CN114213310A - 吲哚啉化合物及其衍生物、制备方法、药物组合物和应用 - Google Patents
吲哚啉化合物及其衍生物、制备方法、药物组合物和应用 Download PDFInfo
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- CN114213310A CN114213310A CN202111671572.9A CN202111671572A CN114213310A CN 114213310 A CN114213310 A CN 114213310A CN 202111671572 A CN202111671572 A CN 202111671572A CN 114213310 A CN114213310 A CN 114213310A
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- dihydro
- ethyl
- indol
- acid
- reduced pressure
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- -1 Indoline compound Chemical class 0.000 title claims abstract description 257
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 claims abstract description 40
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 230000001506 immunosuppresive effect Effects 0.000 claims abstract description 8
- 239000002207 metabolite Substances 0.000 claims abstract description 8
- 239000012453 solvate Substances 0.000 claims abstract description 8
- 230000001404 mediated effect Effects 0.000 claims abstract description 7
- 206010062016 Immunosuppression Diseases 0.000 claims abstract description 6
- 101710120843 Indoleamine 2,3-dioxygenase 1 Proteins 0.000 claims abstract description 6
- 230000002503 metabolic effect Effects 0.000 claims abstract description 5
- 239000013078 crystal Substances 0.000 claims abstract description 4
- 239000002243 precursor Substances 0.000 claims abstract description 4
- 239000000651 prodrug Substances 0.000 claims abstract description 4
- 229940002612 prodrug Drugs 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 35
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 238000005917 acylation reaction Methods 0.000 claims description 13
- 229960000583 acetic acid Drugs 0.000 claims description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- 229940043367 IDO1 inhibitor Drugs 0.000 claims description 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 5
- 238000006722 reduction reaction Methods 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
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- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229960002598 fumaric acid Drugs 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 229960000448 lactic acid Drugs 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098895 maleic acid Drugs 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 229940099690 malic acid Drugs 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229960002510 mandelic acid Drugs 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 229960003424 phenylacetic acid Drugs 0.000 claims description 2
- 239000003279 phenylacetic acid Substances 0.000 claims description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 2
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- 239000011975 tartaric acid Substances 0.000 claims description 2
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- NKCCODPFBDGPRJ-UHFFFAOYSA-N nitridocarbon(1+) Chemical compound N#[C+] NKCCODPFBDGPRJ-UHFFFAOYSA-N 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 239000001117 sulphuric acid Substances 0.000 claims 1
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- 230000000694 effects Effects 0.000 abstract description 13
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- 230000005764 inhibitory process Effects 0.000 abstract description 4
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 555
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 112
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Abstract
本发明公开了一类吲哚啉化合物及其衍生物、制备方法、药物组合物和应用。该类吲哚啉化合物结构如式(I)，其衍生物涉及所述吲哚啉化合物的立体异构体、互变异构体、代谢产物、代谢前体、前药、溶剂化物、溶剂化物的盐、结晶、药学上可接受的盐或它们的混合物。该类吲哚啉化合物及其衍生物对吲哚胺2,3‑双加氧酶1的活性具有显著的抑制作用，可用于制备治疗吲哚胺2,3‑双加氧酶1介导的免疫抑制相关疾病的药物，通过激活宿主免疫应答发挥抗肿瘤活性。
Description
技术领域
本发明涉及一类吲哚啉化合物及其衍生物、制备方法、药物组合物和应用，尤其涉及一种可制备为吲哚胺2,3-双加氧酶1抑制剂药物的吲哚啉化合物及其衍生物、制备方法、药物组合物和应用。
背景技术
吲哚胺2,3-双加氧酶1(IDO1)是人体内催化L-色氨酸氧化代谢的限速酶。IDO1可以催化L-色氨酸代谢生成具有免疫抑制作用的犬尿氨酸及其下游代谢产物，因此IDO1在维护机体免疫稳态和耐受方面发挥重要的作用。此外，如细胞毒性T淋巴细胞相关蛋白4(CTLA-4)、程序性死亡受体1(PD-1)及其配体PD-L1一样，IDO1在肿瘤免疫逃逸中起重要作用。研究表明IDO1在多种人类肿瘤中过度表达。Bin1基因可以抑制IDO1的表达(Muller AJ,et al.NatMed,2005,11:312-319)，而一些细胞因子及免疫检查点分子，如干扰素-γ，toll样受体(TLR)3、TLR4和白介素-6等可上调IDO1的表达(Bernhardt R,Chem Rev,1996,96(1):2841-2888)。
为了营造一种免疫耐受的环境，肿瘤细胞往往可以通过劫持免疫调节因子来躲避机体的免疫攻击，例如上调IDO1的表达(Johnson TS,et al.Immunol Invest,2012,41(6-7):765-797)。事实上，在大多数预后不良的癌症中都发现IDO1过表达和活性增强(Prendergast GC,et al.Cancer Res,2017,77(24):6795-6811)。在肿瘤微环境中，IDO1过表达会导致局部L-色氨酸的消耗和犬尿氨酸及其代谢物的累积，从而导致效应T细胞(Teffs)耗竭，并且促进调节性T(Tregs)细胞的分化和增殖，进而帮助肿瘤细胞逃避免疫攻击(Tang K,et al.J HematolOncol,2021,14(1):68)。
具体而言，IDO1可以通过三种方式影响肿瘤的进展。首先，IDO1促进肿瘤发生和致耐受性抗原呈递细胞(APCs)的形成，增强肿瘤相关抗原的外周血免疫耐受(Pol J,etal.Oncoimmunology,2015,4(4):e974411)。其次，在致耐受性APCs中过表达的IDO1蛋白可以抑制CD8+T效应细胞(Teffs)和NK细胞的活性，但犬尿氨酸等色氨酸代谢产物具有细胞毒性，可以杀灭T细胞和NK细胞(Frumento G,et al.J Exp Med,2002,196(4):459-468；MunnDH,et al.J Clin Invest,2004,114(2):280-290)，而且这些代谢产物还可以通过激活芳香烃受体(AhR)来诱导初始CD4+T细胞分化成Tregs(Mezrich JD,et al.J Immunol,2010,185(6):3190-3198；Mezrich JD,et al.J Immunol,2008,181(8):5396-5404)。IDO1还能促进骨髓衍生抑制细胞(MDSCs)的扩张和激活，诱导巨噬细胞向耐受性表型分化(SchmidtSV,et al.Front Immunol,2014,5:384；Carbotti G,et al.Oncotarget,2015,6(41):43267-43280)。因此，过表达的IDO1不仅可以抑制Teffs和NK细胞的增殖和活性，而且可以诱导Tregs和MDSCs增殖(Liu Y,et al.Nat Commun,2017,8:15207；Blache CA,etal.Cancer Res,2012,72(24):6447-6456.)。此外，MDSCs可通过炎症环境进一步抑制Teffs和NK细胞的功能，诱导肿瘤迁移(Wei L,et al.Front Immunol,2018,9:724)。
众多研究表明，IDO1与很多生理病理过程有关，包括肿瘤免疫逃逸、病毒感染、寄生虫感染、移植耐受、神经退行性疾病、自身免疫性疾病、神经精神疾病、白内障和血压调节等(Platten M,et al.Science,2005,310(5749):850-855；Wang Y,et al.Nat Med,2010,16(3):279-285；Favre D,et al.SciTransl Med,2010,2(32):32-36)。研究还表明麻疹、流感、巨细胞病毒和单纯疱疹病毒感染易受L-色氨酸水平的影响(Schmidt SV,et al.FrontImmunol,2014,5:384；Zhang YJ,et al.Cell Microbiol,2013,15(7):1079-1087)。Favre等研究发现，HIV感染后髓系抗原呈递树突状细胞诱导IDO1表达，进而L-色氨酸分解的代谢物3-羟基邻氨基苯甲酸会导致辅助性T细胞(TH)17丧失，促进微生物转移和持续炎症，同时TH17/Treg比例失调导致了患者的免疫抑制(Favre D,et al.SciTransl Med,2010,2(32):32-36)。此外，IDO1催化的色氨酸代谢产物如犬尿氨酸和喹啉酸等具有神经毒性，并且这些代谢产物与神经退行性疾病如记忆障碍症、阿尔茨海默病、认知障碍症、老年痴呆症、帕金森病、帕金森综合症和运动障碍性疾病的发生密切相关(Malpass K.Nat Rev Neurol,2011,7(8):417；Maddison DC,et al.Semin Cell Dev Biol,2015,40:134-141)。神经精神疾病如抑郁症、精神分裂症、焦虑症也与IDO1过度表达和犬尿氨酸等代谢产物水平升高有关(Myint AM.FEBS J,2012,279(8):1375-1385)。在类风湿关节炎患者滑膜关节组织的DCs高表达IDO1，患者血清中色氨酸浓度降低，而犬尿氨酸浓度和犬尿氨酸/色氨酸比值均明显升高(Widner B,et al.Immunobiology,2000,201(5):621-630)。多项研究表明，在黑色素瘤、肺癌、乳腺癌、胃癌、结肠癌、膀胱癌、胰腺癌、淋巴癌、前列腺癌、肾癌、脑癌、头颈癌、卵巢癌、宫颈癌、子宫内膜癌、间皮癌、甲状腺瘤、肝癌、食管癌和白血病等人类肿瘤中存在IDO1过表达现象，并且发现肿瘤组织内IDO1的表达量与肿瘤的恶性程度以及患者的预后不良密切相关(Uyttenhove C,et al.Nat Med,2003,9(10):1269-1274；Théate I,etal.Cancer Immunol Res,2015,3(2):161-172；Curti A,et al.Blood,2007,109(7):2871-2877.)。
早期研发的第一代IDO1抑制剂主要是作用于含有血红素的IDO1蛋白(holo-IDO1)。至今为止，先后有4款holo-IDO1抑制剂进入临床开发。其中，Epacadostat与PD-1单抗Keytruda联用治疗黑色素瘤III期试验(ECHO-301)曾深受人们瞩目。然而，遗憾的是，ECHO-301试验最终未能达到临床终点。此外，其他3款holo-IDO1抑制剂的临床试验也显示阴性结果。
发明内容
发明目的：针对现有holo-IDO1抑制剂普遍存在的活性较低、成药性不足等问题，本发明旨在提供一类具有高效的apo-IDO1抑制活性以及优异的成药性的吲哚啉化合物及其衍生物、制备方法、药物组合物和应用。
技术方案：作为本发明的涉及的第一方面，本发明的吲哚啉化合物及其衍生物具有式(I)的结构，其衍生物涉及其立体异构体、互变异构体、代谢产物、代谢前体、前药、溶剂化物、溶剂化物的盐、结晶、药学上可接受的盐或它们的混合物：
其中：
X为-C(O)NH-、-S(O)2NH-或-CH2C(O)NH-；
R为氢、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或C3-C8环烷基；
所述D基团为氢、卤素、氰基、羟基、巯基、羧基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或者为被一个或多个卤素取代的C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基；
所述E基团为氢、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或者为被一个或多个卤素取代的C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基；
所述F基团为氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或者为被一个或多个卤素取代的C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基。
本发明设计的吲哚啉化合物为不含血红素的IDO1蛋白(apo-IDO1)的新一代抑制剂，可用于治疗IDO1介导的免疫抑制所引起的上述相关疾病。与holo-IDO1抑制剂相比，apo-IDO1抑制剂具有更高的选择性、更强的结合亲和力、更持久的结合时间和更有效的靶点覆盖率。
优选，所述吲哚啉化合物及其衍生物结构中：
X为-C(O)NH-；
R为C1-C6烷基；
所述D基团为氢、卤素、氰基、羟基、巯基、羧基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或者为被一个或多个卤素取代的C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基；
所述E基团为氢、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或者被一个或多个卤素取代的C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基；
所述F基团为氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或者为被一个或多个卤素取代的C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基。
进一步优选，所述吲哚啉化合物及其衍生物结构中：
R为甲基；
E基团为氢、卤素或C1-C6烷基；
F基团为氢、卤素、氰基或C1-C6烷氧基。
更进一步优选，所述吲哚啉化合物及其衍生物结构中：
所述D基团为氟、氯、溴或氰基；
所述E基团为氢、卤素或甲基；
所述F基团为氢、卤素、氰基或甲氧基。
更具体地，所述吲哚啉化合物为以下任一化合物：
其中，所述药学上可接受的盐为所述吲哚啉化合物与酸形成的盐，所述酸为盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、苹果酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。
作为本发明涉及的第二方面，本发明的吲哚啉化合物及其衍生物的制备方法为以下任一方法：
方法一：
以2,3-二氢吲哚为原料经酰化反应、傅-克酰基化反应、水解反应、酰化反应、缩合反应、还原反应、水解反应、酰化反应得到化合物(I)：
方法二：
以化合物C为原料，经酰化反应、缩合反应、还原反应、水解反应、酰化反应、水解反应、酰化反应得到化合物(Ⅰ)：
其中，
X的定义如前所述；
将相应的酸与以上方法制备的化合物(I)成盐，即得所述吲哚啉化合物的药学上可接受的盐。
更具体地，酰化反应是在碱的作用下进行，所述碱为三乙胺、二异丙基乙胺、吡啶、K2CO3或Cs2CO3；傅-克酰基化反应是在Lewis酸的作用下进行，所述Lewis酸为AlCl3；缩合反应是在手性试剂及脱水剂的作用下进行，所述手性试剂为叔丁基亚磺酰胺，所述脱水剂为钛酸乙酯；还原反应是在金属还原剂的作用下进行，所述金属还原剂为二氯双(4-甲基异丙基苯基)钌(Ⅱ)；水解反应是在酸的作用下进行，所述酸为盐酸、氢溴酸等。
作为本发明涉及的第三方面，本发明的药物组合物包含所述吲哚啉化合物和/或其衍生物以及药学上可接受的载体。
根据治疗目的可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液和悬浮液)等，优选片剂、胶囊、液体、悬浮液和针剂(溶液和悬浮液)。为了使片剂、丸剂或栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油)，制成与血液等渗压的针剂。在制备针剂时，也可以使用本领域内任何常用的载体。例如：水、乙醇、丙二醇、乙氧基化的异硬脂醇、聚乙氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可以加入通常溶解剂和缓冲剂等。
本发明所述的吲哚啉化合物和/或其衍生物在药物组合物中的含量可在很宽的范围内进行选择，通常为5％～95％，优先为30％～85％。
本发明所述的药物组合物的给药方法没有特殊限制，可根据患者年龄、性别和其它条件及症状，选择各种剂型的制剂给药。
作为本发明涉及的第四方面，本发明的吲哚啉化合物及其衍生物或者药物组合物应用于制备吲哚胺2,3-双加氧酶1抑制剂药物；所述药物用于治疗吲哚胺2,3-双加氧酶1介导的免疫抑制相关疾病，具体疾病为癌症、病毒感染、神经变性疾病、白内障、器官移植排斥、抑郁症或自身免疫性疾病。其中，所述癌症为恶性黑色瘤、肺癌、乳腺癌、胃癌、结肠癌、膀胱癌、胰腺癌、淋巴癌、白血病、前列腺癌、睾丸癌、肾癌、脑癌、头颈癌、卵巢癌、宫颈癌、子宫内膜癌、间皮癌、甲状腺瘤、肝癌、食管癌中的一种或多种；所述病毒感染为人类免疫缺陷病毒、乙型肝炎病毒、丙型肝炎病毒、流感病毒、脊髓灰质病毒、巨细胞病毒、柯萨奇病毒、人类乳头状瘤病毒、爱泼斯坦-巴尔病毒、水痘-带状疱疹病毒中的一种或多种引起的感染；所述神经变性疾病为记忆障碍症、阿尔茨海默病、认知障碍症、老年痴呆症、帕金森症、运动障碍性疾病中的一种或多种；所述自身免疫性疾病为类风湿性关节炎、系统性红斑狼疮、皮肌炎、硬皮病、结节性脉管炎、多发性硬化症、重症肌无力、混合性结缔组织病、银屑病、由于感染引起的自身免疫反应中的一种或多种。
进一步地，所述吲哚啉化合物及其衍生物可以与一种或多种其他种类的治疗剂和/或治疗方法联合用于治疗由IDO1介导的相关疾病。所述其他种类的治疗剂和/或治疗方法包括但不限于一种或多种化疗剂、靶向抗肿瘤药物、免疫检查点抑制剂、免疫检查点激动剂、抗肿瘤疫苗、抗病毒剂、抗病毒疫苗、细胞因子疗法、过继性细胞免疫治疗或放射治疗。其中，所述化疗剂不限于烷化剂、微管蛋白抑制剂、拓扑酶抑制剂、铂类药物、抗代谢类药物或激素类抗肿瘤药物；所述靶向抗肿瘤药物不限于蛋白激酶抑制剂、蛋白酶抑制剂、蛋白酶体抑制剂、异柠檬酸脱氢酶抑制剂、基于表观遗传学的抗肿瘤药物或细胞周期信号通路抑制剂；所述免疫检查点抑制剂不限于CTLA-4抑制剂、PD-1抑制剂、PD-L1抑制剂、PD-L2抑制剂、TIM-3抑制剂、VISTA抑制剂、LAG3抑制剂、TIGIT抑制剂、A2AR抑制剂或VTCN1抑制剂；所述免疫检查点激动剂不限于STING激动剂、4-1BB激动剂、OX40激动剂、RORγ激动剂或ICOS激动剂。
有益效果：与现有技术相比，本发明具有如下显著优点：
(1)该类吲哚啉化合物及其衍生物、药物组合物可有效抑制吲哚胺2,3-双加氧酶1活性(IC50最优小于10pM，甚至达到1.7pM)，能够有效逆转IDO1介导的免疫抑制作用；
(2)该类吲哚啉化合物及其衍生物、药物组合物应用广泛，可制备为治疗吲哚胺2,3-双加氧酶1介导的免疫抑制相关疾病药物；所述药物通过激活宿主免疫应答，在分子水平发挥药效，并且疗效优异，最优可达到皮摩尔浓度级别；
(3)化合物制备方法简便，易操作。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
试剂与材料：实验所需要的所有试剂未经特别说明均为市售化学纯或分析纯产品。
仪器：1HNMR用BrukerAV-300和400MHz型核磁共振仪测定，化学位移值(δ)以ppm为单位，耦合常数(J)值以Hz为单位，TMS为内标。质谱(MS)分析仪器为岛津LCMS-2020型质谱仪测定；薄层层析(TLC)使用青岛海洋化学有限公司生产HG/T2354-92型GF254薄层层析硅胶，ZF7型三用紫外分析仪254nm显色；柱色谱使用青岛海洋化工厂粗孔(ZCX-II)型300-400目柱层析硅胶；高效液相色谱(HPLC)分析仪器为Agilent1220 InfinityⅡ，手性柱使用大赛路HPLC用多糖衍生物涂敷型手性色谱柱(正相)(AD-H)，流速设置为1mL/min，检测时长为20min。
实施例1：(R)-N-(1-(1-(环己烷羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(1)合成
N-乙酰基吲哚啉(1A)合成
将2,3-二氢-1H-吲哚(10.00g,83.91mmol)和三乙胺(25.47g,251.73mmol)溶于40mL无水二氯甲烷中，冰浴下缓慢滴加乙酰氯(9.88g,125.87mmol)的无水二氯甲烷(10mL)溶液，室温反应过夜，减压浓缩，加入100mL水，二氯甲烷(3×80mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体11.78g，收率87.1％。MS(ESI)m/z:160.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ(ppm)8.05(d,J＝8.1Hz,1H),7.21(d,J＝7.2Hz,1H),7.14(t,J＝7.5Hz,1H),6.97(t,J＝7.5Hz,1H),4.05(t,J＝7.8Hz,2H),3.12(t,J＝8.4Hz,2H),2.14(s,3H).
1,5-二乙酰基吲哚啉(1B)合成
将1A(6.60g,40.94mmol)溶于25mL无水二氯甲烷中，0℃及氮气氛围下加入无水氯化铝(16.38g,122.83mmol)，缓慢滴加乙酰氯(4.82g,61.41mmol)的无水二氯甲烷溶液(10mL)，半小时后撤去冰浴，回流16h，在冰浴下用水(70mL)淬灭，二氯甲烷(3×60mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体7.32g，收率88.0％。MS(ESI)m/z:202.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ(ppm)8.09(d,J＝8.4Hz,1H),7.83-7.81(m,2H),4.15(t,J＝8.7Hz,2H),3.18(t,J＝8.7Hz,2H),2.52(s,3H),2.20(s,3H).
1-乙酰基吲哚啉(1C)合成
将1B(7.24g,35.62mmol)和浓盐酸(40mL,0.48mol)分别加入120mL封管中，80℃下反应3h，加水(20mL)，2M氢氧化钠溶液调节pH至8，乙酸乙酯(3×70mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体4.62g，收率80.5％。MS(ESI)m/z:160.1[M-H]-；1H NMR(300MHz,Chloroform-d)δ(ppm)7.74(s,2H),6.54(s,1H),4.19(s,1H),3.67(s,2H),3.08(s,2H),2.50(s,3H).
1-(1-(环己烷羰基)-2,3-二氢-1H-吲哚-5-基)乙酮(1D)合成
将1C(1.50g,9.31mmol)和三乙胺(1.41g,13.96mmol)溶于无水二氯甲烷(10mL)中，冰浴下缓慢滴加环己甲酰氯(1.63g,11.17mmol)的无水二氯甲烷(2mL)溶液，室温反应过夜，减压浓缩，加入50mL水，二氯甲烷(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体2.28g，收率90.3％。MS(ESI)m/z:270.2[M-H]-；1H NMR(300MHz,DMSO-d6)δ(ppm)8.15(d,J＝7.2Hz,1H),7.82-7.80(m,2H),4.22(t,J＝8.7Hz,2H),3.18(t,J＝8.4Hz,2H),2.62-2.56(m,1H),2.51(s,3H),1.84-1.65(m,5H),1.46-1.18(m,5H).
(R)-2-甲基-N-(1-(1-(环己烷羰基)-2,3-二氢-1H-吲哚-5-基)亚乙基)丙烷-2-亚磺酰胺(1E)合成
向1D(3.10g,11.42mmol)的无水四氢呋喃(15mL)溶液中加入(R)-(+)-叔丁基亚磺酰胺(2.08g,17.14mmol)和钛酸乙酯(5.21g,22.85mmol)，85℃回流12h。向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(20mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×30mL)萃取，柱层析分离纯化，得黄色固体3.47g，收率81.1％。MS(ESI)m/z:373.2[M-H]-；1H NMR(300MHz,Chloroform-d)δ(ppm)8.19(d,J＝7.8Hz,1H),7.73(s,1H),7.65(d,J＝8.4Hz,1H),4.12(t,J＝8.7Hz,2H),3.15(t,J＝8.1Hz,2H),2.65(s,3H),2.44-2.37(m,1H),1.79(d,J＝9.9Hz,5H),1.69-1.45(m,5H),1.24(s,9H).
(R)-2-甲基-N-(1-(1-(环己烷羰基)-2,3-二氢-1H-吲哚-5-基)乙基)丙烷-2-亚磺酰胺(1F)合成
取
分子筛(2.20g)于100mL圆底烧瓶中，加入8mL异丙醇，2-甲基-2-氨基-1-丙醇(26.18mg,0.29mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(0.097g,0.16mmol)，回流5min，冷却至55℃，加入1E(2.20g,5.87mmol)及叔丁醇钾(0.08g,0.70mmol)，55℃反应12h，加入15mL二氯甲烷稀释，硅藻土抽滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，柱层析分离纯化，得油状液体1.96g，收率88.7％。MS(ESI)m/z:375.2[M-H]-；1H NMR(300MHz,Chloroform-d)δ(ppm)8.23(d,J＝9.0Hz,1H),7.19-7.17(m,2H),4.55-4.48(m,1H),4.15(t,J＝8.4Hz,2H),3.37(d,J＝2.4Hz,1H),3.20(t,J＝8.4Hz,2H),2.47(m,1H),1.86(d,J＝9.6Hz,4H),1.67-1.51(m 3H),1.50(d,J＝6.6Hz,3H),1.35-1.28(m,3H),1.24(s,9H).
(R)-(5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-基)(环己烷)甲酮(1G)合成
将原料1F(0.51g,1.35mmol)溶于无水甲醇(1.5mL)中，加入盐酸二氧六环溶液(1.7M,10mL)，室温反应3h，减压浓缩，饱和NaHCO3溶液调节pH至9，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得黄色油状液体0.37g，收率100％。MS(ESI)m/z:271.2[M-H]-.
(R)-N-(1-(1-(环己烷羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(1)合成
将1G(0.20g,0.77mmol)和三乙胺(0.23g,2.31mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氟苯甲酰氯(0.15g,0.92mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.26g(95.0％ee)，收率86.7％。MS(ESI)m/z:393.2[M-H]-；1H NMR(300MHz,Chloroform-d)δ(ppm)8.16(d,J＝9.0Hz,1H),7.78-7.65(m,2H),7.14-7.12(m,2H),7.02(t,J＝8.7Hz,2H),6.19(d,J＝6.9Hz,1H),5.23-5.14(m,1H),4.06(t,J＝8.4Hz,2H),3.11(t,J＝8.4Hz,2H),2.42-2.33(m,1H),1.79-1.76(m,4H),1.66-1.64(m,1H),1.56-1.50(m,5H),1.26-1.19(m,3H).
实施例2：(R)-N-(1-(1-(环己烷羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(2)合成
将1G(0.080g,0.29mmol)和三乙胺(0.088g,0.87mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.061g,0.35mmol)的无水二氯甲烷(1mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.10g(99.1％ee)，收率83.3％。MS(ESI)m/z:409.2[M-H]-；1H NMR(300MHz,DMSO-d6)δ(ppm)8.82(d,J＝8.1Hz,1H),8.01(d,J＝8.1Hz,1H),7.90(d,J＝8.4Hz,2H),7.54(d,J＝8.7Hz,2H),7.24(s,1H),7.14(d,J＝8.4Hz,1H),5.12-5.08(m,1H),4.14(t,J＝8.4Hz,2H),3.11(t,J＝8.4Hz,2H),1.79-1.64(m,5H),1.44(d,J＝6.9Hz,3H),1.36-1.15(m,5H).
实施例3：(R)-N-(1-(1-(环己烷羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(3)合成
将1G(0.13g,0.48mmol)和三乙胺(0.14g,1.43mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氰基苯甲酰氯(0.080g,0.48mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.17g(99.5％ee)，收率89.5％。MS(ESI)m/z:400.2[M-H]-；1H NMR(300MHz,DMSO-d6)δ(ppm)9.00(d,J＝7.8Hz,1H),8.04-7.95(m,5H),7.25(s,1H),7.15(d,J＝8.7Hz,1H),5.15-5.06(m,1H),4.14(t,J＝8.4Hz,2H),3.11(t,J＝8.1Hz,2H),1.79-1.64(m,5H),1.45(d,J＝7.2Hz,3H),1.40-1.20(m,5H).
实施例4：(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(4)合成
1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙酮(4D)合成
将1C(2.00g,12.41mmol)和三乙胺(1.88g,18.62mmol)溶于10mL无水二氯甲烷中，冰浴下缓慢滴加4,4-二氟环己甲酰氯(2.72g,14.90mmol)的无水二氯甲烷(4mL)溶液，室温反应3h，减压浓缩，加入100mL水，二氯甲烷(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体3.30g，收率86.6％。MS(ESI)m/z:306.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ(ppm)8.15(d,J＝9.0Hz,1H),7.84-7.81(d,J＝6.1Hz,2H),4.26(t,J＝8.4Hz,2H),3.20(t,J＝8.4Hz,2H),2.83-2.76(m,1H),2.52(s,3H),2.12-2.03(m,2H),1.96-1.82(m,4H),1.72-1.60(m,2H).
(R)-2-甲基-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)亚乙基)丙烷-2-亚磺酰胺(4E)合成
向4D(3.10g,10.09mmol)的无水四氢呋喃(15mL)溶液中加入(R)-(+)-叔丁基亚磺酰胺(1.47g,12.11mmol)和钛酸乙酯(4.60g,20.18mmol)，85℃回流12h，向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(10mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体3.69g，收率89.1％。MS(ESI)m/z:409.2[M-H]-；1H NMR(300MHz,DMSO-d6)δ(ppm)8.13(d,J＝8.1Hz,1H),7.81-7.77(m,2H),4.25(t,J＝8.4Hz,2H),3.21(t,J＝8.4Hz,2H),2.82-2.76(m,1H),2.67(s,3H),2.11-2.04(m,2H),1.96-1.82(m,4H),1.72-1.60(m,2H),1.21(s,9H).
(R)-2-甲基-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)丙烷-2-亚磺酰胺(4F)合成
取
分子筛(2.20g)于50mL圆底烧瓶中，加入10mL异丙醇，2-甲基-2-氨基-1-丙醇(23.76mg,0.27mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(88.13mg,0.14mmol)，回流5min，冷却至55℃，加入4E(2.20g,5.36mmol)及叔丁醇钾(71.81mg,0.64mmol)，55℃反应12h，冷却，加入15mL二氯甲烷稀释，硅藻土抽滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得油状液体1.95g，收率88.2％。MS(ESI)m/z:411.2[M-H]-；1H NMR(300MHz,Chloroform-d)δ(ppm)8.21(d,J＝8.4Hz,1H),7.21-7.19(m,2H),4.55-4.49(m,1H),4.16(t,J＝8.4Hz,2H),3.37(d,J＝2.4Hz,1H),3.23(t,J＝8.4Hz,2H),2.59-2.54(m,1H),2.31-2.24(m,2H),2.06-1.96(m,4H),1.88-1.75(m,2H),1.50(d,J＝6.6Hz,3H),1.24(s,9H).
(R)-(5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-基)(4,4-二氟环己烷-1-基)甲酮(4G)合成
将原料4F(0.65g,1.58mmol)溶于2mL无水甲醇中，加入盐酸二氧六环溶液(1.7M,16mL)，室温反应3h，减压浓缩，饱和NaHCO3溶液调节pH至9，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得黄色油状液体0.49g，收率100％。MS(ESI)m/z:307.2[M-H]-.(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(4)合成
将4G(0.15g,0.49mmol)和三乙胺(0.15g,1.44mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氟苯甲酰氯(0.092g,0.58mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.19g(96.2％ee)，收率90.5％。MS(ESI)m/z:429.2[M-H]-；1HNMR(300MHz,Chloroform-d)δ(ppm)8.78(d,J＝8.1Hz,1H),8.08-7.88(m,3H),7.38-7.22(m,3H),7.16(d,J＝8.4Hz,1H),5.16-5.06(m,1H),4.18(t,J＝8.4Hz,2H),3.14(t,J＝8.4Hz,2H),2.79-2.71(m,1H),2.12-1.97(m,3H),1.92-1.81(m,3H),1.71-1.59(m,2H),1.45(d,J＝6.9Hz,3H).
实施例5：(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(5)合成
将4G(0.15g,0.49mmol)和三乙胺(0.15g,1.44mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.10g,0.58mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.18g(95.4％ee)，收率81.0％。MS(ESI)m/z:445.2[M-H]-；1HNMR(300MHz,Chloroform-d)δ(ppm)8.13(d,J＝8.7Hz,1H),7.63(d,J＝8.7Hz,2H),7.32(d,J＝8.4Hz,2H),7.15-7.13(m,2H),6.23(d,J＝7.2Hz,1H),5.22-5.15(m,1H),4.07(t,J＝8.4Hz,2H),3.14(t,J＝8.4Hz,2H),2.50-2.44(m,1H),2.22-2.14(m,2H),1.94-1.86(m,4H),1.79-1.64(m,2H),1.51(d,J＝6.9Hz,3H).
实施例6：(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(6)合成
将4G(0.15g,0.49mmol)和三乙胺(0.15g,1.44mmol)溶于5mL无水二氯甲烷中，0℃下缓慢滴加4-氰基苯甲酰氯(0.095g,0.58mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.18g(99.1％ee)，收率85.7％。MS(ESI)m/z:436.2[M-H]-；1HNMR(300MHz,Chloroform-d)δ(ppm)8.22(d,J＝8.7Hz,1H),7.88(d,J＝8.7Hz,2H),7.72(d,J＝8.4Hz,2H),7.24-7.21(m,2H),6.51(d,J＝7.5Hz,1H),5.32-5.23(m,1H),4.16(t,J＝8.4Hz,2H),3.23(t,J＝8.4Hz,2H),2.61-2.52(m,1H),2.32-2.19(m,2H),2.01-1.94(m,4H),1.91-1.75(m,2H),1.61(d,J＝6.9Hz,3H).
实施例7：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(7)合成
1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙酮(7D)合成
将1C(2.00g,12.41mmol)和三乙胺(3.77g,37.23mmol)溶于15mL无水二氯甲烷中，冰浴下缓慢滴加3-氯苯甲酰氯(2.61g,14.90mmol)的无水二氯甲烷(8mL)溶液，室温反应3h，减压浓缩，加入50mL水，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体3.58g，收率96.2％。MS(ESI)m/z:298.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.21-7.49(m,7H),4.21-4.00(m,2H),3.15(t,J＝8.4Hz,2H),2.54(s,3H).
(R)-2-甲基-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)亚乙基)丙烷-2-亚磺酰胺(7E)合成
向7D(3.58g,11.94mmol)的无水四氢呋喃(15mL)溶液中加入(R)-(+)-叔丁基亚磺酰胺(1.88g,15.52mmol)和钛酸乙酯(5.45g,23.88mmol)，85℃回流12h。向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(10mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体3.78g，收率78.6％。MS(ESI)m/z:401.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ7.89-7.54(m,7H),4.07(t,J＝5.7Hz,2H),3.20-3.13(m,2H),2.70(s,3H),1.22(s,9H).
(R)-2-甲基-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)丙烷-2-亚磺酰胺(7F)合成
取
分子筛(3.70g)于100mL圆底烧瓶中，加入8mL异丙醇，2-甲基-2-氨基-1-丙醇(40.92mg,0.46mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(0.15g,0.25mmol)，回流5min，冷却至55℃，加入7E(3.70g,9.18mmol)及叔丁醇钾(0.13g,1.19mmol)，55℃下反应12h，加入15mL二氯甲烷稀释，硅藻土抽滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得油状液体1.97g，收率53.0％。MS(ESI)m/z:403.1[M-H]-；1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.76-7.50(m,4H),7.31(s,1H),5.57(d,J＝7.6Hz,1H),5.32(s,1H),4.42-4.30(m,1H),4.08-3.93(m,2H),3.08(t,J＝8.2Hz,2H),1.38(d,J＝6.8Hz,3H),1.11(s,9H).
(R)-(5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-基)(3-氯苯基)甲酮(7G)合成
将原料7F(0.85g,2.10mmol)溶于2mL无水甲醇中，加入盐酸二氧六环溶液(14mL,1.7M)，室温反应3h，减压浓缩，饱和NaHCO3溶液调节pH至9，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得黄色油状液体0.63g，收率100％。MS(ESI)m/z:299.1[M-H]-.(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(7)合成
将7G(0.11g,0.37mmol)和三乙胺(0.15g,1.48mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氟苯甲酰氯(0.070g,0.44mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.14g(95.0％ee)，收率87.5％。MS(ESI)m/z:421.1[M-H]-；1H NMR(400MHz,Chloroform-d)δ7.86-7.74(m,2H),7.61-7.53(m,1H),7.50-7.38(m,2H),7.27(s,3H),7.20-7.09(m,3H),6.28(s,1H),5.36-5.22(m,1H),4.21-3.92(m,2H),3.16(d,J＝8.2Hz,2H),1.60(d,J＝7.2Hz,3H).
实施例8：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(8)合成
将7G(0.11g,0.37mmol)和三乙胺(0.15g,1.48mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.078g,0.44mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.15g(96.8％ee)，收率93.8％。MS(ESI)m/z:437.1[M-H]-；1HNMR(400MHz,Chloroform-d)δ(ppm)7.72(d,J＝8.4Hz,2H),7.58-7.34(m,7H),7.26(s,2H),6.34(s,1H),5.34-5.19(m,1H),4.16-3.98(m,2H),3.14(t,J＝9.6Hz,2H),1.59(d,J＝5.2Hz,3H).
实施例9：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-2-氯苯甲酰胺(9)合成
将7G(0.10g,0.33mmol)和三乙胺(0.13g,1.32mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加2-氯苯甲酰氯(0.081g,0.46mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.12g(98.3％ee)，收率80.0％。MS(ESI)m/z:437.1[M-H]-；1HNMR(300MHz,DMSO-d6)δ8.87(d,J＝7.5Hz,1H),7.86(s,1H),7.65(s,1H),7.56(d,J＝8.7Hz,3H),7.49-7.38(m,5H),7.32(s,1H),5.13-5.01(m,1H),4.08-3.95(m,2H),3.09(t,J＝8.1Hz,2H),1.41(d,J＝6.9Hz,3H).
实施例10：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-3-氯苯甲酰胺(10)合成
将7G(0.13g,0.43mmol)和三乙胺(0.17g,1.72mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加3-氯苯甲酰氯(0.098g,0.56mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.14g(99.6％ee)，收率73.7％。MS(ESI)m/z:437.1[M-H]-；1HNMR(300MHz,DMSO-d6)δ8.88(d,J＝6.3Hz,1H),7.98-7.79(m,3H),7.67-7.48(m,6H),7.31(s,1H),7.20(s,1H),5.20-5.04(m,1H),4.08-3.90(m,2H),3.08(t,J＝8.1Hz,2H),1.47(d,J＝6.9Hz,3H).
实施例11：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(11)合成
将7G(0.11g,0.37mmol)和三乙胺(0.15g,1.48mmol)溶于无水二氯甲烷(3mL)中，0℃下缓慢滴加4-氰基苯甲酰氯(0.061g,0.44mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.13g(95.0％ee)，收率81.3％。MS(ESI)m/z:428.1[M-H]-；1HNMR(400MHz,Chloroform-d)δ7.88(d,J＝8.4Hz,2H),7.73(d,J＝6.4Hz,2H),7.55-7.38(m,4H),7.27(s,3H),6.50(s,1H),5.34-5.18(m,1H),4.19-3.93(m,2H),3.15(t,J＝8.4Hz,2H),1.62(d,J＝6.8Hz,3H).
实施例12：(R)-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(12)合成
1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙酮(12D)合成
将1C(1.20g,7.44mmol)和三乙胺(2.26g,22.32mmol)溶于20mL无水二氯甲烷中，冰浴下缓慢滴加3-氟苯甲酰氯(1.42g,8.93mmol)的无水二氯甲烷(8mL)溶液，室温反应3h，减压浓缩，加入50mL水，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体2.00g，收率94.8％。MS(ESI)m/z:282.1[M-H]-；1H NMR(400MHz,Chloroform-d)δ7.86(s,1H),7.81(s,1H),7.50-7.45(m,1H),7.36(d,J＝7.6Hz,1H),7.31-7.19(m,3H),4.14(t,J＝8.4Hz,2H),3.19(t,J＝9.0Hz,2H),2.59(s,3H).
(R)-2-甲基-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)亚乙基)丙烷-2-亚磺酰胺(12E)合成
向12D(2.00g,7.06mmol)的无水四氢呋喃(15mL)溶液中加入(R)-(+)-叔丁基亚磺酰胺(1.03g,8.47mmol)和钛酸乙酯(3.22g,14.12mmol)，85℃回流12h。向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(10mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体2.44g，收率89.2％。MS(ESI)m/z:385.2[M-H]-；1H NMR(400MHz,DMSO-d6)δ7.84(m,3H),7.61-7.53(m,1H),7.52-7.44(m,2H),7.43-7.32(m,1H),4.06(t,J＝8.2Hz,2H),3.15(t,J＝8.4Hz,2H),2.69(s,3H),1.22(s,9H).(R)-2-甲基-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)丙烷-2-亚磺酰胺(12F)合成
取
分子筛(1.80g)于100mL圆底烧瓶中，加入6mL异丙醇，2-甲基-2-氨基-1-丙醇(20.64mg,0.23mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(76.55g,0.13mmol)，回流5min，冷却至55℃，加入12E(1.80g,4.66mmol)及叔丁醇钾(62.34g,0.56mmol)，55℃下反应12h，冷却，加入15mL二氯甲烷稀释，硅藻土抽滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得油状液体1.09g，收率60.2％。MS(ESI)m/z:387.2[M-H]-；1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.70-7.48(m,4H),7.31(s,1H),5.57(d,J＝7.6Hz,1H),5.32(s,1H),4.42-4.30(m,1H),4.12-3.94(m,2H),3.08(t,J＝8.2Hz,2H),1.38(d,J＝6.0Hz,3H),1.11(s,9H).
(R)-(5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-基)(3-氟苯基)甲酮(12G)合成
将原料12F(1.09g,2.81mmol)溶于无水甲醇(1.0mL)中，加入盐酸/1,4-二氧六环溶液(1.7M,14mL)，室温反应3h，减压浓缩，饱和NaHCO3溶液调节pH至9，乙酸乙酯(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得黄色油状液体0.80g，收率100％。MS(ESI)m/z:283.1[M-H]-.
(R)-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(12)合成
将12G(0.13g,0.46mmol)和三乙胺(0.14g,1.38mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氟苯甲酰氯(0.081g,0.51mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.15g(97.8％ee)，收率78.9％。MS(ESI)m/z:405.2[M-H]-；1H NMR(400MHz,DMSO-d6)δ8.80(d,J＝8.0Hz,1H),8.18-7.87(m,3H),7.71-7.13(m,8H),5.21-5.02(m,1H),4.06-3.84(m,2H),3.07(t,J＝8.2Hz,2H),1.46(d,J＝6.8Hz,3H).
实施例13：(R)-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(13)合成
将12G(0.13g,0.46mmol)和三乙胺(0.14g,1.38mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.097g,0.55mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.17g(98.8％ee)，收率89.5％。MS(ESI)m/z:421.1[M-H]-；1H NMR(400MHz,DMSO-d6)δ8.86(d,J＝7.6Hz,1H),7.91(d,J＝8.8Hz,3H),7.55(d,J＝8.4Hz,4H),7.47-7.17(m,4H),5.20-5.06(m,1H),4.07-3.91(m,2H),3.07(t,J＝8.2Hz,2H),1.46(d,J＝7.2Hz,3H).
实施例14：(R)-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(14)合成
将12G(0.13g,0.46mmol)和三乙胺(0.14g,1.38mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氰基苯甲酰氯(0.091g,0.55mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.16g(99.6％ee)，收率84.2％。MS(ESI)m/z:412.2[M-H]-；1H NMR(400MHz,DMSO-d6)δ9.05(d,J＝8.0Hz,1H),8.04(d,J＝8.4Hz,2H),7.97(d,J＝8.4Hz,2H),7.58-7.52(m,1H),7.49-7.19(m,6H),5.17-5.08(m,1H),4.04-3.95(m,2H),3.07(t,J＝8.4Hz,2H),1.47(d,J＝7.2Hz,3H).
实施例15：(R)-N-(1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(15)合成
1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙酮(15D)合成
将1C(1.20g,7.44mmol)和三乙胺(2.26g,22.32mmol)溶于15mL无水二氯甲烷中，冰浴下缓慢滴加3-氰基苯甲酰氯(1.48g,8.93mmol)的无水二氯甲烷(8mL)溶液，室温反应3h，减压浓缩，加入100mL水，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体2.00g，收率92.6％。MS(ESI)m/z:289.1[M-H]-；1H NMR(400MHz,DMSO-d6)δ8.22-7.67(m,7H),4.07(t,J＝8.4Hz,2H),3.15(t,J＝8.4Hz,2H),2.51(d,J＝4.0Hz,3H).
(R)-2-甲基-N-(1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)亚乙基)丙烷-2-亚磺酰胺(15E)合成
向15D(1.45g,4.99mmol)的无水四氢呋喃(15mL)溶液中加入(R)-(+)-叔丁基亚磺酰胺(0.73g,5.99mmol)和钛酸乙酯(2.28g,9.98mmol)，85℃回流12h。向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(10mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体1.41g，收率71.6％。MS(ESI)m/z:392.2[M-H]-；1H NMR(400MHz,DMSO-d6)δ8.34-7.52(m,7H),4.06(t,J＝8.4Hz,2H),3.15(t,J＝8.4Hz,2H),2.70(s,3H),1.22(s,9H).
(R)-2-甲基-N-(1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)丙烷-2-亚磺酰胺(15F)合成
取
分子筛(1.30g)于100mL圆底烧瓶中，加入8mL异丙醇，2-甲基-2-氨基-1-丙醇(15.15mg,0.17mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(54.56g,0.089mmol)，回流5min，冷却至55℃，加入15E(1.30g,3.30mmol)及叔丁醇钾(44.44g,0.40mmol)，55℃下反应12h，加入15mL二氯甲烷稀释，硅藻土抽滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩得油状液体1.31g，收率100％。MS(ESI)m/z:394.2[M-H]-.
(R)-(5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-基)(3-氰基苯基)甲酮(15G)合成
将原料15F(0.28g,0.71mmol)溶于2mL无水甲醇中，加入盐酸二氧六环溶液(1.7M,8mL)，室温反应3h，减压浓缩，饱和NaHCO3溶液调节pH至9，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得黄色油状液体0.21g，收率100％。MS(ESI)m/z:290.1[M-H]-.(R)-N-(1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(15)合成
将15G(0.14g,0.48mmol)和三乙胺(0.15g,1.44mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氟苯甲酰氯(0.091g,0.58mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.17g(97.9％ee)，收率85.0％。MS(ESI)m/z:412.2[M-H]-；1H NMR(400MHz,DMSO-d6)δ8.80(d,J＝8.0Hz,1H),8.09(s,1H),8.04-7.89(m,5H),7.71(t,J＝7.6Hz,1H),7.30(q,J＝8.0Hz,4H),5.18-5.09(m,1H),4.04-3.94(m,2H),3.08(t,J＝8.2Hz,2H),1.47(d,J＝7.2Hz,3H).
实施例16：(R)-N-(1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(16)合成
将16G(0.14g,0.48mmol)和三乙胺(0.15g,1.44mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.096g,0.55mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.19g(99.7％ee)，收率90.5％。MS(ESI)m/z:428.1[M-H]-；1H NMR(400MHz,DMSO-d6)δ8.87(d,J＝8.0Hz,1H),8.20-7.83(m,5H),7.71(t,J＝7.8Hz,1H),7.55(d,J＝8.5Hz,2H),7.41-7.03(m,2H),5.21-5.05(m,1H),4.15-3.89(m,2H),3.08(t,J＝8.2Hz,2H),1.47(d,J＝7.2Hz,3H).
实施例17：(R)-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(17)合成
1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙酮(17D)合成
将1C(1.29g,8.00mmol)和三乙胺(2.43g,24.01mmol)溶于10mL无水二氯甲烷中，冰浴下缓慢滴加2-氯吡啶-4-甲酰氯(1.69g,9.60mmol)的无水二氯甲烷(8mL)溶液，室温反应3h，减压浓缩，加入100mL水，二氯甲烷(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体2.00g，收率83.0％。MS(ESI)m/z:299.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ11.40(s,1H),8.21(s,1H),7.78(d,J＝8.1Hz,1H),7.45(d,J＝8.7Hz,2H),6.69-6.52(m,1H),3.52-3.43(m,2H),2.85-2.72(s,3H),2.67-2.41(m,2H).
(R)-2-甲基-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)亚乙基)丙烷-2-亚磺酰胺(17E)合成
向17D(1.82g,6.05mmol)的无水四氢呋喃(15mL)溶液中加入(R)-(+)-叔丁基亚磺酰胺(0.88g,7.26mmol)和钛酸乙酯(2.76g,12.10mmol)，85℃回流12h。向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(10mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体1.70g，收率69.7％。MS(ESI)m/z:402.1[M-H]-；1H NMR(400MHz,DMSO-d6)δ8.59(d,J＝5.6Hz,1H),8.15(d,J＝6.8Hz,1H),7.88(s,2H),7.80(s,1H),7.65(d,J＝5.2Hz,1H),4.03(t,J＝8.8Hz,2H),3.16(t,J＝8.2Hz,2H),2.70(s,3H),1.22(s,9H).
(R)-2-甲基-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)丙烷-2-亚磺酰胺(17F)合成
取
分子筛(1.65g)于100mL圆底烧瓶中，加入6mL异丙醇，2-甲基-2-氨基-1-丙醇(18.18mg,0.20mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(67.46mg,0.11mmol)，回流5min，冷却至55℃，加入17E(1.65g,4.08mmol)及叔丁醇钾(54.94mg,0.49mmol)，55℃下反应12h，冷却，加入15mL二氯甲烷稀释，抽滤，硅藻土助滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×30mL)萃取，合并有机相，无水硫酸钠干燥，抽滤，减压浓缩，得油状液体1.48g，收率89.2％。MS(ESI)m/z:404.1[M-H]-.
(R)-(5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-基)(2-氯吡啶基)甲酮(17G)合成
将原料17F(1.48g,3.65mmol)溶于3mL无水甲醇中，加入盐酸二氧六环溶液(1.7M,8mL)，室温反应3h，减压浓缩，加水(10mL)，饱和NaHCO3溶液调节pH至9，乙酸乙酯(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得淡黄色油状物1.10g，收率100％。MS(ESI)m/z:300.1[M-H]-.
(R)-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(17)合成
将17G(0.10g,0.33mmol)和三乙胺(0.13g,1.32mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氟苯甲酰氯(0.063g,0.40mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.11g(98.7％ee)，收率78.6％。MS(ESI)m/z:422.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.79(d,J＝7.8Hz,1H),8.56(d,J＝5.1Hz,1H),8.07-7.90(m,3H),7.74(s,1H),7.60(d,J＝5.1Hz,1H),7.31(d,J＝8.7Hz,4H),5.20-5.06(m,1H),3.96(t,J＝7.8Hz,2H),3.08(t,J＝8.1Hz,2H),1.47(d,J＝6.6Hz,3H).
实施例18：(R)-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(18)合成
将17G(0.10g,0.33mmol)和三乙胺(0.13g,1.32mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.069g,0.40mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.12g(98.6％ee)，收率80.0％。MS(ESI)m/z:438.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.85(d,J＝7.5Hz,1H),8.56(d,J＝5.1Hz,1H),8.02(d,J＝7.8Hz,1H),7.91(d,J＝8.4Hz,2H),7.74(s,1H),7.56(t,J＝9.6Hz,3H),7.36-7.22(m,2H),5.15(q,J＝7.8Hz,1H),3.96(t,J＝7.8Hz,3H),3.08(t,J＝8.1Hz,2H),1.47(d,J＝6.6Hz,3H).
实施例19：(R)-N-(1-(1-(4-氯吡啶-2-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(19)合成
5-乙酰-2,3-二氢-1H-吲哚-1-羧酸苄酯(19D)合成
将1C(1.54g,9.55mmol)和三乙胺(1.93g,19.10mmol)溶于15mL无水二氯甲烷中，冰浴下缓慢滴加氯甲酸苄酯(2.44g,14.33mmol)的无水二氯甲烷(8mL)溶液，室温反应3h，减压浓缩，加入80mL水，二氯甲烷(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体2.67g，收率94.7％。MS(ESI)m/z:294.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ7.89-7.31(m,8H),5.26(s,2H),4.07(t,J＝8.7Hz,2H),3.15(t,J＝8.7Hz,2H),2.51(s,3H).
(R,E)-5-(1-((叔丁基亚磺酰基)亚氨基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(19E)合成
向19D(1.70g,5.76mmol)的无水四氢呋喃(15mL)溶液中加入(R)-(+)-叔丁基亚磺酰胺(0.91g,7.49mmol)和钛酸乙酯(2.63g,11.52mmol)，在氮气氛围下85℃回流12h。向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(10mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体1.73g，收率75.2％。MS(ESI)m/z:397.2[M-H]-；1HNMR(300MHz,DMSO-d6)δ7.80(s,3H),7.49-7.31(m,5H),5.30(s,2H),4.06(t,J＝6.6Hz,2H),3.16(t,J＝8.4Hz,2H),2.67(s,3H),1.21(s,9H).
(R)-5-(1-((R)-叔丁基亚磺酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(19F)合成
取
分子筛(0.76g)于100mL圆底烧瓶中，加入6mL异丙醇，2-甲基-2-氨基-1-丙醇(8.51mg,0.096mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(31.58mg,0.052mmol)，回流5min，冷却至55℃，加入19E(0.76g,1.91mmol)及叔丁醇钾(25.72mg,0.23mmol)，55℃下反应12h，加入15mL二氯甲烷稀释，硅藻土抽滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩后，柱层析分离纯化，得油状液体0.70g，收率90.9％。MS(ESI)m/z:399.2[M-H]-；1H NMR(300MHz,DMSO-d6)δ7.65(s,1H),7.48-7.30(m,5H),7.25(s,1H),7.16(d,J＝8.1Hz,1H),5.50(d,J＝6.9Hz,1H),5.23(s,2H),4.29(q,J＝6.9Hz,1H),4.02(t,J＝8.4Hz,2H),3.09(t,J＝8.7Hz,2H),1.36(d,J＝6.6Hz,3H),1.10(s,9H).
(R)-5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(19G)合成
将原料19F(0.62g,1.55mmol)溶于2mL无水甲醇中，加入盐酸二氧六环溶液(1.7M,15mL)，室温反应3h，减压浓缩，加水(10mL)，饱和NaHCO3溶液调节pH至8，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得黄色固体0.46g，收率100％。MS(ESI)m/z:295.2[M-H]-.
(R)-N-5-(1-(4-氯苯甲酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(19H)合成
将19G(0.15g,0.51mmol)和三乙胺(0.15g,1.53mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.11g,0.61mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.19g，收率86.4％。MS(ESI)m/z:433.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.81(d,J＝8.0Hz,1H),8.03-7.86(m,3H),7.60-7.50(m,3H),7.41(d,J＝8.0Hz,4H),7.29-7.13(m,2H),5.23(s,2H),5.12(q,J＝7.5Hz,1H),4.02(t,J＝9.6Hz,2H),3.09(t,J＝6.9Hz,2H),1.45(d,J＝6.6Hz,3H).
(R)-N-(1-(2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺氢溴酸盐(19I)合成
将19H(0.13g,0.30mmol)和33％HBr的乙酸溶液(4mL)加入50mL圆底烧瓶中，室温反应3h，减压浓缩，饱和NaHCO3溶液调节pH至8，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得棕色油状物0.090g，收率100％。MS(ESI)m/z:299.1[M-H]-.
(R)-N-(1-(1-(4-氯吡啶-2-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(19)合成
将19I(0.055g,0.18mmol)和三乙胺(0.093g,0.90mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加4-氯吡啶-2-甲酰氯(0.045g,0.25mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×10mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.078g(97.7％ee)，收率96.3％。MS(ESI)m/z:438.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.87(d,J＝8.1Hz,1H),8.64(d,J＝5.4Hz,1H),8.08(d,J＝8.4Hz,1H),7.91(t,J＝6.9Hz,3H),7.73(d,J＝5.4Hz,1H),7.56(d,J＝8.1Hz,2H),7.37-7.24(m,2H),5.23-5.10(m,1H),4.18(t,J＝7.8Hz,2H),3.11(t,J＝8.1Hz,2H),1.49(d,J＝5.1Hz,3H).
实施例20：(R)-N-(1-(1-(6-氯吡啶-2-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(20)合成
将19I(0.10g,0.33mmol)和三乙胺(0.17g,1.65mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加6-氯-2-吡啶甲酰氯(0.070g,0.40mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.13g(98.5％ee)，收率89.7％。MS(ESI)m/z:438.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.86(d,J＝6.9Hz,1H),8.06(t,J＝6.9Hz,2H),7.92(d,J＝8.1Hz,2H),7.81(d,J＝7.4Hz,1H),7.70(d,J＝8.1Hz,1H),7.55(d,J＝8.1Hz,2H),7.36-7.23(m,2H),5.17(q,J＝8.4,1H),4.17(t,J＝8.1Hz,2H),3.12(t,J＝8.1Hz,2H),1.48(d,J＝6.9Hz,3H).
实施例21：(R)-N-(1-(1-(5-氯吡啶-3-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(21)合成
将19I(0.10g,0.33mmol)和三乙胺(0.13g,1.32mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加5-氯吡啶-3-甲酰氯(0.067g,0.40mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.12g(99.1％ee)，收率82.8％。MS(ESI)m/z:438.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ9.00-8.58(m,3H),8.21(s,1H),8.10-7.80(m,3H),7.57-7.54(m,2H),7.32-7.29(m,2H),5.14(q,J＝9.3Hz,1H),4.05(t,J＝9.6Hz,2H),3.11(t,J＝7.5Hz,2H),1.48(d,J＝5.7Hz,3H).
实施例22：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-5-氯-2-吡啶甲酰胺(22)合成
将7G(0.15g,0.50mmol)和三乙胺(0.15g,1.50mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加5-氯-2-吡啶甲酰氯(0.11g,0.60mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.17g(99.0％ee)，收率77.3％。MS(ESI)m/z:438.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ9.01(d,J＝8.1Hz,1H),8.71(s,1H),8.14-8.11(m,1H),8.02(d,J＝8.4Hz,1H),7.73-7.44(m,4H),7.31-7.28(m,2H),5.20-5.07(m,1H),4.07-3.92(m,2H),3.06(t,J＝8.2Hz,2H),1.51(d,J＝6.6Hz,3H).
实施例23：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺(23)合成
(R)-N-5-(1-(6-氯吡啶-3-甲酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(23H)合成
将19G(0.15g,0.51mmol)和三乙胺(0.21g,2.04mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加6-氯吡啶-3-甲酰氯(0.13g,0.71mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.17g，收率77.3％。MS(ESI)m/z:434.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.99(d,J＝7.8Hz,1H),8.85(d,J＝2.4Hz,1H),8.25(d,J＝5.7Hz,1H),7.63(d,J＝8.4Hz,2H),7.40(d,J＝7.8Hz,4H),7.24-7.21(m,2H),5.22(s,2H),5.12(q,J＝7.2Hz,1H),4.02-3.97(m,2H),3.17-2.98(m,2H),1.45(d,J＝6.9Hz,3H).
(R)-N-(1-(2,3-二氢-1H-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺氢溴酸盐(23I)合成
将23H(0.12g,0.28mmol)和33％HBr的乙酸溶液(6mL)加入50mL圆底烧瓶中，室温反应3h，减压浓缩，加水(3mL)，饱和NaHCO3溶液调节pH至8，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得棕色油状物0.084g，收率100％。MS(ESI)m/z:300.1[M-H]-.
(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺(23)合成
将23I(0.084g,0.28mmol)和三乙胺(0.11g,1.12mmol)溶于无水二氯甲烷(3mL)中，0℃下缓慢滴加3-氯苯甲酰氯(0.069g,0.39mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.093g(98.6％ee)，收率77.5％。MS(ESI)m/z:438.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ9.02(d,J＝7.4Hz,1H),8.84(d,J＝7.1Hz,1H),8.29-8.13(m,1H),7.78(d,J＝8.2Hz,1H),7.59-7.56(m,5H),7.27-7.23(m,2H),5.20-5.07(m,1H),3.99(t,J＝8.1Hz,2H),3.07(t,J＝8.3Hz,2H),1.47(d,J＝6.8Hz,3H).
实施例24：(R)-N-(1-(1-苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(24)合成
(R)-N-5-(1-(4-氟苯甲酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(24H)合成
将19G(0.70g,2.36mmol)和三乙胺(0.95g,9.44mmol)溶于10mL无水二氯甲烷中，0℃下缓慢滴加4-氟苯甲酰氯(0.52g,3.30mmol)的无水二氯甲烷(5mL)溶液，室温反应3h，减压浓缩，加入80mL水，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.73g，收率73.9％。MS(ESI)m/z:417.2[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.76(d,J＝7.8Hz,1H),8.00-7.91(m,2H),7.65(s,1H),7.42(d,J＝7.5Hz,3H),7.38-7.32(m,2H),7.31-7.22(m,3H),7.19(d,J＝7.8Hz,1H),5.24(s,2H),5.12(q,J＝7.2Hz,1H),4.01(t,J＝6.6Hz,2H),3.10(t,J＝8.4Hz,2H),1.46(d,J＝6.6Hz,3H).
(R)-N-(1-(2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺氢溴酸盐(24I)合成
将24H(0.15g,0.36mmol)和33％HBr的乙酸溶液(6mL)加入50mL圆底烧瓶中，室温反应2h，减压浓缩，加水(3mL)，饱和NaHCO3溶液调节pH至8，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩得棕色油状物0.10g，收率100％。MS(ESI)m/z:283.1[M-H]-.(R)-N-(1-(1-(苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(24)合成
将24I(0.10g,0.35mmol)和三乙胺(0.14g,1.40mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加苯甲酰氯(0.069g,0.49mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入40mL水，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.12g(98.7％ee)，收率85.7％。MS(ESI)m/z:387.2[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.77(d,J＝7.8Hz,1H),7.97-7.93(m,3H),7.52(d,J＝8.7Hz,5H),7.38-7.08(m,4H),5.12(q,J＝7.2Hz,1H),3.98(t,J＝7.5Hz,2H),3.07(t,J＝8.1Hz,2H),1.46(d,J＝6.9Hz,3H).
实施例25：(R)-N-(1-(1-(2-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(25)合成
将24I(0.16g,0.56mmol)和三乙胺(0.17g,1.69mmol)溶于8mL无水二氯甲烷中，0℃下缓慢滴加2-氟苯甲酰氯(0.12g,0.73mmol)的无水二氯甲烷(4mL)溶液，室温反应3h，减压浓缩，加入50mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.21g(98.9％ee)，收率91.3％。MS(ESI)m/z:405.2[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.79(d,J＝7.8Hz,1H),8.11-7.87(m,3H),7.55(d,J＝7.2Hz,2H),7.45-7.13(m,6H),5.16-5.12(m,1H),3.83(t,J＝7.8Hz,2H),3.09(t,J＝8.1Hz,2H),1.47(d,J＝7.2Hz,3H).
实施例26：(R)-N-(1-(1-(4-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(32)合成
将24I(0.12g,0.42mmol)和三乙胺(0.13g,1.26mmol)溶于5mL无水二氯甲烷中，0℃下缓慢滴加4-氯苯甲酰氯(0.080g,0.50mmol)的无水二氯甲烷(3mL)溶液，室温反应5h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.16g(96.9％ee)，收率88.9％。MS(ESI)m/z:421.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.77(d,J＝7.8Hz,1H),7.98-7.94(m,3H),7.58(q,J＝8.1Hz,4H),7.37-7.15(m,4H),5.12(q,J＝5.7Hz,1H),3.98(t,J＝8.1Hz,2H),3.07(t,J＝8.1Hz,2H),1.46(d,J＝6.9Hz,3H).
实施例27：(R)-N-(1-(1-(3-溴苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(27)合成
将24I(0.096g,0.34mmol)和三乙胺(0.10g,1.02mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加3-溴苯甲酰氯(0.097g,0.44mmol)的无水二氯甲烷(3mL)溶液，室温反应4h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.14g(99.1％ee)，收率87.5％。MS(ESI)m/z:465.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.78(d,J＝7.5Hz,1H),8.17-7.84(m,3H),7.82-7.63(m,2H),7.58(d,J＝7.5Hz,1H),7.45(t,J＝7.8Hz,1H),7.35-6.99(m,4H),5.20-5.06(m,1H),3.98(t,J＝7.8Hz,2H),3.07(t,J＝8.1Hz,2H),1.46(d,J＝6.9Hz,3H).
实施例28：(R)-N-(1-(1-(3-氯-2-氟苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-氟苯甲酰胺(28)合成
将24I(0.097g,0.34mmol)和三乙胺(0.10g,1.02mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加3-氯-2-氟苯甲酰氯(0.097g,0.44mmol)的无水二氯甲烷(3mL)溶液，室温反应5h，减压浓缩，加入40mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.12g(98.7％ee)，收率80.0％。MS(ESI)m/z:439.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.80(d,J＝8.1Hz,1H),8.08-7.90(m,3H),7.73(t,J＝7.8Hz,1H),7.53(d,J＝6.6Hz,1H),7.42-7.18(m,5H),5.15(q,J＝7.2Hz,1H),3.84(t,J＝7.8Hz,3H),3.11(d,J＝8.4Hz,2H),1.47(d,J＝7.2Hz,3H).
实施例29：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-氯-2-氟苯甲酰胺(29)合成
(R)-N-5-(1-(4-氯-2-氟苯甲酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(29H)合成
将19G(0.20g,0.67mmol)和三乙胺(0.27g,2.68mmol)溶于8mL无水二氯甲烷中，0℃下缓慢滴加4-氯-2-氟苯甲酰氯(0.16g,0.80mmol)的无水二氯甲烷(3mL)溶液，室温反应3h，减压浓缩，加入50mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.27g，收率93.1％。MS(ESI)m/z:451.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.77(d,J＝7.8Hz,1H),7.63-7.50(m,3H),7.44-7.38(m,6H),7.27-7.13(m,2H),5.24(s,2H),5.05(q,J＝7.5Hz,1H),4.01(t,J＝8.1Hz,2H),3.09(t,J＝8.7Hz,2H),1.41(d,J＝7.2Hz,3H).
(R)-N-(1-(2,3-二氢-1H-吲哚-5-基)乙基)-4-氯-2-氟苯甲酰胺氢溴酸盐(29I)合成
将29H(0.093g,0.21mmol)和33％HBr的乙酸溶液(3mL)加入圆底烧瓶中，室温反应2h，减压浓缩，加水(5mL)，饱和NaHCO3溶液调节pH至8，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩后得棕色固体0.067g，收率100％。MS(ESI)m/z:317.1[M-H]-.(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯-2-氟苯甲酰胺(29)合成
将29I(0.067g,0.21mmol)和三乙胺(0.085g,0.84mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加3-氯苯甲酰氯(0.048g,0.27mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入20mL水，二氯甲烷(3×10mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.089g(98.0％ee)，收率92.7％。MS(ESI)m/z:455.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.81(d,J＝7.8Hz,1H),8.14-7.05(m,10H),5.17-5.00(m,1H),4.00(t,J＝8.1Hz,2H),3.09(t,J＝8.1Hz,2H),1.42(d,J＝6.9Hz,3H).
实施例30：(R)-N-(1-(1-(3-氯-2-氟苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-氯-2-氟苯甲酰胺(30)合成
将29I(0.080g,0.25mmmol)和三乙胺(0.10g,1.00mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加3-氯-2-氟苯甲酰氯(0.063g,0.33mmol)的无水二氯甲烷(3mL)溶液，室温反应5h，减压浓缩，加入40mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.097g(98.3％ee)，收率80.8％。MS(ESI)m/z:473.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.83(d,J＝7.5Hz,1H),8.07(d,J＝8.1Hz,1H),7.74(t,J＝7.8Hz,1H),7.58-7.51(m,3H),7.41-7.25(m,4H),5.15-5.03(m,1H),3.86(t,J＝8.1Hz,2H),3.12(t,J＝8.1Hz,2H),1.43(d,J＝6.3Hz,3H).
实施例31：(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-溴苯甲酰胺(31)合成
(R)-N-5-(1-(4-溴苯甲酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(31H)合成
将19G(0.15g,0.51mmol)和三乙胺(0.15g,1.53mmol)溶于6mL无水二氯甲烷中，0℃下缓慢滴加4-溴苯甲酰氯(0.17g,0.77mmol)的无水二氯甲烷(3mL)溶液，室温反应3h，减压浓缩，加入40mL水，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.21g，收率87.5％。MS(ESI)m/z:477.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.80(d,J＝8.1Hz,1H),7.91-7.66(m,7H),7.44-7.34(m,3H),7.24(s,1H),7.17(d,J＝7.5Hz,1H),5.23(s,2H),5.15-5.00(m,1H),3.99(t,J＝8.7Hz,2H),3.10(t,J＝8.1Hz,2H),1.44(d,J＝6.9Hz,3H).
(R)-N-(1-(2,3-二氢-1H-吲哚-5-基)乙基)-4-溴苯甲酰胺氢溴酸盐(31I)合成
将31H(0.10g,0.21mmol)和33％HBr的乙酸溶液(5mL)加入圆底烧瓶中，室温反应3h，减压浓缩，饱和NaHCO3溶液调节pH至8，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩后得棕色油状物0.072g，收率100％。MS(ESI)m/z:343.1[M-H]-.
(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-溴苯甲酰胺(31)合成
将31I(0.072g,0.21mmol)和三乙胺(0.064g,0.63mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加苯甲酰氯(0.051g,0.29mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.096g(98.4％ee)，收率95％。MS(ESI)m/z:481.0[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.84(d,J＝7.8Hz,1H),8.12-7.77(m,3H),7.75-7.42(m,6H),7.28-7.23(m,2H),5.15-5.11(m,1H),4.00(t,J＝7.8Hz,2H),3.08(t,J＝8.1Hz,2H),1.46(d,J＝5.7Hz,3H).
实施例32：(S)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(32)合成
(S,E)-5-(1-((叔丁基亚磺酰基)亚氨基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(32E)合成
向19D(0.70g,2.37mmol)的无水四氢呋喃(10mL)溶液中加入(S)-(+)-叔丁基亚磺酰胺(0.43g,3.55mmol)和钛酸乙酯(1.08g,4.73mmol)，在氮气氛围下85℃回流12h。向反应液中加入100mL水，80mL乙酸乙酯，剧烈搅拌15min，抽滤，乙酸乙酯(10mL)洗涤滤饼，滤液减压浓缩，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得黄色固体0.69g，收率73.4％。MS(ESI)m/z:397.2[M-H]-；1H NMR(300MHz,DMSO-d6)δ7.80(s,3H),7.41-7.35(m,5H),5.30(s,2H),4.06(t,J＝6.6Hz,2H),3.16(t,J＝8.4Hz,2H),2.67(s,3H),1.21(s,9H).
(S)-5-(1-((S)-叔丁基亚磺酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(32F)合成
取
分子筛(0.69g)于100mL圆底烧瓶中，加入10mL异丙醇，2-甲基-2-氨基-1-丙醇(7.8mg,0.087mmol)和二氯双(4-甲基异丙基苯基)钌(Ⅱ)(27.10mg,0.044mmol)，回流5min，冷却至55℃，加入32E(0.69g,1.73mmol)及叔丁醇钾(23.83g,0.21mmol)，55℃下反应12h，冷却，加入15mL二氯甲烷稀释，抽滤，硅藻土助滤，21mL二氯甲烷：甲醇混合溶液(20:1,V/V)洗涤滤饼，滤液减压浓缩，二氯甲烷(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，柱层析分离纯化，得油状液体0.52g，收率75.4％。MS(ESI)m/z:399.2[M-H]-；1H NMR(300MHz,DMSO-d6)δ7.65(s,1H),7.38(dd,J＝18.8,7.0Hz,5H),7.25(s,1H),7.16(d,J＝8.1Hz,1H),5.50(d,J＝6.6Hz,1H),5.23(s,2H),4.29(q,J＝6.6Hz,1H),4.02(t,J＝8.4Hz,2H),3.09(t,J＝8.7Hz,2H),1.36(d,J＝6.6Hz,3H),1.10(s,9H).
(S)-5-(1-氨基乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(32G)合成
将原料32F(0.52g,1.30mmol)溶于无水甲醇(1.0mL)中，加入盐酸二氧六环溶液(1.7M,10mL)，室温反应3h，减压浓缩，加水(10mL)，饱和NaHCO3溶液调节pH至8，乙酸乙酯(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得黄色油状液体0.38g，收率100％。MS(ESI)m/z:295.2[M-H]-.
(S)-N-5-(1-(4-氯苯甲酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(32H)合成
将32G(0.15g,0.51mmol)和三乙胺(0.26g,2.55mmol)溶于无水二氯甲烷(3mL)中，0℃下缓慢滴加4-氯苯甲酰氯(0.12g,0.77mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.20g，收率90.9％。MS(ESI)m/z:433.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.81(d,J＝8.1Hz,1H),8.03-7.86(m,3H),7.60-7.50(m,3H),7.41(d,J＝8.1Hz,4H),7.25-7.21(m,2H),5.23(s,2H),5.12(q,J＝7.5Hz,1H),4.02(t,J＝9.6Hz,2H),3.09(t,J＝6.9Hz,2H),1.45(d,J＝6.6Hz,3H).
(S)-N-(1-(2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺氢溴酸盐(32I)合成
将32H(0.13g,0.30mmol)和33％HBr的乙酸溶液(4mL)加入50mL圆底烧瓶中，室温反应3h，减压浓缩，加水(10mL)，饱和NaHCO3溶液调节pH至8，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，得棕色固体0.090g，收率100％。MS(ESI)m/z:299.1[M-H]-.(S)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(32)合成
将32I(0.090g,0.30mmol)和三乙胺(0.12g,1.20mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加3-氯苯甲酰氯(0.068g,0.39mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加水(30mL)，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.12g(96.8％ee)，收率92.3％。MS(ESI)m/z:437.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.83(d,J＝8.1Hz,1H),7.90(d,J＝8.4Hz,3H),7.75-7.49(m,6H),7.36-7.07(m,2H),5.22-5.05(m,1H),3.99(t,J＝8.4Hz,2H),3.07(t,J＝8.1Hz,2H),1.46(d,J＝6.6Hz,3H).
实施例33：(R)-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺(33)合成
将23I(0.12g,0.40mmol)和三乙胺(0.16g,1.60mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加2-氯吡啶-4-甲酰氯(0.11g,0.60mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.16g(98.9％ee)，收率88.9％。MS(ESI)m/z:439.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ9.06-9.03(m,1H),8.87-8.84(m,1H),8.57(t,J＝4.5Hz,1H),8.17-8.14(m,2H),7.85-7.58(m,3H),7.34-7.31(m,2H),5.22-5.07(m,1H),3.98-3.94(m,2H),3.17-3.02(m,2H),1.48(d,J＝6.6Hz,3H).
实施例34：(R)-N-(1-(1-(3-氯-2-甲基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(34)合成
将19I(0.072g,0.24mmol)和三乙胺(0.073g,0.72mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加3-氯-2-甲基苯甲酰氯(0.054g,0.29mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.089g(97.9％ee)，收率80.9％。MS(ESI)m/z:451.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.86(d,J＝7.8Hz,1H),8.10(d,J＝8.1Hz,1H),7.90(d,J＝8.4Hz,2H),7.66-7.51(m,3H),7.40-7.21(m,4H),5.20-5.06(m,1H),4.28-4.10(m,2H),3.11-3.03(m,2H),2.27(s,3H),1.47(d,J＝6.9Hz,3H).
实施例35：(R)-N-(1-(1-(5-氯-2-甲基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(35)合成
将19I(0.072g,0.24mmol)和三乙胺(0.073g,0.72mmol)溶于3mL无水二氯甲烷中，0℃下缓慢滴加5-氯-2-甲基苯甲酰氯(0.054g,0.29mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.093g(98.9％ee)，收率84.5％。MS(ESI)m/z:451.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.86(d,J＝7.8Hz,1H),8.09(d,J＝8.1Hz,1H),7.91(d,J＝8.1Hz,2H),7.55(d,J＝8.1Hz,2H),7.46-7.22(m,5H),5.20-5.08(m,1H),3.77-3.66(m,2H),3.14-3.03(m,2H),2.24(s,3H),1.47(d,J＝6.6Hz,3H).
实施例36：(R)-N-(1-(1-(3-甲氧基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(36)合成
将19I(0.10g,0.33mmol)和三乙胺(0.10g,0.99mmol)溶于5mL无水二氯甲烷中，0℃下缓慢滴加3-甲氧基苯甲酰氯(0.068g,0.40mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.13g(97.9％ee)，收率92.9％。MS(ESI)m/z:433.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.85(d,J＝9.9Hz,1H),8.08-7.82(m,3H),7.54(d,J＝8.4Hz,2H),7.39(d,J＝6.9Hz,1H),7.33-6.91(m,5H),5.17-5.06(m,1H),4.07-3.92(m,2H),3.80(s,3H),3.12-2.99(m,2H),1.46(d,J＝7.5Hz,3H).
实施例37：(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-吲哚-5-基)乙基)-6-氟吡啶-3-甲酰胺(37)合成
(R)-N-5-(1-(6-氟吡啶-3-甲酰胺基)乙基)-2,3-二氢-1H-吲哚-1-羧酸苄酯(37H)合成
将19G(0.17g,0.57mmol)和N,N-二异丙基乙胺(0.30g,2.29mmol)溶于4mL无水二氯甲烷，0℃下缓慢滴加6-氟吡啶-3-甲酰氯(0.11g,0.69mmol)的无水二氯甲烷(3mL)溶液，室温反应3h，减压浓缩，加入30mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.21g，收率87.5％。MS(ESI)m/z:418.2[M-H]-；1H NMR(300MHz,DMSO-d6)δ8.96(d,J＝7.8Hz,1H),8.80-8.69(m,1H),8.47-8.36(m,1H),7.66(s,1H),7.50-7.12(m,8H),5.23(s,2H),5.11(q,J＝7.5Hz,1H),4.00(t,J＝7.5Hz,2H),3.09(t,J＝8.7Hz,2H),1.46(d,J＝6.9Hz,3H).
(R)-N-(1-(2,3-二氢-1H-吲哚-5-基)乙基)-6-氟吡啶-3-甲酰胺氢溴酸盐(37I)合成
将37H(0.11g,0.26mmol)和33％HBr的乙酸溶液(5mL)加入50mL圆底烧瓶中，室温反应3h，减压浓缩，加水(3mL)，饱和NaHCO3溶液调节pH至8，乙酸乙酯(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，得棕色油状物0.075g，收率100％。MS(ESI)m/z:284.1[M-H]-.
(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-吲哚-5-基)乙基)-6-氟吡啶-3-甲酰胺(37)合成
将37I(0.075g,0.26mmol)和N,N-二异丙基乙胺(0.14g,1.05mmol)溶于无水二氯甲烷(3mL)中，0℃下缓慢滴加4,4-二氟环己甲酰氯(0.072g,0.39mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入20mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.089g(97.3％ee)，收率80.9％。MS(ESI)m/z:430.2[M-H]-；1H NMR(300MHz,Chloroform-d)δ8.61(s,1H),8.30-8.17(m,2H),7.30-7.20(m,2H),6.99(d,J＝8.4Hz,1H),6.61(d,J＝6.3Hz,1H),5.38-5.20(m,1H),4.15(t,J＝7.8Hz,2H),3.23(d,J＝6.6Hz,2H),3.19-2.97(m,1H),2.58-2.49(m,1H),2.29-2.24(m,1H),1.98-1.90(m,5H),1.60(d,J＝6.9Hz,3H),0.96-0.82(m,1H).
实施例38：(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺(38)合成
将23I(0.079g,0.26mmol)和N,N-二异丙基乙胺(0.14g,1.05mmol)溶于无水二氯甲烷(2mL)中，0℃下缓慢滴加4,4-二氟环己甲酰氯(0.057g,0.31mmol)的无水二氯甲烷(2mL)溶液，室温反应3h，减压浓缩，加入20mL水，二氯甲烷(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸镁干燥，抽滤，减压浓缩，柱层析分离纯化，得白色固体0.092g(96.8％ee)，收率76.7％。MS(ESI)m/z:446.1[M-H]-；1H NMR(300MHz,DMSO-d6)δ9.01(d,J＝7.8Hz,1H),8.84(d,J＝7.5Hz,1H),8.33-8.12(m,1H),7.96(d,J＝8.1Hz,1H),7.81-7.61(m,1H),7.31-7.13(m,2H),5.11(q,J＝7.5Hz,1H),4.07(t,J＝8.1Hz,2H),3.12(t,J＝8.4Hz,2H),3.00-2.56(m,1H),2.50-2.45(m,1H),2.36-1.89(m,4H),1.46(d,J＝6.6Hz,3H),1.42-1.03(m,2H),0.93-0.72(m,1H).
实施例39：基于HeLa细胞的IDO1抑制活性测试
1、实验材料和主要仪器
HeLa细胞株：ATCC，离心机：Eppendorf(CHINA)，电热恒温鼓风干燥箱(DHG-924385-Ⅲ)：上海新苗医疗器械制造有限公司，乙酸(冰醋酸)：南京化学试剂股份有限公司，三氟乙酸：上海凌峰化学试剂有限公司，电子天平：Sartorius，对二甲氨基苯甲醛(CAS：100-10-7)：Aladdin，Recombinant Human IFN-γ(Catalog#AF-300-02)：PEPROTECH。
2、实验方法
从ATCC购买的HeLa细胞保存在最低基础培养基(2mM L-谷氨酰胺和调成含有1.5g/L碳酸氢钠、0.1mM非必需氨基酸、1mM丙铜酸钠和10％胎牛血清的Earle氏BSS)中。在37℃下将HeLa细胞保存在提供5％CO2的控湿培养箱中。实验设置空白组、模型组组(IFN-γ+L-色氨酸)和加药组(IFN-γ+L-色氨酸+受试化合物)。按5×103细胞/孔的密度将HeLa细胞接种在96孔培养板中，并培养过夜。第二天，含有IFN-γ(终浓度100ng/mL)、L-色氨酸(终浓度100μM)和化合物的系列稀释液(总体积200μL培养基)加给细胞。温育24h后将140μL上清液/孔移至新的96孔板中，加入10μL 6.1mol/L的三氯乙酸，在恒温烘箱中50℃温育30min以使产生的N-甲酰基犬尿氨酸水解为犬尿氨酸。然后以4000rpm将反应混合物离心10min以去除沉淀物。将100μL上清液/孔移至另一96孔板中，与等体积2％(w/v)对-二甲氨基苯甲醛的乙酸溶液混合。使用酶标仪在490nm处检测吸光值，所得结果利用GraphPad Prism软件处理。每个浓度设3个复孔，实验重复三次。
IDO1酶活抑制率(％)＝[(模型组-加药组)/(模型组-空白组)]×100％
此外，采用MTT法检测各组HeLa细胞的存活率，目的是为了考察化合物是否是通过抑制HeLa细胞的增殖来抑制IDO1的活性。
具体操作：在基于HeLa细胞的IDO1抑制活性的实验中，每孔吸取140μL上清液加至96孔板中，每孔加入20μL，4mg/mL MTT溶液，放入细胞培养箱，于37℃孵育4h，终止培养，离心后吸去孔内培养液。每孔加入200μL二甲基亚砜，置摇床上低速振荡10min，使结晶物充分溶解。在酶联免疫检测仪570nm处测量各孔的吸光值。
细胞存活率(％)＝加药组OD值/空白组OD值×100％
3、实验结果
按公式计算受试化合物的抑制率，IC50由百分抑制率和对数浓度值作图求得，分析结果见表1。指示为“A”的值表示对IDO1的抑制活性(IC50)介于1×10-3nM与1×10-1nM之间，指示为“B”的值表示IC50介于1×10-1nM与1nM之间。
表1本发明化合物对HeLa细胞增殖和IDO1活性的影响
a表示在1μM浓度下HeLa细胞的存活率；bLY-3381916为阳性对照化合物。
如表1所示，本发明的化合物对HeLa细胞的IDO1均有显著的抑制作用，所有化合物的IC50值均达到纳摩尔级别，而且其活性均优于阳性对照组LY-3381916；其中，化合物2、7～8、11、13的IC50值甚至小于10pM。此外，MTT检测结果表明，各组HeLa细胞在检测浓度下的存活率均保持在90％以上，表明这些化合物并不是通过抑制HeLa细胞的增殖来抑制IDO1活性，而是通过激活宿主免疫应答来发挥抗肿瘤活性。
Claims (10)
1.一种吲哚啉化合物及其衍生物，其特征在于，具有式(I)的结构，所述衍生物为所述吲哚啉化合物的立体异构体、互变异构体、代谢产物、代谢前体、前药、溶剂化物、溶剂化物的盐、结晶、药学上可接受的盐或它们的混合物：
其中：
X为-C(O)NH-、-S(O)2NH-或-CH2C(O)NH-；
R为氢、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或C3-C8环烷基；
所述D基团为氢、卤素、氰基、羟基、巯基、羧基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或者为被一个或多个卤素取代的C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基；
所述E基团为氢、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或者为被一个或多个卤素取代的C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基；
所述F基团为氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或者为被一个或多个卤素取代的C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基。
2.根据权利要求1所述的吲哚啉化合物及其衍生物，其特征在于，所述吲哚啉化合物及其衍生物结构中：
X为-C(O)NH-；
R为C1-C6烷基；
所述D基团为氢、卤素、氰基、羟基、巯基、羧基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或者为被一个或多个卤素取代的C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基；
所述E基团为氢、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或者为被一个或多个卤素取代的C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基；
所述F基团为氢、卤素、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6烷氨基或者为被一个或多个卤素取代的C1-C6烷基、C1-C6烷氧基或C1-C6烷氨基。
3.根据权利要求1或2所述的吲哚啉化合物及其衍生物，其特征在于，所述吲哚啉化合物及其衍生物结构中：
R为甲基；
E基团为氢、卤素或C1-C6烷基；
F基团为氢、卤素、氰基或C1-C6烷氧基。
4.根据权利要求1或2所述的吲哚啉化合物及其衍生物，其特征在于，所述吲哚啉化合物及其衍生物结构中：
所述D基团为氟、氯、溴或氰基；
所述E基团为氢、卤素或甲基；
所述F基团为氢、卤素、氰基或甲氧基。
5.根据权利要求1或2所述的吲哚啉化合物及其衍生物，其特征在于，所述吲哚啉化合物为以下任一化合物：
(R)-N-(1-(1-(环己基羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(1)，
(R)-N-(1-(1-(环己基羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(2)，
(R)-N-(1-(1-(环己基羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(3)，
(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(4)，
(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(5)，
(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(6)，
(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(7)，
(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(8)，
(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-2-氯苯甲酰胺(9)，
(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-3-氯苯甲酰胺(10)，
(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(11)，
(R)-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(12)，
(R)-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(13)，
(R)-N-(1-(1-(3-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氰基苯甲酰胺(14)，
(R)-N-(1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(15)，
(R)-N-(1-(1-(3-氰基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(16)，
(R)-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(17)，
(R)-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(18)，
(R)-N-(1-(1-(4-氯吡啶-2-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(19)，
(R)-N-(1-(1-(6-氯吡啶-2-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(20)，
(R)-N-(1-(1-(5-氯吡啶-3-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(21)，
(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-5-氯吡啶-2-甲酰胺(22)，
(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺(23)，
(R)-N-(1-(1-苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(24)，
(R)-N-(1-(1-(2-氟苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(25)，
(R)-N-(1-(1-(4-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(26)，
(R)-N-(1-(1-(3-溴苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氟苯甲酰胺(27)，
(R)-N-(1-(1-(3-氯-2-氟苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-氟苯甲酰胺(28)，
(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-氯-2-氟苯甲酰胺(29)，
(R)-N-(1-(1-(3-氯-2-氟苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-氯-2-氟苯甲酰胺(30)，
(R)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-5-基)乙基)-4-溴苯甲酰胺(31)，
(S)-N-(1-(1-(3-氯苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(32)，
(R)-N-(1-(1-(2-氯吡啶-4-甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺(33)，
(R)-N-(1-(1-(3-氯-2-甲基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(34)，
(R)-N-(1-(1-(5-氯-2-甲基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(35)，
(R)-N-(1-(1-(3-甲氧基苯甲酰基)-2,3-二氢-1H-吲哚-5-基)乙基)-4-氯苯甲酰胺(36)，
(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-吲哚-5-基)乙基)-6-氟吡啶-3-甲酰胺(37)，
(R)-N-(1-(1-(4,4-二氟环己烷-1-羰基)-2,3-二氢-1H-吲哚-吲哚-5-基)乙基)-6-氯吡啶-3-甲酰胺(38)。
6.根据权利要求1或2所述的吲哚啉化合物，其特征在于，所述药学上可接受的盐为所述吲哚啉化合物与酸形成的盐，所述酸为盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。
7.一种权利要求1～6任一所述的吲哚啉化合物的制备方法，其特征在于，所述制备方法为以下任一方法：
方法一：
以2,3-二氢吲哚为原料，经酰化反应、傅-克酰基化反应、水解反应、酰化反应、缩合反应、还原反应、水解反应、酰化反应得到化合物(I)：
方法二：
以化合物C为原料，经酰化反应、缩合反应、还原反应、水解反应、酰化反应、水解反应、酰化反应得到化合物(Ⅰ)：
其中，
X的定义如权利要求1～5任一所述；
将相应的酸与以上方法制备的化合物(I)成盐完全，即得所述吲哚啉化合物的药学上可接受的盐。
8.一种药物组合物，其特征在于，所述药物组合物包含权利要求1～6任一所述吲哚啉化合物及其衍生物以及药学上可接受的载体。
9.一种权利要求1～6任一所述的吲哚啉化合物及其衍生物或者权利要求8所述的药物组合物在制备吲哚胺2,3-双加氧酶1抑制剂药物中的应用。
10.根据权利要求9所述的应用，其特征在于，所述药物为治疗吲哚胺2,3-双加氧酶1介导的免疫抑制相关疾病的药物。
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