CN115073427B - 吲哚联氮杂环化合物及其合成方法和应用 - Google Patents
吲哚联氮杂环化合物及其合成方法和应用 Download PDFInfo
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- CN115073427B CN115073427B CN202210380012.6A CN202210380012A CN115073427B CN 115073427 B CN115073427 B CN 115073427B CN 202210380012 A CN202210380012 A CN 202210380012A CN 115073427 B CN115073427 B CN 115073427B
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- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title claims abstract description 154
- 150000001875 compounds Chemical class 0.000 title claims abstract description 79
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title claims abstract description 78
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title claims abstract description 78
- 238000001308 synthesis method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 81
- 239000005708 Sodium hypochlorite Substances 0.000 claims abstract description 14
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 12
- 229940126062 Compound A Drugs 0.000 claims abstract description 9
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000002391 heterocyclic compounds Chemical class 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
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- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 10
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003242 anti bacterial agent Substances 0.000 claims description 8
- 241000192125 Firmicutes Species 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 5
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
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- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
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- 230000000844 anti-bacterial effect Effects 0.000 abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 abstract description 5
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 abstract description 5
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 abstract description 5
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- 229940054051 antipsychotic indole derivative Drugs 0.000 abstract 1
- 150000002475 indoles Chemical class 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 119
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- 239000011734 sodium Substances 0.000 description 51
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 239000000460 chlorine Substances 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 22
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- 239000000243 solution Substances 0.000 description 16
- 230000000694 effects Effects 0.000 description 15
- ZFRKQXVRDFCRJG-UHFFFAOYSA-N skatole Chemical compound C1=CC=C2C(C)=CNC2=C1 ZFRKQXVRDFCRJG-UHFFFAOYSA-N 0.000 description 14
- 206010028980 Neoplasm Diseases 0.000 description 11
- 229940125904 compound 1 Drugs 0.000 description 10
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- 229910052736 halogen Inorganic materials 0.000 description 9
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 6
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- -1 N-acetylethylamino, indolylmethyl Chemical group 0.000 description 5
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- 238000002474 experimental method Methods 0.000 description 5
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- 125000000547 substituted alkyl group Chemical group 0.000 description 5
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- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 description 4
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- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 4
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- 238000012360 testing method Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 3
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
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- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1h-indole Chemical group BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 description 2
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- YTYIMDRWPTUAHP-UHFFFAOYSA-N 6-Chloroindole Chemical group ClC1=CC=C2C=CNC2=C1 YTYIMDRWPTUAHP-UHFFFAOYSA-N 0.000 description 2
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明属于有机化学及药物化学领域，具体涉及涉及一类吲哚联氮杂环化合物及其合成方法和在抗肿瘤和抗菌活性的应用。解决了现有的C‑N偶联方法反应条件苛刻的问题。本发明的吲哚联氮杂环化合物的合成方法包括：在次氯酸钠溶液和弱碱的作用下，以化合物A和化合物B为底物反应合成所述吲哚联氮杂环化合物；所述化合物A包括吲哚、吲哚衍生物、色氨酸或含有色氨酸的多肽；所述化合物B包括氮杂环组分、组氨酸或含组氨酸的多肽。本发明的方法具有温和、高效，产率高等显著优点，解决了现有的C‑N偶联方法反应条件苛刻的问题，且通过本发明合成方法合成的部分杂环化合物，具有抗肿瘤和抗菌的效果。
Description
技术领域
本发明涉及有机化学及药物化学领域，具体而言，本发明涉及一类吲哚联氮杂环化合物及其合成方法和在抗肿瘤和抗菌活性的应用。
背景技术
含氮杂环是许多具有重要生物活性的天然有机化合物和合成药物的基本骨架。近些年来,在创新性药物的设计和合成中，含氮杂环往往作为药效的核心单元使用。在工业生产中平均每六个化学转化就会涉及到一个C-N键形成的反应，而通过C-N偶联反应构建含氮杂环衍生物,可以比较容易地获得具有潜在生物活性的先导化合物。
C–N键的构建非常重要，因为它为在有机分子中引入氮原子开辟了新途径。尽管在这一领域取得了重大进展，但由于涉及苛刻的反应条件或在许多情况下会使用昂贵的催化剂，C-N键的构建仍然是有目前有机化学面临的主要挑战。因此，开发更加温和、高效、经济和环境友好的C-N偶联方法是一个挑战。
癌症，又称为恶性肿瘤，它是一种细胞增殖和生长不受控制，最终形成肿瘤组织的疾病。癌症是严重影响全球人类健康的最常见的致命疾病，是严重危害人类健康的主要公共卫生问题之一。随着我国老龄化人口持续增多、工业化和城镇化进程也在不断加快，与慢性感染、严重的环境污染、不良的生活习惯等危险致病因素的不断累加，防癌治癌的形势仍然很严峻。
在许多癌症治疗方法中，无论是单独使用，还是与其他疗法(手术切除疗法或放射性疗法)一起使用，化疗都是应用最广泛的治疗手段。传统化疗通常只具有较低的治疗窗口期而且一般并不是特异性地作用于肿瘤细胞，它们还可以作用于细胞增殖分裂能力较强的其他正常细胞，而这也会致使癌症患者出现危及生命的毒副作用。综上所述，现在急需研发出特异性更强，活性更高，毒副作用更小的抗癌药物。
抗生素的发现和引入改变了人类历史，开启了治疗致命传染病的黄金时代。然而，由于这些药物在人类和动物中持续过度使用，细菌对这些药物产生了耐药性，细菌耐药性的出现并且在微生物中的传播和升级，使得抗感染治疗面临严峻的挑战。目前，抗生素耐药性(AMR)已成为世界卫生组织(WHO)报告的三大公共卫生威胁之一，研发新型高效的抗菌药对于抵抗日益严重的耐药性具有重要意义。
发明内容
针对以上问题，本发明的目的在于提供一类吲哚联氮杂环化合物。
本发明的吲哚联氮杂环化合物，具有结构Ⅰ，所述结构Ⅰ的通式为
其中X,Y,Z表示碳或氮原子，R1任意选自卤素、C1-C6的烷基、C1-C6取代烷基、氨基酸及寡肽；R2任意选自氢、卤素、C1-C6的烷基、烷氧基、C1-C6取代烷基；R3任意选自氢、卤素、氨基酸及寡肽；R4任意选自氢、卤素、C1-C6的烷基。
本发明中，卤素指氟、氯、溴、碘；本发明中优选氯。
本发明中，取代烷基指含有取代基的烷基，优选三氟甲基、N-乙酰基乙胺基、吲哚基甲基、N,N二甲基乙基、恶唑啉酮基甲基。
优选的，本发明吲哚联氮杂环化合物，
其中，R1为氯，或R1为甲基，或R1任意选自三氟甲基、N-乙酰基乙胺基、吲哚基甲基、N,N二甲基乙基，或R1为色氨酸或包含色氨酸的寡肽；
或者，R2为氯，R2为氢，或R2为甲基，或R2为甲氧基或苄氧基，或R2为恶唑啉酮基甲基；
或者，R3为溴，或R3为氢，或R3为组氨酸或包含组氨酸的寡肽；
或者，R4为氯，或R4为氢，或R4为甲基。
优选的，所述的吲哚联氮杂环化合物为如下化合物1-化合物57中的任一种：
本发明的再一目的在于针对目前现有方法的缺点与不足，提供了一种温和、高效合成上述吲哚联氮杂环化合物的合成方法。本发明的吲哚联氮杂环化合物的合成方法包括：在次氯酸钠溶液和弱碱的作用下，以化合物A和化合物B为底物反应合成所述吲哚联氮杂环化合物；
所述化合物A为
其中，R1任意选自卤素、C1-C6的烷基、C1-C6取代烷基；R2任意选自氢、卤素、C1-C6的烷基、烷氧基、C1-C6取代烷基；
或者，所述化合物A为氨基酸或寡肽。
所述化合物B为
其中，X,Y,Z表示碳或氮原子，R3任意选自氢、卤素；R4任意选自氢、卤素、C1-C6的烷基；
或者，所述化合物B为氨基酸或寡肽。
优选的，所述化合物A、化合物B、次氯酸钠的摩尔比为1：0.5-2：0.5-5，所述弱碱与所述化合物B的摩尔比为1:0.5-2。
优选的，所述弱碱为碳酸氢钠、碳酸钠，碳酸铯、三乙胺中的一种。
有机溶剂能够提高底物的分散性，所以为了进一步提高反应效率，将弱碱溶于有机溶剂中。所述的合成方法包括：将化合物A与化合物B混合，得到第一混合体系，向所述第一混合体系中加入溶于有机溶剂的弱碱并搅拌，得到第二混合体系；向所述第二混合体系中加入次氯酸钠溶液继续搅拌反应,得到含有所述吲哚联氮杂环化合物的第三混合体系；所述合成方法的反应式为：
优选的，所述合成方法的反应的温度为0℃-80℃；向所述第二混合体系中加入次氯酸钠溶液之后搅拌反应的时间为1-6h；
所述有机溶剂为非质子性溶剂，且所述有机溶剂为乙腈、二氯甲烷、N，N二甲基甲酰胺中的一种；
所述合成方法还包括从所述第三混合体系中分离纯化得到所述吲哚联氮杂环化合物，所述分离纯化方法包括减压蒸馏、萃取、干燥、过滤、柱层析分离提纯。
本发明的再一目的在于提供上述吲哚联氮杂环化合物的应用。
所述应用包括：
所述吲哚联氮杂环化合物在制备抗肿瘤药物中的应用；
或者，所述的吲哚联氮杂环化合物在制备抗菌剂中的应用。
本发明中，肿瘤指恶性肿瘤。
进一步所述应用包括：
所述的吲哚联氮杂环化合物在制备抗肺癌肿瘤药物中的应用；或者，所述的吲哚联氮杂环化合物在制备针对革兰氏阳性菌和革兰氏阴性菌的抗菌剂的应用，所述革兰氏阳性菌包括：金黄色葡萄球菌；革兰氏阴性菌包括：大肠杆菌、鲍曼不动杆菌、铜绿假单胞菌。
进一步所述应用包括：
所述化合物1-6、8、9、11、12、13、15、17、18、21-35、37、38、40-43、45、46、51-54、57在制备抗肺腺癌细胞株A549的药物中的应用；
所述化合物1-6、8、9、11-13、15、17、18、21-43、45-49、51-55、57在制备抗肺腺癌细胞株NCI-H1975的药物中的应用；
所述化合物2、3、5、6、15、18、21、22、23、24、25.26、27、29、30、32、33、34、37在制备抑制革兰氏阳性菌的抗菌剂的应用；
所述化合物为6、8、15、21、22、23、24、25、26在制备抑制革兰氏阴性菌的抗菌剂的应用。
本发明的有益效果：
本发明采用价廉易得的吲哚及其衍生物和氮杂环为原料，在次氯酸钠的作用下，吲哚及其衍生物先通过亲电氯化生成亚胺中间体，再在弱碱的作用下，含氮杂环去质子化，亲核进攻亚胺中间体得到目标产物。本发明的方法具有温和、高效，产率高等显著优点；克服了传统方法中条件剧烈，反应时间长等缺点；该方法所用原料绿色、经济，不涉及金属催化剂，对环境友好，符合绿色化学的理念；发明的合成方法，底物兼容性好，不仅可以与不同的氮杂环及其衍生物反应，还可以对药物直接进行后期修饰改造，以及对组氨酸、色氨酸及其多肽进行化学修饰，极大地丰富了此类化合物库；
通过体外癌细胞抑制试验表明，本发明所述的化合物对人肺腺癌细胞(A549，NCI-H1975)有显著抑制作用，其中化合物2对A549的IC50为4.76，化合物21对NCI-H1975的IC50为1.17μmol，表明该化合物具有良好的抗癌效果。
通过体外抗菌试验表明，本发明所述的化合物对革兰氏阳性菌(S.aureusATCC25923)有显著抑制作用，其中化合物29的MIC为2μg/mL，表明该化合物具有良好的抗菌效果。
本发明涉及的新型化合物在抗癌、抗菌中的用途属于首次公开，而且骨架类型属于全新骨架类型，具备突出的实质性特点，为新型抗肿瘤和抗菌药物开辟了新的发展空间。
附图说明
图1为实验例1中本发明化合物对细胞株A549细胞活性影响的结果图；
图2为实验例1中本发明化合物对细胞株NCI-H1975细胞活性影响的结果图。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
以下结合具体实施例及附图对本发明的技术方案作进一步详细的描述，但本发明的保护范围及实施方式不限于此。
本发明公开的化合物，可由市售的起始原料与本发明公开的内容一起合成。
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道商购买得到的常规产品。
实施例1化合物1的合成
称取0.10mmol 3-甲基吲哚、0.20mmol咪唑置于干净的反应管中、加入2.0mL含有0.20mmol碳酸氢钠的乙腈溶液，搅拌至吲哚组分和氮杂环组分充分溶解，最后加入0.3mmol次氯酸钠溶液，在25℃环境下搅拌1h；停止搅拌，减压浓缩，用二氯甲烷萃取两次，合并有机相并使用无水硫酸镁干燥，过滤，再次减压浓缩，最后通过柱层析分离纯化，柱层析分离提纯条件为：石油醚：乙酸乙酯＝(0.5-20):1或者二氯甲烷：甲醇＝(20-80)：1。
得到目标产物，产率为90％。所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.54(s,1H),7.87(s,J＝1.4Hz,1H),7.57–7.48(m,2H),7.43(td,J＝7.6,1.5Hz,1H),7.32(td,J＝7.5,1.3Hz,1H),7.23(t,J＝1.1Hz,1H),2.04(s,3H).13C NMR(75MHz,Chloroform-d)δ164.5,149.3,139.5,136.2,130.8,130.6,127.0,122.0,120.9,117.0,66.1,27.2.HRMS(ESI)found:m/z 254.0456,[M+Na]+calcd.for C12H10ClN3Na+254.0455.
实施例2化合物2的合成
本实施例中将实施例1中的吲哚组分换为5-溴-3-甲基吲哚，搅拌时长6h，其他参数及反应条件同实施例1，产率为61％，所得目标产物的化学表征信息如下所示:1H NMR(300MHz,CDCl3)δ8.49(t,J＝1.0Hz,1H),7.82(t,J＝1.4Hz,1H),7.61(d,J＝1.9Hz,1H),7.55(dd,J＝8.2,2.0Hz,1H),7.38(d,J＝8.2Hz,1H),7.25–7.17(m,1H),2.03(s,3H).13CNMR(75MHz,CDCl3)δ164.6,148.3,141.4,136.2,133.6,131.0,125.5,122.3,120.2,116.9,65.7,27.1.HRMS(ESI)found:m/z 331.9557,[M+Na]+calcd.for C12H9BrClN3Na+331.9561.
实施例3化合物3的合成
本实施例中将实施例1中的吲哚组分换为5-氯-3-甲基吲哚，搅拌时长6h，其他参数及反应条件同实施例1，产率为42％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.49(t,J＝1.1Hz,1H),7.82(t,J＝1.5Hz,1H),7.49–7.41(m,2H),7.38(dd,J＝8.2,2.0Hz,1H),7.22(dd,J＝1.7,0.8Hz,1H),2.03(s,3H).13C NMR(75MHz,CDCl3)δ164.6,147.8,141.1,136.2,132.6,131.0,130.7,122.7,121.9,116.9,65.8,27.1.HRMS(ESI)found:m/z 288.0062,[M+Na]+calcd.for C12H9Cl2N3Na+288.0066
实施例4化合物4的合成
本实施例中将实施例1中的吲哚组分换为5-氟-3-甲基吲哚，搅拌时长6h，其他参数及反应条件同实施例1，产率为55％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.53(t,J＝1.0Hz,1H),7.84(t,J＝1.5Hz,1H),7.48(dd,J＝8.5,4.5Hz,1H),7.29–7.19(m,2H),7.12(td,J＝8.8,2.6Hz,1H),2.04(s,3H).13C NMR(75MHz,CDCl3)δ164.3,163.4,160.1,145.1,141.4,141.2,136.1,130.7,122.1,122.0,117.4,117.0,116.9,110.3,65.8,27.1.19F NMR(282MHz,CDCl3)δ-113.36(ddd,J＝9.1,7.4,4.5Hz).HRMS(ESI)found:m/z 272.0359,[M+Na]+calcd.for C12H9ClFN3Na+272.0361.
实施例5化合物5的合成
本实施例中将实施例1中的吲哚组分换为6-溴-3-甲基吲哚，搅拌时长2h，其他参数及反应条件同实施例1，产率为89％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.52(s,1H),7.84(s,1H),7.67(d,J＝1.7Hz,1H),7.50–7.40(m,1H),7.37(d,J＝8.0Hz,1H),7.24(s,1H),2.03(s,3H).13C NMR(75MHz,CDCl3)δ165.5,150.7,138.4,136.2,131.0,129.8,124.4,124.1,123.2,117.0,65.7,27.1.HRMS(ESI)found:m/z 331.9554,[M+Na]+calcd.for C12H9BrClN3Na+331.9561.
实施例6化合物6的合成
本实施例中将实施例1中的吲哚组分换为6-氯-3-甲基吲哚，搅拌时长2h，其他参数及反应条件同实施例1，产率为71％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.52(d,J＝1.2Hz,1H),7.84(t,J＝1.3Hz,1H),7.52(d,J＝1.7Hz,1H),7.44(d,J＝8.0Hz,1H),7.34–7.27(m,1H),7.26–7.19(m,1H),2.04(s,3H).13CNMR(75MHz,CDCl3)δ165.7,150.6,137.9,136.3,136.3,131.0,126.90,122.9,121.5,117.0,65.7,27.2.HRMS(ESI)found:m/z288.0061,[M+Na]+calcd.for C12H9Cl2N3Na+288.0066.
实施例7化合物7的合成
本实施例中将实施例1中的氮杂环组分换为吡唑，搅拌时长1.5h，其他参数及反应条件同实施例1，产率为76％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.48(d,J＝2.8Hz,1H),7.88(d,J＝1.6Hz,1H),7.56–7.44(m,2H),7.40(td,J＝7.7,1.3Hz,1H),7.33–7.22(m,1H),6.54(dd,J＝2.8,1.6Hz,1H),2.26(s,3H).13C NMR(75MHz,CDCl3)δ166.7,149.6,144.0,140.3,130.2,129.4,126.5,122.0,120.5,109.1,67.0,26.4.HRMS(ESI)found:m/z 254.0454,[M+Na]+calcd.for C12H10ClN3Na+254.0455.
实施例8化合物8的合成
本实施例中将实施例1中的氮杂环组分换为吲唑，其他参数及反应条件同实施例1，产率为61％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.97(s,1H),7.78(d,J＝8.9Hz,1H),7.68(d,J＝8.6Hz,1H),7.56(dd,J＝12.0,7.5Hz,2H),7.47–7.38(m,1H),7.38–7.26(m,2H),7.11(dd,J＝8.5,6.5Hz,1H),2.37(d,J＝1.5Hz,3H).13C NMR(75MHz,CDCl3)δ167.7,151.3,149.3,140.9,130.2,128.5,127.2,124.1,122.8,122.2,122.1,121.6,120.9,118.9,67.1,26.5.HRMS(ESI)found:m/z 304.0607,[M+Na]+calcd.for C16H12ClN3Na+304.0612.
实施例9化合物9的合成
本实施例中将实施例1中的氮杂环组分换为苯并咪唑，其他参数及反应条件同实施例1，产率为99％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.93(s,1H),8.72(m,1H),7.89(dd,J＝7.4,1.5Hz,1H),7.61(d,J＝7.7Hz,1H),7.56–7.38(m,4H),7.34–7.26(m,1H),2.11(s,3H).13C NMR(75MHz,CDCl3)δ165.1,150.1,143.5,140.4,138.9,132.3,130.6,126.6,125.6,125.0,121.9,120.9,120.4,116.6,66.9,27.8.HRMS(ESI)found:m/z 282.0780,[M+H]+calcd.forC16H13ClN3282.0793.
实施例10化合物10的合成
本实施例中将实施例1中的氮杂环组分换为1,2,3-三氮唑，搅拌时长2h，其他参数及反应条件同实施例1，产率为86％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.55(d,J＝1.3Hz,1H),7.87(d,J＝1.3Hz,1H),7.58(ddd,J＝6.8,5.2,1.3Hz,2H),7.43(m,J＝20.4,1.2Hz,2H),2.31(s,3H).13C NMR(75MHz,CDCl3)δ165.1,148.7,140.5,133.8,130.4,127.9,122.7,122.3,121.6,66.8,26.0.HRMS(ESI)found:m/z 255.0408,[M+Na]+calcd.for C11H9ClN4Na+255.0408.
实施例11化合物11的合成
本实施例中将实施例1中的氮杂环组分换为1,2,4-三氮唑，搅拌时长2h，其他参数及反应条件同实施例1，产率为80％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ9.15(s,1H),8.21(s,1H),7.57–7.47(m,2H),7.45(td,J＝7.5,1.4Hz,1H),7.36(td,J＝7.5,1.2Hz,1H),2.23(s,3H).13C NMR(75MHz,CDCl3)δ164.7,153.6,148.9,143.9,140.1,130.4,127.5,122.2,121.3,66.9,25.6.HRMS(ESI)found:m/z255.0406,[M+Na]+calcd.for C11H9ClN4Na+255.0408.
实施例12化合物12的合成
本实施例中将实施例1中的氮杂环组分换为3H-咪唑并[4,5-b]吡啶，搅拌时长3h，其他参数及反应条件同实施例1，产率为62％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ9.13(s,1H),8.64(d,J＝4.8Hz,1H),8.25–8.02(m,1H),7.71(d,J＝7.6Hz,1H),7.53(d,J＝7.4Hz,1H),7.48–7.38(m,2H),7.38–7.30(m,1H),2.25(s,3H).13C NMR(75MHz,CDCl3)δ164.7,149.4,146.1,142.3,139.4,135.9,130.4,128.8,127.2,124.2,121.9,121.8,120.4,67.8,26.4.HRMS(ESI)found:m/z 305.0555,[M+Na]+calcd.for C15H11ClN4Na+305.0564.
实施例13化合物13的合成
本实施例中将实施例1中的氮杂环组分换为苯并三氮唑，其他参数及反应条件同实施例1，产率为98％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.67(dt,J＝8.3,1.0Hz,1H),8.19(dt,J＝8.3,1.0Hz,1H),7.72(ddd,J＝8.3,7.1,1.1Hz,1H),7.67–7.61(m,1H),7.61–7.51(m,2H),7.46(td,J＝7.6,1.4Hz,1H),7.36(td,J＝7.5,1.1Hz,1H),2.40(s,3H).13C NMR(75MHz,CDCl3)δ166.4,149.8,145.8,139.8,131.8,130.3,130.0,127.2,126.1,122.2,121.3,120.2,115.2,67.7,26.5.HRMS(ESI)found:m/z 305.0554,[M+Na]+calcd.for C15H11ClN4Na+305.0564
实施例14化合物14的合成
本实施例中将实施例1中的氮杂环组分换为4-溴吡唑，搅拌时长2h，其他参数及反应条件同实施例1，产率为76％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.49(d,J＝0.7Hz,1H),7.80(d,J＝0.7Hz,1H),7.51–7.43(m,2H),7.43–7.38(m,1H),7.30(td,J＝7.4,1.3Hz,1H),2.23(s,3H).
13C NMR(75MHz,CDCl3)δ165.8,149.3,144.4,140.3,130.3,129.2,126.8,122.1,120.8,98.6,66.7,26.2.HRMS(ESI)found:m/z 331.9559,[M+Na]+calcd.for C12H9BrClN3Na+331.9561.
实施例15化合物15的合成
本实施例中将实施例1中的吲哚组分换为3-三氟甲基吲哚，其他参数及反应条件同实施例1，产率为51％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.53(s,1H),7.86(s,1H),7.63(d,J＝7.7Hz,1H),7.56(d,J＝7.4Hz,2H),7.38(t,J＝7.1Hz,1H),7.22(s,1H).13C NMR(75MHz,CDCl3)δ158.0,150.9,136.9,132.6,132.2,131.39,130.7,127.6,124.6,121.6,117.9,110.9.19F NMR(282MHz,CDCl3)δ-72.87.HRMS(ESI)found:m/z 286.0351,[M+H]+calcd.for C12H8ClF3N3286.0353
实施例16化合物16的合成
本实施例中将实施例1中的吲哚组分换为褪黑素，其他参数及反应条件同实施例1，产率为37％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.46(s,1H),7.81(d,J＝1.6Hz,1H),7.44(d,J＝8.5Hz,1H),7.19(s,1H),7.04(d,J＝2.4Hz,1H),6.94(dd,J＝8.5,2.5Hz,1H),5.92(t,J＝5.5Hz,1H),3.87(s,3H),3.18–2.93(m,1H),2.73(q,J＝9.4Hz,3H),1.68(s,3H).13C NMR(75MHz,CDCl3)δ170.3,161.9,159.3,143.0,138.7,135.8,130.5,121.7,116.8,115.3,109.3,68.0,55.9,39.5,35.4,22.6.HRMS(ESI)found:m/z 333.1103.,[M+H]+calcd.forC16H18ClN4O2333.1113
实施例17化合物17的合成
本实施例中将实施例1中的吲哚组分换为褪黑素，氮杂环组分换为苯并咪唑，其他参数及反应条件同实施例1，产率为44％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.93(s,1H),8.64(d,1H),7.89–7.86(d,1H),7.54–7.43(m,3H),7.07(d,1H),6.96(dt,J＝8.5,1.7Hz,1H),3.86(d,J＝1.1Hz,3H),3.39(hept,J＝6.8,6.2Hz,2H),2.89(t,J＝6.6Hz,2H),1.76(s,3H).13C NMR(75MHz,CDCl3)δ172.0,161.6,158.8,144.0,143.1,139.9,137.3,132.0,125.4,124.8,121.7,120.3,116.2,115.3,108.9,68.1,55.8,47.4,37.7,21.2.HRMS(ESI)found:m/z 383.1261.,[M+H]+calcd.forC20H20ClN4O2383.1269
实施例18化合物18的合成
本实施例中将实施例1中的吲哚组分换为二吲哚甲烷，搅拌时长2h，其他参数及反应条件同实施例1，产率为52％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.52(s,1H),8.03(s,1H),7.79(d,J＝1.8Hz,1H),7.64–7.53(m,1H),7.39–7.27(m,3H),7.23(s,1H),7.18(d,J＝8.2Hz,1H),7.04(t,J＝7.4Hz,1H),6.90–6.78(m,2H),6.21(d,J＝2.5Hz,1H),3.99–3.81(m,2H).13C NMR(75MHz,CDCl3)δ163.7,150.4,138.4,136.3,135.2,130.6,126.8,126.7,123.7,122.8,122.1,120.7,119.8,117.5,117.1,111.0,106.5,77.2,69.1,36.3.HRMS(ESI)found:m/z 369.0871,[M+Na]+calcd.for C20H15ClN4Na+369.0877.
实施例19化合物19的合成
本实施例中将实施例1中的吲哚组分换为佐米曲普坦，其他参数及反应条件同实施例1，产率为39％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,MeOD)δ8.67(s,1H),8.02(s,1H),7.56–7.46(m,2H),7.45–7.36(m,1H),7.24(s,1H),4.46–4.36(m,1H),4.29–4.17(m,2H),2.98(t,J＝4.8Hz,2H),2.82(dd,J＝9.5,6.3Hz,2H),2.18–2.06(m,1H),2.01(m,J＝19.8Hz,7H).13C NMR(75MHz,MeOD)δ165.5,165.5,162.0,150.4,139.2,139.0,137.8,137.3,137.1,133.5,133.5,130.9,125.3,125.1,121.9,118.8,70.5,70.2,69.8,69.7,55.0,54.9,54.7,54.34,45.1,44.9,41.5,41.2,38.4,38.2.HRMS(ESI)found:m/z 388.1520.,[M+H]+calcd.forC19H23ClN5O2388.1535
实施例20化合物20的合成
本实施例中将实施例1中的吲哚组分换为佐米曲普坦，氮杂环组分换为苯并咪唑，其他参数及反应条件同实施例1，产率为45％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,MeOD)δ9.14(s,1H),8.66–8.63(m,1H),7.81–7.79(m,1H),7.58–7.48(m,4H),7.46–7.36(m,1H),4.44(m,J＝5.9Hz,1H),4.21(tt,J＝10.4,5.2Hz,2H),2.97(d,J＝5.0Hz,2H),2.93–2.74(m,2H),2.05–1.84(m,2H),1.81(m,J＝7.8Hz,6H).13C NMR(75MHz,MeOD)δ166.1,162.1,151.3,143.9,142.3,138.6,138.5,136.9,136.7,133.5,133.4,126.8,126.3,125.0,124.8,121.8,120.7,117.8,70.7,70.5,70.2,55.255.1,54.7,54.5,45.1,45.0,41.3,39.3.39.2HRMS(ESI)found:m/z 438.1683.,[M+H]+calcd.forC23H25ClN5O5438.1691
实施例21化合物21的合成
本实施例中将实施例1中的吲哚组分换为吲哚，其他参数及反应条件同实施例1，产率为74％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.60(s,1H),7.88(t,J＝1.4Hz,1H),7.73–7.65(m,1H),7.54–7.44(m,2H),7.37(ddd,J＝7.3,6.1,2.7Hz,1H),7.26(d,J＝3.6Hz,1H).13CNMR(75MHz,Chloroform-d)δ160.2,147.4,137.3,136.5,132.2,131.0,127.7,122.9,121.2,117.0,77.2.HRMS(ESI)found:m/z 252.0090,[M+H]+calcd.forC11H8Cl2N3252.0090.
实施例22化合物22的合成
本实施例中将实施例1中的吲哚组分换为5-甲氧基吲哚，其他参数及反应条件同实施例1，产率为61％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.56(d,J＝1.1Hz,1H),7.85(t,J＝1.4Hz,1H),7.41(d,J＝8.5Hz,1H),7.24(d,2H),6.97(dd,J＝8.6,2.6Hz,1H),3.89(s,3H).13C NMR(75MHz,CDCl3)δ159.7,158.8,140.4,138.8,136.2,130.7,121.9,116.9,116.8,109.3,77.2,56.0.HRMS(ESI)found:m/z304.0017,[M+Na]+calcd.for C12H9Cl2N3Na+O 304.0015
实施例23化合物23的合成
本实施例中将实施例1中的吲哚组分换为5-溴吲哚，其他参数及反应条件同实施例1，产率为51％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.58(s,1H),7.85(d,J＝1.7Hz,1H),7.65(s,1H),7.59–7.48(m,2H),7.26(s,1H).13C NMR(75MHz,Chloroform-d)δ161.1,148.7,136.5,136.1,131.2,130.6,126.0,124.6,123.9,116.9,77.2.HRMS(ESI)found:m/z 351.9013,[M+Na]+calcd.for C11H6BrCl2N3Na+351.9014
实施例24化合物24的合成
本实施例中将实施例1中的吲哚组分哚换为5-氟吲哚，其他参数及反应条件同实施例1，产率为52％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.56(s,1H),7.84(s,1H),7.51–7.34(m,2H),7.26(s,1H),7.18(td,J＝8.7,2.6Hz,1H).13C NMR(75MHz,CDCl3)δ163.6,160.3,160.2,143.3,143.3,138.9,138.8,136.3,131.1,122.4,122.3,119.0,118.7,116.9,111.2,110.8,77.2.19F NMR(282MHz,CDCl3)δ-111.84(ddd,J＝8.7,7.1,4.4Hz).HRMS(ESI)found:m/z 291.9817,[M+Na]+calcd.for C11H6Cl2FN3Na+291.9815
实施例25化合物25的合成
本实施例中将实施例1中的吲哚组分换为5-甲基吲哚，其他参数及反应条件同实施例1，产率为48％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.57(t,J＝1.0Hz,1H),7.86(t,J＝1.4Hz,1H),7.50(d,J＝1.7Hz,1H),7.37(d,J＝7.9Hz,1H),7.30–7.21(m,2H),2.45(s,3H).13C NMR(75MHz,CDCl3)δ159.7,145.1,138.2,137.4,136.4,132.7,130.9,123.5,120.9,117.0,77.3,21.5.HRMS(ESI)found:m/z 288.0071,[M+Na]+calcd.for C12H9Cl2N3Na+288.0066
实施例26化合物26的合成
本实施例中将实施例1中的吲哚组分换为6-氯吲哚，其他参数及反应条件同实施例1，产率为55％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.58(s,1H),7.86(d,J＝1.4Hz,1H),7.62(d,J＝8.0Hz,1H),7.49(d,J＝1.8Hz,1H),7.36(dd,J＝8.1,1.8Hz,1H),7.27(s,1H).13C NMR(75MHz,CDCl3)δ161.3,148.7,138.1,136.5,135.6,131.2,127.7,123.7,121.8,117.0.77.2.HRMS(ESI)found:m/z 307.9519,[M+Na]+calcd.for C11H6Cl3N3Na+307.9520.
实施例27化合物27的合成
本实施例中将实施例1中的吲哚组分换为5-氯基吲哚，其他参数及反应条件同实施例1，产率为64％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.58(s,1H),7.85(t,J＝1.5Hz,1H),7.62(d,J＝8.1Hz,1H),7.49(d,J＝1.8Hz,1H),7.36(dd,J＝8.1,1.9Hz,1H),7.29–7.23(m,1H).
13C NMR(75MHz,CDCl3)δ160.3,145.9,138.7,136.5,133.4,132.3,131.1,123.4,122.2,117.0,77.2HRMS(ESI)found:m/z 285.9698,[M+H]+calcd.for C11H7Cl3N3285.9700.
实施例28化合物28的合成
本实施例中将实施例1中的吲哚组分换为5-苄氧基吲哚，其他参数及反应条件同实施例1，产率为31％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.55(s,1H),7.83(s,1H),7.47–7.36(m,6H),7.33(d,J＝2.5Hz,1H),7.26(s,1H),7.04-7.02(dd,J＝8.6,2.5Hz,1H),5.12(s,2H).13C NMR(75MHz,CDCl3)δ158.9,158.8,140.6,138.8,136.3,136.1,130.8,128.8,128.4,127.6,121.9,117.6,116.9,110.4,77.2,70.9.HRMS(ESI)found:m/z 380.0324,[M+Na]+calcd.forC18H13Cl2N3ONa+380.0328.
实施例29化合物29的合成
本实施例中将实施例1中的吲哚组分换为吲哚，氮杂环组分换为苯并咪唑，其他参数及反应条件同实施例1，产率为73％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ9.02(s,1H),8.64(d,J＝7.8Hz,1H),7.90(d,J＝7.7Hz,1H),7.72(d,J＝7.5Hz,1H),7.62–7.42(m,4H),7.37(t,J＝7.5Hz,1H).13C NMR(75MHz,CDCl3)δ160.7,148.1,143.5,140.7,136.6,132.3,131.9,127.4,125.9,125.4,122.8,121.1,120.6,116.5,77.8.HRMS(ESI)found:m/z324.0063,[M+Na]+calcd.for C15H9Cl2N3Na+324.0066.
实施例30化合物30的合成
称取0.10mmol Boc-L-组氨酸甲酯、0.20mmol吲哚置于干净的反应管中、加入2.0mL含有0.10mmol碳酸氢钠的二氯甲烷溶液，搅拌至吲哚组分和氮杂环组分充分溶解，最后加入0.6mmol次氯酸钠溶液，在25℃环境下搅拌1h；停止搅拌，减压浓缩，用二氯甲烷萃取两次，合并有机相并使用无水硫酸镁干燥，过滤，再次减压浓缩，最后通过柱层析分离纯化，得到目标产物，产率为40％。所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.52(s,1H),7.70–7.65(m,2H),7.48(d,J＝4.3Hz,2H),7.43–7.31(m,1H),5.76(d,J＝8.5Hz,1H),4.67(q,J＝5.9Hz,1H),3.76(s,3H),3.17(m,J＝9.7,7.7Hz,2H),1.45(s,9H).13C NMR(75MHz,CDCl3)δ172.3,159.8,155.5,147.3,139.4,137.2,136.3,132.2,127.8,122.9,121.2,114.5,79.9,77.2,53.1,52.5,30.3,28.3.HRMS(ESI)found:m/z 453.1082.,[M]+calcd.for C20H23Cl2N4O4453.1091.
实施例31化合物31的合成
本实施例中将实施例30中的吲哚组分换为4-甲氧基吲哚，其他参数及反应条件同实施例30，产率为25％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.51(s,J＝1.3Hz,1H),7.65(s,1H),7.44(t,J＝8.1Hz,1H),7.09(d,J＝7.6Hz,1H),6.89(d,J＝8.5Hz,1H),5.82(d,J＝8.4Hz,1H),4.67(dt,J＝9.3,5.3Hz,1H),4.03(s,3H),3.75(s,3H),3.24–3.10(m,2H),1.45(s,9H).13C NMR(75MHz,CDCl3)δ172.2,160.3,155.4,148.9,139.3,136.4,133.8,121.9,117.3114.4,113.6,110.8,79.73,76.7,56.1,53.0,52.3,30.2,28.3.HRMS(ESI)found:m/z 483.1183,[M+H]+calcd.for C21H25Cl2N4O5483.1197.
实施例32化合物32的合成
本实施例中将实施例30中的吲哚组分换为5-甲基吲哚，其他参数及反应条件同实施例30，产率为40％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.48(s,1H),7.62(s,1H),7.49(s,1H),7.35(dd,J＝7.9,1.4Hz,1H),7.26(d,J＝7.9Hz,1H),5.77(d,J＝8.5Hz,1H),4.66(q,J＝6.1Hz,1H),3.75(d,J＝1.4Hz,3H),3.30–3.15(m,2H),2.45(s,3H),1.45(s,9H).13C NMR(75MHz,CDCl3)δ172.3,159.3,155.5,145.0,139.4,138.1,137.3,136.2,132.6,123.5,120.8,114.4,79.9,77.2,53.1,52.4,30.3,28.3,21.5.HRMS(ESI)found:m/z 467.1239.,[M+H]+calcd.forC21H25Cl2N4O4467.1247.
实施例33化合物33的合成
本实施例中将实施例30中的吲哚组分换为5-溴吲哚，其他参数及反应条件同实施例30，产率为36％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.47(d,J＝1.3Hz,1H),7.80(d,J＝1.8Hz,1H),7.60(dd,J＝8.2,1.7Hz,2H),7.34(s,1H),5.78(d,J＝8.4Hz,1H),4.68(dt,J＝9.2,5.3Hz,1H),3.76(s,3H),3.33–2.98(m,2H),1.45(s,9H).13C NMR(75MHz,CDCl3)δ172.1,159.7,155.3,146.3,139.7,138.7,136.2,135.1,126.1,122.4,120.7,114.2,79.8,76.3,52.9,52.3,30.2,28.2.HRMS(ESI)found:m/z531.0183.,[M+H]+calcd.for C20H22BrCl2N4O4531.0196
实施例34化合物34的合成
本实施例中将实施例30中的吲哚组分换为6-氯吲哚，其他参数及反应条件同实施例30，产率为33％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.48(d,J＝1.3Hz,1H),7.60(d,J＝8.6Hz,2H),7.47(d,J＝1.8Hz,1H),7.34(dd,J＝8.1,1.8Hz,1H),5.75(d,J＝8.4Hz,1H),4.67(dt,J＝9.9,5.4Hz,1H),3.76(s,3H),3.25–3.08(m,2H),1.45(s,9H).13C NMR(75MHz,CDCl3)δ172.2,160.9,155.4,148.6,139.8,138.0,136.3,135.5,127.6,123.6,121.7,114.3,79.9,76.4,53.0,52.4,30.3,28.3.HRMS(ESI)found:m/z 487.0686.,[M+H]+calcd.forC20H22Cl3N4O4487.0701.
实施例35化合物35的合成
本实施例中将实施例30中的吲哚组分换为6-氟吲哚，其他参数及反应条件同实施例30，产率为30％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.49(s,1H),7.64(m,J＝13.5Hz,2H),7.19(dt,J＝8.4,1.6Hz,1H),7.05(td,J＝9.1,8.5,2.3Hz,1H),5.74(d,J＝8.4Hz,1H),4.67(q,J＝6.1Hz,1H),3.76(s,J＝1.2Hz,3H),3.16(q,J＝9.8,7.1Hz,2H),1.45(s,9H).13C NMR(75MHz,CDCl3)δ172.3,166.7,163.4,161.4,155.5,149.5,149.3,139.9,136.4,133.0,133.0,124.2,124.1,114.5,114.4,114.2,109.6,109.2,80.0,76.5,53.1,52.5,30.4,28.4.19FNMR(282MHz,CDCl3)δ-106.08(td,J＝8.6,4.9Hz).HRMS(ESI)found:m/z 471.0996.,[M+H]+calcd.for C20H22Cl2FN4O4471.0997
实施例36化合物36的合成
本实施例中将实施例30中的吲哚组分换为3-甲基吲哚，其他参数及反应条件同实施例30，产率为51％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.44(s,1H),7.65(s,1H),7.49(d,J＝7.4Hz,2H),7.41(t,J＝7.3Hz,1H),7.32(d,J＝7.4Hz,1H),5.88(d,J＝8.4Hz,1H),4.67(dt,J＝10.0,5.4Hz,1H),3.75(s,J＝2.0Hz,3H),3.15(q,J＝9.7,7.6Hz,2H),2.01(d,J＝2.5Hz,3H),1.45(s,9H).13C NMR(75MHz,CDCl3)δ172.1,164.0,155.3,149.1,139.3,139.1,135.8,130.4,126.7,121.8,120.7,114.3,79.6,65.9,53.0,52.2,30.1,28.2,27.0.HRMS(ESI)found:m/z433.1624.,[M+H]+calcd.for C21H26ClN4O4433.1637.
1H NMR(300MHz,CDCl3)δ7.65–7.61(m,2H),7.40–7.30(m,2H),7.29–7.21(m,1H),6.91(s,1H),5.96(d,J＝8.5Hz,1H),4.66(dt,J＝10.1,5.3Hz,1H),3.72(s,3H),3.49(s,3H),3.15(q,J＝9.4,7.3Hz,2H),1.45(s,9H).13C NMR(75MHz,CDCl3)δ172.3,155.4,138.6,138.4,133.5,127.3,124.1,123.6,121.1,118.7,118.3,109.8,100.6,79.6,53.4,52.1,30.3,29.5,28.2.HRMS(ESI)found:m/z 433.1624.,[M+H]+calcd.forC21H26ClN4O4433.1637.
实施例37化合物37的合成
本实施例中将实施例30中的氮杂环组分换为Boc-L-组氨酸-L-苯丙氨酸甲酯，其他参数及反应条件同实施例30，产率为33％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.47(d,J＝1.2Hz,1H),7.76–7.60(m,2H),7.46(dd,J＝3.9,2.4Hz,2H),7.39–7.27(m,2H),7.23(q,J＝7.4,6.8Hz,3H),7.05–7.00(m,2H),6.13(d,J＝7.4Hz,1H),4.83(q,J＝6.1Hz,1H),4.54–4.53(m,1H),3.64(s,3H),3.26–3.11(m,1H),3.04(m,J＝9.6,6.2Hz,3H),1.44(s,9H).13C NMR(75MHz,CDCl3)δ171.4,170.9,159.8,155.5,147.3,140.0,137.1,135.9,135.8,132.2,129.2,128.4,127.7,126.9,122.7,121.1,114.5,80.0,77.0,54.0,53.3,52.1,37.9,30.1,28.2.HRMS(ESI)found:m/z600.1769.,[M+H]+calcd.for C29H32Cl2N5O5600.1775.
实施例38化合物38的合成
本实施例中将实施例30中的氮杂环组分换为Boc-L-苯丙氨酸-L-组氨酸甲酯，吲哚组分换为3-甲基吲哚，其他参数及反应条件同实施例30，产率为31％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.36(s,1H),7.61(s,1H),7.49(dd,J＝7.6,3.6Hz,2H),7.41(t,J＝7.5Hz,1H),7.34–7.19(m,7H),5.29(d,J＝8.1Hz,1H),4.89(qd,J＝5.7,3.8,2.5Hz,1H),4.48(q,J＝7.3Hz,1H),3.72(s,3H),3.22–2.95(m,4H),2.00(d,J＝3.9Hz,3H),1.37(s,9H).13C NMR(75MHz,CDCl3)δ171.4,171.2,164.1,155.3,149.2,139.4,139.0,137.0,135.9,130.6,129.5,128.5,127.0,126.7,122.0,120.9,114.6,79.8,66.1,55.6,52.5,51.9,38.6,29.8,28.3,27.1.HRMS(ESI)found:m/z 580.2305.,[M+H]+calcd.forC30H35ClN5O5580.2321.
实施例39化合物39的合成
本实施例中将实施例30中的氮杂环组分换为Boc-N-叔丁氧羰基-L-赖氨酸-L-组氨酸甲酯，吲哚组分换为3-甲基吲哚，其他参数及反应条件同实施例30，产率为30％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.44(s,1H),7.66(s,1H),7.50(d,J＝7.4Hz,3H),7.43(t,J＝7.5Hz,1H),7.32(d,J＝14.4Hz,1H),5.38(d,J＝8.0Hz,1H),4.96–4.74(m,2H),4.20(q,J＝7.3,6.9Hz,1H),3.74(s,J＝1.5Hz,3H),3.13(m,J＝26.9,11.6,6.1Hz,4H),2.03(d,J＝3.8Hz,3H),1.84(p,J＝5.9Hz,1H),1.67(t,J＝10.5Hz,1H),1.42(m,22H).13C NMR(75MHz,CDCl3)δ172.0,171.5,164.1,156.1,155.6,149.2,139.5,139.0,136.0,130.6,127.0,122.0,120.9,114.6,79.8,78.9,66.0,54.2,52.5,51.9,40.0,32.5,29.5,28.4,28.3,27.1,22.2.HRMS(ESI)found:m/z 661.3103.,[M+H]+calcd.for C32H46ClN6O7661.3111
实施例40化合物40的合成
本实施例中将实施例30中的氮杂环组分换为Boc-L-组氨酸-L-亮氨酸-L-苯丙氨酸甲酯，吲哚组分换为3-甲基吲哚，其他参数及反应条件同实施例30，产率为32％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.41(d,J＝5.3Hz,2H),7.67(d,J＝7.9Hz,2H),7.50(dd,J＝7.6,2.5Hz,4H),7.42(t,J＝7.5Hz,2H),7.27(ddd,J＝20.1,10.9,6.4Hz,10H),7.11(d,J＝7.2Hz,4H),6.99(d,J＝8.6Hz,1H),6.86(d,J＝8.4Hz,1H),6.14(d,J＝6.0Hz,2H),4.88–4.71(m,2H),4.57–4.33(m,4H),3.67(t,J＝1.7Hz,6H),3.18–3.00(m,8H),2.02(d,J＝7.5Hz,6H),1.60(d,J＝11.2Hz,2H),1.42(s,24H),0.81(dt,J＝11.6,5.4Hz,12H).13C NMR(75MHz,CDCl3)δ171.8,171.5,171.1,164.1,155.7,149.2,139.5,139.3,136.1,135.9,130.6,129.3,129.2,128.5,127.0,122.0,120.9,114.9,114.8,80.2,66.1,66.054.2,53.3,52.2,51.8,51.7,40.6,40.5,37.7,30.1,28.3,28.1,27.3,27.1,24.6,24.5,23.0,21.7,21.6.HRMS(ESI)found:m/z 693.3140.,[M+H]+calcd.forC36H46ClN6O6 693.3162
实施例41化合物41的合成
本实施例中将实施例30中的氮杂环组分换为Boc-L-亮氨酸-L-苯丙氨酸-L-组氨酸甲酯，吲哚组分换为3-甲基吲哚，其他参数及反应条件同实施例30，产率为43％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.41(d,J＝9.8Hz,2H),7.60(d,J＝7.5Hz,2H),7.50(dt,J＝7.4,4.1Hz,5H),7.41(q,J＝7.6Hz,3H),7.34–7.28(m,2H),7.19(t,J＝7.7Hz,10H),6.93(d,J＝7.9Hz,1H),6.81(d,J＝8.1Hz,1H),5.27(t,J＝6.7Hz,1H),5.12–4.98(m,1H),4.91–4.69(m,4H),4.13(tt,J＝9.9,5.8Hz,2H),3.74–3.63(m,6H),3.10(dtt,J＝14.5,8.6,4.4Hz,8H),2.08–1.96(m,6H),1.64–1.49(m,4H),1.42(s,20H),0.86(q,J＝5.8,5.3Hz,12H).13C NMR(75MHz,CDCl3)δ172.5,172.3,171.3,171.1,170.6,170.4,164.1,155.5,149.1,139.4,138.8,136.4,136.0,130.5,129.5,129.2,128.5,128.3,126.9,126.8,126.7121.9,120.8,114.5,114.4,79.9,66.0,65.9,54.0,53.1,52.4,52.0,41.4,41.2,37.9,29.6,28.2,27.1,27.0,24.6,22.9,21.8.21.0HRMS(ESI)found:m/z693.3142.,[M+H]+calcd.for C36H46ClN6O6 693.3162
实施例42化合物42的合成
本实施例中将实施例30中的氮杂环组分换为Boc-L-亮氨酸-N-叔丁氧羰基L-色氨酸-L-组氨酸甲酯，吲哚组分换为3-甲基吲哚，其他参数及反应条件同实施例30，产率为32％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.22(s,1H),8.13(d,J＝8.2Hz,1H),7.74(d,J＝7.5Hz,1H),7.55(d,J＝3.3Hz,2H),7.48(dd,J＝7.6,3.4Hz,2H),7.44–7.36(m,2H),7.35–7.12(m,5H),4.98(t,J＝6.8Hz,1H),4.83(dd,J＝7.9,4.7Hz,1H),4.14(d,J＝11.4Hz,1H),3.68(d,J＝2.1Hz,3H),3.30–3.14(m,2H),3.13–2.96(m,2H),1.99(d,J＝13.1Hz,3H),1.64(d,J＝3.5Hz,12H),1.40(d,J＝1.9Hz,9H),0.92–0.87(m,6H).13C NMR(75MHz,CDCl3)δ172.5,171.0,170.4,164.1,155.6,149.6,149.2,139.5,139.5,138.8,135.9,135.5,130.5,130.4,126.9,124.9,124.4,122.6,122.0,120.9,119.4,115.3,115.3,115.1,114.4,83.4,80.0,66.1,53.1,52.4,52.0,41.4,29.5,28.2,28.2,27.1,24.7,23.1,21.8HRMS(ESI)found:m/z 832.3762.,[M+H]+calcd.for C43H55ClN7O8832.3795
实施例43化合物43的合成
本实施例中将实施例30中的氮杂环组分换为Boc-L-亮氨酸-N-叔丁氧羰基L-色氨酸-L-组氨酸甲酯，其他参数及反应条件同实施例30，产率为31％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,CDCl3)δ8.29(s,1H),8.14(d,J＝8.3Hz,1H),7.74(d,J＝7.6Hz,1H),7.67(d,J＝7.5Hz,1H),7.54(s,2H),7.47(d,J＝4.2Hz,2H),7.36(ddd,J＝11.6,9.1,5.4Hz,2H),7.30–7.21(m,3H),6.99(t,J＝7.8Hz,1H),4.90–4.78(m,2H),4.24–4.03(m,1H),3.68(s,3H),3.30–3.02(m,4H),1.64(m,12H),1.40(s,9H),0.90(d,J＝5.8Hz,6H).13CNMR(75MHz,CDCl3)δ172.4,170.9,170.3,159.8,155.6,149.6,147.3,139.1,137.2,136.1,135.5,132.2,130.4,127.7,124.9,124.5,122.8,122.7,121.1,119.3,115.2,115.2,114.3,83.4,80.1,77.3,53.1,52.4,52.1,52.0,41.4,29.5,28.2,28.2,24.7,23.0,21.8.HRMS(ESI)found:m/z 852.3213.,[M+H]+calcd.for C42H52Cl2N7O8 852.3249
实施例44化合物44的合成
称取0.10mmol Boc-L-色氨酸甲酯、0.20mmol苯并咪唑置于干净的反应管中、加入2.0mL含有0.20mmol碳酸氢钠的二氯甲烷溶液，搅拌至吲哚组分和氮杂环组分充分溶解，最后加入0.3mmol次氯酸钠溶液，在25℃环境下搅拌1h；停止搅拌，减压浓缩，用二氯甲烷萃取两次，合并有机相并使用无水硫酸镁干燥，过滤，再次减压浓缩，最后通过柱层析分离纯化，得到目标产物，产率为63％。所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.85(d,J＝5.8Hz,2H),8.71(dd,J＝13.3,8.0Hz,2H),7.93–7.80(m,2H),7.64–7.56(m,2H),7.54–7.40(m,8H),7.38–7.28(m,2H),4.81(d,J＝7.2Hz,1H),4.45(d,J＝9.4Hz,1H),4.27
–4.09(m,1H),3.81–3.70(m,1H),3.55(s,3H),3.30(d,J＝11.8Hz,6H),3.03(dd,J＝14.6,10.4Hz,1H),1.12(s,9H),1.02(s,9H).13C NMR(75MHz,Chloroform-d)δ170.9,170.0,164.7,164.2,154.4,151.4,143.4,143.4,140.2,140.1,135.50,135.4,132.4,132.2,131.2,131.2,126.8,126.1,125.6,125.0,123.2,122.3,121.3,121.2,120.4,120.3,116.9,80.3,68.5,68.3,52.7,52.5,50.9,50.7,42.5,42.3,27.8,27.7.HRMS(ESI)found:m/z 491.1449.,[M+Na]+calcd.for C24H25ClN4NaO4491.1457
实施例45化合物45的合成
本实施例中将实施例44中的氮杂环组分换为5-甲基苯并咪唑，其他参数及反应条件同实施例44，产率为57％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.81–8.72(m,2H),8.54(dd,J＝14.0,8.4Hz,2H),7.70(dd,J＝12.5,8.1Hz,1H),7.59(dd,J＝15.6,6.3Hz,3H),7.49(dd,J＝17.1,7.5Hz,4H),7.37–7.27(m,3H),7.22(d,J＝9.0Hz,1H),4.83(dd,J＝7.3,3.4Hz,1H),4.69(dd,J＝20.8,9.6Hz,1H),4.21(dd,J＝10.8,5.6Hz,1H),3.78(q,J＝13.3,10.0Hz,1H),3.54(d,J＝1.8Hz,3H),3.32(s,3H),3.25(d,J＝5.0Hz,2H),3.09–2.92(m,2H),2.58(d,J＝4.5Hz,3H),2.51(d,J＝7.8Hz,3H),1.15(d,J＝7.4Hz,9H),1.04(d,J＝4.9Hz,9H).13C NMR(75MHz,Chloroform-d)δ170.9,170.1,164.2,164.1,154.6,154.4,151.5,143.7,143.8,141.5,141.3,140.2,140.1,139.6,135.8,135.6,135.5,134.9,134.8,132.4,131.2,131.1,130.4,130.2,126.8,126.7,126.4,126.0,123.2,122.3,121.2,121.1,120.3,120.1,119.8,119.7,116.8,116.3,80.2,68.5,68.4,68.3,68.2,52.7,52.4,50.9,50.6,42.4,42.4,27.9,27.8,27.7,22.0,22.0,21.5.HRMS(ESI)found:m/z 505.1607.,[M+Na]+calcd.for C25H27ClN4NaO4 505.1613
实施例46化合物46的合成
本实施例中将实施例44中的氮杂环组分换为5-氯苯并咪唑，其他参数及反应条件同实施例44，产率为32％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.84(d,J＝4.7Hz,2H),8.76(d,J＝15.8Hz,2H),7.75(dd,J＝14.0,8.5Hz,2H),7.64(d,J＝7.8Hz,2H),7.56–7.31(m,8H),4.82(d,J＝6.8Hz,1H),4.62(d,J＝9.4Hz,1H),4.31–4.11(m,1H),3.76(dd,J＝18.5,9.0Hz,1H),3.59(s,3H),3.33(d,J＝11.2Hz,6H),3.02(dd,J＝14.7,10.9Hz,1H),1.16(s,10H),1.02(s,8H).13C NMR(75MHz,Chloroform-d)δ170.9,169.9,164.5,163.9,154.7,154.5,151.1,141.8,141.48,140.74,140.64,135.31,135.20,132.76,132.56,131.38,131.32,127.09,126.27,125.61,123.23,122.23,121.53,121.39,121.03,120.84,117.14,117.05,80.38,77.24,68.29,68.06,52.80,52.53,50.90,50.54,42.25,27.80,27.67.HRMS(ESI)found:m/z 525.1062.,[M+Na]+calcd.for C24H24Cl2N4NaO4 525.1067
实施例47化合物47的合成
本实施例中将实施例44中的吲哚组分换为Boc-N-叔丁氧羰基-L-赖氨酸-L-色氨酸甲酯，搅拌时长1.5h，其他参数及反应条件同实施例44，产率为53％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.85(d,J＝6.5Hz,2H),8.72(dd,J＝21.8,7.6Hz,2H),7.87(t,J＝6.8Hz,2H),7.63(dd,J＝12.9,7.6Hz,2H),7.57–7.42(m,8H),7.34(q,J＝7.5Hz,2H),6.74(d,J＝7.6Hz,1H),6.51(d,J＝8.4Hz,1H),4.70(q,J＝6.1Hz,2H),4.49(dd,J＝23.8,7.4Hz,2H),4.33(q,J＝6.0Hz,2H),4.00(s,1H),3.73(dq,J＝12.8,7.4Hz,1H),3.49–3.39(m,3H),3.32–3.13(m,7H),3.00(p,J＝7.2,6.5Hz,4H),1.50–1.38(m,36H),1.35–0.97(m,12H).13C NMR(75MHz,Chloroform-d)δ172.2,171.9,170.1,169.7,164.0,163.6,156.1,155.5,151.1,151.1,143.2,143.1,140.4,135.7,135.5,132.1,132.0,131.3,131.2,130.9,128.8,126.8,126.4,125.9,125.3,123.2,122.6,121.4,121.2,120.6,120.4,116.8,80.2,79.1,68.4,68.3,53.8,52.9,52.6,49.5,42.0,39.9,31.1,30.3,29.4,28.9,28.5,28.3,28.3,22.5,22.1.HRMS(ESI)found:m/z 719.2919.,[M+Na]+calcd.for C35H45ClN6NaO7719.2930
实施例48化合物48的合成
本实施例中将实施例44中的吲哚组分换为Boc-L-苯丙氨酸-L-色氨酸甲酯，搅拌时长1.5h，其他参数及反应条件同实施例44，产率为53％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.86(d,J＝5.2Hz,2H),8.73(dd,J＝14.3,8.2Hz,2H),7.94–7.83(m,2H),7.65–7.40(m,10H),7.34–7.25(m,2H),7.24–7.14(m,6H),6.99–6.86(m,4H),6.55(d,J＝7.3Hz,1H),6.42(s,1H),4.43–4.12(m,4H),4.00(q,J＝7.6Hz,1H),3.82(td,J＝8.2,5.8Hz,1H),3.35(s,3H),3.29–3.02(m,7H),2.85(ddd,J＝43.5,14.2,5.7Hz,2H),2.60–2.27(m,2H),1.35(d,J＝15.6Hz,18H).13C NMR(75MHz,Chloroform-d)δ171.2,171.1,169.8,169.4,163.8,163.4,155.1,151.0,151.0,143.1,143.0,140.4,136.5,135.6,135.4,132.0,131.9,131.2,131.1,129.1,129.0,128.4,128.3,126.6,126.6,126.4,125.8,125.2,123.0,122.6,121.3,121.1,120.5,120.5,116.7,80.0,68.1,68.0,55.2,55.0,52.7,52.5,49.7,49.2,41.7,37.5,28.2.HRMS(ESI)found:m/z 638.2146.,[M+Na]+calcd.for C33H34ClN5NaO5 638.2141
实施例49化合物49的合成
本实施例中将实施例44中的吲哚组分换为Boc-L-O-甲基-谷氨酸-L-色氨酸甲酯，搅拌时长1.5h，其他参数及反应条件同实施例44，产率为53％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.90(d,J＝11.6Hz,2H),8.79–8.62(m,2H),7.92–7.79(m,2H),7.62(dd,J＝11.4,7.6Hz,2H),7.56–7.41(m,8H),7.34(qd,J＝7.4,1.1Hz,2H),6.97(d,J＝8.1Hz,1H),6.86(dd,J＝8.1,4.7Hz,1H),4.78(dd,J＝8.4,3.1Hz,2H),4.27(td,J＝7.1,5.1Hz,1H),4.19
–4.02(m,1H),3.80(dq,J＝7.9,5.2,4.1Hz,2H),3.61(d,J＝13.7Hz,6H),3.43(s,3H),3.30(s,4H),3.25–3.04(m,3H),2.35–2.06(m,4H),1.90(dtd,J＝14.5,7.3,5.3Hz,2H),1.45(s,11H),1.42(s,7H).13C NMR(75MHz,Chloroform-d)δ173.7,173.6,171.5,171.2,170.1,169.8,163.7,163.6,155.3,151.1,151.0,143.2,143.1,140.4,140.3,135.7,135.6,132.1,132.0,131.3,131.2,126.8,126.5,125.9,125.8,125.,123.1,122.6,121.4,121.2,120.5,120.3,116.7,68.3,68.3,52.8,52.7,51.8,49.4,41.9,41.6,30.1,28.3,28.3,27.5.HRMS(ESI)found:m/z 634.2033.,[M+Na]+calcd.forC30H34ClN5NaO7634.2039
实施例50化合物50的合成
本实施例中将实施例44中的吲哚组分换为Boc-L-色氨酸-L-丙氨酸甲酯，搅拌时长1.5h，其他参数及反应条件同实施例44，产率为54％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.89(d,J＝3.3Hz,2H),8.67(dd,J＝23.8,8.1Hz,2H),7.82(d,J＝7.7Hz,1H),7.73(d,J＝8.0Hz,1H),7.62–7.51(m,4H),7.50–7.41(m,4H),7.34(dq,J＝14.3,7.2Hz,4H),6.57(dd,J＝21.6,7.4Hz,2H),5.29(d,J＝9.5Hz,1H),4.90(d,J＝8.5Hz,1H),4.35(p,J＝7.1Hz,1H),4.04(dd,J＝22.3,15.2Hz,2H),3.70(d,J＝8.5Hz,7H),3.43–3.32(m,1H),3.20(dd,J＝14.5,5.3Hz,1H),3.05(dt,J＝15.2,8.6Hz,2H),1.29(s,8H),1.22(d,J＝7.1Hz,5H),1.15(d,J＝6.4Hz,11H).13C NMR(75MHz,Chloroform-d)δ172.7,172.6,169.6,168.7,164.2,163.9,151.3,150.8,143.3,140.4,140.3,136.5,135.7,132.2,132.1,131.1,130.9,126.9,126.6,125.5,124.9,122.7,122.4,121.3,121.2,120.4,120.1,117.0,116.6,80.5,68.6,68.4,52.4,51.5,51,1,48.2,48.1,41.9,41.5,28.1,27.8,18.1.HRMS(ESI)found:m/z 562.1820.,[M+Na]+calcd.forC27H30ClN5NaO5 562.1828
实施例51化合物51的合成
本实施例中将实施例44中的吲哚组分换为Boc-L-缬氨酸-L-色氨酸甲酯，搅拌时长1.5h，其他参数及反应条件同实施例44，产率为57％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.89(d,J＝2.5Hz,2H),8.77–8.65(m,2H),7.91–7.77(m,2H),7.65–7.41(m,10H),7.37–7.31(m,2H),6.75(d,J＝8.3Hz,1H),6.42(d,J＝8.3Hz,1H),4.83(d,J＝8.8Hz,2H),4.40–4.18(m,2H),3.72(dd,J＝8.9,5.8Hz,1H),3.52(dd,J＝8.6,5.5Hz,1H),3.40(dd,J＝14.8,5.1Hz,1H),3.32(s,3H),3.28(s,3H),3.17–3.03(m,3H),1.94(h,J＝6.7Hz,1H),1.79(dt,J＝13.3,6.6Hz,1H),1.49(s,9H),1.45(s,9H),0.81–0.64(m,12H).13C NMR(75MHz,Chloroform-d)δ171.4,171.2,170.1,170.0,163.5,155.5,150.9,150.9,143.2,143.0,140.3,140.2,135.6,135.6,132.1,132.0,131.3,131.3,126.7,126.7,125.9,125.8,125.3,125.2,123.0,122.8,121.3,121.2,120.4,120.3,116.7,116.6,79.9,79.7,68.2,68.1,59.2,59.0,52.8,52.7,49.4,49.1,42.1,41.3,30.8,30.6,28.3,28.3,18.9,17.3HRMS(ESI)found:m/z 590.2132.,[M+Na]+calcd.for C29H34ClN5NaO5 590.2141
实施例52化合物52的合成
本实施例中将实施例44中的吲哚组分换为Boc-L-苏氨酸-L-色氨酸甲酯，搅拌时长1.5h，其他参数及反应条件同实施例44，产率为50％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.92(d,J＝13.0Hz,2H),8.71(dd,J＝7.9,5.5Hz,2H),7.85(dd,J＝7.9,3.9Hz,2H),7.63(dd,J＝16.1,7.6Hz,2H),7.56–7.40(m,8H),7.38–7.26(m,4H),5.36–5.11(m,2H),4.24(t,J＝6.5Hz,1H),4.16–4.06(m,1H),4.03–3.88(m,1H),3.72(dd,J＝7.9,3.0Hz,3H),3.48(s,2H),3.33(s,4H),3.18(dtd,J＝27.1,13.5,12.2,5.7Hz,4H),1.48(s,12H),1.39(s,6H),1.02(d,J＝6.4Hz,4H),0.84(d,J＝6.3Hz,2H).13C NMR(75MHz,Chloroform-d)δ171.2,170.7,170.0,169.9,163.6,155.9,155.6,151.1,150.9,143.0,142.7,140.6,140.30,135.7,135.5,132.1,131.8,131.3,131.1,126.8,126.5,125.9,125.8,125.2,122.9,122.8,122.5,121.3,121.2,120.3,120.2,116.6,80.1,79.9,68.3,66.4,65.9,58.1,57.3,52.8,52.7,49.3,41.7,28.3,17.8,17.2.HRMS(ESI)found:m/z 570.2105.,[M+H]+calcd.for C28H33ClN5O6 570.2114
实施例53化合物53的合成
本实施例中将实施例44中的吲哚组分换为Boc-L-色氨酸-L-亮氨酸甲酯，搅拌时长1.5h，其他参数及反应条件同实施例44，产率为65％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.89(d,J＝4.0Hz,2H),8.66(dd,J＝23.1,8.1Hz,2H),7.87–7.80(m,1H),7.69(d,J＝8.0Hz,1H),7.63–7.51(m,4H),7.50–7.42(m,4H),7.40–7.27(m,4H),6.44(d,J＝8.0Hz,1H),6.27(d,J＝8.3Hz,1H),5.33(d,J＝9.6Hz,1H),4.68(d,J＝8.6Hz,1H),4.52–4.36(m,1H),4.29–4.14(m,1H),3.93(s,1H),3.68(d,J＝1.9Hz,7H),3.43–3.01(m,4H),1.57–1.35(m,6H),1.31(s,10H),1.17(s,8H),0.82–0.68(m,12H).13C NMR(75MHz,Chloroform-d)δ172.8,172.7,170.1,169.2,164.4,163.8,155.2,154.8,151.3,150.8,143.2,143.0,140.5,136.8,135.8,132.2,132.0,131.2,130.9,127.0,126.7,125.5,125.4,125.0,125.0,122.6,122.4,121.3,121.2,120.4,120.0,117.0,116.6,80.5,80.4,68.6,68.4,52.4,51.3,50.9,50.8,50.7,41.3,40.9,28.1,27.9,24.5,22.7,22.6,21.8,21.6.HRMS(ESI)found:m/z 582.2468.,[M+H]+calcd.forC30H37ClN5O5 582.2478
实施例54化合物54的合成
本实施例中将实施例44中的吲哚组分换为Boc-L-色氨酸-L-甘氨酸叔丁酯，搅拌时长1.5h，其他参数及反应条件同实施例44，产率为58％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.89(s,2H),8.68(dd,J＝17.7,8.0Hz,2H),7.84(d,J＝7.7Hz,1H),7.75(d,J＝8.1Hz,1H),7.62–7.52(m,4H),7.45(d,J＝7.6Hz,4H),7.35(qd,J＝7.9,3.2Hz,4H),6.41(s,2H),5.04(d,J＝9.9Hz,1H),4.97–4.78(m,1H),3.98(d,J＝15.8Hz,1H),3.76–3.57(m,4H),3.42(d,J＝15.5Hz,2H),3.17(s,1H),3.08–2.95(m,2H),1.42(d,J＝1.0Hz,8H),1.39(d,J＝1.0Hz,10H),1.32–1.28(m,8H),1.18(s,10H).13C NMR(75MHz,Chloroform-d)δ170.3,168.2,164.3,154.8,151.2,142.9,140.5,135.7,132.2,132.0,131.1,130.9,126.9,126.7,125.6,125.4,125.0,124.9,122.8,122.5,121.3,120.3,120.0,116.9,116.7,82.4,82.3,80.5,68.6,68.4,53.5,51.2,42.0,41.4,28.3,28.1,28.0,28.0.HRMS(ESI)found:m/z 568.2311.,[M+H]+calcd.forC29H35ClN5O5568.2321
实施例55化合物55的合成
本实施例中将实施例44中的吲哚组分换为Boc-L-色氨酸-L-丙氨酸-L-缬氨酸甲酯，搅拌时长1.5h，其他参数及反应条件同实施例44，产率为44％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.89(d,J＝2.2Hz,2H),8.69(dd,J＝16.5,8.0Hz,2H),7.81(t,J＝7.4Hz,2H),7.64–7.57(m,2H),7.55–7.48(m,2H),7.48–7.31(m,8H),6.91(s,2H),6.64(d,J＝7.4Hz,1H),6.55(d,J＝7.7Hz,1H),5.24(d,J＝8.6Hz,1H),5.05(d,J＝9.7Hz,1H),4.55–4.48(m,1H),4.37(dq,J＝7.3,5.2Hz,3H),4.21(q,J＝7.5,5.5Hz,1H),4.03(s,1H),3.60(s,3H),3.57(s,3H),3.40(d,J＝14.7Hz,1H),3.20–2.97(m,3H),2.13–2.00(m,2H),1.59–1.47(m,6H),1.34(s,10H),1.13(s,8H),0.87(dd,J＝8.6,3.0Hz,8H),0.81(d,J＝6.8Hz,4H).13C NMR(75MHz,Chloroform-d)δ172.6,172.5,171.8,170.4,169.6,164.3,154.9,151.2,150.7,143.0,140.6,140.4,136.4,132.2,131.2,131.0,126.9,126.8,125.6,125.1,123.0,122.5,121.2,120.2,120.1,117.1,116.7,80.6,68.7,68.5,57.1,52.2,52.1,51.7,51.1,48.7,41.8,31.0,28.5,28.2,27.8,19.1,19.0,17.7.HRMS(ESI)found:m/z 661.2509.,[M+Na]+calcd.for C32H39ClN6NaO6 661.2512
实施例56化合物56的合成
本实施例中将实施例44中的吲哚组分换为Boc-L-丙氨酸-L-色氨酸-L-丙氨酸甲酯，搅拌时长1.5h，其他参数及反应条件同实施例44，产率为60％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.92(s,1H),8.82–8.61(m,1H),7.82–7.69(m,1H),7.64–7.55(m,2H),7.46(dddd,J＝8.8,7.5,3.8,1.8Hz,2H),7.35(tdd,J＝11.8,6.3,2.8Hz,3H),7.11(d,J＝9.6Hz,1H),4.55(d,J＝5.7Hz,1H),4.34(p,J＝7.3Hz,1H),4.11(td,J＝9.9,2.7Hz,1H),3.75(dd,J＝14.7,4.1Hz,1H),3.65(s,3H),3.18(t,J＝6.8Hz,1H),2.97(dd,J＝14.9,10.1Hz,1H),1.30(d,J＝9.5Hz,12H),0.83(d,J＝6.9Hz,3H).13CNMR(75MHz,Chloroform-d)δ173.5,172.7,169.7,163.9,155.7,151.1,143.0,140.7,135.6,132.2,131.2,127.0,125.6,125.1,122.8,121.2,120.2,116.9,80.4,68.9,52.4,50.6,49.5,48.6,41.8,28.1,16.9,16.0.HRMS(ESI)found:m/z 611.2368.,[M+H]+calcd.for C30H36ClN6O6 611.2379
实施例57化合物57的合成
本实施例中将实施例44中的吲哚组分换为Boc-L-丙氨酸-L-异亮氨酸-L-色氨酸甲酯，搅拌时长1.5h，其他参数及反应条件同实施例44，产率为51％，所得目标产物的化学表征信息如下所示:
1H NMR(300MHz,Chloroform-d)δ8.91–8.88(m,2H),8.69(t,J＝8.2Hz,2H),7.86(d,J＝7.6Hz,2H),7.54(ddt,J＝33.8,13.0,6.0Hz,10H),7.33(td,J＝13.5,12.4,6.2Hz,4H),6.71(d,J＝8.5Hz,1H),6.62(d,J＝8.3Hz,1H),5.35(d,J＝7.2Hz,1H),5.23(t,J＝6.4Hz,1H),4.30–4.02(m,5H),3.85(dd,J＝8.7,5.5Hz,1H),3.50(s,1H),3.42(dd,J＝14.8,5.1Hz,1H),3.35(s,2H),3.23(d,J＝14.9Hz,3H),3.12(d,J＝6.2Hz,2H),3.04(dd,J＝15.0,6.7Hz,1H),1.91–1.54(m,3H),1.41(s,18H),1.38–1.32(m,6H),1.31–1.21(m,3H),0.85–0.56(m,12H).13C NMR(75MHz,Chloroform-d)δ172.6,172.4,171.1,170.8,170.7,170.1,170.1,163.7,163.6,163.5,155.7,150.9,143.2,143.1,143.1,140.7,140.4,140.3135.7,135.6,135.5,132.2,132.1,131.3,131.2,127.0,126.8,126.7,125.9,125.7,125.2,125.1,123.2,123.1,123.0,121.34,120.4,120.3,116.8,116.7,116.7,80.5,80.3,68.7,68.5,68.4,68.3,57.3,57.1,55.6,52.8,52.6,52.5,50.3,49.5,49.3,49.2,41.7,41.5,41.4,37.0,28.4,28.3,26.4,26.3,24.5,24.4,17.8,15.2,15.0,14.0,13.8,11.6,11.3.HRMS(ESI)found:m/z 675.2663.,[M+Na]+calcd.for C33H41ClN6NaO6 675.2668
实施例58化合物1的合成
本实施例中将实施例1中的弱碱换为碳酸钠，其他参数及反应条件同实施例1，产率为55％，所得目标产物的化学表征信息与实施例1一致。
实施例59化合物1的合成
本实施例中将实施例1中的弱碱换为碳酸铯，其他参数及反应条件同实施例1，产率为30％，所得目标产物的化学表征信息与实施例1一致。
实施例60化合物1的合成
本实施例中将实施例1中的弱碱换为三乙胺，其他参数及反应条件同实施例1，产率为45％，所得目标产物的化学表征信息与实施例1一致。
实施例61化合物1的合成
实施例中将实施例1中的次氯酸钠溶液倍量换为0.05mmol，其他参数及反应条件同实施例1，产率为20％，所得目标产物的化学表征信息与实施例1一致。
实施例62化合物1的合成
实施例中将实施例1中的次氯酸钠溶液倍量换为0.5mmol，其他参数及反应条件同实施例1，产率为67％，所得目标产物的化学表征信息与实施例1一致。
实施例63化合物1的合成
实施例中将反应管置于0℃的环境中，其他参数及反应条件同实施例1，产率为75％，所得目标产物的化学表征信息与实施例1一致。
实施例64化合物1的合成
实施例中将反应管置于80℃的环境中，其他参数及反应条件同实施例1，产率为40％，所得目标产物的化学表征信息与实施例1一致。
实施例65化合物1的合成
实施例中将溶剂换为N,N二甲基甲酰胺，其他参数及反应条件同实施例1，产率为47％，所得目标产物的化学表征信息与实施例1一致。
实验例1：本发明的化合物抗肿瘤活性实验：
实验方法如下：
(1)细胞培养：
人肺腺癌细胞株A549与NCI-H1975来自于美国菌种保存中心(ATCC)，使用RPMI-1640培养基(ThermoFisher，Waltham，USA)进行培养，添加适量胎牛血清(ThermoFisher，Waltham，USA)，使培养基中血清终浓度为10％，然后将培养皿放置5％CO2的37℃恒温水套式二氧化碳培养箱培养(Yihe，Shanghai，China)。待细胞传2-3代后，消化计数种板子，进行药物活性测定实验。
(2)细胞活性测定：
取生长状态良好的A549或NCI-H1975细胞消化后，悬浮计数，按照每孔3000个种于96孔板，待贴壁后，按照100μM，10μM，1μM药物浓度，分别添加化合物1-57以及对照组(添加相同体积的培养基)，处理细胞72h，每孔添加10μL 1mg/mL刃天青钠溶液(Sangon，Shanghai，China))37℃孵育2h，孵育完成后，Flexstation3酶标仪(Molecular Devices，Sunnyvale，Silicon Valley，USA)测定555nm/585nm完成荧光值测定，使用GraphPad Prism7.0软件进行数据处理。实验结果如图1和图2所示。
图1为本发明化合物1-57对肺腺癌细胞株A549细胞活性影响结果图；图2为本发明化合物1-57对肺腺癌细胞株NCI-H1975细胞活性的影响结果；(图1和图2中1#代表化合物1，其他化合物表示方法相同)，由图1可知，化合物1-6、8、9、11、12、13、17、18、21-35、37、38、40-43、45、46、51-54、57，对肺腺癌细胞株A549细胞具有明显的抑制作用。由图2可知，化合物1-6、8、9、15、17、18、21-43、45-49、51-55、57对肺腺癌细胞株NCI-H1975细胞具有明显的抑制作用。
(3)IC50的测定：
取生长状态良好的A549或NCI-H1975细胞消化后，悬浮计数，按照每孔3000个种于96孔板，待贴壁后，选择化合物2/5/6/35/36/38、、39/44/48以及阳性对照(Osimertinib)按照100μM，20μM，4μM，0.8μM，0.16μM药物浓度处理72h，每孔添加10μL 1mg/mL刃天青钠溶液(Sangon，Shanghai，China))37℃孵育2h，孵育完成后，Flexstation3酶标仪(MolecularDevices，Sunnyvale，Silicon Valley，USA)测定555nm/585nm完成荧光值测定，使用GraphPad Prism 7.0软件进行数据处理计算IC50。IC50计算结果如表1所示。
由表1可知，所选化合物对A549或NCI-H197的IC50均在50μM以下，且针对A549，化合物2、21的IC50在10μM以下；针对NCI-H1975细胞，化合物2、21、23、24的IC50在10μM以下。
表1部分化合物IC50结果
实验例2：本发明化合物抗菌活性实验
实验所用细菌菌株包括：(1)革兰氏阳性菌：金黄色葡萄球菌(S.aureus)(2)革兰氏阴性菌：大肠杆菌(E.coli ATCC 25922)，鲍曼不动杆菌(A.baumannii ATCC 19606)，铜绿假单胞菌(P.aeruginosa ATCC 27853)。
实验方法如下：
①将在冻存在-80℃的菌株放在常温解冻，将解冻后的细菌接种在装有3mL液体肉汤培养基的试管中，放在37℃，180rpm的震荡培养箱中过夜培养。用接种环蘸取少量菌浊液涂布在在MH固体培养基上，放置37℃培养箱恒温培养过夜。挑取单克隆菌落接种到含有3mL肉汤液体培养基中，塞好塞子，放在37℃，180rpm的震荡培养箱中培养6-8h至对数生长期。
②取2mL EP管，每个管中称取2mg的样品，做好标记。用去离子水配成2048μg/ml的母液。使用MH液体培养基将样品母液使用2倍稀释法稀释成256μg/ml，128μg/mL，64μg/mL，32μg/mL，16μg/mL，梯度的药品。
③将生长至对数生长期的菌液使用麦氏比浊管比浊。稀释成1*106CFU/mL的菌液。
④使用96孔板，每孔加入50μL的样品和50μL的稀释后的菌液混匀。(此时样品的终浓度为128-2μg/mL)每个样品的每个浓度三个平行。每次实验加入阿莫西林作为对照组，按上述方法稀释至梯度(2-0.125μg/mL)，加入金黄色葡萄球菌(S.aureus ATCC 25923)的稀释后的菌液。阿莫西林溶液的终浓度为(1-0.0625μg/mL)。放入37℃恒温培养箱中孵育16-18h。
⑤孵育时间到，观察实验结果，肉眼观察到的清澈孔所对应的最小浓度就是该样品的MIC值。实验结果以三次独立重复试验相同结果为准。抗菌活性结果如表2所示。
由表2可知，化合物2、3、5、6、15、18、21、22、23、24、25、26、27、29、30、32、33、34、37对革兰氏阳性菌有明显的抑制作用；化合物为6、8、15、21、22、23、24、25、26对革兰氏阴性菌有明显的抑制作用。其中化合物29对S.aureus的MIC为2μg/mL，表现出良好的抑菌作用。
表2抗菌活性测定结果
以上，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，可轻易想到变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应以权利要求的保护范围为准。
Claims (3)
1.一种吲哚联氮杂环化合物，其特征在于，所述的吲哚联氮杂环化合物为如下化合物中的任一种：
。
2.权利要求1所述吲哚联氮杂环化合物的合成方法，其特征在于，所述的合成方法包括：
将化合物A与化合物B混合，得到第一混合体系，向所述第一混合体系中加入溶于有机溶剂的弱碱并搅拌，得到第二混合体系；向所述第二混合体系中加入次氯酸钠溶液继续搅拌反应，得到含有所述吲哚联氮杂环化合物的第三混合体系；所述合成方法的反应式为：
；
所述化合物A为，
所述化合物B为，
所述吲哚联氮杂环化合物为 ，
所述化合物A、化合物B、次氯酸钠的摩尔比为1：0.5-2：0.5-5；
所述弱碱与所述化合物B的摩尔比为1:0.5-2；
所述弱碱为碳酸氢钠、碳酸钠、碳酸铯、三乙胺中的一种；
所述合成方法的反应的温度为0℃-80℃；向所述第二混合体系中加入次氯酸钠溶液之后搅拌反应的时间为1-6h；
所述有机溶剂为非质子性溶剂，且所述有机溶剂为乙腈、二氯甲烷、N，N二甲基甲酰胺中的一种；
所述合成方法还包括从所述第三混合体系中分离纯化得到所述吲哚联氮杂环化合物，所述分离纯化方法包括减压蒸馏、萃取、干燥、过滤、柱层析分离提纯；
其中：R1、R2、R3、R4、X、Y、Z、Ar分别表示权利要求1中具体化合物所对应的基团和/或原子。
3.权利要求1所述吲哚联氮杂环化合物在制备抗癌和抗菌药物中的应用，其特征在于，
所述化合物1至6、8、9、11、12、13、15、17、18、21至35、37、38、40至43、45、46、51至54、57在制备抗肺腺癌细胞株A549的药物中的应用；
所述化合物1至6、8、9、11至13、15、17、18、21至43、45至49、51至55、57在制备抗肺腺癌细胞株NCI-H1975的药物中的应用；
所述化合物2、3、5、6、15、18、21、22、23、24、25、26、27、29、30、32、33、34、37在制备抑制革兰氏阳性菌的抗菌剂的应用；
所述化合物为6、8、15、21、22、23、24、25、26在制备抑制革兰氏阴性菌的抗菌剂的应用。
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