EI)m/z:[M] + 354.24.
实施例5Example 5
化合物I-5
Figure PCTCN2021107218-appb-000012
Compound I-5
Figure PCTCN2021107218-appb-000012
以化合物2、相应的硼酸1为原料，参照化合物I-1的方法来获得I-5(38mg,41％)。 1H NMR(400MHz,CDCl 3)δ8.38–8.33(m,1H),8.25(ddd,J＝8.2,2.3,1.1Hz,1H),7.84–7.77(m,1H),7.67(t,J＝7.9Hz,1H),6.53(s,2H),4.76(s,2H),1.61–1.53(m,2H),1.27(s,6H),1.26–1.19(m,6H),1.15–1.04(m,2H),0.86(t,J＝6.8Hz,3H).GC-MS(EI)m/z:[M] +357.19. Using compound 2 and the corresponding boronic acid 1 as raw materials, referring to the method of compound I-1, I-5 (38 mg, 41%) was obtained. 1 H NMR (400MHz, CDCl 3 ) δ 8.38-8.33 (m, 1H), 8.25 (ddd, J=8.2, 2.3, 1.1 Hz, 1H), 7.84-7.77 (m, 1H), 7.67 (t, J = 7.9Hz, 1H), 6.53(s, 2H), 4.76(s, 2H), 1.61–1.53(m, 2H), 1.27(s, 6H), 1.26–1.19(m, 6H), 1.15–1.04( m,2H),0.86(t,J＝6.8Hz,3H).GC-MS(EI)m/z:[M] + 357.19.
实施例6Example 6
化合物I-6
Figure PCTCN2021107218-appb-000013
Compound I-6
Figure PCTCN2021107218-appb-000013
以化合物2、相应的硼酸1为原料，参照化合物I-1的方法来获得I-6(100mg,64％)。 1H NMR(400MHz,CDCl 3)δ7.81–7.75(m,2H),7.67–7.61(m,2H), 7.54–7.46(m,4H),7.43–7.36(m,1H),6.59(s,2H),4.87(s,2H),1.63–1.56(m,2H),1.29(s,6H),1.27–1.20(m,6H),1.17–1.09(m,2H),0.87(t,J＝6.8Hz,3H).MS(ESI)m/z:389.2[M+H] +. Using compound 2 and the corresponding boronic acid 1 as raw materials, referring to the method of compound I-1, I-6 (100 mg, 64%) was obtained. 1 H NMR (400MHz, CDCl 3 ) δ 7.81-7.75 (m, 2H), 7.67-7.61 (m, 2H), 7.54-7.46 (m, 4H), 7.43-7.36 (m, 1H), 6.59 (s) ,2H),4.87(s,2H),1.63–1.56(m,2H),1.29(s,6H),1.27–1.20(m,6H),1.17–1.09(m,2H),0.87(t,J =6.8Hz,3H).MS(ESI)m/z:389.2[M+H] + .
2.化合物I-7合成路线如下：2. The synthetic route of compound 1-7 is as follows:
Figure PCTCN2021107218-appb-000014
Figure PCTCN2021107218-appb-000014
实施例7Example 7
化合物I-7Compound I-7
Figure PCTCN2021107218-appb-000015
Figure PCTCN2021107218-appb-000015
化合物4制备：取25ml单口瓶，加入化合物3(125mg,0.30mmol)，甲醇1.5ml，THF 1.5ml置于50℃油浴中，反应12h，TLC检测反应完毕。减压除去溶剂，加水后，再加1N HCl调pH 3～5。加入乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，减压浓缩，柱层析(Hexanes:EA:AcOH＝4:1:0.05)得中间体4(110mg，91％)。Preparation of compound 4: Take a 25ml single-necked bottle, add compound 3 (125mg, 0.30mmol), 1.5ml of methanol, and 1.5ml of THF, put it in a 50°C oil bath, react for 12h, and TLC detects the completion of the reaction. The solvent was removed under reduced pressure, and after adding water, 1N HCl was added to adjust the pH to 3-5. Ethyl acetate was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (Hexanes:EA:AcOH=4:1:0.05) to obtain Intermediate 4 (110 mg, 91%).
取25ml反应管，加入化合物4(50mg,0.13mmol)，DCM 1.2mL，置于冰乙醇浴中(-15℃)，缓慢滴加0.6ml BBr 3(1.0M in DCM)，自然升温反应12h，TLC检测反应完毕，置于冰水浴中，加入0.2ml MeOH淬灭，二氯甲烷，分液萃取，无水硫酸钠干燥，减压浓缩，制备分离纯化(Hexanes/Acetone＝1:1)得化合物I-7(10mg,20％)。 1H NMR(400MHz,Acetone)δ7.94–7.83(m, 2H),7.72(s,2H),7.37(d,J＝7.9Hz,1H),6.54(s,2H),2.23(s,3H),1.63–1.55(m,2H),1.26(s,6H),1.25–1.21(m,6H),1.14(d,J＝4.6Hz,2H),0.85(t,J＝6.8Hz,3H).MS(ESI)m/z:371[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 23H 31O 4 +371.2217；Found 371.2216. Take a 25 ml reaction tube, add compound 4 (50 mg, 0.13 mmol), 1.2 mL of DCM, put it in an ice-ethanol bath (-15 °C), slowly add 0.6 ml of BBr 3 (1.0 M in DCM) dropwise, and react at natural temperature for 12 h, TLC detection reaction completed, placed in ice water bath, quenched by adding 0.2ml MeOH, dichloromethane, liquid separation extraction, drying over anhydrous sodium sulfate, concentration under reduced pressure, preparation separation and purification (Hexanes/Acetone=1:1) to obtain the compound 1-7 (10 mg, 20%). 1 H NMR(400MHz, Acetone)δ7.94-7.83(m, 2H), 7.72(s, 2H), 7.37(d, J=7.9Hz, 1H), 6.54(s, 2H), 2.23(s, 3H) ), 1.63–1.55 (m, 2H), 1.26 (s, 6H), 1.25–1.21 (m, 6H), 1.14 (d, J=4.6Hz, 2H), 0.85 (t, J=6.8Hz, 3H) .MS(ESI) m/z: 371[M+H] + .HRMS(ESI) m/z: [M+H] + Calcd for C 23 H 31 O 4 + 371.2217; Found 371.2216.
3.化合物I-8、I-9合成通式如下：3. The synthetic general formula of compound I-8 and I-9 is as follows:
Figure PCTCN2021107218-appb-000016
Figure PCTCN2021107218-appb-000016
实施例8Example 8
化合物I-8Compound I-8
Figure PCTCN2021107218-appb-000017
Figure PCTCN2021107218-appb-000017
取25ml反应管，加入化合物4(30mg，0.075mmol)、DMAP(1mg,0.01mmol)，EDCI(17.2mg,0.09mmol)，Et 3N(26ul,0.19mmol)室温下搅拌30min，后加入1-萘肼盐酸盐(0.15mmol)，反应12h,TLC检测反应完毕。加入饱和NaHCO 3，二氯甲烷萃取，合并有机相，饱和NaCl洗，无水硫酸钠干燥，减压浓缩，柱层析分离得到酰胺中间体5。 Take a 25ml reaction tube, add compound 4 (30mg, 0.075mmol), DMAP (1mg, 0.01mmol), EDCI (17.2mg, 0.09mmol), Et3N (26ul, 0.19mmol) and stir at room temperature for 30min, and then add 1- Naphthylhydrazine hydrochloride (0.15mmol) was reacted for 12h, and the reaction was completed by TLC detection. Saturated NaHCO 3 was added, extracted with dichloromethane, the organic phases were combined, washed with saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain the amide intermediate 5.
取25ml反应管，加入底物酰胺5(0.038mmol)，DCM 1mL，置于冰乙醇浴中(-15℃)，缓慢滴加0.2ml BBr 3(1.0M in DCM)，自然升温反应12h， TLC检测反应完毕。置于冰水浴中，加入0.1ml MeOH淬灭，加入2ml饱和碳酸氢钠，二氯甲烷，分液萃取，无水硫酸钠干燥，减压浓缩，制备分离纯化得化合物I-8(23mg,57％). 1H NMR(400MHz,Acetone)δ:9.84(d,J＝3.7Hz,1H),8.31–8.22(m,1H),7.90(dd,J＝7.9,1.9Hz,1H),7.87–7.83(m,2H),7.77–7.71(m,3H),7.52–7.47(m,2H),7.43–7.35(m,2H),7.34–7.29(m,1H),7.04(d,J＝7.4Hz,1H),6.55(s,2H),2.24(s,3H),1.63–1.56(m,3H),1.31–1.21(m,6H),1.27(s,6H),1.19–1.12(m,2H),0.86(t,J＝6.8Hz,3H).MS(ESI)m/z:511[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 33H 39N 2O 3 +511.2955；Found 511.2959. Take a 25ml reaction tube, add substrate amide 5 (0.038mmol), 1mL of DCM, put it in an ice-ethanol bath (-15°C), slowly add 0.2ml of BBr3 (1.0M in DCM) dropwise, and naturally heat up and react for 12h, TLC The detection reaction is completed. Placed in an ice-water bath, quenched by adding 0.1 ml MeOH, adding 2 ml saturated sodium bicarbonate, dichloromethane, liquid separation extraction, drying over anhydrous sodium sulfate, concentration under reduced pressure, preparation, separation and purification to obtain compound I-8 (23 mg, 57 %). 1 H NMR (400MHz, Acetone) δ: 9.84 (d, J=3.7Hz, 1H), 8.31–8.22 (m, 1H), 7.90 (dd, J=7.9, 1.9Hz, 1H), 7.87– 7.83 (m, 2H), 7.77–7.71 (m, 3H), 7.52–7.47 (m, 2H), 7.43–7.35 (m, 2H), 7.34–7.29 (m, 1H), 7.04 (d, J=7.4 Hz, 1H), 6.55 (s, 2H), 2.24 (s, 3H), 1.63–1.56 (m, 3H), 1.31–1.21 (m, 6H), 1.27 (s, 6H), 1.19–1.12 (m, 2H),0.86(t,J=6.8Hz,3H).MS(ESI)m/z:511[M+H] + .HRMS(ESI)m/z:[M+H] + Calcd for C 33 H 39 N 2 O 3 + 511.2955; Found 511.2959.
实施例9Example 9
化合物I-9
Figure PCTCN2021107218-appb-000018
Compound I-9
Figure PCTCN2021107218-appb-000018
以化合物4、正丁胺为原料，参照化合物I-8的方法来获得I-9(14mg,46％)。 1H NMR(400MHz,CDCl3)δ:7.81(dd,J＝7.9,1.8Hz,1H),7.61(d,J＝1.7Hz,1H),7.46(d,J＝8.0Hz,1H),6.57(s,2H),6.09(s,1H),4.68(s,2H),3.43(dd,J＝13.0,7.0Hz,2H),2.22(s,3H),1.63–1.52(m,4H),1.40(dd,J＝15.1,7.4Hz,2H),1.28(s,6H),1.24(d,J＝10.8Hz,6H),1.12(s,2H),0.95(t,J＝7.3Hz,3H),0.86(t,J＝6.8Hz,3H).MS(ESI)m/z:426[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 27H 40NO 3 +426.3003；Found 426.3000。 Using compound 4 and n-butylamine as raw materials, referring to the method of compound I-8, I-9 (14 mg, 46%) was obtained. 1 H NMR (400 MHz, CDCl3) δ: 7.81 (dd, J=7.9, 1.8 Hz, 1H), 7.61 (d, J=1.7 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 6.57 ( s, 2H), 6.09(s, 1H), 4.68(s, 2H), 3.43(dd, J=13.0, 7.0Hz, 2H), 2.22(s, 3H), 1.63–1.52(m, 4H), 1.40 (dd,J=15.1,7.4Hz,2H),1.28(s,6H),1.24(d,J=10.8Hz,6H),1.12(s,2H),0.95(t,J=7.3Hz,3H) ,0.86(t,J=6.8Hz,3H).MS(ESI)m/z:426[M+H] + .HRMS(ESI)m/z:[M+H] + Calcd for C 27 H 40 NO 3 + 426.3003; Found 426.3000.
4.化合物I-10～I-14、I-21合成通式如下：4. The general formula for the synthesis of compounds I-10～I-14 and I-21 is as follows:
Figure PCTCN2021107218-appb-000019
Figure PCTCN2021107218-appb-000019
实施例10Example 10
化合物I-10Compound I-10
Figure PCTCN2021107218-appb-000020
Figure PCTCN2021107218-appb-000020
取25ml反应管，加入化合物I-7(30mg，0.08mmol)、s构型脯氨酸甲酯盐酸盐(20mg，0.12mmol),HATU(46.2mg,0.12mmol)，DIPEA(35ul,0.19mmol)室温下搅拌，反应12h,TLC检测反应完毕。加入饱和NaHCO 3，二氯甲烷萃取，合并有机相，饱和NaCl洗，无水硫酸钠干燥，减压浓缩，柱层析分离得到化合物I-10(29mg，75％)。 1H NMR(400MHz,CDCl 3)δ7.61(d,J＝7.8Hz,1H),7.53(s,1H),7.45(d,J＝7.9Hz,1H),6.56(s,2H),4.65(dd,J＝8.4,4.7Hz,1H),3.76(s,3H),3.74–3.65(m,1H),3.64–3.52(m,1H),2.80(s,2H),2.37–2.24(m,1H),2.20(s,3H),2.10–1.84(m,3H),1.59–1.50(m,2H),1.26(s,6H),1.25–1.17(m,6H),1.16–1.05(m,2H),0.85(t,J＝6.7Hz,3H). Take a 25ml reaction tube, add compound I-7 (30mg, 0.08mmol), s-configuration proline methyl ester hydrochloride (20mg, 0.12mmol), HATU (46.2mg, 0.12mmol), DIPEA (35ul, 0.19mmol) ) was stirred at room temperature, and the reaction was completed for 12 h, and the completion of the reaction was detected by TLC. Saturated NaHCO 3 was added, extracted with dichloromethane, the organic phases were combined, washed with saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain compound I-10 (29 mg, 75%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (d, J=7.8 Hz, 1H), 7.53 (s, 1H), 7.45 (d, J=7.9 Hz, 1H), 6.56 (s, 2H), 4.65 (dd,J=8.4,4.7Hz,1H),3.76(s,3H),3.74–3.65(m,1H),3.64–3.52(m,1H),2.80(s,2H),2.37–2.24(m ,1H),2.20(s,3H),2.10–1.84(m,3H),1.59–1.50(m,2H),1.26(s,6H),1.25–1.17(m,6H),1.16–1.05(m ,2H),0.85(t,J＝6.7Hz,3H).
MS(ESI)m/z:482[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 29H 40NO 5 +482.2901；Found 482.2894. MS(ESI) m/z: 482[M+H] + .HRMS(ESI) m/z: [M+H] + Calcd for C 29 H 40 NO 5 + 482.2901; Found 482.2894.
实施例11Example 11
化合物I-11
Figure PCTCN2021107218-appb-000021
Compound I-11
Figure PCTCN2021107218-appb-000021
以化合物I-7,S构型的酪氨酸甲酯为原料，参照化合物I-10的方法来获得化合物I-11(26mg，47％)。 1H NMR(400MHz,CDCl 3)δ7.65–7.53(m,2H),7.36(d,J＝7.9Hz,1H),7.00–6.90(m,2H),6.82(d,J＝7.8Hz,1H),6.72–6.61(m,2H),6.60–6.51(m,2H),5.75(s,1H),5.08–4.95(m,2H),4.83(s,1H),3.71(s,3H),3.19(dd,J＝14.0,5.7Hz,1H),3.05(dd,J＝14.0,6.4Hz,1H),2.19(s,3H),1.61–1.51(m,2H),1.26(s,6H),1.25–1.18(m,6H),1.17–1.05(m,2H),0.85(t,J＝6.7Hz,3H).MS(ESI)m/z:548[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 33H 42NO 6 +548.3007；Found 548.3004. Compound I-11 (26 mg, 47%) was obtained by referring to the method of compound I-10 using compound I-7, tyrosine methyl ester of S configuration as raw material. 1 H NMR (400MHz, CDCl 3 ) δ 7.65-7.53 (m, 2H), 7.36 (d, J=7.9Hz, 1H), 7.00-6.90 (m, 2H), 6.82 (d, J=7.8Hz, 1H), 6.72–6.61 (m, 2H), 6.60–6.51 (m, 2H), 5.75 (s, 1H), 5.08–4.95 (m, 2H), 4.83 (s, 1H), 3.71 (s, 3H) ,3.19(dd,J＝14.0,5.7Hz,1H),3.05(dd,J＝14.0,6.4Hz,1H),2.19(s,3H),1.61–1.51(m,2H),1.26(s,6H) ),1.25–1.18(m,6H),1.17–1.05(m,2H),0.85(t,J=6.7Hz,3H).MS(ESI)m/z:548[M+H] + .HRMS( ESI) m/z: [M+H] + Calcd for C 33 H 42 NO 6 + 548.3007; Found 548.3004.
实施例12Example 12
化合物I-12
Figure PCTCN2021107218-appb-000022
Compound I-12
Figure PCTCN2021107218-appb-000022
以化合物I-7,S构型的组氨酸甲酯二盐酸盐为原料，参照化合物I-10的方法来获得化合物I-12(25mg，60％)。 1H NMR(400MHz,CDCl 3)δ7.83(d,J＝7.4Hz,1H),7.64(s,1H),7.60(d,J＝8.4Hz,1H),7.35(s,1H),7.27(s,1H),6.69(s,1H),6.54(d,J＝4.6Hz,2H),4.93–4.82(m,1H),3.67(s,3H),3.15–3.01(m,2H),2.18(s,3H),1.61–1.48(m,2H),1.24(s,6H),1.21(s,6H),1.14–1.06(m,2H),0.85(t,J＝6.8Hz,3H).MS(ESI)m/z:522[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 30H 40N 3O 5 +522.2962；Found 522.2960. Compound I-12 (25 mg, 60%) was obtained by using compound I-7, histidine methyl ester dihydrochloride in S configuration as raw material and referring to the method of compound I-10. 1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (d, J=7.4 Hz, 1H), 7.64 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 6.69 (s, 1H), 6.54 (d, J=4.6Hz, 2H), 4.93–4.82 (m, 1H), 3.67 (s, 3H), 3.15–3.01 (m, 2H), 2.18(s, 3H), 1.61-1.48(m, 2H), 1.24(s, 6H), 1.21(s, 6H), 1.14-1.06(m, 2H), 0.85(t, J=6.8Hz, 3H) .MS(ESI) m/z: 522[M+H] + .HRMS(ESI) m/z: [M+H] + Calcd for C 30 H 40 N 3 O 5 + 522.2962; Found 522.2960.
实施例13Example 13
化合物I-13
Figure PCTCN2021107218-appb-000023
Compound I-13
Figure PCTCN2021107218-appb-000023
以化合物I-7,对溴苯肼为原料，参照化合物I-10的方法来获得化合物I-13(14mg，32％)。 1H NMR(400MHz,Acetone)δ9.75–9.66(m,1H),7.83(dd,J＝8.0,1.9Hz,1H),7.77(d,J＝1.8Hz,1H),7.69(s,2H),7.37(d,J＝8.0Hz,1H),7.35–7.28(m,2H),6.94–6.88(m,2H),6.54(s,2H),2.81(s,2H),2.22(s,3H),1.65–1.55(m,2H),1.26(s,6H),1.25–1.21(m,6H),1.18–1.12(m,2H),0.85(t,J＝6.8Hz,3H).MS(ESI)m/z:539[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 29H 36BrN 2O 3 +539.1904；Found 539.1898. Using compound I-7 and p-bromophenylhydrazine as raw materials, referring to the method of compound I-10, compound I-13 (14 mg, 32%) was obtained. 1 H NMR (400MHz, Acetone) δ 9.75-9.66 (m, 1H), 7.83 (dd, J=8.0, 1.9Hz, 1H), 7.77 (d, J=1.8Hz, 1H), 7.69 (s, 2H) ), 7.37(d, J=8.0Hz, 1H), 7.35-7.28(m, 2H), 6.94-6.88(m, 2H), 6.54(s, 2H), 2.81(s, 2H), 2.22(s, 3H),1.65–1.55(m,2H),1.26(s,6H),1.25–1.21(m,6H),1.18–1.12(m,2H),0.85(t,J=6.8Hz,3H).MS (ESI) m/z: 539[M+H] + .HRMS(ESI) m/z: [M+H] + Calcd for C 29 H 36 BrN 2 O 3 + 539.1904; Found 539.1898.
实施例14、15Example 14, 15
化合物I-14和化合物I-21Compound I-14 and Compound I-21
Figure PCTCN2021107218-appb-000024
Figure PCTCN2021107218-appb-000024
以化合物I-7,3-氨基苯酚为原料，参照化合物I-10的方法来获得化合物I-14(3mg，8％)和I-21(4mg，10％)。化合物I-14: 1H NMR(400MHz,Acetone)δ9.47(s,1H),8.30(brs,1H),7.86(dd,J＝7.9,2.0Hz,1H),7.77(d,J＝1.9Hz,1H),7.68(brs,2H),7.57(t,J＝2.1Hz,1H),7.37(d,J＝8.0Hz,1H),7.29–7.20(m,1H),7.11(t,J＝8.1Hz,1H),6.59–6.53(m,3H),2.21(s,3H),1.60(dd,J＝9.8,6.4Hz,2H),1.27(s,6H),1.26–1.21(m,6H),1.19–1.13(m,2H),0.86(t,J ＝6.8Hz,3H).MS(ESI)m/z:462[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 29H 36NO 4 +462.2639；Found 462.2636.化合物I-21: 1H NMR(400MHz,Acetone)δ8.00–7.95(m,2H),7.86–7.77(m,2H),7.50–7.42(m,1H),7.08(t,J＝8.0Hz,1H),6.61–6.52(m,4H),6.48–6.42(m,1H),4.82(brs,2H),2.79(s,2H),2.26(s,3H),1.63–1.55(m,2H),1.26(s,6H),1.25–1.21(m,6H),1.18–1.10(m,2H),0.85(t,J＝6.7Hz,3H).MS(ESI)m/z:462[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 29H 36NO 4 +462.2639；Found 462.2635. Compound I-14 (3 mg, 8%) and I-21 (4 mg, 10%) were obtained by using compound I-7,3-aminophenol as raw material and referring to the method of compound I-10. Compound I-14: 1 H NMR (400 MHz, Acetone) δ 9.47 (s, 1H), 8.30 (brs, 1H), 7.86 (dd, J=7.9, 2.0 Hz, 1H), 7.77 (d, J=1.9 Hz,1H),7.68(brs,2H),7.57(t,J=2.1Hz,1H),7.37(d,J=8.0Hz,1H),7.29–7.20(m,1H),7.11(t,J = 8.1Hz, 1H), 6.59–6.53 (m, 3H), 2.21 (s, 3H), 1.60 (dd, J=9.8, 6.4Hz, 2H), 1.27 (s, 6H), 1.26–1.21 (m, 6H),1.19–1.13(m,2H),0.86(t,J=6.8Hz,3H).MS(ESI)m/z:462[M+H] + .HRMS(ESI)m/z:[M +H] + Calcd for C 29 H 36 NO 4 + 462.2639; Found 462.2636. Compound I-21: 1 H NMR (400 MHz, Acetone) δ 8.00–7.95 (m, 2H), 7.86–7.77 (m, 2H) ,7.50–7.42(m,1H),7.08(t,J=8.0Hz,1H),6.61–6.52(m,4H),6.48–6.42(m,1H),4.82(brs,2H),2.79(s , 2H), 2.26(s, 3H), 1.63–1.55(m, 2H), 1.26(s, 6H), 1.25–1.21(m, 6H), 1.18–1.10(m, 2H), 0.85(t, J =6.7Hz,3H).MS(ESI)m/z:462[M+H] + .HRMS(ESI)m/z:[M+H] + Calcd for C 29 H 36 NO 4 + 462.2639; Found 462.2635 .
5.化合物I-15合成路线如下：5. The synthetic route of compound I-15 is as follows:
Figure PCTCN2021107218-appb-000025
Figure PCTCN2021107218-appb-000025
实施例16Example 16
化合物I-15
Figure PCTCN2021107218-appb-000026
Compound I-15
Figure PCTCN2021107218-appb-000026
取25ml反应管，加入I-2(70mg,0.19mmol)、甲苯2ml、2,2-DMP(35μl，0.29mmol)、PPTS(2.4mg,0.01mmol)加热回流，TLC跟踪检测，6h后基本反应完毕。停止加热，冷却至室温，加入饱和碳酸氢钠，DCM分液萃取，合并有机相，饱和食盐水洗一次，无水硫酸钠干燥，减压浓缩，柱层析(Hexanes/EA＝10:1)，得化合物I-15(34mg,47％)。 1H NMR(400MHz,CDCl3)δ:6.89(d,J＝7.8Hz,1H),6.82(dd,J＝7.9,1.6Hz,1H),6.77(d,J＝1.6 Hz,1H),6.55(s,2H),4.88(s,2H),1.73(s,6H),1.60–1.52(m,2H),1.26(s,6H),1.25–1.16(m,6H),1.15–1.06(m,2H),0.86(t,J＝6.8Hz,3H).GC-MS(EI)m/z：384.24[M] +。 Take a 25ml reaction tube, add I-2 (70mg, 0.19mmol), 2ml of toluene, 2,2-DMP (35μl, 0.29mmol), PPTS (2.4mg, 0.01mmol), heat to reflux, TLC tracking detection, the basic reaction after 6h complete. Stop heating, cool to room temperature, add saturated sodium bicarbonate, extract with DCM, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and perform column chromatography (Hexanes/EA=10:1), Compound I-15 was obtained (34 mg, 47%). 1 H NMR (400MHz, CDCl3) δ: 6.89 (d, J=7.8 Hz, 1H), 6.82 (dd, J=7.9, 1.6 Hz, 1H), 6.77 (d, J=1.6 Hz, 1H), 6.55 ( s, 2H), 4.88 (s, 2H), 1.73 (s, 6H), 1.60–1.52 (m, 2H), 1.26 (s, 6H), 1.25–1.16 (m, 6H), 1.15–1.06 (m, 2H), 0.86 (t, J=6.8 Hz, 3H). GC-MS (EI) m/z: 384.24 [M] + .
6.化合物I-16合成路线如下：6. The synthetic route of compound I-16 is as follows:
Figure PCTCN2021107218-appb-000027
Figure PCTCN2021107218-appb-000027
实施例17Example 17
化合物I-16
Figure PCTCN2021107218-appb-000028
Compound I-16
Figure PCTCN2021107218-appb-000028
取25ml反应管，加入I-3(23mg,0.07mmol)，THF 1ml，Boc 2O(20ul,0.084mmol)加热回流12h，TLC检测基本反应完毕。冷却至室温，加入饱和碳酸氢钠，减压除去溶剂，DCM分液萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥。减压浓缩，柱层析纯化(Hexanes/EA＝3:1)得化合物I-16(24mg,80％)。 1H NMR(400MHz,CDCl3)δ:7.54–7.38(m,3H),7.09(d,J＝7.2Hz,1H),6.55(brs,3H),4.86(s,2H),1.59–1.54(m,2H),1.53(s,9H),1.31–1.17(m,6H),1.26(s,6H),1.15–1.06(m,2H),0.86(t,J＝6.8Hz,3H).MS(ESI)m/z:428[M+H] +HRMS(ESI)m/z:[M+H] +Calcd for C 26H 38NO 4 +428.2795；Found 428.2789. Take a 25 ml reaction tube, add I-3 (23 mg, 0.07 mmol), 1 ml of THF, and Boc 2 O (20 ul, 0.084 mmol), and heat under reflux for 12 h. TLC detects that the reaction is basically complete. Cool to room temperature, add saturated sodium bicarbonate, remove the solvent under reduced pressure, extract with DCM, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrated under reduced pressure, purified by column chromatography (Hexanes/EA=3:1) to obtain compound I-16 (24 mg, 80%). 1 H NMR (400MHz, CDCl3)δ: 7.54-7.38(m, 3H), 7.09(d, J=7.2Hz, 1H), 6.55(brs, 3H), 4.86(s, 2H), 1.59-1.54(m ,2H),1.53(s,9H),1.31–1.17(m,6H),1.26(s,6H),1.15–1.06(m,2H),0.86(t,J=6.8Hz,3H).MS( ESI) m/z: 428[M+H] + HRMS(ESI) m/z: [M+H] + Calcd for C 26 H 38 NO 4 + 428.2795; Found 428.2789.
6.化合物I-17合成路线如下：6. The synthetic route of compound I-17 is as follows:
Figure PCTCN2021107218-appb-000029
Figure PCTCN2021107218-appb-000029
实施例18Example 18
化合物I-17
Figure PCTCN2021107218-appb-000030
Compound I-17
Figure PCTCN2021107218-appb-000030
取25ml反应管，加入化合物I-3(30mg,0.09mmol)、HoBt(15mg,0.11mmol)，EDCI(21.2mg,0.11mmol)、DCM 1ml,室温下搅拌30min，后加入4-苯基丁酸(18mg，0.11mmol)，反应12h,TLC检测反应完毕。加入饱和NaHCO 3，二氯甲烷萃取，合并有机相，饱和NaCl洗，无水硫酸钠干燥，减压浓缩，柱层析分离得到化合物I-17(34mg，78％)。 1H NMR(400MHz,CDCl3)δ:7.65–7.56(m,1H),7.52–7.44(m,2H),7.33–7.26(m,3H),7.23–7.12(m,5H),6.55(s,2H),4.93(brs,1H),2.71(t,J＝7.5Hz,2H),2.35(t,J＝7.6Hz,2H),2.11–2.02(m,2H),1.61–1.52(m,2H),1.26(s,6H),1.24–1.19(m,6H),1.15–1.05(m,2H),0.86(t,J＝6.8Hz,3H).MS(ESI)m/z:474[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 31H 40NO 3 +474.3003；Found 474.2996 Take a 25 ml reaction tube, add compound I-3 (30 mg, 0.09 mmol), HoBt (15 mg, 0.11 mmol), EDCI (21.2 mg, 0.11 mmol), 1 ml of DCM, stir at room temperature for 30 min, and then add 4-phenylbutyric acid (18 mg, 0.11 mmol), the reaction was completed for 12 h, and the reaction was detected by TLC. Saturated NaHCO 3 was added, extracted with dichloromethane, the organic phases were combined, washed with saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain compound I-17 (34 mg, 78%). 1 H NMR (400MHz, CDCl3)δ: 7.65-7.56(m,1H), 7.52-7.44(m,2H), 7.33-7.26(m,3H), 7.23-7.12(m,5H), 6.55(s, 2H), 4.93 (brs, 1H), 2.71 (t, J=7.5Hz, 2H), 2.35 (t, J=7.6Hz, 2H), 2.11–2.02 (m, 2H), 1.61–1.52 (m, 2H) ),1.26(s,6H),1.24-1.19(m,6H),1.15-1.05(m,2H),0.86(t,J＝6.8Hz,3H).MS(ESI)m/z:474[M +H] + .HRMS(ESI)m/z:[M+H] + Calcd for C 31 H 40 NO 3 + 474.3003; Found 474.2996
7.化合物I-18～I-20、I-22合成通式如下：7. The general formula for the synthesis of compounds I-18～I-20 and I-22 is as follows:
Figure PCTCN2021107218-appb-000031
Figure PCTCN2021107218-appb-000031
实施例19Example 19
化合物I-18
Figure PCTCN2021107218-appb-000032
Compound I-18
Figure PCTCN2021107218-appb-000032
化合物6制备：以化合物2和3-氨基硼酸为原料，参照化合物3方法获得化合物6(88mg,50％)。Preparation of compound 6: Using compound 2 and 3-aminoboronic acid as raw materials, referring to the method of compound 3, compound 6 (88 mg, 50%) was obtained.
化合物7制备：取25ml反应管，加入化合物6(25mg,0.07mmol)、DMAP(1.3mg,0.01mmol)，EDCI(20mg,0.10mmol)，DIPEA(36ul,0.21mmol)室温下搅拌30min，后加入N-乙酰-L-异亮氨酸(0.08mmol)，反应12h,TLC检测反应完毕。加入饱和NaHCO 3，二氯甲烷萃取，合并有机相，饱和NaCl洗，无水硫酸钠干燥，减压浓缩，柱层析分离得到酰胺中间体7。 Preparation of compound 7: take a 25ml reaction tube, add compound 6 (25mg, 0.07mmol), DMAP (1.3mg, 0.01mmol), EDCI (20mg, 0.10mmol), DIPEA (36ul, 0.21mmol) at room temperature and stir for 30min at room temperature, then add N-acetyl-L-isoleucine (0.08mmol), the reaction was carried out for 12h, and the completion of the reaction was detected by TLC. Saturated NaHCO 3 was added, extracted with dichloromethane, the organic phases were combined, washed with saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain amide intermediate 7.
化合物I-18制备：取25ml反应管，加入上述酰胺中间体7(0.038mmol)，DCM 1mL，置于冰乙醇浴中(-15℃)，缓慢滴加0.2ml BBr 3(1.0M in DCM)，自然升温反应12h，TLC检测反应完毕。置于冰水浴中，加入0.1ml MeOH 淬灭，加入2ml饱和碳酸氢钠，二氯甲烷，分液萃取，无水硫酸钠干燥，减压浓缩，制备分离纯化得化合物I-18(10mg,30％)。MS(ESI)m/z:483[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 29H 43N 2O 4 +483.3217；Found 483.3213. Preparation of compound I-18: take a 25ml reaction tube, add the above amide intermediate 7 (0.038mmol), 1mL of DCM, put it in an ice-ethanol bath (-15°C), slowly add 0.2ml of BBr3 (1.0M in DCM) dropwise , the reaction was naturally heated for 12h, and the reaction was completed by TLC detection. Placed in an ice-water bath, quenched by adding 0.1 ml MeOH, adding 2 ml saturated sodium bicarbonate, dichloromethane, liquid separation extraction, drying over anhydrous sodium sulfate, concentrating under reduced pressure, preparation, separation and purification to obtain compound I-18 (10 mg, 30 %). MS(ESI) m/z: 483[M+H] + .HRMS(ESI) m/z: [M+H] + Calcd for C 29 H 43 N 2 O 4 + 483.3217; Found 483.3213.
实施例20Example 20
化合物I-19
Figure PCTCN2021107218-appb-000033
Compound I-19
Figure PCTCN2021107218-appb-000033
以化合物6，N-乙酰基甘氨酸为起始原料，参照化合物I-18的合成方法来获得化合物I-19(19mg，30％)。 1H NMR(400MHz,Acetone)δ9.15(s,1H),7.68–7.55(m,4H),7.44(brs,1H),7.29(t,J＝7.9Hz,1H),7.13–7.08(m,1H),6.50(s,2H),3.98(d,J＝5.7Hz,2H),1.97(s,3H),1.63–1.52(m,2H),1.33–1.18(m,12H),1.17–1.07(m,2H),0.85(t,J＝6.8Hz,3H).MS(ESI)m/z:427[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 25H 35N 2O 4 +427.2591；Found 427.2587. Using compound 6, N-acetylglycine as the starting material, referring to the synthesis method of compound I-18, compound I-19 (19 mg, 30%) was obtained. 1 H NMR (400MHz, Acetone)δ9.15(s,1H),7.68-7.55(m,4H),7.44(brs,1H),7.29(t,J=7.9Hz,1H),7.13-7.08(m ,1H),6.50(s,2H),3.98(d,J＝5.7Hz,2H),1.97(s,3H),1.63–1.52(m,2H),1.33–1.18(m,12H),1.17– 1.07(m,2H),0.85(t,J=6.8Hz,3H).MS(ESI)m/z:427[M+H] + .HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 35 N 2 O 4 + 427.2591; Found 427.2587.
实施例21Example 21
化合物I-20
Figure PCTCN2021107218-appb-000034
Compound I-20
Figure PCTCN2021107218-appb-000034
以化合物6，N-乙酰基甘氨酸为起始原料，参照化合物I-18的合成方法来获得化合物I-20(12mg，35％)。 1H NMR(400MHz,Acetone)δ9.73(s,1H),8.14(d,J＝8.0Hz,1H),7.81–7.71(m,2H),7.62(d,J＝8.0Hz,1H),7.38(t,J＝8.0Hz,1H),7.21(d,J＝7.7Hz,1H),6.52(s,2H),2.91(s,2H),1.66–1.52(m,2H),1.33–1.19(m,12H),1.16–1.07(m,2H),0.85(t,J＝6.8Hz,3H).MS(ESI)m/z:501[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 27H 31Cl 2N 2O 3 +501.1706；Found 501.1702. Using compound 6, N-acetylglycine as the starting material, referring to the synthesis method of compound I-18, compound I-20 (12 mg, 35%) was obtained. 1 H NMR (400MHz, Acetone) δ9.73(s, 1H), 8.14(d, J=8.0Hz, 1H), 7.81-7.71(m, 2H), 7.62(d, J=8.0Hz, 1H), 7.38 (t, J=8.0Hz, 1H), 7.21 (d, J=7.7Hz, 1H), 6.52 (s, 2H), 2.91 (s, 2H), 1.66–1.52 (m, 2H), 1.33–1.19 (m,12H),1.16–1.07(m,2H),0.85(t,J=6.8Hz,3H).MS(ESI)m/z:501[M+H] + .HRMS(ESI)m/z :[M+H] + Calcd for C 27 H 31 Cl 2 N 2 O 3 + 501.1706; Found 501.1702.
实施例22Example 22
化合物I-22
Figure PCTCN2021107218-appb-000035
Compound I-22
Figure PCTCN2021107218-appb-000035
取25ml反应管，加入化合物I-3(10mg,0.03mmol)、HATU(14mg,0.036mmol)，DIPEA(16ul,0.09mmol),1-金刚烷酸(7mg，0.036mmol)，反应12h,TLC检测反应完毕。加入饱和NaHCO 3，二氯甲烷萃取，合并有机相，饱和NaCl洗，无水硫酸钠干燥，减压浓缩，柱层析分离得到化合物I-22(1.5mg，10％)。MS(ESI)m/z:490[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 32H 44NO 3 +490.3316；Found 490.3306. Take a 25ml reaction tube, add compound I-3 (10mg, 0.03mmol), HATU (14mg, 0.036mmol), DIPEA (16ul, 0.09mmol), 1-adamantane acid (7mg, 0.036mmol), react for 12h, TLC detects The reaction is complete. Saturated NaHCO 3 was added, extracted with dichloromethane, the organic phases were combined, washed with saturated NaCl, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain compound I-22 (1.5 mg, 10%). MS(ESI) m/z: 490[M+H] + .HRMS(ESI) m/z: [M+H] + Calcd for C 32 H 44 NO 3 + 490.3316; Found 490.3306.
8.化合物I-23、I-24合成路线如下：8. The synthetic routes of compound I-23 and I-24 are as follows:
Figure PCTCN2021107218-appb-000036
Figure PCTCN2021107218-appb-000036
实施例23、24Example 23, 24
化合物I-23和化合物I-24Compound I-23 and Compound I-24
Figure PCTCN2021107218-appb-000037
Figure PCTCN2021107218-appb-000037
取25ml反应管，加入化合物6(25mg,0.07mmol)，DMF 1ml,TBAI(2.6mg，0.007mmol)，K2CO3(19.3mg，0.14mmol),卞溴(10ul,0.084mmol)混合均匀后置于80℃油浴中，反应12h,TLC检测反应完毕，冷却至室温，加水乙醚分液萃取，无水硫酸钠干燥，减压浓缩，柱层析纯化得到单苄基产物8(12mg，38％)和双苄基产物9(25mg,60％)。(Hexanes:EA＝20:1)Get 25ml reaction tube, add compound 6 (25mg, 0.07mmol), DMF 1ml, TBAI (2.6mg, 0.007mmol), K CO (19.3mg, 0.14mmol), Bian bromine (10ul, 0.084mmol) is mixed and placed in 80 In an oil bath, the reaction was completed for 12 h, TLC detected the reaction, cooled to room temperature, added water and ether for liquid separation, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the monobenzyl product 8 (12 mg, 38%) and Bisbenzyl product 9 (25 mg, 60%). (Hexanes:EA=20:1)
另取两个10ml反应管，分别加入上述苄基产物，DCM 1ml,置于冰乙醇中，缓慢低加入5.0eq BBr 3(1.0M in DCM),自然升温反应5h，加入甲醇和饱和碳酸氢钠淬灭，DCM分液，减压浓缩，柱层析得到化合物I-23(8mg，27％) 1H NMR(400MHz,CDCl 3)δ7.40–7.28(m,6H),6.75–6.68(m,2H),6.67–6.62(m,1H),6.56(s,2H),4.99(s,2H),4.35(s,2H),4.26(brs,1H),1.59–1.53 (m,2H),1.26(s,6H),1.23–1.17(m,6H),1.16–1.07(m,2H),0.85(t,J＝6.8Hz,3H).MS(ESI)m/z:418[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 28H 36NO 2 +418.2741Found 418.2731.化合物I-24(16mg，45％) 1H NMR(400MHz,CDCl 3)δ7.40–7.31(m,5H),7.30–7.20(m,6H),6.85–6.78(m,1H),6.75–6.67(m,2H),6.51(s,2H),4.96(s,2H),4.69(s,4H),1.58–1.49(m,2H),1.29–1.15(m,12H),1.14–1.05(m,2H),0.84(t,J＝6.8Hz,3H).MS(ESI)m/z:508[M+H] +.HRMS(ESI)m/z:[M+H] +Calcd for C 35H 42NO 2 +508.3210；Found 508.3200. Take another 10ml reaction tube, add the above benzyl product, 1ml of DCM, put it in ice ethanol, slowly add 5.0eq BBr3 (1.0M in DCM), naturally heat up and react for 5h, add methanol and saturated sodium bicarbonate Quenching, DCM separation, concentration under reduced pressure, column chromatography to obtain compound I-23 (8 mg, 27%) 1 H NMR (400 MHz, CDCl 3 ) δ 7.40-7.28 (m, 6H), 6.75-6.68 (m ,2H),6.67–6.62(m,1H),6.56(s,2H),4.99(s,2H),4.35(s,2H),4.26(brs,1H),1.59–1.53(m,2H), 1.26(s,6H),1.23-1.17(m,6H),1.16-1.07(m,2H),0.85(t,J＝6.8Hz,3H).MS(ESI)m/z:418[M+H ] + .HRMS (ESI) m/z: [M+H] + Calcd for C 28 H 36 NO 2 + 418.2741 Found 418.2731. Compound I-24 (16 mg, 45%) 1 H NMR (400 MHz, CDCl 3 ) δ7 .40–7.31 (m, 5H), 7.30–7.20 (m, 6H), 6.85–6.78 (m, 1H), 6.75–6.67 (m, 2H), 6.51 (s, 2H), 4.96 (s, 2H) ,4.69(s,4H),1.58-1.49(m,2H),1.29-1.15(m,12H),1.14-1.05(m,2H),0.84(t,J＝6.8Hz,3H).MS(ESI )m/z: 508[M+H] + .HRMS(ESI)m/z:[M+H] + Calcd for C 35 H 42 NO 2 + 508.3210; Found 508.3200.
抗肿瘤活性测试部分Antitumor activity test section
具体试验方法如下：The specific test methods are as follows:
1、种细胞1. kind of cells
人肝癌细胞HepG2、人肺癌细胞A549用DMEM完全培养液(含10％胎牛血清和1X青霉素-链霉素双抗溶液)在培养皿中培养，取对数生长期细胞,当细胞培养生长至70％-80％融合时，胰酶消化后用培养液重悬细胞并计数，配制成密度约7×104个/mL细胞悬液，以每孔100μL细胞悬液将细胞接种于96孔板，37℃培养箱中培养至细胞贴壁。Human hepatoma cells HepG2 and human lung cancer cells A549 were cultured in a petri dish with DMEM complete medium (containing 10% fetal bovine serum and 1X penicillin-streptomycin double antibody solution), and cells in logarithmic growth phase were taken. At 70%-80% confluence, after trypsinization, resuspend the cells in culture medium and count them, prepare a cell suspension with a density of about 7×104 cells/mL, and inoculate the cells in a 96-well plate with 100 μL of cell suspension per well. Incubate in a 37°C incubator until cells adhere.
2、加药2. Dosing
以DMSO为溶剂配制浓度20mg/mL的受试化合物，实验时用培养液稀释至所需工作浓度。96孔板弃培养液后，实验组分别加入不同工作浓度的化合物溶液100μL，空白对照组加入培养液100μL，阳性对照组加入不同浓度的抗肿瘤药物顺铂、吉西他滨溶液100μL，将96孔板继续放置培养箱中培养。DMSO was used as the solvent to prepare the test compound with a concentration of 20 mg/mL, and the culture medium was used to dilute to the required working concentration during the experiment. After discarding the culture medium in the 96-well plate, 100 μL of compound solutions with different working concentrations were added to the experimental group, 100 μL of culture medium was added to the blank control group, and 100 μL of antitumor drug cisplatin and gemcitabine solutions of different concentrations were added to the positive control group. Place in an incubator for culture.
3、CCK8检测法3. CCK8 detection method
培养48h后每孔加入10μL的CCK8试剂，轻轻拍打培养板以帮助混匀，37℃培养箱中孵育1-2小时，用酶标仪测定450nm吸光度值。实验重复3次后取平均值。上述化合物测试浓度为2.5μg/mL、5μg/mL、10μg/mL、20μg/mL、40μg/mL，结果如下表2所示。After culturing for 48 hours, add 10 μL of CCK8 reagent to each well, tap the culture plate lightly to help mix, incubate in a 37°C incubator for 1-2 hours, and measure the absorbance at 450 nm with a microplate reader. The experiment was repeated 3 times and the average value was taken. The test concentrations of the above compounds were 2.5 μg/mL, 5 μg/mL, 10 μg/mL, 20 μg/mL, and 40 μg/mL, and the results are shown in Table 2 below.
表2.化合物对肝癌(HepG2)和肺癌(A549)细胞的抑制活性Table 2. Inhibitory activity of compounds on liver cancer (HepG2) and lung cancer (A549) cells
化合物编号Compound number HepG2 IC 50(μM) HepG2 IC 50 (μM) A549 IC 50(μM) A549 IC 50 (μM)
I-1I-1 23.4323.43 51.5451.54
I-2I-2 21.9421.94 62.9162.91
I-3I-3 52.0452.04 55.7455.74
I-4I-4 2.582.58 16.4416.44
I-5I-5 14.7414.74 20.3920.39
I-6I-6 9.409.40 74.2574.25
I-7I-7 >161>161 >161>161
I-8I-8 24.3824.38 45.0445.04
I-9I-9 26.3226.32 28.7128.71
I-10I-10 18.3618.36 46.6546.65
I-11I-11 29.7129.71 18.0718.07
I-12I-12 52.3952.39 38.4738.47
I-13I-13 10.6410.64 14.0114.01
I-14I-14 18.3818.38 24.0024.00
I-15I-15 29.2529.25 26.9126.91
I-16I-16 20.3620.36 21.6621.66
I-17I-17 22.1922.19 22.9522.95
I-18I-18 6.406.40 32.5932.59
I-19I-19 ＞140>140 ＞140>140
I-20I-20 6.036.03 14.5114.51
I-21I-21 8.648.64 15.5115.51
I-22I-22 17.1517.15 6.656.65
I-23I-23 14.2614.26 17.3717.37
I-24I-24 >118>118 >118>118
顺铂Cisplatin 37.5337.53 6.016.01
吉西他滨Gemcitabine 2.932.93 0.000540.00054
实验结果与讨论：Experimental results and discussion:
除化合物I-3、I-7、I-12、I-19和I-24外，其余化合物对HepG2细胞的抑制效果均优于阳性药顺铂，其中化合物I-4对HepG2细胞的抑制效果与阳性药物吉西他滨相当；上述化合物对肺癌A549细胞也有抑制效果，但抑制活性稍逊于阳性药物顺铂和吉西他滨。Except for compounds I-3, I-7, I-12, I-19 and I-24, the inhibitory effect of other compounds on HepG2 cells was better than that of the positive drug cisplatin, and the inhibitory effect of compound I-4 on HepG2 cells was Equivalent to the positive drug gemcitabine; the above compounds also have inhibitory effect on lung cancer A549 cells, but the inhibitory activity is slightly inferior to the positive drugs cisplatin and gemcitabine.
由以上实验结果可知，本发明提供的具有生物活性的1,1'-联苯-2，6-二酚类化合物具有抑制肿瘤细胞增殖的活性，具有重大的药物研发潜力，可作为先导化合物用于抗癌药物的开发。It can be seen from the above experimental results that the biologically active 1,1'-biphenyl-2,6-diphenol compounds provided by the present invention have the activity of inhibiting the proliferation of tumor cells, have great potential for drug research and development, and can be used as lead compounds. in the development of anticancer drugs.
需要说明的是，在本文中，诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来，而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。而且，术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含，从而使得包括一系列要素的过程、方法、物品或者终端设备不仅包括那些要素，而且还包括没有明确列出的其他要素，或者是还包括为这种过程、方法、物品或者终端设备所固有的要素。在没有更多限制的情况下，由语句“包括……”或“包含……”限定的要素，并不排除在包括所述要素的过程、方法、物品或者终端设备中还存在另外的要素。此外，在本文中，“大于”、“小于”、“超过”等理解为不包括本数；“以上”、“以下”、“以内”等理解为包括本数。It should be noted that, in this document, relational terms such as first and second are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any relationship between these entities or operations. any such actual relationship or sequence exists. Moreover, the terms "comprising", "comprising" or any other variation thereof are intended to encompass non-exclusive inclusion such that a process, method, article or terminal device that includes a list of elements includes not only those elements, but also a non-exclusive list of elements. other elements, or also include elements inherent to such a process, method, article or terminal equipment. Without further limitation, an element defined by the phrase "comprises..." or "comprises..." does not preclude the presence of additional elements in the process, method, article, or terminal device that includes the element. In addition, in this text, "greater than", "less than", "exceeds" and the like are understood as not including the number; "above", "below", "within" and the like are understood as including the number.
尽管已经对上述各实施例进行了描述，但本领域内的技术人员一旦得知了基本创造性概念，则可对这些实施例做出另外的变更和修改，所以以上所述仅为本发明的实施例，并非因此限制本发明的专利保护范围，凡是利用本发明说明书内容所作的等效结构或等效流程变换，或直接或间接运用在其他相关的技术领域，均同理包括在本发明的专利保护范围之内。Although the above embodiments have been described, those skilled in the art can make additional changes and modifications to these embodiments once the basic inventive concept is known, so the above description is only the implementation of the present invention For example, it does not limit the scope of patent protection of the present invention. Any equivalent structure or equivalent process transformation made by using the contents of the description of the present invention, or directly or indirectly used in other related technical fields, are similarly included in the patent of the present invention. within the scope of protection.

Claims (5)

1,1'-联苯-2，6-二酚类化合物、其药学上可接受的盐或其立体异构体，其特征在于，其化学结构式如式(I)所示：1,1'-biphenyl-2,6-diphenol compound, its pharmaceutically acceptable salt or its stereoisomer, is characterized in that, its chemical structural formula is as shown in formula (I):
Figure PCTCN2021107218-appb-100001
Figure PCTCN2021107218-appb-100001
其中：in:
R1，R2，R3，R4各自独立地选自：R1, R2, R3, R4 are each independently selected from:
氢，卤素，硝基，氰基，氨基或取代氨基，C1-3的醛基，C1-6烷基或取代烷基，羧基或取代羧基，羟基或取代羟基，芳基或被0～5个基团取代的芳基，杂芳基或0～5个基团取代的杂芳基；Hydrogen, halogen, nitro, cyano, amino or substituted amino, C1-3 aldehyde group, C1-6 alkyl or substituted alkyl, carboxyl or substituted carboxyl, hydroxyl or substituted hydroxyl, aryl or by 0 to 5 group-substituted aryl group, heteroaryl group or 0-5 group-substituted heteroaryl group;
所述杂芳基为包含N、S、O中的1～3种杂原子的3～10元杂芳基。The heteroaryl group is a 3-10-membered heteroaryl group containing 1-3 kinds of heteroatoms in N, S, and O.
根据权利要求1所述的1,1'-联苯-2，6-二酚类化合物、其药学上可接受的盐或其立体异构体，其特征在于，R1，R2，R3，R4分别选自：The 1,1'-biphenyl-2,6-diphenol compound, its pharmaceutically acceptable salt or its stereoisomer according to claim 1, wherein R1, R2, R3, and R4 are respectively Selected from:
Figure PCTCN2021107218-appb-100002
Figure PCTCN2021107218-appb-100002
一种药物组合物，其特征在于，包含式(I)所示的1,1'-联苯-2，6-二酚类化合物。A pharmaceutical composition, characterized in that it comprises a 1,1'-biphenyl-2,6-diphenol compound represented by formula (I).
式(I)所示1,1'-联苯-2，6-二酚类化合物、其药学上可接受的盐或其立体异构体及包含1,1'-联苯-2，6-二酚类化合物的药物组合物在制备抗肿瘤药物中的用途。1,1'-biphenyl-2,6-diphenol compounds represented by formula (I), pharmaceutically acceptable salts or stereoisomers thereof, and compounds comprising 1,1'-biphenyl-2,6- Use of a pharmaceutical composition of a diphenolic compound in the preparation of an antitumor drug.
根据权利要求4所述的用途，其特征在于，用于抑制肿瘤细胞增殖。The use according to claim 4, characterized in that it is used to inhibit the proliferation of tumor cells.
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DATABASE REGISTRY ANONYMOUS : "[1,1'-Biphenyl]-2,6-diol, 4-(1,1-dimethylheptyl)-2'-(2-hydroxyethyl)- (CA INDEX NAME) OTHER CA INDEX NAMES: CN -4-(1,1-Dimethylheptyl)-2'-(2-hydroxyethyl)[1,1'-biphenyl]-2,6-diol MF -C23 H32 O3 SR -Other Sources Database: GVK BIO **PROPERTY DATA AVAILABLE IN THE 'PROP' FORMAT**", XP055942149, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "[1,1'-Biphenyl]-2,6-diol, 4-(1,1-dimethylheptyl)-2'-(3-hydroxypropyl)- (CA INDEX NAME) OTHER CA INDEX NAMES: CN -4-(1,1-Dimethylheptyl)-2'-(3-hydroxypropyl)[1,1'-biphenyl]-2,6-diol MF -C24 H34 O3 SR -Other Sources Database: GVK BIO **PROPERTY DATA AVAILABLE IN THE 'PROP' FORMAT**", XP055942146, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "[1,1'-Biphenyl]-2,6-diol, 4-(1,1-dimethylheptyl)-2'-(hydroxymethyl)-5'- (trifluoromethyl)-(CA INDEX NAME) OTHER CA INDEX NAMES: CN -4-(1,1-Dimethylheptyl)-2'-(hydroxymethyl)-5'-(trifluoromethyl)[1,1'- biphenyl]-2,6-diol MF -C23 H29 F3 O3 SR -Other Sources Database: GVK BIO 1/1 -(C) FILE REGISTRY RN ", XP055942131, retrieved from STN *
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DATABASE REGISTRY ANONYMOUS : "1,1'-Biphenyl]-2,6-diol, 4-(1,1-dimethylheptyl)-2'-(hydroxymethyl)-5'- (trifluoromethyl)-(CA INDEX NAME) OTHER CA INDEX NAMES: CN -4-(1,1-Dimethylheptyl)-2'-(hydroxymethyl)-5'-(trifluoromethyl)[1,1'- biphenyl]-2,6-diol MF -C23 H29 F3 O3 SR -Other Sources Database: GVK BIO **PROPERTY DATA AVAILABLE I", XP055942122, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "1,1'-Biphenyl]-2,6-diol, 4-(1,1-dimethylheptyl)-3'-methyl- (CA INDEX NAME) OTHER CA INDEX NAMES: CN -4-(1,1-Dimethylheptyl)-3'-methyl[1,1'-biphenyl]-2,6-diol MF -C22 H30 O2 SR -Other Sources Database: GVK BIO **PROPERTY DATA AVAILABLE IN THE 'PROP' FORMAT**", XP055942116, retrieved from STN *
DATABASE REGISTRY ANONYMOUS : "1,1'-Biphenyl]-3,5-dicarboxylic acid, 4'-(1,1-dimethylheptyl)-2',6'-dihydroxy-, 3,5-dimethyl ester (CA INDEX NAME) OTHER CA INDEX NAMES: CN -3,5-Dimethyl 4'-(1,1-dimethylheptyl)-2',6'-dihydroxy[1,1'-biphenyl]-3,5- dicarboxylate MF -C25 H32 O6 SR -Other Sources Database: GVK BIO **PROPERTY DATA AVAIL", XP055942105, retrieved from STN *
GAREAU YVES, DUFRESNE CLAUDE, GALLANT MICHEL, ROCHETTE CHANTAL, SAWYER NICOLE, SLIPETZ DEBORAH M, TREMBLAY NATHALIE, WEECH PHILIP : "Structure activity relationships of tetrahydrocannabinol analogues on human cannabinoid receptors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 6, no. 2, 1 January 1996 (1996-01-01), AMSTERDAM, NL , pages 189 - 194, XP055942160, ISSN: 0960-894X, DOI: 10.1016/0960-894X(95)00573-C *
MINUTOLO F. ET AL.: "Metabolically Labile Cannabinoid Esters: A 'Soft Drug' Approach for the Development of Cannabinoid-Based Therapeutic Drugs", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 17, no. 17, 20 June 2007 (2007-06-20), XP022184927, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2007.06.055 *

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