WO2021212740A1 - 一类具有吲哚啉骨架的化合物、制备方法及其医药用途 - Google Patents

一类具有吲哚啉骨架的化合物、制备方法及其医药用途 Download PDF

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WO2021212740A1
WO2021212740A1 PCT/CN2020/117584 CN2020117584W WO2021212740A1 WO 2021212740 A1 WO2021212740 A1 WO 2021212740A1 CN 2020117584 W CN2020117584 W CN 2020117584W WO 2021212740 A1 WO2021212740 A1 WO 2021212740A1
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尤启冬
姜正羽
周海山
陆朦辰
郭小可
徐晓莉
王磊
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中国药科大学
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    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to a type of Keap1-Nrf2PPI inhibitor with indoline as a basic skeleton with anti-inflammatory activity, and specifically relates to a type of compound with indoline skeleton, a preparation method and medical use thereof.
  • ROS reactive oxygen species
  • RNS reactive nitrogen
  • Nrf2 combines with the antioxidant response element ARE (antioxidant response element) to induce the transcription of antioxidant proteins, phase I and phase II metabolic enzymes, transporters and other related genes to activate cellular antioxidant defense mechanisms, thereby improving the unfavorable environment and protecting cells .
  • ARE antioxidant response element
  • Nrf2 activity is mainly regulated by Keap1 (Kelch-like ECH-related protein-1).
  • Keap1 as the adaptor protein of the Cul3 ubiquitin E3 ligase, participates in mediating the ubiquitination of Nrf2, and then degrades Nrf2, so that the Nrf2 in the cell is maintained at a low level, thereby keeping the cell protection system at a low level. Active state.
  • Keap1 Under stress, the key cysteine residues on Keap1 (such as Cys151, Cys257, Cys273, Cys288 and Cys297) can be oxidized or covalently modified, resulting in a conformational change of Keap1 protein and inactivation, thereby inhibiting Keap1 mediation.
  • the guided Nrf2 is degraded.
  • the newly synthesized Nrf2 enters the nucleus and combines with ARE to activate the transcription function of downstream genes, and finally activate the cell protection system to fight stress. Therefore, the Keap1-Nrf2-ARE pathway is a key way for cells to resist oxidation and maintain cell homeostasis.
  • Nrf2 activators can be developed as therapeutic drugs for a series of inflammatory diseases.
  • Nrf2 activators are a series of covalently bound compounds with unsaturated structures.
  • dimethyl fumarate has been approved by the FDA for the treatment of multiple sclerosis, and CDDO-Me is undergoing a phase II clinical trial for the treatment of pulmonary hypertension (PAH).
  • PAH pulmonary hypertension
  • Nrf2 activators have the characteristics of competition, specificity, reversibility and high selectivity, avoiding the potential toxicity of covalent modification to activate Nrf2, and is a hot spot in the current research on Nrf2 activators as therapeutic drugs for inflammatory diseases.
  • the present invention aims to overcome the shortcomings of the prior art, and provide a class of compounds with indoline skeletons, preparation methods and uses thereof.
  • a class of compounds with an indoline skeleton the chemical structure is as shown in the general formula I, II, III, IV or V:
  • reaction parameters in the synthetic route (a) NaBH 3 CN, TFA, DCM, rt2h, 75%; (b) NBS, AIBN, CCl 4 , 80°C, 4h, 65%; (c) NaH, DMF, rt4h , 50%; (d) LiOH, MeOH/H 2 O, rt2h, 80%; (e) substituted sulfonamides, EDCI, DMAP, DCM, 35°C, 2-6h, 30-70%; (f) SnCl 2 , EA, 80°C, 4h; (g) pyridine, THF, 80°C, 4h, 30-65%; (h) K 2 CO 3 , DMF, rt4h, 58-82%; (i) LiOH, MeOH/H 2 O, rt2h, 60-86%.
  • reaction parameters in the synthetic route (a) NaBH 3 CN, TFA, DCM, rt2h, 75%; (b) NBS, AIBN, CCl 4 , 80°C, 4h, 65%; (c) NaH, DMF, rt4h , 50%; (d) LiOH, MeOH/H 2 O, rt2h, 80%; (e) substituted sulfonamides, EDCI, DMAP, DCM, 35°C, 2-6h, 30-70%; (f) SnCl 2 , EA, 80°C, 4h; (g) pyridine, THF, 80°C, 4h, 30-65%; (h) K 2 CO 3 , DMF, rt4h, 58-82%; (i) LiOH, MeOH/H 2 O, rt2h, 60-86%.
  • reaction parameters in the synthetic route (a) NaBH 3 CN, TFA, DCM, rt2h, 75%; (b) NBS, AIBN, CCl 4 , 80°C, 4h, 65%; (c) NaH, DMF, rt4h , 50%; (d) LiOH, MeOH/H 2 O, rt2h, 80%; (e) substituted sulfonamides, EDCI, DMAP, DCM, 35°C, 2-6h, 30-70%; (f) SnCl 2 , EA, 80°C, 4h; (g) pyridine, THF, 80°C, 4h, 30-65%; (h) K 2 CO 3 , DMF, rt4h, 58-82%; (i) LiOH, MeOH/H 2 O, rt2h, 60-86%; (j) EDCI, DMAP, DCM, 35°C, 2-6h, 30-70%.
  • reaction parameters in the synthetic route (a) NaBH 3 CN, TFA, DCM, rt2h, 75%; (b) NBS, AIBN, CCl 4 , 80°C, 4h, 65%; (c) NaH, DMF, rt4h , 50%; (d) LiOH, MeOH/H 2 O, rt2h, 80%; (e) substituted sulfonamides, EDCI, DMAP, DCM, 35°C, 2-6h, 30-70%; (f) SnCl 2 , EA, 80°C, 4h; (g) pyridine, THF, 80°C, 4h, 30-65%; (h) K 2 CO 3 , DMF, rt4h, 58-82%; (i) LiOH, MeOH/H 2 O, rt2h, 60-86%; (j) EDCI, DMAP, DCM, 35°C, 2-6h, 30-70%.
  • reaction parameters in the synthetic route (a) NaBH 3 CN, TFA, DCM, rt2h, 75%; (b) NBS, AIBN, CCl 4 , 80°C, 4h, 65%; (c) NaH, DMF, rt4h , 50%; (d) LiOH, MeOH/H 2 O, rt2h, 80%; (e) substituted sulfonamides, EDCI, DMAP, DCM, 35°C, 2-6h, 30-70%; (f) SnCl 2 , EA, 80°C, 4h; (g) pyridine, THF, 80°C, 4h, 30-65%; (h) K 2 CO 3 , DMF, rt4h, 58-82%; (i) LiOH, MeOH/H 2 O, rt2h, 60-86%; (j) EDCI, DMAP, DCM, 35°C, 2-6h, 30-70%.
  • any of the above-mentioned compounds having an indoline skeleton and pharmaceutically acceptable salts thereof for the preparation of drugs for treating or relieving inflammation of diseases, the diseases being inflammatory diseases or neurodegenerative diseases, including myocarditis, chronic obstructive pulmonary Diseases, Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic kidney disease, diabetes, intestinal inflammation, rheumatoid arthritis.
  • diseases being inflammatory diseases or neurodegenerative diseases, including myocarditis, chronic obstructive pulmonary Diseases, Alzheimer's disease, Parkinson's disease, atherosclerosis, chronic kidney disease, diabetes, intestinal inflammation, rheumatoid arthritis.
  • the indoline skeleton-containing compound provided by the present invention can interfere with Keap1-Nrf2 interaction, activate Nrf2 and downstream factors, reduce cell inflammatory factors and enhance cell antioxidant capacity, thereby reducing inflammatory damage, having potential anti-inflammatory activity, and being useful It is prepared into anti-inflammatory drugs for inflammatory damage of many inflammation-related diseases, including myocarditis, chronic obstructive pulmonary disease (COPD), Alzheimer’s disease, Parkinson’s, atherosclerosis, chronic kidney disease (CKD), Diabetes, intestinal inflammation, rheumatoid arthritis, etc.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • CKD chronic kidney disease
  • Diabetes intestinal inflammation
  • rheumatoid arthritis etc.
  • the chemical reagents used in the present invention are all commercially available chemically pure or analytically pure.
  • the melting point was determined using MP50 Melting PointSystem (the thermometer is not calibrated).
  • the 1 H-NMR and 13 C-NMR nuclear magnetic resonance spectra were measured by Bruker AV300 (300MHz) nuclear magnetic resonance instrument (TMS is the internal standard), and the mass spectrum was measured by Agilent 1946A-MSD mass spectrometer (ESI-MS), Water Q-Tof
  • the purity was determined by HPLC.
  • the chromatographic column was an Agilent C18 (4.6 ⁇ 150mm, 3.5 ⁇ M) reverse phase column.
  • the solvent was concentrated using the N-1100 rotary evaporator (at 40°C) produced by EYELA Instrument Co., Ltd.
  • the silica gel for column chromatography was 200-300 mesh silica gel (Qingdao Ocean Chemical Plant Branch), and the eluent was Petroleum ether (boiling range 60-90°C) and ethyl acetate.
  • the reaction was monitored with a GF254 thin layer chromatography silica gel plate (Yantai Dexin) with a size of 0.25 ⁇ 0.75mm, and the ultraviolet absorption was detected by irradiation with a ZF-1 three-purpose ultraviolet analyzer (Hangzhou David Science and Education Instrument Co., Ltd.).
  • the rat cardiomyocyte H9c2 cell line was purchased from the cell bank of Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences.
  • Example 1 N-(Mestrimethylbenzenesulfonyl))-N-(1-(1-(3-methoxyphenyl)-2-oxo-2-(phenylsulfonamido)ethyl Yl)indol-4-yl)glycine (S1)
  • Example 7 N-(Mes-trimethylbenzenesulfonyl)-N-(1-(1-(1-(3-methoxyphenyl)-2-((4-methylphenyl)sulfonamide) (Yl)-2-oxoethyl)indol-4-yl)glycine (S7)
  • Example 11 N-(Mestrimethylbenzenesulfonyl)-N-(1-(1-(1-(3-methoxyphenyl)-2-oxo-2-((4-(tri (Fluoromethyl)phenyl)sulfonamido)ethyl)indol-4-yl)glycine (S11)
  • Example 12 N-(Mestrimethylbenzenesulfonyl)-N-(1-(1-(1-(3-methoxyphenyl)-2-((2-methoxyphenyl)sulfonyl) Amido)-2-oxoethyl)indol-4-yl)glycine (S12)
  • Example 16 N-(Mes-trimethylbenzenesulfonyl)-N-(1-(1-(1-(3-methoxyphenyl)-2-((2-ethylphenyl)sulfonamide) (Yl)-2-oxoethyl)indol-4-yl)glycine (S16)
  • Example 20 N-(Mestrimethylbenzenesulfonyl)-N-(1-(1-(1-(3-methoxyphenyl)-2-oxo-2-((2-(three (Fluoromethyl)phenyl)sulfonamido)ethyl)indol-4-yl)glycine (S20)
  • Example 21 N-(Mestrimethylbenzenesulfonyl)-N-(1-(1-(1-(3-methoxyphenyl)-2-oxo-2-((2-(tri (Fluoromethoxy)phenyl)sulfonamido)ethyl)indol-4-yl)glycine (S21)
  • Example 27 N-(Mes-trimethylbenzenesulfonyl)-N-(1-(1-(1-(3-methoxyphenyl)-2-oxo-2-((2-(tri (Fluoromethyl)phenyl)sulfonamido)ethyl)indol-4-yl)glycine (S27)
  • Example 28 N-(((2-methoxy-4-methylphenyl)sulfonyl)-2-(4-((4-methoxy-N-(2-oxo-2-( (Phenylsulfonamido)ethyl)phenyl)sulfonamido)indol-1-yl)-2-)3-methoxyphenyl)acetamide (S28)
  • Example 31 2-(4-((4-acetamido-N-(2-oxo-2-(phenylsulfonamido)ethyl)phenyl)sulfonamido)indol-1-yl )-N-((2-methoxy-4-methylphenyl)sulfonyl)-2-(3-methoxyphenyl)acetamide (S31)
  • Example 33 N-(((2-methoxy-4-methylphenyl)sulfonyl)-2-(4-((3-methoxy-N-(2-oxo-2-( (Phenylsulfonamido)ethyl)phenyl)sulfonamido)indol-1-yl)-2-)3-methoxyphenyl)acetamide (S33)
  • Example 35 2-(4-((N-(2-(Cyclopropanesulfonamido)-2-oxoethyl)-4-methoxyphenyl)sulfonamido)indol-1-yl) -N-(((2-methoxy-4-methylphenyl)sulfonyl)-2-(3-methoxyphenyl)acetamide (S35)
  • Example 36 N-(((2-methoxy-4-methylphenyl)sulfonyl)-2-(4-((4-methoxy-N-(2-(methylsulfonamide) )-2-oxoethyl)phenyl)sulfonamido)indol-1-yl)-2-(3-methoxyphenyl)acetamide (S36)
  • Example 37 N-(((2-methoxy-4-methylphenyl)sulfonyl)-2-(4-((4-methoxy-N-(2-(trifluoromethylsulfonyl) Amido)-2-oxoethyl)phenyl)sulfonamido)indol-1-yl)-2-(3-methoxyphenyl)acetamide (S37)
  • Example 38 N-(((2-methoxy-4-methylphenyl)sulfonyl)-2-(4-((4-methoxy-N-(2-oxo-2-( (Pyridine-3-sulfonamido)-2-ethyl)phenyl)sulfonamido)indol-1-yl)-2-(3-methoxyphenyl)acetamide (S38)
  • Example 40 N-(((2-methoxy-4-methylphenyl)sulfonyl)-2-(4-((4-methoxy-N-((4-methoxyphenyl) )-2-oxoethyl)phenyl)sulfonamido)indol-1-yl)-2-(3-methoxyphenyl)acetamide (S40)
  • Example 42 2-(4-((N-(2-(((4-fluorophenyl)sulfonamido)-2-oxoethyl)-4-methoxyphenyl)sulfonamido) Indol-1-yl)-N-(((2-methoxy-4-methylphenyl)sulfonyl)-2-(3-methoxyphenyl)acetamide (S42)
  • Example 43 N-(((2-methoxy-4-methylphenyl)sulfonyl)-2-(4-((4-methoxy-N-((4-ethylphenyl) -2-oxoethyl)phenyl)sulfonamido)indol-1-yl)-2-(3-methoxyphenyl)acetamide (S43)
  • Example 45 2-(4-((N-(2-(((4-hydroxyphenyl)sulfonamido)-2-oxoethyl)-4-methoxyphenyl)sulfonamido) Indol-1-yl)-N-(((2-methoxy-4-methylphenyl)sulfonyl)-2-(3-methoxyphenyl)acetamide (S45)
  • Example 46 2-(4-((N-(2-(((4-ethoxyphenyl)sulfonamido)-2-oxoethyl)-4-methoxyphenyl)sulfonamide Yl)indol-1-yl)-N-(((2-methoxy-4-methylphenyl)sulfonyl)-2-(3-methoxyphenyl)acetamide (S46)
  • Example 47 2-(4-((N-(2-(((2-methoxyphenyl)sulfonamido)-2-oxoethyl)-4-methoxyphenyl)sulfonamide Yl)indol-1-yl)-N-(((2-methoxy-4-methylphenyl)sulfonyl)-2-(3-methoxyphenyl)acetamide (S47)
  • Example 48 2-(4-((N-(2-(((3-methoxyphenyl)sulfonamido)-2-oxoethyl)-4-methoxyphenyl)sulfonamide Yl)indol-1-yl)-N-(((2-methoxy-4-methylphenyl)sulfonyl)-2-(3-methoxyphenyl)acetamide (S48)
  • the instrument used in the FP experiment is SpectraMax Multi-Mode Microplate Reader (Molecular Devices), and the excitation light and emission wavelength of the instrument are selected according to the corresponding fluorophore.
  • Corning 3676 384-well plate was used for experimental work, and the reaction system of the well plate was 40 ⁇ L.
  • the experimental group contains 10 ⁇ L of 4nM FITC-9mer Nrf2 polypeptide fluorescent probe, 10 ⁇ L of 12nM Keap1 Kelch domain protein solution and 20 ⁇ L of inhibitor of corresponding concentration; positive control uses 20 ⁇ L 100nM CPUY192002+10 ⁇ L probe+10 ⁇ L protein solution; negative control It is 10 ⁇ L probe+10 ⁇ L protein solution+20 ⁇ L HEPES buffer; blank control is 10 ⁇ L probe+30 ⁇ L HEPES buffer. Mix and incubate for 30 minutes at room temperature before testing.
  • the probe fluorophore is fluorescein
  • the excitation wavelength is 485nm
  • the emission wavelength is 535nm.
  • the horizontal and vertical fluorescence intensities (F ⁇ and F ⁇ ) are used to calculate the millipolarization (mP) reaction polarization. Changes in light.
  • the method of calculating the inhibition rate of an inhibitor at a certain concentration is:
  • Inhibition rate % (1-(P obs -P min )/(P max -P min )) ⁇ 100%.
  • P max , P min and P obs represent the polarization value of Keap1 and the fluorescent probe hole, the polarization value of the fluorescent probe hole and the polarization value of the hole containing inhibitor, respectively.
  • Compound inhibition curves calculated IC 50 - Use of the inhibitor concentrations.
  • Keap1-Nrf2 PPI competitive inhibition experiment (FP experiment) based on fluorescence polarization was used to test the target activity of compounds S1-S5. The results are shown in Table 1.
  • Keap1-Nrf2 PPI competitive inhibition experiment (FP experiment) based on fluorescence polarization was used to test the target activity of compounds S40-S48. The results are shown in Table 5.
  • compound S40 showed excellent inhibitory activity in the in vitro target experiment (FP experiment).
  • IL-1 ⁇ IL-1 ⁇ ELISA kit, EK0393, Boster
  • IL-6 IL-6 ELISA kit, EK0412, Boster
  • TNF - ⁇ TNF- ⁇ (TNF- ⁇ ELISA kit,EK0526,Boster).
  • H9c2 cells were pre-treated with 10 ⁇ M compound S40 for 12h, and 1 ⁇ g/mL LPS was added to continue culture for 12h to determine the ratio of inflammatory factors (A) IL-1 ⁇ , (B) IL-6 and (C) TNF- ⁇ .
  • LPS can significantly increase the secretion of inflammatory factors in cells
  • 10 ⁇ M compound S40 can significantly reduce the content of inflammatory factors after pretreatment.
  • mice Male C57BL/6 mice (6-8 weeks old, 18-22g/mouse) were randomly divided into four groups: blank control group, model (LPS: 10mg/kg) control group, compound S40 high-dose (40mg/kg) Group and compound S40 low-dose (10mg/kg) group, 8 mice in each group.
  • the compound group received prophylactic intraperitoneal injection at a given dose for 3 days, and the blank control group and model control group were intraperitoneally injected with the same amount of normal saline. Then the model control group and the compound group were intraperitoneally injected with LPS (15 mg/kg), and the blank control group was given the same amount of normal saline. After 10 hours, the mice were sacrificed, blood was taken from the eyeball and the heart was taken out for subsequent testing. The serum levels of inflammatory factors (IL-6, IL-1 ⁇ , TNF- ⁇ ) in each group of mice were tested by the Elisa method.
  • IL-6, IL-1 ⁇ , TNF- ⁇ The serum levels of
  • Indoline compounds can effectively inhibit the Keap1-Nrf2 interaction in FP experiments. Furthermore, it was verified that compound S40 reduces the level of inflammatory factors produced by LPS-induced H9c2 cardiomyocytes. In in vivo mouse inflammation model studies, compound S40 can significantly reduce the production of inflammatory factors in the serum of mice.
  • the present invention provides a class of indoline Keap1-Nrf2 PPI small molecule inhibitors with good activity, novel structure and more drug-making potential, which can interfere with the Keap1-Nrf2 interaction, activate Nrf2 and downstream factors, reduce cell inflammatory factors and enhance Cell antioxidant capacity, thereby reducing inflammatory damage, has potential anti-inflammatory activity, can be used to prepare anti-inflammatory drugs for inflammatory damage of many inflammation-related diseases, including myocarditis, chronic obstructive pulmonary disease (COPD), Alz Hymer's disease, Parkinson's disease, atherosclerosis, chronic kidney disease (CKD), diabetes, intestinal inflammation, rheumatoid arthritis, etc.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • CKD chronic kidney disease
  • diabetes intestinal inflammation
  • rheumatoid arthritis etc.

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  • Indole Compounds (AREA)

Abstract

一类具有吲哚啉骨架的化合物、制备方法及其医药用途。提供的含吲哚啉骨架的化合物可以干扰Keap1-Nrf2相互作用，激活Nrf2及下游因子，降低细胞炎症因子和增强细胞抗氧化能力，从而减轻炎性损伤，具有潜在的抗炎活性，可用于制备成抗炎药物用于众多炎症相关疾病的炎性损伤，包括心肌炎，慢性阻塞性肺疾病(COPD)、阿尔茨海默症、帕金森、动脉粥样硬化、慢性肾脏疾病(CKD)、糖尿病、肠部炎症、类风湿性关节炎等。

Description

一类具有吲哚啉骨架的化合物、制备方法及其医药用途 技术领域
本发明属于药物化学领域，涉及一类具有抗炎活性的以吲哚啉为基本骨架的Keap1-Nrf2PPI抑制剂，具体涉及一类具有吲哚啉骨架的化合物、制备方法及其医药用途。
背景技术
人体经常遭受一些内源性和外源性亲电子物质侵害，其中包括活性氧(ROS)和活性氮(RNS)。当细胞连续暴露于高水平的ROS和RNS时，它们将处于氧化应激状态。持续的应激状态会损害细胞内核酸、蛋白质和脂质等生物大分子的正常生理功能，进而会导致多种相关炎性疾病，包括癌症，心血管疾病和神经退行性疾病。为了抵御这些损伤，细胞已经进化出了复杂的细胞保护系统，该系统可以上调细胞保护因子来维持体内稳态。Nrf2是细胞内保护系统的关键调节因子。Nrf2通过与抗氧化反应元件ARE(antioxidant response element)结合，诱导抗氧化蛋白、I相和II相代谢酶、转运蛋白等相关基因的转录，激活细胞抗氧化防御机制，从而改善不利环境、保护细胞。在体内，Nrf2活性主要受Keap1(Kelch-样ECH相关蛋白-1)调节。在生理条件下，Keap1作为Cul3泛素E3连接酶的接头蛋白参与介导Nrf2的泛素化，进而降解Nrf2，使得细胞内的Nrf2维持在较低的水平，从而使细胞保护系统处于较低的激活状态。在应激状态下，Keap1上的关键半胱氨酸残基(如Cys151、Cys257、Cys273、Cys288和Cys297)可被氧化或共价修饰，从而导致Keap1蛋白构象改变而失活，进而抑制Keap1介导的Nrf2降解。新合成的Nrf2入核并与ARE结合激活下游基因转录功能，最终激活细胞保护系统，对抗应激状态。因此，Keap1-Nrf2-ARE途径是细胞抵抗氧化和维持细胞稳态的关键途径，Nrf2活化剂可被开发为一系列炎性疾病的治疗药物。
目前，研究较多的Nrf2激活剂是一系列具有不饱和结构的共价结合化合物。如富马酸二甲酯已经被FDA批准用于治疗多发性硬化症，CDDO-Me正在开展治疗肺动脉高压(PAH)的二期临床。但这类激活剂由于结合特性，很难达到治疗的选择性和专一性。而最近大量文献报道，竞争性干扰Keap1-Nrf2相互作用也可有效抑制Keap1对Nrf2的负调控作用从而激活Nrf2。此种激活Nrf2的方式具有竞争性、特异性、可逆性和高选择性的特点，避免了共价修饰激活Nrf2的潜在毒性，是当前研究Nrf2激活剂作为炎性疾病治疗药物的热点。
发明内容
本发明旨在克服现有技术不足，提供一类具有吲哚啉骨架的化合物、制备方法及其用途。
一类具有吲哚啉骨架的化合物，化学结构如通式Ⅰ、Ⅱ、Ⅲ、Ⅳ或Ⅴ所示：
Figure PCTCN2020117584-appb-000001
其中，通式I中，取代基R为：
Figure PCTCN2020117584-appb-000002
通式Ⅱ中，取代基R为：
Figure PCTCN2020117584-appb-000003
通式Ⅲ中，取代基R为:
Figure PCTCN2020117584-appb-000004
通式Ⅳ中，取代基R为：
Figure PCTCN2020117584-appb-000005
Figure PCTCN2020117584-appb-000006
通式Ⅴ中，取代基R为：
Figure PCTCN2020117584-appb-000007
一种制备上述通式Ⅰ所示化合物的方法，步骤和合成路线如下：
4-硝基吲哚还原为中间体2，原料3经溴代得到中间体4，中间体2和4在碳酸钾条件下发生亲核取代反应得到中间体5，中间体5在LiOH的作用下脱甲酯得到关键中间体6，中间体6在EDCI和DMAP条件下与取代磺酰胺缩合得到中间体7，中间体7还原硝基得到中间体8，再与2,4,6-均三甲基苯磺酰氯反应得到中间体9，中间体9在碳酸钾的作用下与溴乙酸甲酯反应得到中间体10，中间体10在LiOH的作用下脱甲酯得到通式Ⅰ化合物；
Figure PCTCN2020117584-appb-000008
其中，合成路线中反应参数：(a)NaBH 3CN,TFA,DCM,r.t.2h,75％；(b)NBS,AIBN,CCl 4,80℃,4h,65％；(c)NaH,DMF,r.t.4h,50％；(d)LiOH,MeOH/H 2O,r.t.2h,80％；(e)substituted sulfonamides,EDCI,DMAP,DCM,35℃,2-6h,30-70％；(f)SnCl 2,EA,80℃,4h；(g)pyridine,THF,80℃,4h,30-65％；(h)K 2CO 3,DMF,r.t.4h,58-82％；(i)LiOH,MeOH/H 2O,r.t.2h,60-86％.
一种制备上述通式Ⅱ所示化合物的方法，步骤和合成路线如下：
4-硝基吲哚还原为中间体2，原料3经溴代得到中间体4，中间体2和4在碳酸钾条件下发生亲核取代反应得到中间体5，中间体5在LiOH的作用下脱甲酯得到关键中间体6，中间体6在EDCI和DMAP条件下与取代苯磺酰胺缩合得到中间体11，中间体11还原硝基再与2,4,6-均三甲基苯磺酰氯反应得到中间体12，中间体12在碳酸钾的作用下与溴乙酸甲酯反应 得到中间体13，中间体13在LiOH的作用下脱甲酯得到通式Ⅱ化合物；
Figure PCTCN2020117584-appb-000009
其中，合成路线中反应参数：(a)NaBH 3CN,TFA,DCM,r.t.2h,75％；(b)NBS,AIBN,CCl 4,80℃,4h,65％；(c)NaH,DMF,r.t.4h,50％；(d)LiOH,MeOH/H 2O,r.t.2h,80％；(e)substituted sulfonamides,EDCI,DMAP,DCM,35℃,2-6h,30-70％；(f)SnCl 2,EA,80℃,4h；(g)pyridine,THF,80℃,4h,30-65％；(h)K 2CO 3,DMF,r.t.4h,58-82％；(i)LiOH,MeOH/H 2O,r.t.2h,60-86％.
一种制备上述通式Ⅲ所示化合物的方法，步骤和合成路线如下：
4-硝基吲哚还原为中间体2，原料3经溴代得到中间体4，中间体2和4在碳酸钾条件下发生亲核取代反应得到中间体5，中间体5在LiOH的作用下脱甲酯得到关键中间体6，中间体6在EDCI和DMAP条件下与4-甲氧基-2甲基苯磺酰胺缩合得到中间体14，中间体14还原硝基再与取代苯磺酰氯反应得到中间体15，中间体15在碳酸钾的作用下与溴乙酸甲酯反应得到中间体16，中间体16在LiOH的作用下脱甲酯得到中间体17，中间体17在EDCI和DMAP条件下与苯磺酰胺缩合得到通式Ⅲ化合物；
Figure PCTCN2020117584-appb-000010
其中，合成路线中反应参数：(a)NaBH 3CN,TFA,DCM,r.t.2h,75％；(b)NBS,AIBN,CCl 4,80℃,4h,65％；(c)NaH,DMF,r.t.4h,50％；(d)LiOH,MeOH/H 2O,r.t.2h,80％；(e)substituted sulfonamides,EDCI,DMAP,DCM,35℃,2-6h,30-70％；(f)SnCl 2,EA,80℃,4h；(g)pyridine,THF,80℃,4h,30-65％；(h)K 2CO 3,DMF,r.t.4h,58-82％；(i)LiOH,MeOH/H 2O,r.t.2h,60-86％；(j)EDCI,DMAP,DCM,35℃,2-6h,30-70％.
一种制备上述通式Ⅳ所示化合物的方法，步骤和合成路线如下：
4-硝基吲哚还原为中间体2，原料3经溴代得到中间体4，中间体2和4在碳酸钾条件下发生亲核取代反应得到中间体5，中间体5在LiOH的作用下脱甲酯得到关键中间体6，中间体6在EDCI和DMAP条件下与4-甲氧基-2甲基苯磺酰胺缩合得到中间体14，中间14还原硝基再与4-甲氧基苯磺酰氯反应得到中间体18，中间体18在碳酸钾的作用下与溴乙酸甲酯 反应得到中间体19，中间体19在LiOH的作用下脱甲酯得到中间体20，中间体20在EDCI和DMAP条件下与取代磺酰胺缩合得到通式Ⅳ化合物；
Figure PCTCN2020117584-appb-000011
其中，合成路线中反应参数：(a)NaBH 3CN,TFA,DCM,r.t.2h,75％；(b)NBS,AIBN,CCl 4,80℃,4h,65％；(c)NaH,DMF,r.t.4h,50％；(d)LiOH,MeOH/H 2O,r.t.2h,80％；(e)substituted sulfonamides,EDCI,DMAP,DCM,35℃,2-6h,30-70％；(f)SnCl 2,EA,80℃,4h；(g)pyridine,THF,80℃,4h,30-65％；(h)K 2CO 3,DMF,r.t.4h,58-82％；(i)LiOH,MeOH/H 2O,r.t.2h,60-86％；(j)EDCI,DMAP,DCM,35℃,2-6h,30-70％.
一种制备上述通式Ⅴ所示化合物的方法，步骤和合成路线如下：
4-硝基吲哚还原为中间体2，原料3经溴代得到中间体4，中间体2和4在碳酸钾条件下发生亲核取代反应得到中间体5，中间体5在LiOH的作用下脱甲酯得到关键中间体6，中间体6在EDCI和DMAP条件下与4-甲氧基-2甲基苯磺酰胺缩合得到中间体14，中间体14还原硝基再与4-甲氧基苯磺酰氯反应得到中间体18，中间体18在碳酸钾的作用下与溴乙酸甲酯反应得到中间体19，中间体19在LiOH的作用下脱甲酯得到中间体20，中间体20在EDCI和DMAP条件下与取代磺酰胺缩合得到通式Ⅴ化合物；
Figure PCTCN2020117584-appb-000012
其中，合成路线中反应参数：(a)NaBH 3CN,TFA,DCM,r.t.2h,75％；(b)NBS,AIBN,CCl 4,80℃,4h,65％；(c)NaH,DMF,r.t.4h,50％；(d)LiOH,MeOH/H 2O,r.t.2h,80％；(e)substituted sulfonamides,EDCI,DMAP,DCM,35℃,2-6h,30-70％；(f)SnCl 2,EA,80℃,4h；(g)pyridine,THF,80℃,4h,30-65％；(h)K 2CO 3,DMF,r.t.4h,58-82％；(i)LiOH,MeOH/H 2O,r.t.2h,60-86％；(j)EDCI,DMAP,DCM,35℃,2-6h,30-70％.
上述任一所述具有吲哚啉骨架的化合物或其药学上可接受的盐用于制备Keap1-Nrf2蛋白-蛋白相互作用抑制剂的用途。
上述任一具有吲哚啉骨架的化合物及其药学上可接受的盐用于制备治疗或缓解疾病炎症 药物的用途，所述疾病为炎性疾病或神经退行性疾病，包括心肌炎、慢性阻塞性肺疾病、阿尔茨海默症、帕金森、动脉粥样硬化、慢性肾脏疾病、糖尿病、肠部炎症、类风湿性关节炎。
有益效果：
本发明提供的含吲哚啉骨架的化合物可以干扰Keap1-Nrf2相互作用，激活Nrf2及下游因子，降低细胞炎症因子和增强细胞抗氧化能力，从而减轻炎性损伤，具有潜在的抗炎活性，可用于制备成抗炎药物用于众多炎症相关疾病的炎性损伤，包括心肌炎，慢性阻塞性肺疾病(COPD)、阿尔茨海默症、帕金森、动脉粥样硬化、慢性肾脏疾病(CKD)、糖尿病、肠部炎症、类风湿性关节炎等。
附图说明
图1为化合物S40对LPS诱导炎症因子(A)IL-1β、(B)IL-6和(C)TNF-α的影响，数值表示为平均值±标准偏差(n＝3)，***P<0.001,**P<0.01,and*P<0.05,one-way ANOVA with Tukey-Kramer posttest；
图2为化合物S40对LPS诱导小鼠血清炎症因子(A)IL-1β、(B)IL-6和(C)TNF-α的影响，数值表示为平均值±标准偏差(n＝8)，***P<0.001,**P<0.01,and*P<0.05,one-way ANOVA with Tukey-Kramer posttest。
具体实施方式
下面结合附图和实施例具体介绍本发明实质性内容，但并不以此限定本发明的保护范围。
本发明所用的化学试剂均为市售的化学纯或者分析纯。熔点使用M.P.50Melting PointSystem进行测定(温度计未经校正)。 1H-NMR、 13C-NMR核磁共振图谱由Bruker AV300型(300MHz)核磁共振仪测定(TMS为内标物)，质谱由Agilent 1946A-MSD型质谱仪(ESI-MS)、Water Q-Tof型质谱仪(HRMS)测定，纯度由HPLC测定，色谱柱为Agilent C18(4.6×150mm,3.5μM)型反相柱，流动相采用甲醇：水：三氟乙酸＝85：15：0.1。
溶剂的浓缩使用的是EYELA仪器有限公司生产的N-1100旋转蒸发仪(在40℃下进行)，柱层析用硅胶为200-300目硅胶(青岛海洋化工厂分厂)，洗脱剂为石油醚(沸程60-90℃)和乙酸乙酯。采用0.25×0.75mm规格的GF254薄层层析硅胶板(烟台德信)监测反应，紫外吸收在ZF-1型三用紫外分析仪(杭州大卫科教仪器有限公司)下照射检测。
大鼠心肌细胞H9c2细胞株购自中国科学院上海生物化学与细胞生物学研究所细胞库。
一、化合物制备
实施例1：N-(均三甲基苯磺酰基))-N-(1-(1-(3-甲氧基苯基)-2-氧代-2-(苯基磺酰胺基)乙基)吲哚-4-基)甘氨酸(S1)
(1)4-硝基吲哚啉(2)
将原料4-硝基吲哚(3.0g,18.5mmol)溶于20.0mL DCM中，加入6.0mL三氟乙酸(TFA),冰浴下分批加入4倍当量的腈基硼氢化钠，室温搅拌4小时。反应结束后，加入饱和NaHCO 3调节pH至近中性，有机层用饱和NaCl溶液洗涤3遍，无水硫酸钠干燥，旋干溶剂，柱层析得到2.4g红色固体，产率为79％； 1H NMR(300MHz,Chloroform-d)δ7.14(dd,J＝8.0,1.3Hz,1H),7.04(t,J＝8.0Hz,1H),6.65(dd,J＝7.9,1.3Hz,1H),3.34(t,J＝5.5Hz,2H),2.94(t,J＝6.5Hz,2H)；ESI-MS m/z:165.1(M+H) +。
(2)2-溴-2-(3-甲氧基苯基)乙酸甲酯(4)
将原料3(3g,16.7mmol)溶于四氯化碳(20.0ml)中，加入NBS(N-溴代丁二酰亚胺)(2.9g,16.7mmol)、AIBN(催化量)加热至80℃。TLC显示反应完全(约4h)，硅胶柱层析(洗脱剂PE:EA＝20：1)，分离纯化得红色油状物2.4g，产率为56％； 1H NMR(300MHz,Chloroform-d)δ7.16(dd,J＝8.2,1.5Hz,1H),7.06(t,J＝8.0Hz,2H),6.68(dd,J＝7.7,1.5Hz,1H),5.91(s,1H),3.82(s,3H),3.74(s,3H)；ESI-MS m/z:258.9(M+H) +。
(3)2-(3-甲氧基苯基)-2-(4-硝基吲哚-1-基)乙酸甲酯(5)
将中间体2(1.0g，6.1mmol)溶于5.0mL DMF中，冰浴下加入氢化钠(364.0mg,9.1mmol)，最后加入中间体4(1.5g，6.1mmol)于室温下搅拌。反应2h,向溶液中加入水， 用饱和NH 4Cl溶液调节pH至7，固体抽滤，硅胶柱层析分离得红色固体726.0mg，产率为59％； 1H NMR(300MHz,Chloroform-d)δ7.51(d,J＝8.3Hz,1H),7.38(t,J＝7.8Hz,1H),7.23(t,J＝8.1Hz,1H),7.02-6.92(m,3H),6.66(d,J＝7.9Hz,1H),5.35(s,1H),3.87(d,J＝1.7Hz,3H),3.83(d,J＝1.7Hz,3H),3.65-3.52(m,1H),3.52-3.39(m,1H),3.38-3.26(m,1H),3.05-2.91(m,1H)；ESI-MS m/z:343.1(M+H) +。
(4)2-(3-甲氧基苯基)-2-(4-硝基吲哚-1-基)乙酸(6)
将中间体5(342.0mg,1.0mmol)溶解在10.0mL甲醇中，加入5.0mL水，最后加入LiOH(2.0g,83.3mmol)，于室温下搅拌2h，向体系中加入少量水至溶液变浑浊，用盐酸溶液调节pH至4，溶液变浑浊，有灰色固体析出，抽滤、烘干得275.0mg白色固体，产率为84％； 1H NMR(300MHz,Chloroform-d)δ7.52(d,J＝8.5Hz,1H),7.34(t,J＝7.8Hz,1H),7.21(t,J＝8.1Hz,1H),7.01-6.94(m,3H),6.67(d,J＝7.7Hz,1H),5.35(s,1H),3.82(d,J＝1.7Hz,3H),3.65-3.52(m,1H),3.52-3.39(m,1H),3.36-3.24(m,2H)；ESI-MS m/z:329.1(M+H) +。
(5)2-(3-甲氧基苯基)-2-(4-硝基吲哚-1-基)-N-(苯磺酰基)乙酰胺(7)
将中间体6(328.0mg,1.0mmol)溶解在10.0mL DCM中，依次加入2倍当量的EDCI和DMAP，搅拌溶解后加入苯磺酰胺(158mg,1.0mmol)，加热至40℃搅拌，反应4h，向溶液中加入水，用饱和NH 4Cl溶液调节pH至7，有机层用饱和NaCl溶液洗涤3遍，无水硫酸钠干燥，旋干溶剂，柱层析得到334mg红色固体，产率为72％； 1H NMR(300MHz,DMSO-d 6)δ12.82(s,1H),7.89(d,J＝8.1Hz,2H),7.63(t,J＝7.8Hz,2H),7.21(s,2H),6.96-6.87(m,3H),6.66(s,2H),6.56(d,J＝7.7Hz,1H),5.17(d,J＝8.5Hz,1H),3.78(s,3H),3.47(s,2H),3.22(s,2H)；ESI-MS m/z:468.1(M+H) +。
(6)2-(3-甲氧基苯基)-N-(苯磺酰基)-2-(4-(((2,4,6-三甲基苯基)磺酰胺基)吲哚-1-基)乙酰胺(9)
将中间体7(467mg,1.0mmol)溶于15mL四氢呋喃和甲醇混合溶液(体积比1:1)，加入催化量的钯碳，反应溶液室温搅拌4小时后，硅藻土助滤除去钯碳，滤液减压蒸馏得到油状物中间体，不经纯化，溶于四氢呋喃，加入2,4,6-均三甲基苯磺酰氯(262mg,1.2mmol)和吡啶(237mg,3.0mmol)，加热至80℃，氮气保护反应4小时，冷却至室温，减压蒸去溶剂，硅胶柱层析得到315mg灰白色产物，两步总产率为51％； 1H NMR(300MHz,DMSO-d 6)δ12.40(s,1H),7.62(d,J＝8.3Hz,2H),7.42(t,J＝7.8Hz,2H),7.26(s,2H),6.97-6.87(m,3H),6.61(s,2H),6.52(d,J＝7.3Hz,1H),6.19(d,J＝7.8Hz,1H),5.19(d,J＝8.7Hz,1H),3.47(s,2H),3.02(s,2H),2.22(dd,J＝13.0,6.9Hz,9H)；ESI-MS m/z:620.2(M+H) +。
(7)N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-氧代-2-(苯基磺酰胺基)乙基)吲哚-4-基)甘氨酸酯(10)
将中间体9(300mg,0.48mmol)溶于5.0mL DMF中，加入碳酸钾(100mg,0.72mmol)，最后加入溴乙酸甲酯(88mg,0.57mmol)于室温下搅拌。反应3h，向溶液中加入水，至溶液变浑浊，用饱和NH 4Cl溶液调节pH至7，有灰色固体析出，抽滤烘干得白色固体258mg，产率为79％； 1H NMR(300MHz,DMSO-d 6)δ12.42(s,1H),7.97(d,J＝7.1Hz,2H),7.72(t,J＝8.6Hz,2H),7.31(s,2H),6.93-6.81(m,3H),6.76(s,2H),6.66(d,J＝7.9Hz,1H),6.29(d,J＝7.8Hz,1H),5.21(d,J＝8.0Hz,1H),4.28(d,J＝8.2Hz,2H),3.77(s,3H),3.40(s,2H),3.22(s,2H),2.22(dd,J＝13.0,6.9Hz,9H)；ESI-MS m/z:692.2(M+H) +。
(8)N-(均三甲基苯磺酰基))-N-(1-(1-(3-甲氧基苯基)-2-氧代-2-(苯基磺酰胺基)乙基)吲哚-4-基)甘氨酸(S1)
Figure PCTCN2020117584-appb-000013
将中间体10(200mg,0.29mmol)溶解在10mL甲醇中，加入5.0mL水，最后加入LiOH(2.0g,83.3mmol)，于室温下搅拌4h，向体系中加入少量水至溶液变浑浊，用盐酸溶液调节pH至4，溶液变浑浊，有灰色固体析出，抽滤、烘干得145mg白色固体，产率为74％； 1H NMR(300MHz,DMSO-d 6)12.91(s,2H),δ8.05(s,1H),7.78(d,J＝1.9Hz,1H),7.29(t,J＝7.9Hz,1H),6.95(d,J＝7.8Hz,1H),6.90(s,1H),6.70(d,J＝10.3Hz,2H),6.56(d,J＝8.0Hz,1H),6.23(d,J＝7.9Hz,1H),5.20(s,1H),4.29(s,2H),3.72(s,3H),3.25(d,J＝8.5Hz,1H),2.66(d,J＝8.2Hz,1H),2.40(s,2H),2.21(s,9H)；EI-MS HRMS(ESI):found 678.1934(C 28H 32N 2NaO 4S.[M+Na]+requires 678.1938)。
实施例2：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-(甲基磺酰胺基)-2-氧代乙基)吲哚-4-基)甘氨酸(S2)
Figure PCTCN2020117584-appb-000014
S2的合成与实施例1相同，将苯磺酰胺替换为甲基磺酰胺，得到白色固体167.0mg，产率为68％； 1H NMR(300MHz,DMSO-d 6)δ12.88(s,2H),8.03(s,1H),7.82(d,J＝1.8Hz,1H),7.49(t,J＝7.9Hz,1H),6.99(d,J＝7.2Hz,1H),6.91(s,1H),6.74(d,J＝10.5Hz,2H),6.57(d,J＝8.0Hz,1H),6.25(d,J＝7.7Hz,1H),5.21(s,1H),4.28(s,2H),3.73(s,3H),3.26(d,J＝8.5Hz,1H),2.94(s,3H),2.67(d,J＝8.2Hz,1H),2.41(s,2H),2.21(s,9H)；EI-MS HRMS(ESI):found 616.1735(C 29H 34N 3O 8S 2.[M+H]+requires 616.1746)。
实施例3：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-氧代-2-(三氟甲基)磺酰胺基)乙基)吲哚-4-基)甘氨酸(S3)
Figure PCTCN2020117584-appb-000015
S3的合成与实施例1相同，将苯磺酰胺替换为三氟甲磺酰胺，得到白色固体142.0mg，产率为64％； 1H NMR(300MHz,DMSO-d 6)12.91(s,2H),δ8.05(s,1H),7.78(d,J＝1.9Hz,1H),7.29(t,J＝7.9Hz,1H),6.95(d,J＝7.8Hz,1H),6.90(s,1H),6.70(d,J＝10.3Hz,2H),6.56(d,J＝8.0Hz,1H),6.23(d,J＝7.9Hz,1H),5.20(s,1H),4.29(s,2H),3.72(s,3H),3.25(d,J＝8.5Hz,1H),2.66(d,J＝8.2Hz,1H),2.40(s,2H),2.21(s,9H)；EI-MS HRMS(ESI):found 670.1422(C 29H 31F 3N 3O 8S 2.[M+H]+requires 670.1412)。
实施例4：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-氧代-2-(吡啶-3-磺酰胺基)乙基)吲哚-4-基)甘氨酸(S4)
Figure PCTCN2020117584-appb-000016
S4的合成与实施例1相同，将苯磺酰胺替换为吡啶-3-磺酰胺，得到白色固体142.0mg，产率为64％； 1H NMR(300MHz,DMSO-d 6)δ12.82(s,2H),8.90(d,J＝4.1,1.5Hz,1H),8.42(dd,J＝5.1,1.4Hz,1H),7.83(d,J＝3.9Hz,1H),7.27(t,J＝8.3Hz,1H),7.17(t,J＝4.6Hz,1H), 6.91(s,3H),6.67(d,J＝6.3Hz,2H),6.57(d,J＝8.1Hz,1H),6.15(d,J＝7.7Hz,1H),5.18(s,1H),4.29(s,2H),3.69(s,3H),3.26(d,J＝8.5Hz,1H),2.69-2.60(m,1H),2.24(d,J＝6.4Hz,9H)；EI-MS HRMS(ESI):found 679.1879(C 33H 35N 4O 8S 2.[M+H]+requires 679.1890)。
实施例5：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-氧代-2-(噻吩-2-磺酰胺基)乙基)吲哚-4-基)甘氨酸(S5)
Figure PCTCN2020117584-appb-000017
S5的合成与实施例1相同，将苯磺酰胺替换为噻吩-2-磺酰胺，得到白色固体118.0mg，产率为65％； 1H NMR(300MHz,DMSO-d 6)δ12.73(s,2H),8.05(dd,J＝5.1,1.4Hz,1H),7.75(d,J＝3.7Hz,1H),7.26(t,J＝8.1Hz,1H),7.18(t,J＝4.4Hz,1H),6.90(s,3H),6.66(d,J＝6.1Hz,2H),6.55(d,J＝8.1Hz,1H),6.19(d,J＝7.9Hz,1H),5.17(s,1H),4.28(s,2H),3.68(s,3H),3.25(d,J＝8.3Hz,1H),2.68-2.60(m,1H),2.20(d,J＝6.4Hz,9H)；EI-MS HRMS(ESI):found 706.1316(C 32H 33N 3NaO 8S 3.[M+Na]+requires 706.1322)。
实施例6：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-((4-甲氧基苯基)磺酰胺基)-2-氧代乙基)吲哚-4-基)甘氨酸(S6)
Figure PCTCN2020117584-appb-000018
S6的合成与实施例1相同，将苯磺酰胺替换为4-甲氧基苯磺酰胺，得到白色固体156.0mg，产率为76％；H NMR(300MHz,DMSO-d 6)δ12.39(s,2H),7.80(dt,J＝9.5,5.8Hz,2H),7.25(q,J＝7.5Hz,1H),7.16-7.06(m,2H),6.91(s,4H),6.62(s,2H),6.21-6.10(m,1H),5.15(d,J＝7.6Hz,1H),4.27(d,J＝8.0Hz,2H),3.87-3.79(m,3H),3.25(d,J＝8.6Hz,1H),2.62(s,1H),2.47(s,2H),2.19(d,J＝7.9Hz,9H)；EI-MS HRMS(ESI):found 708.2038(C 35H 38N 3O 9S 2.[M+H]+requires 708.2044)。
实施例7：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-((4-甲基苯基)磺酰胺基)-2-氧代乙基)吲哚-4-基)甘氨酸(S7)
Figure PCTCN2020117584-appb-000019
S7的合成与实施例1相同，将苯磺酰胺替换为4-甲基苯磺酰胺，得到白色固体159.0mg，产率为77％； 1H NMR(300MHz,DMSO-d 6)δ12.80(s,2H),7.75(s,2H),7.41(s,2H),7.25(d,J＝11.5Hz,2H),6.92(s,4H),6.64(d,J＝11.5Hz,2H),6.17(d,J＝8.1Hz,1H),5.16(s,1H),4.28(s,2H),3.79(s,3H),3.13(s,2H),2.63(s,2H),2.39(s,3H),2.22(d,J＝8.0Hz,9H)；EI-MS HRMS(ESI):found 692.2097(C 35H 38N 3O 8S 2.[M+H]+requires 692.2094)。
实施例8：N-(1-(2-(((4-氟苯基)磺酰胺基)-1-(3-甲氧基苯基)-2-氧代乙基)吲哚-4-基)-N-(均三甲基苯磺酰基)甘氨酸(S8)
Figure PCTCN2020117584-appb-000020
S8的合成与实施例1相同，将苯磺酰胺替换为4-氟苯磺酰胺，得到白色固体121.0mg，产率为76％； 1H NMR(300MHz,DMSO-d 6)δ12.87(s,2H),7.97(d,J＝8.4Hz,2H),7.78(d,J＝8.2Hz,2H),7.27(t,J＝8.2Hz,1H),6.99(d,J＝9.2Hz,1H),6.92(s,2H),6.87(d,J＝8.0Hz,1H),6.69(d,J＝7.6Hz,1H),6.64(s,1H),6.56(d,J＝8.3Hz,1H),6.18(d,J＝7.8Hz,1H),5.19(s,1H),4.29(s,2H),3.79(s,3H),3.25(d,J＝8.5Hz,1H),2.64(d,J＝7.8Hz,1H),2.32(d,J＝13.8Hz,2H),2.20(s,9H)；EI-MS HRMS(ESI):found 696.1846(C 34H 35FN 3O 8S 2.[M+H]+requires 696.1844)。
实施例9：N-(1-(2-(((4-氯苯基)磺酰胺基)-1-(3-甲氧基苯基)-2-氧代乙基)吲哚-4-基)-N-(均三甲基苯磺酰基)甘氨酸(S9)
Figure PCTCN2020117584-appb-000021
S9的合成与实施例1相同，将苯磺酰胺替换为4-氯苯磺酰胺，得到白色固体136.0mg，产率为80％； 1H NMR(300MHz,DMSO-d 6)δ12.69(s,2H),7.87(d,J＝8.6Hz,2H),7.70(d,J＝8.4Hz,2H),7.28(t,J＝8.0Hz,1H),6.95(d,J＝9.0Hz,1H),6.91(s,2H),6.86(d,J＝8.2Hz,1H),6.69(d,J＝7.4Hz,1H),6.62(s,1H),6.54(d,J＝8.1Hz,1H),6.18(d,J＝7.8Hz,1H),5.19(s,1H),4.29(s,2H),3.78(s,9H)3.25(d,J＝8.5Hz,1H),2.64(d,J＝7.8Hz,1H),2.32(d,J＝13.8Hz,2H),2.20(s,9H)；EI-MS HRMS(ESI):found 712.1539(C 34H 35ClN 3O 8S 2.[M+H]+requires 712.1548)。
实施例10：N-(1-(2-(((4-溴苯基)磺酰胺基)-1-(3-甲氧基苯基)-2-氧代乙基)吲哚-4-基)-N-(均三甲基苯磺酰基)甘氨酸(S10)
Figure PCTCN2020117584-appb-000022
S10的合成与实施例1相同，将苯磺酰胺替换为4-溴苯磺酰胺，得到白色固体179.0mg，产率为79％； 1H NMR(300MHz,DMSO-d 6)δ12.80(s,1H),12.57(s,1H),7.88(d,J＝7.7Hz,2H),7.73(t,J＝7.3Hz,1H),7.61(t,J＝7.6Hz,2H),7.25(d,J＝8.1Hz,1H),6.92(d,J＝7.6Hz,3H),6.66(d,J＝5.0Hz,2H),6.55(d,J＝8.1Hz,1H),6.18(d,J＝7.8Hz,1H),5.17(s,1H),4.29(s,2H),3.69(s,3H),3.23(d,J＝8.5Hz,1H),2.61(t,J＝8.0Hz,1H),2.28(d,J＝10.1Hz,2H),2.21(s,9H)；EI-MS HRMS(ESI):found 756.1045(C 34H 35BrN 3O 8S 2.[M+H]+requires 756.1032)。
实施例11：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-氧代-2-((4-(三氟甲基)苯基)磺酰胺基)乙基)吲哚-4-基)甘氨酸(S11)
Figure PCTCN2020117584-appb-000023
S11的合成与实施例1相同，将苯磺酰胺替换为4-三氟甲基苯磺酰胺，得到白色固体134.0mg，产率为74％； 1H NMR(300MHz,DMSO-d 6)δ12.91(s,2H),8.08(t,J＝6.8Hz,2H),8.04-7.94(m,2H),7.64(s,2H)7.29-7.22(m,1H),7.01-6.87(m,3H),6.83(d,J＝6.0Hz,1H),6.67(d,J＝7.0Hz,1H),6.60(s,1H),4.28(d,J＝5.3Hz,2H),3.73-3.62(m,3H),3.25(d,J＝8.7Hz,1H),2.61(s,1H),2.28(d,J＝10.1Hz,2H),2.31-2.08(m,9H)；EI-MS HRMS(ESI):found 768.1632(C 35H 34F 3N 3NaO 8S 2.[M+Na]+requires 768.1631)。
实施例12：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-((2-甲氧基苯基)磺酰胺基)-2-氧代乙基)吲哚-4-基)甘氨酸(S12)
Figure PCTCN2020117584-appb-000024
S12的合成与实施例1相同，将苯磺酰胺替换为2-甲氧基苯磺酰胺，得到白色固体112.0mg，产率为69％； 1H NMR(300MHz,DMSO-d 6)δ12.79(s,2H),7.82(d,J＝7.7Hz,1H),7.66(t,J＝7.7Hz,1H),7.29(t,J＝7.8Hz,2H),7.19-7.11(m,2H),6.91(d,J＝7.0Hz,3H),6.73-6.66(m,2H),6.57(d,J＝8.1Hz,1H),6.26(d,J＝7.8Hz,1H),5.22(s,1H),4.29(s,2H),3.70(s,3H),3.68(s,3H),3.65(s,2H),3.21(dd,J＝17.6,8.3Hz,2H),2.24(s,3H),2.19(s,6H)；EI-MS HRMS(ESI):found 708.2042(C 35H 38N 3O 9S 2.[M+H]+requires 708.2044)。
实施例13：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-((2-甲基苯基)磺酰胺基)-2-氧代乙基)吲哚-4-基)甘氨酸(S13)
Figure PCTCN2020117584-appb-000025
S13的合成与实施例1相同，将苯磺酰胺替换为2-甲基苯磺酰胺，得到白色固体123.0mg，产率为71％； 1H NMR(300MHz,DMSO-d 6)δ12.63(s,2H),7.95(d,J＝8.0Hz,1H),7.57(d,J＝7.5Hz,1H),7.42(s,1H),7.36(d,J＝7.5Hz,2H),6.93(s,2H),6.89(s,2H),6.66(s,2H),6.57(d,J＝7.9Hz,1H),6.26(d,J＝7.9Hz,1H),5.21(s,1H),4.29(s,2H),3.69(s,3H),3.22(d,J＝9.8Hz,2H),2.28(s,2H),2.20(s,9H),2.03(s,3H)；EI-MS HRMS(ESI):found 714.1913(C 35H 37N 3NaO 8S 2.[M+Na]+requires 714.1914)。
实施例14：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-((3-甲基苯基)磺酰胺基)-2-氧代乙基)吲哚-4-基)甘氨酸(S14)
Figure PCTCN2020117584-appb-000026
S14的合成与实施例1相同，将苯磺酰胺替换为3-甲基苯磺酰胺，得到白色固体145.0mg，产率为79％； 1H NMR(300MHz,DMSO-d 6)δ12.77(s,1H),12.50(s,1H),7.65(d,J＝7.7Hz,1H),7.61(s,1H),7.52(d,J＝7.6Hz,1H),7.49(d,J＝7.3Hz,1H),7.26(t,J＝8.2Hz,1H),6.95-6.91(m,1H),6.89(s,2H),6.85(d,J＝7.8Hz,1H),6.69-6.62(m,2H),6.54(d,J＝8.1Hz,1H),6.18(d,J＝7.9Hz,1H),5.15(s,1H),4.27(s,2H),3.68(d,J＝4.8Hz,3H),3.23(d,J＝8.3Hz,1H),2.62(d,J＝7.9Hz,1H),2.35(s,3H),2.28-2.23(m,2H),2.19(d,J＝2.6Hz,9H)；EI-MS HRMS(ESI):found 692.2092(C 35H 38N 3O 8S 2.[M+H]+requires 692.2094)。
实施例15：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-((2-乙氧基苯基)磺酰胺基)-2-氧代乙基)吲哚-4-基)甘氨酸(S15)
Figure PCTCN2020117584-appb-000027
S15的合成与实施例1相同，将苯磺酰胺替换为2-乙氧基苯磺酰胺，得到白色固体114.0mg，产率为65％； 1H NMR(300MHz,DMSO-d 6)δ12.76(s,2H),7.83(dd,J＝7.8,1.6Hz,1H),7.64(s,1H),7.28(d,J＝7.4Hz,1H),7.19(d,J＝8.5Hz,1H),7.11(s,1H),6.95(d,J＝8.3Hz,2H),6.88(s,2H),6.67(d,J＝8.9Hz,2H),6.56(d,J＝8.0Hz,1H),6.32(d,J＝7.8Hz,1H),5.26(s,1H),4.28(s,2H),3.88-3.81(m,2H),3.71(d,J＝10.1Hz,3H),3.63-3.51(m,2H),2.27(d,J＝13.2Hz,2H),2.19(s,9H),1.34(s,3H)；EI-MS HRMS(ESI):found 722.2158(C 36H 40N 3O 9S 2.[M+H]+requires 722.2154)。
实施例16：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-((2-乙基苯基)磺酰胺基)-2-氧代乙基)吲哚-4-基)甘氨酸(S16)
Figure PCTCN2020117584-appb-000028
S16的合成与实施例1相同，将苯磺酰胺替换为2-乙基苯磺酰胺，得到白色固体114.0mg，产率为65％； 1H NMR(300MHz,DMSO-d 6)δ12.65(s,2H),7.98(d,J＝8.1Hz,1H),7.60(d,J＝7.7Hz,1H),7.40(s,1H),7.37(d,J＝7.7Hz,1H),6.95(s,2H),6.90(s,2H),6.64(s,2H),6.58(d,J＝7.9Hz,1H),6.27(d,J＝7.7Hz,1H),5.20(s,1H),4.28(s,2H),3.69(s,3H),3.21(d,J＝9.8Hz,1H),2.65(s,2H),2.28(s,2H),2.21(s,9H),1.28(s,3H)；EI-MS HRMS(ESI):found 722.2158(C 36H 40N 3O 9S 2.[M+H]+requires 722.2154)。
实施例17：N-(1-(2-(((2-氟苯基)磺酰胺基)-1-(3-甲氧基苯基)-2-氧代乙基)吲哚-4-基)-N-(均三甲基苯磺酰基)甘氨酸(S17)
Figure PCTCN2020117584-appb-000029
S17的合成与实施例1相同，将苯磺酰胺替换为2-氟苯磺酰胺，得到白色固体121.0mg，产率为74％； 1H NMR(300MHz,DMSO-d 6)δ12.95(s,2H),7.92(t,J＝7.5Hz,1H),7.78(d,J＝7.5Hz,1H),7.43(t,J＝8.3Hz,2H),7.30(t,J＝8.1Hz,1H),6.96(d,J＝10.3Hz,2H),6.90(s,2H),6.71(d,J＝7.7Hz,2H),6.57(d,J＝8.0Hz,1H),6.27(d,J＝7.8Hz,1H),5.24(s,1H),4.29(s,2H),3.72(s,3H),3.23(d,J＝8.6Hz,2H),2.42(d,J＝8.0Hz,2H),2.20(s,3H),2.18(s,6H)；EI-MS HRMS(ESI):found 718.1657(C 34H 34FN 3NaO 8S 2.[M+Na]+requires 718.1663)。
实施例18：N-(1-(2-(((2-氯苯基)磺酰胺基)-1-(3-甲氧基苯基)-2-氧代乙基)吲哚-4-基)-N-(均三甲基苯磺酰基)甘氨酸(S18)
Figure PCTCN2020117584-appb-000030
S18的合成与实施例1相同，将苯磺酰胺替换为2-氯苯磺酰胺，得到白色固体134.0mg，产率为74％； 1H NMR(300MHz,DMSO-d 6)δ12.93(s,2H),7.91(t,J＝7.7Hz,1H),7.79(d,J＝7.3Hz,2H),7.44(t,J＝8.5Hz,2H),7.31(t,J＝8.1Hz,1H),6.96(d,J＝10.3Hz,2H),6.91(s,1H),6.72(d,J＝7.9Hz,2H),6.56(d,J＝8.0Hz,1H),6.26(d,J＝7.8Hz,1H),5.23(s,1H),4.28(s,2H),3.71(s,3H),3.235(d,J＝8.6Hz,2H),2.41(d,J＝8.0Hz,2H),2.21(s,3H),2.18(s,6H)；EI-MS HRMS(ESI):found 734.1362(C 34H 34ClN 3NaO 8S 2.[M+Na]+requires 734.1368)。
实施例19：N-(1-(2-(((2-溴苯基)磺酰胺基)-1-(3-甲氧基苯基)-2-氧代乙基)吲哚-4-基)-N-(均三甲基苯磺酰基)甘氨酸(S19)
Figure PCTCN2020117584-appb-000031
S19的合成与实施例1相同，将苯磺酰胺替换为2-溴苯磺酰胺，得到白色固体138.0mg，产率为78％； 1H NMR(300MHz,DMSO-d 6)δ13.01(s,2H),8.16–8.10(m,1H),7.87-7.81(m,1H),7.62(d,J＝6.3Hz,2H),7.29(d,J＝8.2Hz,1H),6.99–6.92(m,2H),6.90(d,J＝5.6Hz,2H),6.76-6.69(m,2H),6.57(d,J＝8.1Hz,1H),6.37(d,J＝7.9Hz,1H),5.32(s,1H),4.29(s,2H),3.71(s,3H),3.67(s,2H),3.23(d,J＝8.7Hz,1H),2.66(d,J＝8.2Hz,1H),2.20(s,3H),2.18(s,6H)；EI-MS HRMS(ESI):found 756.1018(C 34H 35BrN 3O 8S 2.[M+H]+requires 756.1043)。
实施例20：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-氧代-2-((2-(三氟甲基)苯基)磺酰胺基)乙基)吲哚-4-基)甘氨酸(S20)
Figure PCTCN2020117584-appb-000032
S20的合成与实施例1相同，将苯磺酰胺替换为2-三氟甲基苯磺酰胺，得到白色固体178.0mg，产率为69％； 1H NMR(300MHz,DMSO-d 6)δ12.82(s,2H),8.30(s,1H),7.96(d,J＝16.3Hz,3H),7.27(t,J＝8.0Hz,1H),6.95(d,J＝8.3Hz,1H),6.90(d,J＝7.1Hz,3H),6.70-6.62(m,2H),6.57(d,J＝8.0Hz,1H),6.27(d,J＝7.7Hz,1H),5.27(s,1H),4.29(s,2H),3.69(d,J＝2.2Hz,3H),3.25(d,J＝9.0Hz,1H),2.65(d,J＝8.5Hz,1H),2.27(d,J＝12.4Hz,2H),2.19(d,J＝6.9Hz,9H)；EI-MS HRMS(ESI):found 746.1817(C 35H 35F 3N 3O 8S 2.[M+H]+requires 746.1812)。
实施例21：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-氧代-2-((2-(三氟甲氧基)苯基)磺酰胺基)乙基)吲哚-4-基)甘氨酸(S21)
Figure PCTCN2020117584-appb-000033
S21的合成与实施例1相同，将苯磺酰胺替换为2-三氟甲氧基苯磺酰胺，得到白色固体112.0mg，产率为68％； 1H NMR(300MHz,DMSO-d 6)δ12.94(s,2H),8.06(d,J＝8.0Hz,1H),7.85(t,J＝8.0Hz,1H),7.58(q,J＝8.5,8.1Hz,2H),7.30(t,J＝7.9Hz,1H),6.99-6.91(m,2H),6.89(s,2H),6.72(t,J＝6.4Hz,2H),6.57(d,J＝8.0Hz,1H),6.27(d,J＝7.9Hz,1H),5.26(s,1H),4.29(s,2H),3.72(s,3H),3.69(s,2H),3.24(d,J＝8.6Hz,1H),2.66(d,J＝8.2Hz,1H),2.19(d,J＝5.1Hz,9H)；EI-MS HRMS(ESI):found 784.1574(C 35H 34F 3N 3NaO 9S 2.[M+Na]+requires 784.1580)。
实施例22：N-(1-(2-(((2,4-二甲基苯基)磺酰胺基)-1-(3-甲氧基苯基)-2-氧代乙基)吲哚-4-基)-N-(均三甲基苯磺酰基)甘氨酸(S22)
Figure PCTCN2020117584-appb-000034
S22的合成与实施例1相同，将苯磺酰胺替换为2,4-二甲基苯磺酰胺，得到白色固体78.0mg，产率为69％； 1H NMR(300MHz,DMSO-d 6)δ12.92(s,2H),7.95(d,J＝8.0Hz,1H),7.42(d,J＝6.8Hz,1H),7.37-7.27(m,2H),7.08(d,J＝9.9Hz,2H),7.02(s,2H),6.81(d,J＝7.6Hz,1H),6.77-6.66(m,2H),6.40(d,J＝7.9Hz,1H),5.35(s,1H),4.42(s,2H),3.81(s,3H),3.37(d,J＝8.8Hz,1H),2.80-2.74(m,1H),2.54(s,2H),2.33(s,9H),2.12(s,6H)；EI-MS HRMS(ESI):found 706.2247(C 36H 40N 3O 8S 2.[M+H]+requires 706.2251)。
实施例23：N-(均三甲基苯磺酰基)-N-(1-(2-(((2-甲氧基-4-甲基苯基)磺酰胺基)-1-(3-甲氧基苯基)-2-氧代乙基)吲哚-4-基)甘氨酸(S23)
Figure PCTCN2020117584-appb-000035
S23的合成与实施例1相同，将苯磺酰胺替换为2-甲氧基-4-甲基苯磺酰胺，得到白色固体234.0mg，产率为78％； 1H NMR(300MHz,DMSO-d 6)δ12.92(s,2H),7.69(d,J＝8.0Hz,1H),7.28(d,J＝7.9Hz,1H),7.00-6.92(m,4H),6.89(s,2H),6.71(d,J＝7.6Hz,1H),6.65(s,1H),6.57(d,J＝8.0Hz,1H),6.28(d,J＝7.8Hz,1H),5.22(s,1H),4.29(s,2H),3.69(s,3H),3.64(s,3H),3.60(s,2H),3.25(d,J＝8.6Hz,1H),2.64(d,J＝7.7Hz,1H),2.37(s,3H),2.20(s,9H),2.04(s,3H)；EI-MS HRMS(ESI):found 722.2190(C 36H 40N 3O 9S 2.[M+H]+requires 722.2200)。
实施例24：N-(1-(2-(((2,4-二甲氧基苯基)磺酰胺基)-1-(3-甲氧基苯基)-2-氧代乙基)吲哚-4-基)-N-(均三甲基苯磺酰基)甘氨酸(S24)
Figure PCTCN2020117584-appb-000036
S24的合成与实施例1相同，将苯磺酰胺替换为2,4-二甲氧基苯磺酰胺，得到白色固体118.0mg，产率为68％； 1H NMR(300MHz,DMSO-d 6)δ12.91(s,2H),7.93(d,J＝8.0Hz,1H),7.46(d,J＝6.8Hz,1H),7.38-7.26(m,2H),7.13(d,J＝9.9Hz,2H),7.04(s,2H),6.80(d,J＝7.6Hz,1H),6.78-6.66(m,2H),6.43(d,J＝7.9Hz,1H),5.34(s,1H),4.41(s,2H),3.95(d,J＝3.3Hz,6H),3.80(s,3H),3.36(d,J＝8.8Hz,1H),2.81-2.73(m,1H),2.53(s,2H),2.35(s,9H)；EI-MS HRMS(ESI):found 760.1963(C 36H 39N 3NaO 10S 2.[M+H]+requires 760.1969)。
实施例25：N-(1-(2-(((3,5-二甲基苯基)磺酰胺基)-1-(3-甲氧基苯基)-2-氧代乙基)吲哚-4-基)-N-(均三甲基苯磺酰基)甘氨酸(S25)
Figure PCTCN2020117584-appb-000037
S25的合成与实施例1相同，将苯磺酰胺替换为2,5-二甲基苯磺酰胺，得到白色固体113.0mg，产率为66％； 1H NMR(300MHz,DMSO-d 6)δ12.93(s,2H),7.96(d,J＝8.0Hz,1H),7.40(d,J＝6.4Hz,1H),7.32-7.23(m,2H),7.12(d,J＝9.7Hz,2H),7.06(s,2H),6.80(d,J＝7.6Hz,1H),6.77-6.66(m,2H),6.40(d,J＝7.9Hz,1H),5.35(s,1H),4.41(s,2H),3.82(s,3H),3.36(d,J＝8.6Hz,1H),2.81-2.76(m,1H),2.54(s,2H),2.32(s,9H),2.22(s,6H)；EI-MS HRMS(ESI):found 706.2247(C 36H 40N 3O 8S 2.[M+H]+requires 706.2251)。
实施例26：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-(萘-1-磺酰胺基)-2-氧代乙基)吲哚-4-基)甘氨酸(S26)
Figure PCTCN2020117584-appb-000038
S26的合成与实施例1相同，将苯磺酰胺替换为萘-1-苯磺酰胺，得到白色固体245.0mg，产率为71％； 1H NMR(300MHz,DMSO-d 6)δ12.86(s,2H),8.32(s,2H),7.96(d,J＝16.7Hz,3H),7.25(t,J＝8.6Hz,2H),6.99(d,J＝8.5Hz,2H),6.91(d,J＝7.1Hz,3H),6.72-6.62(m,2H),6.58(d,J＝8.0Hz,1H),6.29(d,J＝7.9Hz,1H),5.26(s,1H),4.28(s,2H),3.79(d,J＝2.2Hz,3H),3.27(s,1H),2.65(s,1H),2.29(d,J＝12.2Hz,2H),2.18(d,J＝6.9Hz,9H)；EI-MS HRMS(ESI):found 728.2095(C 38H 38N 3O 8S 2.[M+H]+requires 728.2094)。
实施例27：N-(均三甲基苯磺酰基)-N-(1-(1-(1-(3-甲氧基苯基)-2-氧代-2-((2-(三氟甲基)苯基)磺酰胺基)乙基)吲哚-4-基)甘氨酸(S27)
Figure PCTCN2020117584-appb-000039
将S23(721.0mg,1.0mmol)溶解在10.0mLDCM中，依次加入2倍当量的EDCI和DMAP，搅拌溶解后加入苯磺酰胺(158mg,1.0mmol)，加热至40℃搅拌，反应4h，向溶液中加入水，用饱和NH 4Cl溶液调节pH至7，有机层用饱和NaCl溶液洗涤3遍，无水硫酸钠干燥，旋干溶剂，柱层析得到361mg白色固体，产率为42％； 1H NMR(300MHz,DMSO-d 6)δ12.32(s,2H),7.73(d,J＝8.0Hz,1H),7.71-7.65(m,2H),7.45(dt,J＝14.4,7.0Hz,3H),7.32(t,J＝7.9Hz,1H),7.05-6.92(m,3H),6.86(d,J＝7.1Hz,3H),6.77(d,J＝7.8Hz,1H),6.71(t,J＝2.0Hz,1H),6.45(d,J＝8.0Hz,1H),6.24(d,J＝7.8Hz,1H),5.17(s,1H),4.14(s,2H),3.74(s,3H),3.68(s,3H),3.19(q,J＝8.5Hz,2H),2.41(s,2H),2.36(s,3H),2.22(s,3H),2.18(s,6H)；EI-MS HRMS(ESI):found 883.2119(C 42H 44N 4NaO 10S 3.[M+Na]+requires 883.2111)。
实施例28：N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(4-((4-甲氧基-N-(2-氧代-2-(苯基磺酰胺基)乙基)苯基)磺酰胺基)吲哚-1-基)-2-)3-甲氧基苯基)乙酰胺(S28)
Figure PCTCN2020117584-appb-000040
S28的合成与实施例27相同，将2,4,6-均三甲基苯磺酰氯替换为4-甲氧基苯磺酰氯，得到白色固体135.0mg，产率为40％； 1H NMR(300MHz,DMSO-d 6)δ12.54(s,2H),7.68(d,J＝7.9Hz,1H),7.63-7.56(m,2H),7.51(d,J＝8.9Hz,2H),7.28(t,J＝7.9Hz,1H),7.04-6.95(m,3H),6.91(dq,J＝10.2,3.6,3.1Hz,4H),6.82(dd,J＝15.0,7.5Hz,4H),6.14(d,J＝7.9Hz,1H),6.00(d,J＝8.1Hz,1H),5.01(s,1H),3.91(d,J＝2.9Hz,2H),3.82(s,3H),3.78(s,3H),3.71(s,3H),3.64(s,2H),2.82-2.72(m,2H),2.37(s,3H)；EI-MS HRMS(ESI):found 871.1754(C 40H 40N 4NaO 11S 3.[M+Na]+requires 871.1747)。
实施例29：N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(4-((4-甲基-N-(2-氧代-2-(苯基磺酰胺基)乙基)苯基)磺酰胺基)吲哚-1-基)-2-)3-甲氧基苯基)乙酰胺(S29)
Figure PCTCN2020117584-appb-000041
S29的合成与实施例27相同，将2,4,6-均三甲基苯磺酰氯替换为4-甲基苯磺酰氯，得到白色固体123.0mg，产率为52％； 1H NMR(300MHz,DMSO-d 6)δ12.84(s,2H),7.79(d,J＝8.9Hz,1H),7.66-7.58(m,3H),7.50(d,J＝8.5Hz,2H),7.38(t,J＝7.4Hz,1H),7.07-6.99(m,3H),6.91(t,J＝3.1Hz,3H),6.83(dd,J＝12.2,7.3Hz,4H),6.15(d,J＝7.3Hz,1H),6.00(d,J＝8.1Hz,1H),5.01(s,1H),3.91(d,J＝2.9Hz,2H),3.84(s,3H),3.72(s,3H),3.64(s,2H),2.82-2.72(m,1H),2.37(s,6H)；EI-MS HRMS(ESI):found 833.1935(C 40H 40N 4O 10S 3.[M+H]+requires 833.1928)。
实施例30：2-(4-((4-氟-N-(2-氧代-2-(苯基磺酰胺基)乙基)苯基)磺酰胺基)吲哚-1-基)-N-((2-甲氧基-4-甲基苯基)磺酰基)-2-(3-甲氧基苯基)乙酰胺(S30)
Figure PCTCN2020117584-appb-000042
S30的合成与实施例27相同，将2,4,6-均三甲基苯磺酰氯替换为4-氟苯磺酰氯，得到白色固体69.0mg，产率为48％； 1H NMR(300MHz,DMSO-d 6)δ12.58(s,2H),7.78(d,J＝7.1Hz,1H),7.66-7.58(m,1H),7.50(d,J＝8.9Hz,2H),7.35(t,J＝7.9Hz,2H),7.11-6.99(m,3H),6.92(dq,J＝10.4,3.2,3.1Hz,4H),6.81(dd,J＝15.2,7.9Hz,4H),6.18(d,J＝7.5Hz,1H),6.08(d,J＝8.3Hz,1H),5.11(s,1H),3.92(d,J＝2.9Hz,2H),3.81(s,3H),3.79(s,3H),3.65(s,2H),2.82-2.72(m,2H)；EI-MS HRMS(ESI):found 859.1541(C 39H 37FN 4NaO 10S 3.[M+Na]+requires 859.1548)。
实施例31：2-(4-((4-乙酰胺基-N-(2-氧代-2-(苯基磺酰胺基)乙基)苯基)磺酰胺基)吲哚-1-基)-N-((2-甲氧基-4-甲基苯基)磺酰基)-2-(3-甲氧基苯基)乙酰胺(S31)
Figure PCTCN2020117584-appb-000043
S31的合成与实施例27相同，将2,4,6-均三甲基苯磺酰氯替换为4-乙酰胺基苯磺酰氯，得到白色固体79.0mg，产率为43％； 1H NMR(300MHz,DMSO-d 6)δ12.71(s,2H),10.41(s,1H),7.69(d,J＝7.9Hz,2H),7.63-7.59(m,2H),7.52(d,J＝8.9Hz,1H),7.32(t,J＝7.9Hz,1H),7.14-7.05(m,2H),6.91(dd,J＝4.6,3.3Hz,3H),6.82(dd,J＝12.3,7.6Hz,4H),6.15(d,J＝7.9Hz,2H),6.00(d,J＝8.1Hz,1H),5.01(s,1H),3.92(d,J＝2.1Hz,2H),3.82(s,3H),3.78(s,3H),3.64 (s,2H),2.81-2.72(m,2H),2.37(s,3H),2.02(s,3H)；EI-MS HRMS(ESI):found 898.2048(C 41H 41N 5NaO 11S 3.[M+Na]+requires 898.2052)。
实施例32：N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(4-((2-甲氧基-N-(2-氧代-2-(苯基磺酰胺基)乙基)苯基)磺酰胺基)吲哚-1-基)-2-)3-甲氧基苯基)乙酰胺(S32)
Figure PCTCN2020117584-appb-000044
S32的合成与实施例27相同，将2,4,6-均三甲基苯磺酰氯替换为2-甲氧基苯磺酰氯，得到白色固体109.0mg，产率为50％； 1H NMR(300MHz,DMSO-d 6)δ12.33(s,2H),7.86(t,J＝9.1Hz,2H),7.75-7.65(m,2H),7.53(d,J＝32.6Hz,6H),7.36-7.27(m,2H),7.22(d,J＝6.1Hz,2H),6.97(t,J＝8.6Hz,2H),6.81(dd,J＝18.6,9.0Hz,2H),6.24(d,J＝7.7Hz,1H),5.09(d,J＝19.7Hz,1H),4.41(s,1H),4.13(s,1H),4.02(s,2H),3.92(d,J＝3.0Hz,3H),3.74(d,J＝2.9Hz,3H),3.66(d,J＝12.1Hz,3H),3.20(s,2H),2.40(s,3H)；EI-MS HRMS(ESI):found 871.1754(C 40H 40N 4NaO 11S 3.[M+Na]+requires 871.1747)。
实施例33：N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(4-((3-甲氧基-N-(2-氧代-2-(苯基磺酰胺基)乙基)苯基)磺酰胺基)吲哚-1-基)-2-)3-甲氧基苯基)乙酰胺(S33)
Figure PCTCN2020117584-appb-000045
S33的合成与实施例27相同，将2,4,6-均三甲基苯磺酰氯替换为3-甲氧基苯磺酰氯，得到白色固体105.0mg，产率为54％； 1H NMR(300MHz,DMSO-d 6)δ12.76(s,2H),7.98(d,J＝7.9Hz,1H),7.73-7.66(m,2H),7.59(d,J＝8.9Hz,2H),7.27(t,J＝5.9Hz,2H),7.12-7.04(m,3H),6.91(dq,J＝10.2,3.6,3.1Hz,3H),6.82(dd,J＝15.0,7.5Hz,4H),6.14(d,J＝7.9Hz,1H),6.00(d,J＝8.1Hz,1H),5.06(s,1H),3.95(d,J＝2.9Hz,2H),3.83(s,3H),3.79(s,3H),3.72(s,3H),3.62(s,2H),2.82-2.72(m,2H),2.24(s,3H)；EI-MS HRMS(ESI):found 871.1754(C 40H 40N 4NaO 11S 3.[M+Na]+requires 871.1747)。
实施例34：N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(4-((4-甲氧基-N-(2-氧代-2-(苯基磺酰胺基)乙基)苯基)磺酰胺基)吲哚-1-基)-2-)3-甲氧基苯基)乙酰胺(S34)
Figure PCTCN2020117584-appb-000046
S34的合成与实施例27相同，将2,4,6-均三甲基苯磺酰氯替换为苯磺酰氯，得到白色固体56.0mg，产率为43％； 1H NMR(300MHz,DMSO-d 6)δ12.51(s,2H),7.72(d,J＝7.9Hz,1H),7.69(d,J＝7.9Hz,2H),7.57(d,J＝8.2Hz,2H),7.27(t,J＝5.3Hz,2H),7.05-6.95(m,3H), 6.91(m,4H),6.81(dd,J＝12.2,7.5Hz,4H),6.17(d,J＝7.7Hz,1H),6.06(d,J＝8.8Hz,1H),5.12(s,1H),3.99(d,J＝2.5Hz,2H),3.88(s,3H),3.73(s,3H),3.62(s,2H),2.82-2.72(m,2H),2.34(s,3H)；EI-MS HRMS(ESI):found 819.1829(C 39H 39N 4O 10S 3.[M+H]+requires 819.1824)。
实施例35：2-(4-((N-(2-(环丙烷磺酰胺基)-2-氧乙基)-4-甲氧基苯基)磺酰胺基)吲哚-1-基)-N-(((2-甲氧基-4-甲基苯基)磺酰基)-2–(3-甲氧基苯基)乙酰胺(S35)
(1)N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(3-甲氧基苯基)-2-(4-(((4-甲氧基苯基)磺酰胺基)吲哚-1-基)乙酰胺(18)
将中间体14(511mg,1.0mmol)溶于15mL四氢呋喃和甲醇混合溶液(体积比1:1)，加入催化量的钯碳，反应溶液室温搅拌4小时后，硅藻土助滤除去钯碳，滤液减压蒸馏得到油状物中间体，不经纯化，溶于四氢呋喃，加入4-甲氧基苯磺酰氯(247mg,1.2mmol)和吡啶(237mg,3.0mmol)，加热至80℃，氮气保护反应4小时，冷却至室温，减压蒸去溶剂，硅胶柱层析得到319mg灰白色产物，两步总产率为49％； 1H NMR(300MHz,DMSO-d 6)δ12.41(s,1H),7.81(d,J＝7.9Hz,1H),7.66-7.58(m,2H),7.52(d,J＝8.9Hz,2H),7.24(t,J＝7.9Hz,1H),7.01-6.94(m,3H),6.82(dd,J＝15.0,7.5Hz,4H),6.11(d,J＝7.9Hz,1H),6.03(d,J＝8.1Hz,1H),5.11(s,1H),3.81(s,3H),3.77(s,3H),3.71(s,3H),3.64(s,2H),2.82–2.72(m,2H),2.37(s,3H)；ESI-MS m/z:652.1(M+H) +。
(2)甲基N-(1-(2-(((2-甲氧基-4-甲基苯基)磺酰胺基)-1-(3-甲氧基苯基)-2-氧代乙基)吲哚-4-基)-N-((4-甲氧基苯基)磺酰基甘氨酸盐(19)
将中间体18(651mg,1.0mmol)溶于5.0mL DMF中，加入碳酸钾(207mg,1.5mmol)，最后加入溴乙酸甲酯(183mg,1.2mmol)于室温下搅拌。反应3h，向溶液中加入水，至溶液变浑浊，用饱和NH 4Cl溶液调节pH至7，有灰色固体析出，抽滤烘干得白色固体513mg,产率为71％； 1H NMR(300MHz,Chloroform-d)δ9.79(s,1H),7.98(d,J＝8.1Hz,1H),7.68(d,J＝2.1Hz,1H),7.66(d,J＝1.9Hz,1H),7.31(s,1H),6.99(d,J＝2.1Hz,1H),6.97(d,J＝2.0Hz,1H),6.96-6.90(m,3H),6.90(d,J＝3.5Hz,1H),6.87-6.82(m,1H),6.71(s,1H),6.34(d,J＝7.9Hz,1H),6.25(d,J＝7.8Hz,1H),4.64(s,1H),4.30(q,J＝17.6Hz,2H),3.92(s,3H),3.78(s,3H),3.72(s,3H),3.60(s,3H),3.37(td,J＝8.2,3.6Hz,1H),3.00(s,2H),2.93(s,2H),2.45(s,3H)；ESI-MS m/z:724.2(M+H) +。
(3)N-(1-(2-(((2-甲氧基-4-甲基苯基)磺酰胺基)-1-(3-甲氧基苯基)-2-氧代乙基)吲哚-4-基)-N-((4-甲氧基苯基)磺酰基)甘氨酸(20)
将中间体19(360mg,0.5mmol)溶解在10mL甲醇中,加入5.0mL水，最后加入LiOH(2.0g,83.3mmol)，于室温下搅拌4h，向体系中加入少量水至溶液变浑浊，用盐酸溶液调节pH至4，溶液变浑浊，有灰色固体析出，抽滤、烘干得550mg白色固体，产率为78％； 1H NMR(300MHz,DMSO-d 6)δ12.45(s,1H),7.72(d,J＝8.0Hz,1H),7.60-7.53(m,2H),7.34(t,J＝7.9Hz,1H),7.08(d,J＝2.0Hz,1H),7.06(d,J＝2.0Hz,1H),7.04(s,1H),6.99(dd,J＝8.2,2.5Hz,1H),6.93(t,J＝8.1Hz,2H),6.82(d,J＝7.7Hz,1H),6.76(t,J＝2.0Hz,1H),6.19(t,J＝8.6Hz,2H),5.17(s,1H),4.19(s,2H),3.85(s,3H),3.74(s,3H),3.68(s,3H),2.73(d,J＝8.8Hz,2H),2.40(s,3H)；ESI-MS m/z:711.2(M+H) +。
(4)2-(4-((N-(2-(环丙烷磺酰胺基)-2-氧乙基)-4-甲氧基苯基)磺酰胺基)吲哚-1-基)-N-(((2-甲氧基-4-甲基苯基)磺酰基)-2–(3-甲氧基苯基)乙酰胺(S35)
Figure PCTCN2020117584-appb-000047
将S31(100mg,0.14mmol)溶解在10.0mL DCM中,依次加入2倍当量的EDCI和DMAP，搅拌溶解后加入苯磺酰胺(34mg,1.0mmol)，加热至40℃搅拌，反应4h，向溶液中加入水，用饱和NH 4Cl溶液调节pH至7，有机层用饱和NaCl溶液洗涤3遍，无水硫酸钠干燥，旋干溶剂，柱层析得到58mg白色固体，产率为51％； 1H NMR(300MHz,DMSO-d 6)δ12.25(s,2H),7.61(dd,J＝8.0,5.3Hz,3H),7.25(t,J＝7.8Hz,1H),7.07(d,J＝8.6Hz,2H),6.90(dd,J＝15.8,8.8Hz,4H),6.76(t,J＝8.3Hz,2H),6.22(d,J＝7.8Hz,1H),6.00(d,J＝8.0Hz,1H),4.79(s,1H),3.93(d,J＝3.5Hz,1H),3.85(s,3H),3.74(s,3H),3.66(s,3H),3.20(s,1H),2.85(d,J＝8.5Hz,2H),2.66-2.57(m,1H),2.34(s,3H),0.73(d,J＝4.5Hz,2H),0.69–0.60(m,2H)；EI-MS HRMS(ESI):found 835.1746(C 37H 40N 4NaO 11S 3.[M+Na]+requires 835.1747)。
实施例36：N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(4-((4-甲氧基-N-(2-(甲基磺酰胺基)-2-氧乙基)苯基)磺酰胺基)吲哚-1-基)-2-(3-甲氧基苯基)乙酰胺(S36)
Figure PCTCN2020117584-appb-000048
S36的合成与实施例35相同，将环丙烷磺酰胺替换为甲基磺酰胺，得到白色固体46.0mg，产率为45％； 1H NMR(300MHz,DMSO-d 6)δ12.45(s,2H),7.91(d,J＝8.0Hz,3H),7.65(t,J＝7.6Hz,1H),7.37(d,J＝8.4Hz,2H),7.10(dd,J＝15.8,8.8Hz,4H),6.96(t,J＝8.3Hz,2H),6.21(d,J＝7.8Hz,1H),6.12(d,J＝8.4Hz,1H),4.88(s,1H),3.95(d,J＝3.7Hz,1H),3.86(s,3H),3.72(s,3H),3.65(s,3H),3.22(s,1H),2.96(s,3H),2.87(d,J＝8.5Hz,2H),2.66-2.56(m,1H),2.32(s,3H)；EI-MS HRMS(ESI):found 787.1752(C 35H 39N 4O 11S 3.[M+H]+requires 787.1748)。
实施例37：N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(4-((4-甲氧基-N-(2-(三氟甲基磺酰胺基)-2-氧乙基)苯基)磺酰胺基)吲哚-1-基)-2-(3-甲氧基苯基)乙酰胺(S37)
Figure PCTCN2020117584-appb-000049
S37的合成与实施例35相同，将环丙烷磺酰胺替换为三氟甲基磺酰胺，得到白色固体87.0mg，产率为46％； 1H NMR(300MHz,DMSO-d 6)δ12.71(s,1H),12.21(s,1H),7.61(t,J＝10.7Hz,3H),7.26(d,J＝8.8Hz,2H),7.07(d,J＝8.6Hz,2H),6.91(s,4H),6.85-6.72(m,2H),6.20(d,J＝7.9Hz,1H),6.04(d,J＝7.9Hz,1H),5.79(s,1H),4.15(s,2H),4.00(s,2H),3.85(s,3H),3.74(s,3H),3.66(s,3H),3.20(s,1H),2.85(d,J＝26.5Hz,1H),2.36(s,3H)；EI-MS HRMS(ESI):found 863.1298(C 35H 35F 3N 4NaO 11S 3.[M+Na]+requires 863.1308)。
实施例38：N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(4-((4-甲氧基-N-(2-氧代-2-(吡啶-3-磺酰胺基)-2-乙基)苯基)磺酰胺基)吲哚-1-基)-2-(3-甲氧基苯基)乙酰胺(S38)
Figure PCTCN2020117584-appb-000050
S38的合成与实施例35相同，将环丙烷磺酰胺替换为吡啶-3-磺酰胺，得到白色固体76.0mg，产率为44％； 1H NMR(300MHz,DMSO-d 6)δ12.57(s,2H),7.78(d,J＝7.1Hz,1H),7.71-7.66(m,2H),7.52(d,J＝8.9Hz,2H),7.29(t,J＝7.9Hz,1H),7.14-705(m,2H),6.91(s,2H),6.82(dd,J＝15.0,7.5Hz,4H),6.14(d,J＝7.9Hz,2H),6.02(d,J＝8.3Hz,2H),5.01(s,1H),3.91(d,J＝2.9Hz,2H),3.82(s,3H),3.79(s,3H),3.71(s,3H),3.64(s,2H),2.82(s,2H),2.37(s,3H)；EI-MS HRMS(ESI):found 872.1821(C 39H 39N 5NaO 11S 3.[M+Na]+requires 872.1825)。
实施例39：N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(4-((4-甲氧基-N-(2-氧代-2-(噻吩-3-磺酰胺基)-2-乙基)苯基)磺酰胺基)吲哚-1-基)-2-(3-甲氧基苯基)乙酰胺(S39)
Figure PCTCN2020117584-appb-000051
S39的合成与实施例35相同，将环丙烷磺酰胺替换为噻吩-2-磺酰胺，得到白色固体66.0mg，产率为43％； 1H NMR(300MHz,DMSO-d 6)δ12.49(s,2H),7.93(d,J＝8.2Hz,3H),7.69(t,J＝7.6Hz,2H),7.38(d,J＝8.4Hz,2H),7.10(dd,J＝15.8,8.8Hz,4H),6.99(t,J＝8.3Hz,3H),6.21(d,J＝7.8Hz,1H),6.14(d,J＝8.6Hz,2H),4.99(s,1H),3.98(d,J＝3.9Hz,1H),3.87(s,3H),3.73(s,3H),3.69(s,3H),3.22(s,1H),2.87(d,J＝8.5Hz,2H),2.66-2.56(m,1H),2.32(s,3H)；EI-MS HRMS(ESI):found 877.1453(C 38H 38N 4NaO 11S 4.[M+Na]+requires 877.1464)。
实施例40：N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(4-((4-甲氧基-N-((4-甲氧基苯基)-2-氧乙基)苯基)磺酰胺基)吲哚-1-基)-2-(3-甲氧基苯基)乙酰胺(S40)
Figure PCTCN2020117584-appb-000052
S40的合成与实施例35相同，将环丙烷磺酰胺替换为4-甲氧基苯磺酰胺，得到白色固体256.0mg，产率为53％； 1H NMR(300MHz,DMSO-d 6)δ12.21(s,2H),7.63(d,J＝7.6Hz,1H),7.56(dd,J＝8.8,3.1Hz,4H),7.26(s,1H),7.03(d,J＝8.5Hz,2H),6.96-6.83(m,6H),6.75(d,J＝9.5Hz,2H),6.18(d,J＝7.8Hz,2H),5.94(d,J＝8.2Hz,1H),4.83(s,1H),4.45(s,1H),3.86(s,1H),3.84(s,3H),3.79(d,J＝2.1Hz,3H),3.73(s,3H),3.65(s,3H),3.19(d,J＝3.9Hz,1H),2.80(s,2H),2.35(s,3H)；EI-MS HRMS(ESI):found 901.1841(C 41H 42N 4NaO 12S 3.[M+Na]+requires 901.1853)。
实施例41：N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(4-((4-甲氧基-N-((4-甲基苯基)-2-氧乙基) 苯基)磺酰胺基)吲哚-1-基)-2-(3-甲氧基苯基)乙酰胺(S41)
Figure PCTCN2020117584-appb-000053
S41的合成与实施例35相同，将环丙烷磺酰胺替换为4-甲基苯磺酰胺，得到白色固体124.0mg，产率为48％； 1H NMR(300MHz,DMSO-d 6)δ12.41(s,2H),7.83(d,J＝7.9Hz,1H),7.66(dd,J＝8.6,4.1Hz,3H),7.36(s,1H),7.23(d,J＝8.7Hz,2H),7.06–6.93(m,5H),6.79(d,J＝9.9Hz,3H),6.48(d,J＝7.8Hz,3H),5.94(d,J＝8.2Hz,2H),4.93(s,1H),4.46(s,1H),3.96(s,1H),3.85(s,3H),3.79(d,J＝2.1Hz,3H),3.73(s,3H),3.19(d,J＝3.9Hz,1H),2.88(s,2H),2.35(s,6H)；EI-MS HRMS(ESI):found 885.1894(C 41H 42N 4NaO 11S 3.[M+Na]+requires 885.1904)。
实施例42：2-(4-((N-(2-(((4-氟苯基)磺酰胺基)-2-氧代乙基)-4-甲氧基苯基)磺酰胺基)吲哚-1-基)-N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(3-甲氧基苯基)乙酰胺(S42)
Figure PCTCN2020117584-appb-000054
S42的合成与实施例35相同，将环丙烷磺酰胺替换为4-氟苯磺酰胺，得到白色固体78.0mg，产率为43％； 1H NMR(300MHz,DMSO-d 6)δ12.41(s,1H),9.41(s,1H),7.63(t,J＝7.1Hz,3H),7.56(d,J＝8.5Hz,2H),7.26(d,J＝8.0Hz,1H),7.15(t,J＝8.9Hz,2H),7.03(d,J＝8.5Hz,2H),6.91(s,4H),6.82-6.67(m,2H),6.19(d,J＝8.7Hz,1H),5.93(d,J＝8.1Hz,1H),4.83(s,1H),3.91(s,1H),3.85(d,J＝2.4Hz,3H),3.80(d,J＝11.4Hz,1H),3.74(s,3H),3.67(s,3H),2.82(s,2H),2.35(d,J＝6.4Hz,3H)；EI-MS HRMS(ESI):found 889.1651(C 40H 39N 4NaO 11S 3.[M+Na]+requires 889.1653)。
实施例43：N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(4-((4-甲氧基-N-((4-乙基苯基)-2-氧乙基)苯基)磺酰胺基)吲哚-1-基)-2-(3-甲氧基苯基)乙酰胺(S43)
Figure PCTCN2020117584-appb-000055
S43的合成与实施例35相同，将环丙烷磺酰胺替换为4-氟苯磺酰胺，得到白色固体67.0mg，产率为44％； 1H NMR(300MHz,DMSO-d 6)δ12.41(s,2H),7.68(d,J＝7.8Hz,1H),7.54(dd,J＝8.6,3.1Hz,3H),7.23(s,1H),7.13(d,J＝8.5Hz,3H),6.95-6.82(m,6H),6.72(d,J＝9.5Hz,2H),6.28(d,J＝7.8Hz,2H),5.95(d,J＝8.2Hz,1H),4.83(s,1H),4.42(s,1H),3.88(s,1H),3.84(s,3H),3.72(s,3H),3.66(s,3H),3.16(d,J＝3.9Hz,1H),2.82(s,2H),2.36(s,3H)； EI-MS HRMS(ESI):found 939.1741(C 41H 39N 4NaO 11S 3.[M+Na] +requires 939.1743)。
实施例44：N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(4-((4-甲氧基-N-((4-乙基苯基)-2-氧乙基)苯基)磺酰胺基)吲哚-1-基)-2-(3-甲氧基苯基)乙酰胺(S44)
Figure PCTCN2020117584-appb-000056
S44的合成与实施例35相同，将环丙烷磺酰胺替换为4-乙基苯磺酰胺，得到白色固体98.0mg，产率为45％； 1H NMR(300MHz,DMSO-d 6)δ12.51(s,2H),8.23(d,J＝7.3Hz,2H),8.16(dd,J＝8.6,4.1Hz,2H),7.86(s,1H),7.73(d,J＝8.7Hz,2H),7.56-7.47(m,5H),7.19(d,J＝9.7Hz,3H),6.88(d,J＝7.8Hz,2H),6.34(d,J＝8.2Hz,2H),4.99(s,1H),4.56(s,1H),4.02-4.09(m,2H),3.96(s,1H),3.85(s,3H),3.77(d,J＝2.1Hz,3H),3.72(s,3H),3.19(d,J＝3.9Hz,1H),2.88(s,2H),2.35(s,3H),1.34-1.25(m,3H)；EI-MS HRMS(ESI):found 899.2054(C 42H 44N 4NaO 11S 3.[M+Na]+requires 899.2060)。
实施例45：2-(4-((N-(2-(((4-羟基苯基)磺酰胺基)-2-氧代乙基)-4-甲氧基苯基)磺酰胺基)吲哚-1-基)-N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(3-甲氧基苯基)乙酰胺(S45)
Figure PCTCN2020117584-appb-000057
S45的合成与实施例35相同，将环丙烷磺酰胺替换为4-羟基苯磺酰胺，得到白色固体64.0mg，产率为45％； 1H NMR(300MHz,DMSO-d 6)δ12.62(s,2H),10.02(s,1H),8.11(d,J＝7.6Hz,2H),8.15(dd,J＝8.6,4.1Hz,2H),7.76(s,1H),7.70(d,J＝8.7Hz,2H),7.59-7.48(m,5H),7.18(d,J＝7.7Hz,3H),6.99(d,J＝7.8Hz,2H),6.64(d,J＝8.2Hz,2H),4.95(s,1H),4.58(s,1H),3.90(s,1H),3.85(s,3H),3.79(d,J＝2.1Hz,3H),3.74(s,3H),3.19(d,J＝3.9Hz,1H),2.86(s,2H),2.34(s,3H)；EI-MS HRMS(ESI):found 887.1862(C 42H 44N 4NaO 11S 3.[M+Na]+requires 887.1864)。
实施例46：2-(4-((N-(2-(((4-乙氧基苯基)磺酰胺基)-2-氧代乙基)-4-甲氧基苯基)磺酰胺基)吲哚-1-基)-N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(3-甲氧基苯基)乙酰胺(S46)
Figure PCTCN2020117584-appb-000058
S46的合成与实施例35相同，将环丙烷磺酰胺替换为4-乙氧基苯磺酰胺，得到白色固体 47.0mg，产率为42％； 1H NMR(300MHz,DMSO-d 6)δ12.51(s,2H),8.13(d,J＝8.6Hz,2H),8.05(dd,J＝8.4,4.3Hz,2H),7.86(s,1H),7.78(d,J＝8.5Hz,2H),7.58-7.48(m,4H),7.18(d,J＝7.7Hz,3H),6.99(d,J＝7.8Hz,3H),6.65(d,J＝8.2Hz,2H),4.97(s,1H),4.57(s,1H),4.04-4.08(m,2H),3.91(s,1H),3.88(s,3H),3.76(s,3H),3.74(s,3H),3.23(d,J＝3.9Hz,1H),2.86(s,2H),2.34(s,3H),1.40-1.46(m,3H)；EI-MS HRMS(ESI):found 915.2131(C 42H 44N 4NaO 12S 3.[M+Na]+requires 915.2134)。
实施例47：2-(4-((N-(2-(((2-甲氧基苯基)磺酰胺基)-2-氧代乙基)-4-甲氧基苯基)磺酰胺基)吲哚-1-基)-N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(3-甲氧基苯基)乙酰胺(S47)
Figure PCTCN2020117584-appb-000059
S47的合成与实施例35相同，将环丙烷磺酰胺替换为2-甲氧基苯磺酰胺，得到白色固体112.0mg，产率为42％； 1H NMR(300MHz,DMSO-d 6)δ12.27(s,1H),9.10(s,1H),7.71-7.49(m,3H),7.36(dd,J＝17.6,8.5Hz,3H),7.06(dd,J＝17.8,8.3Hz,5H),6.89(d,J＝18.4Hz,6H),6.27-5.89(m,2H),4.02(d,J＝12.9Hz,1H),3.88-3.82(m,3H),3.79-3.71(m,3H),3.68(t,J＝5.8Hz,3H),3.64-3.52(m,3H),2.34(d,J＝14.0Hz,3H)；EI-MS HRMS(ESI):found 879.2031(C 4H 43N 4O 12S 3.[M+H]+requires 879.2034)。
实施例48：2-(4-((N-(2-(((3-甲氧基苯基)磺酰胺基)-2-氧代乙基)-4-甲氧基苯基)磺酰胺基)吲哚-1-基)-N-(((2-甲氧基-4-甲基苯基)磺酰基)-2-(3-甲氧基苯基)乙酰胺(S48)
Figure PCTCN2020117584-appb-000060
S48的合成与实施例35相同，将环丙烷磺酰胺替换为3-甲氧基苯磺酰胺，得到白色固体125.0mg，产率为42％； 1H NMR(300MHz,DMSO-d 6)δ12.65(s,1H),12.21(s,1H),7.84(dd,J＝8.8,3.1Hz,4H),7.66(d,J＝8.8Hz,4H),7.46(s,1H),7.23(d,J＝8.7Hz,2H),6.90-6.80(m,6H),6.77(d,J＝9.5Hz,2H),6.19(d,J＝3.8Hz,2H),5.97(d,J＝8.2Hz,1H),4.83(s,1H),4.47(s,1H),3.88(s,1H),3.82(s,3H),3.79(s,3H),3.73(s,3H),3.66(s,3H),3.23(d,J＝3.9Hz,1H),2.88(s,2H),2.34(s,3H)；EI-MS HRMS(ESI):found 879.2031(C 4H 43N 4O 12S 3.[M+H]+requires 879.2034)。
二、化合物部分药理学实验及结果
1、基于荧光偏振的Keap1-Nrf2蛋白-蛋白相互作用抑制实验(FP实验)
FP实验所使用的仪器是SpectraMax Multi-Mode Microplate Reader(Molecular Devices)，根据相应荧光基团选择仪器的激发光和发射光的波长。使用Corning 3676 384孔板进行实验工作，孔板的反应体系为40μL。其中实验组包含10μL的4nM FITC-9mer Nrf2多肽荧光探针，10μL的12nM Keap1 Kelch结构域蛋白溶液和20μL相应浓度的抑制剂；阳性对照采用20μL 100nM CPUY192002+10μL探针+10μL蛋白溶液；阴性对照为10μL探针+10μL蛋白溶液+20μL HEPES缓冲液；空白对照为10μL探针+30μL HEPES缓冲液。在测试前预先在室温下混匀、孵育30分钟。本实验中探针荧光基团为荧光素，其激发光波长为485nm，发 射光波长为535nm，使用水平方向和垂直方向的荧光强度(F║和F ┴)计算毫偏值(mP)反应偏振光的变化情况。抑制剂在某浓度下的抑制率计算方法为：
抑制率％＝(1-(P obs-P min)/(P max-P min))×100％。
P max、P min和P obs分别代表Keap1和荧光探针孔的偏振值、荧光探针孔的偏振值以及含有抑制剂孔的偏振值。使用抑制剂的浓度-抑制率曲线计算化合物的IC 50。
采用基于荧光偏振的Keap1-Nrf2 PPI竞争性抑制实验(FP实验)对化合物S1-S5进行靶标活性测试，结果如表1所示。
表1化合物S1-S5 IC 50值
Figure PCTCN2020117584-appb-000061
采用基于荧光偏振的Keap1-Nrf2 PPI竞争性抑制实验(FP实验)对化合物S6-S26进行靶标活性测试，结果如表2所示。
表2化合物S6-S26 IC 50值
Figure PCTCN2020117584-appb-000062
采用基于荧光偏振的Keap1-Nrf2 PPI竞争性抑制实验(FP实验)对化合物S27-S34进行靶标活性测试，结果如表3所示。
表3化合物S27-S34 IC 50值
Figure PCTCN2020117584-appb-000063
采用基于荧光偏振的Keap1-Nrf2 PPI竞争性抑制实验(FP实验)对化合物S35-S39进行靶标活性测试，结果如表4所示。
表4化合物S35-S39 IC 50值
Figure PCTCN2020117584-appb-000064
采用基于荧光偏振的Keap1-Nrf2 PPI竞争性抑制实验(FP实验)对化合物S40-S48进行靶标活性测试，结果如表5所示。
表5化合物S40-S48 IC 50值
Figure PCTCN2020117584-appb-000065
其中，化合物S40在体外靶点实验(FP实验)中表现出优异的抑制活性。
2、化合物S40对LPS诱导H9c2细胞产生炎症因子的影响
Nrf2激活后，可通过缓解细胞内的炎症反应来保护细胞免受LPS诱导损伤，因此检测化合物S40对LPS诱导炎症因子产生的影响，选择IL-1β、IL-6和TNF-α这几个常见的炎症因子作为反应化合物在细胞层面抗炎作用的指标。IL-1β、IL-6、和TNF-α表达量使用如下试剂盒测定：IL-1β(IL-1βELISA kit,EK0393,Boster)，IL-6(IL-6 ELISA kit,EK0412,Boster)，TNF-α(TNF-αELISA kit,EK0526,Boster)。H9c2细胞用10μM化合物S40预作用12h后，加入1μg/mL LPS继续培养12h，进行炎症因子(A)IL-1β、(B)IL-6和(C)TNF-α的比值测定。
结果如图1所示，LPS可显著升高细胞炎症因子的分泌，而10μM化合物S40预作用后， 可显著降低炎症因子的含量。
3、化合物S40在LPS诱导的小鼠炎症模型中抗炎作用考察
将雄性C57BL/6小鼠(6-8周龄，18-22g/只)随机分为四组：空白对照组、模型(LPS:10mg/kg)对照组、化合物S40高剂量(40mg/kg)组和化合物S40低剂量(10mg/kg)组，每组8只小鼠。化合物组以给定剂量接受预防性腹腔注射给药3天，空白对照组和模型对照组腹腔注射给与等量的生理盐水。然后模型对照组和化合物组腹腔注射LPS(15mg/kg)，空白对照组给与等量生理盐水，10h后处死小鼠，经眼球取血及取出心脏进行后续检测。通过Elisa方法测试了各组小鼠血清中的炎症因子(IL-6、IL-1β、TNF-α)含量。
结果如图2所示。可以看出，与空白对照组小鼠相比，模型对照组小鼠血清中的炎症因子显著上调。S40 10mg/kg和40mg/kg均可以剂量依赖性的下调小鼠血清中炎症因子IL-6、IL-1β、TNF-α的含量。由以上结果分析可得出，化合物S40可以通过下调血清中的炎症因子发挥抗炎效果。
吲哚啉化合物在FP实验中均能有效地抑制Keap1-Nrf2相互作用。进一步地，又验证化合物S40降低LPS诱导H9c2心肌细胞产生的炎症因子水平。体内小鼠炎症模型研究中，化合物S40可通过显著降低小鼠血清中炎症因子的产生。
本发明提供一类活性好、结构新颖并更具成药性潜力的吲哚啉类Keap1-Nrf2 PPI小分子抑制剂，可以干扰Keap1-Nrf2相互作用，激活Nrf2及下游因子，降低细胞炎症因子和增强细胞抗氧化能力，从而减轻炎性损伤，具有潜在的抗炎活性，可用于制备成抗炎药物用于众多炎症相关疾病的炎性损伤，包括心肌炎，慢性阻塞性肺疾病(COPD)、阿尔茨海默症、帕金森、动脉粥样硬化、慢性肾脏疾病(CKD)、糖尿病、肠部炎症、类风湿性关节炎等。
上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。

Claims (8)

  1. 一类具有吲哚啉骨架的化合物，其特征在于，化学结构如通式Ⅰ、Ⅱ、Ⅲ、Ⅳ或Ⅴ所示：
    Figure PCTCN2020117584-appb-100001
    其中，通式I中，取代基R为：
    Figure PCTCN2020117584-appb-100002
    通式Ⅱ中，取代基R为：
    Figure PCTCN2020117584-appb-100003
    Figure PCTCN2020117584-appb-100004
    通式Ⅲ中，取代基R为:
    Figure PCTCN2020117584-appb-100005
    通式Ⅳ中，取代基R为：
    Figure PCTCN2020117584-appb-100006
    通式Ⅴ中，取代基R为：
    Figure PCTCN2020117584-appb-100007
  2. 一种制备权利要求1中通式Ⅰ所示化合物的方法，其特征在于，步骤和合成路线如下：
    4-硝基吲哚还原为中间体2，原料3经溴代得到中间体4，中间体2和4在碳酸钾条件下发生亲核取代反应得到中间体5，中间体5在LiOH的作用下脱甲酯得到关键中间体6，中间体6在EDCI和DMAP条件下与取代磺酰胺缩合得到中间体7，中间体7还原硝基得到中间体8，再与2,4,6-均三甲基苯磺酰氯反应得到中间体9，中间体9在碳酸钾的作用下与溴乙酸 甲酯反应得到中间体10，中间体10在LiOH的作用下脱甲酯得到通式Ⅰ化合物；
    Figure PCTCN2020117584-appb-100008
    其中，合成路线中反应参数：(a)NaBH 3CN,TFA,DCM,r.t.2h,75％；(b)NBS,AIBN,CCl 4,80℃,4h,65％；(c)NaH,DMF,r.t.4h,50％；(d)LiOH,MeOH/H 2O,r.t.2h,80％；(e)substituted sulfonamides,EDCI,DMAP,DCM,35℃,2-6h,30-70％；(f)SnCl 2,EA,80℃,4h；(g)pyridine,THF,80℃,4h,30-65％；(h)K 2CO 3,DMF,r.t.4h,58-82％；(i)LiOH,MeOH/H 2O,r.t.2h,60-86％.
  3. 一种制备权利要求1中通式Ⅱ所示化合物的方法，其特征在于，步骤和合成路线如下：
    4-硝基吲哚还原为中间体2，原料3经溴代得到中间体4，中间体2和4在碳酸钾条件下发生亲核取代反应得到中间体5，中间体5在LiOH的作用下脱甲酯得到关键中间体6，中间体6在EDCI和DMAP条件下与取代苯磺酰胺缩合得到中间体11，中间体11还原硝基再与2,4,6-均三甲基苯磺酰氯反应得到中间体12，中间体12在碳酸钾的作用下与溴乙酸甲酯反应得到中间体13，中间体13在LiOH的作用下脱甲酯得到通式Ⅱ化合物；
    Figure PCTCN2020117584-appb-100009
    其中，合成路线中反应参数：(a)NaBH 3CN,TFA,DCM,r.t.2h,75％；(b)NBS,AIBN,CCl 4,80℃,4h,65％；(c)NaH,DMF,r.t.4h,50％；(d)LiOH,MeOH/H 2O,r.t.2h,80％；(e)substituted sulfonamides,EDCI,DMAP,DCM,35℃,2-6h,30-70％；(f)SnCl 2,EA,80℃,4h；(g)pyridine,THF,80℃,4h,30-65％；(h)K 2CO 3,DMF,r.t.4h,58-82％；(i)LiOH,MeOH/H 2O,r.t.2h,60-86％.
  4. 一种制备权利要求1中通式Ⅲ所示化合物的方法，其特征在于，步骤和合成路线如下：
    4-硝基吲哚还原为中间体2，原料3经溴代得到中间体4，中间体2和4在碳酸钾条件下发生亲核取代反应得到中间体5，中间体5在LiOH的作用下脱甲酯得到关键中间体6，中间体6在EDCI和DMAP条件下与4-甲氧基-2甲基苯磺酰胺缩合得到中间体14，中间体14还原硝基再与取代苯磺酰氯反应得到中间体15，中间体15在碳酸钾的作用下与溴乙酸甲酯反应得到中间体16，中间体16在LiOH的作用下脱甲酯得到中间体17，中间体17在EDCI和DMAP条件下与苯磺酰胺缩合得到通式Ⅲ化合物；
    Figure PCTCN2020117584-appb-100010
    其中，合成路线中反应参数：(a)NaBH 3CN,TFA,DCM,r.t.2h,75％；(b)NBS,AIBN,CCl 4,80℃,4h,65％；(c)NaH,DMF,r.t.4h,50％；(d)LiOH,MeOH/H 2O,r.t.2h,80％；(e)substituted sulfonamides,EDCI,DMAP,DCM,35℃,2-6h,30-70％；(f)SnCl 2,EA,80℃,4h；(g)pyridine,THF,80℃,4h,30-65％；(h)K 2CO 3,DMF,r.t.4h,58-82％；(i)LiOH,MeOH/H 2O,r.t.2h,60-86％；(j)EDCI,DMAP,DCM,35℃,2-6h,30-70％.
  5. 一种制备权利要求1中通式Ⅳ所示化合物的方法，其特征在于，步骤和合成路线如下：
    4-硝基吲哚还原为中间体2，原料3经溴代得到中间体4，中间体2和4在碳酸钾条件下发生亲核取代反应得到中间体5，中间体5在LiOH的作用下脱甲酯得到关键中间体6，中间体6在EDCI和DMAP条件下与4-甲氧基-2甲基苯磺酰胺缩合得到中间体14，中间14还原硝基再与4-甲氧基苯磺酰氯反应得到中间体18，中间体18在碳酸钾的作用下与溴乙酸甲酯反应得到中间体19，中间体19在LiOH的作用下脱甲酯得到中间体20，中间体20在EDCI和DMAP条件下与取代磺酰胺缩合得到通式Ⅳ化合物；
    Figure PCTCN2020117584-appb-100011
    其中，合成路线中反应参数：(a)NaBH 3CN,TFA,DCM,r.t.2h,75％；(b)NBS,AIBN,CCl 4,80℃,4h,65％；(c)NaH,DMF,r.t.4h,50％；(d)LiOH,MeOH/H 2O,r.t.2h,80％；(e)substituted sulfonamides,EDCI,DMAP,DCM,35℃,2-6h,30-70％；(f)SnCl 2,EA,80℃,4h；(g)pyridine,THF,80℃,4h,30-65％；(h)K 2CO 3,DMF,r.t.4h,58-82％；(i)LiOH,MeOH/H 2O,r.t.2h,60-86％；(j)EDCI,DMAP,DCM,35℃,2-6h,30-70％.
  6. 一种制备权利要求1中通式Ⅴ所示化合物的方法，其特征在于，步骤和合成路线如下：
    4-硝基吲哚还原为中间体2，原料3经溴代得到中间体4，中间体2和4在碳酸钾条件下发生亲核取代反应得到中间体5，中间体5在LiOH的作用下脱甲酯得到关键中间体6，中间体6在EDCI和DMAP条件下与4-甲氧基-2甲基苯磺酰胺缩合得到中间体14，中间体14还原硝基再与4-甲氧基苯磺酰氯反应得到中间体18，中间体18在碳酸钾的作用下与溴乙酸甲 酯反应得到中间体19，中间体19在LiOH的作用下脱甲酯得到中间体20，中间体20在EDCI和DMAP条件下与取代磺酰胺缩合得到通式Ⅴ化合物；
    Figure PCTCN2020117584-appb-100012
    其中，合成路线中反应参数：(a)NaBH 3CN,TFA,DCM,r.t.2h,75％；(b)NBS,AIBN,CCl 4,80℃,4h,65％；(c)NaH,DMF,r.t.4h,50％；(d)LiOH,MeOH/H 2O,r.t.2h,80％；(e)substituted sulfonamides,EDCI,DMAP,DCM,35℃,2-6h,30-70％；(f)SnCl 2,EA,80℃,4h；(g)pyridine,THF,80℃,4h,30-65％；(h)K 2CO 3,DMF,r.t.4h,58-82％；(i)LiOH,MeOH/H 2O,r.t.2h,60-86％；(j)EDCI,DMAP,DCM,35℃,2-6h,30-70％.
  7. 权利要求1所述的具有吲哚啉骨架的化合物或其药学上可接受的盐用于制备Keap1-Nrf2蛋白-蛋白相互作用抑制剂的用途。
  8. 权利要求1所述的具有吲哚啉骨架的化合物及其药学上可接受的盐用于制备治疗或缓解疾病炎症的药物的用途，所述疾病为炎性疾病或神经退行性疾病，包括心肌炎、慢性阻塞性肺疾病、阿尔茨海默症、帕金森、动脉粥样硬化、慢性肾脏疾病、糖尿病、肠部炎症、类风湿性关节炎。
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