CN107176921B

CN107176921B - Indole compounds with antiviral activity in isatis root and derivatives thereof

Info

Publication number: CN107176921B
Application number: CN201610136059.2A
Authority: CN
Inventors: 石建功; 郭颖; 徐成博; 霸明宇; 陈明华; 陈勍; 朱承根; 杨颖�; 蒋建东; 曹颖莉; 郭庆兰; 张超; 林生; 唐克; 杨永春; 郭家梅
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2016-03-10
Filing date: 2016-03-10
Publication date: 2020-03-31
Anticipated expiration: 2036-03-10
Also published as: CN107176921A

Abstract

The invention discloses indole compounds extracted from isatis roots and shown in a general formula (I), derivatives thereof, pharmaceutically acceptable salts thereof, a preparation method of the compounds and a pharmaceutical composition thereof. The compound has obvious anti-HIV activity and anti-influenza virus activity, and can be used for preparing anti-HIV or anti-influenza virus medicines or health products.

Description

Indole compounds with antiviral activity in isatis root and derivatives thereof

Technical Field

The invention relates to indole derivatives and pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition containing the compounds, and application of the compounds in resisting HIV virus and influenza virus, belonging to the technical field of medicines.

Background

Human Immunodeficiency Virus (HIV) destroys the immune system of the body by infecting immune cells of the body, causing the patient to eventually die of complications such as severe infection or secondary tumors. The disease caused by the virus is called Acquired Immunodeficiency Syndrome (Acquired Immunodeficiency Syndrome), i.e. AIDS^[1]。

The united nations aids planning agency (uneds) report shows that, by the end of 2012, the total number of aids virus infections worldwide is 3500 ten thousand [ 3220-3880 ten thousand ], including 330 ten thousand children [ 300-370 ten thousand ]. 230 million [ 190-270 million ] newly infected people with AIDS Worldwide in 2012, and 160 million [ 140-190 million ] dead people all the year round [ http:// www.actoronto.org/home. The data statistics in 2012 show that the accumulated reports of AIDS virus infected persons and AIDS patients in China are 43.4 thousands, and 8.8 thousands of people die. By the end of 2011, 15.4 million people of AIDS patients living in China are estimated [ http:// www.avert.org/hiv-aids-china. The report also shows that the number of people infected with AIDS in China is increased year by year, and the epidemic situation is serious in some areas, so that the work of preventing and treating AIDS still needs to be deeply developed.

HIV belongs to the group of human lentiviruses of the genus lentivirus of the family Retroviridae, and is divided into human immunodeficiency virus type I (HIV-1) and human immunodeficiency virus type II (HIV-2), most AIDS patients in China are caused by HIV-1 type virus infection, and HIV-2 is mainly distributed in western Africa^[2]. Aids cannot be cured yet and there is no prophylactic vaccine. Currently, highly active-antiretroviral therapy (HAART) is mainly used, i.e. several (usually 3 or 4) antiretroviral drugs are administered simultaneously, wherein the combination of two nucleoside reverse transcriptase inhibitors and one non-nucleoside reverse transcriptase inhibitor or protease inhibitor is a conventional regimen^[3]. By the end of 2013, 26 drugs have been approved for the treatment of aids on the market, which are classified into 6 classes by their mechanism of action: 7 nucleoside reverse transcriptase inhibitors; 5 Non-Nucleoside Reverse transcription Inhibitors (Non-nucleotide Reverse Transcriptase Inhibitors, NNRTIs); 10 protease inhibitors; 2 integrase inhibitors; 1 fusion inhibitor; 1 CCR5 inhibitor. The virus replication speed can be effectively reduced through drug combination, the immune function of a patient is recovered, and the purpose of prolonging the life of the patient is achieved. However, since the virus cannot be completely eliminated and the patient needs to take the medicine for a lifetime, resistant virus is inevitably generated, resulting in a significant decrease in the therapeutic effect of HAART. Therefore, the research and development of new drugs with high drug resistance against HIV-1 virus is an important subject in the field of AIDS treatment.

HIV-1 Reverse Transcriptase (RT) is a functional group necessary for completing reverse transcription of single-stranded RNA into double-stranded DNA, and plays a vital role in the life cycle of HIV-1, so RT becomes a classical target of AIDS treatment drugs^[4]. RT is a heterodimer composed of a p66 subunit and a p51 subunit, p66 isA functional subunit having RNA-dependent DNA polymerase activity, DNA-dependent DNA polymerase activity and ribonuclease H (RNase H) activity. The p66 subunit is divided into a polymerase activity region and an RNase H activity region, wherein the polymerase activity region has a highly conserved sequence similar to the right hand, and comprises a region of a finger (residues 1-85 and 118-155), a palm (residues 86-117), a thumb (residue 238-318) and a joining region (residue 319-426), and the polymerase activity center is positioned in the center of the palm and is a highly conserved region (comprising D110, D185 and D186). The non-nucleoside reverse transcriptase inhibitor acts on a hydrophobic pocket (NNIBP) at 1nm from the active central site of the reverse transcriptase, and after the drug is combined with the reverse transcriptase, the effective conformation of the active region of the reverse transcriptase is changed, so that the combination of the enzyme and the substrate is inhibited^[5]. Currently marketed non-nucleoside reverse transcriptase inhibitors are delavirdine, nevirapine, efavirenz, etravirine and rilpivirine, respectively.

Non-nucleoside reverse transcriptase inhibitors are important components of highly effective antiretroviral therapy and are commonly used in combination with nucleoside reverse transcriptase inhibitors. With the long-term widespread use of HAART, resistant viruses have come along and are characterized by multidrug resistance, resulting in therapeutic failure. Statistically, at least 50% of patients clinically have a drug-resistant virus. Through more than ten years of clinical application of nevirapine and efavirenz, stable drug-resistant strains appear^[6]. Clinical studies find that after the etravirine and rilpivirine are taken for 48 weeks, drug-resistant viruses aiming at the etravirine and rilpivirine can be generated in vivo. Therefore, the development of novel non-nucleoside reverse transcriptase inhibitors is the focus of the anti-AIDS field.

Table 1: clinically common NNRTIs drug-resistant mutation sites, incidence rate and drug-resistant times

Viral diseases are the main infectious diseases of human beings, and common diseases caused by viruses are: (1) epidemic diseases such as influenza, measles, mumps, etc.; (2) chronic infectious diseases, such as AIDS and hepatitis B; (3) latent infectious diseases such as herpetic keratitis and the like; (4) some tumors, such as nasopharyngeal carcinoma, cervical carcinoma, etc. The prevention and treatment of viral diseases are important research subjects in the current medical and pharmaceutical fields, and the research and invention of medicaments for treating viral diseases, particularly for simultaneously treating various viral diseases, have important potential application values.

Influenza viruses are the causative agents of influenza and are one of the leading causes of human death. Influenza viruses belong to the family orthomyxoviridae, and are classified into three types, a (a), B (B), and C (C), according to the difference in antigenicity of internal proteins, and most closely related to humans are influenza a viruses, whose genome consists of 8 single-stranded negative-strand RNAs, encoding at least 10 proteins: hemagglutinin (HA), Neuraminidase (NA), Polymerase (Polymerase basic protein1, PB 1; Polymerase basic protein 2, PB 2; Polymerase acidic protein 3, PA), Nucleoprotein (NP), Matrix protein (Matrix protein1, M1; Matrix protein 2, M2), nonstructural protein (Non-structural protein1, NS 1; Non-structural protein 2, NS 2). Influenza virus strains are numerous, influenza A virus is divided into a plurality of subtypes according to the antigenicity difference of virus envelope proteins hemagglutinin HA and neuraminidase NA, 17 HA and 10 NA are found, and the HA and NA subtypes can form different combinations, such as H1N1, H2N2, H3N2, H5N1, H7N9 subtypes and the like.

The anti-influenza drugs clinically applied at present are mainly divided into two types according to the action mechanism: one class is amantadine and rimantadine, which inhibit the M2 ion channel protein; the other is neuraminidase inhibitor which inhibits the release of influenza virus, oseltamivir, zanavir and peramivir. Statistical data show that all anti-influenza drugs on the market at present have drug-resistant virus strains, and the American centers for disease control and prevention have suggested amantadine and rimantadine drugs not to be used as clinical treatment because the drug resistance is too severe. Besides the anti-influenza medicines, various single-ingredient and compound traditional Chinese medicine preparations, such as isatis root granules, Shuanghuanglian oral liquid and the like, are also effective treatment medicines for resisting influenza viruses.

The Isatis root is the root of Isatis tinctoria L and Isatis tinctoria Fort of Cruciferae, is cultivated all over the country, is rich in resources, is also a traditional common traditional Chinese medicine in China, has the effects of clearing heat and removing toxicity, cooling blood and relieving sore throat, and is mainly used for treating viral infection diseases such as influenza, mumps, hepatitis B, herpes simplex virus keratitis, pharyngitis, verruca plana, pinkeye, dacryocystitis, varicella, measles and the like^[7,8]. The 2010 version of Chinese pharmacopoeia defines that the isatis root has the efficacies of clearing away heat and toxic material, cooling blood and relieving sore throat, and is used for epidemic seasonal toxicities, fever and pharyngalgia, epidemic macula, mumps, erysipelas, major head plague, erysipelas and carbuncle swelling. Especially, the isatis root and the preparation thereof play an important role as one of Chinese recommended emergent Chinese medicine varieties in the prevention and treatment of SARS and avian influenza.

The previous pharmacological research of radix Isatidis mainly focuses on the activity evaluation of its water or alcohol extract, injection prepared from it and separated parts, and the related research results show that radix Isatidis injection has effects of inhibiting infection and proliferation, and has obvious virucidal effect on hemorrhagic fever virus and herpes simplex virus^[7]Has significant inhibitory effect on hepatitis B surface antigen (HBsA g), hepatitis B virus antigen (HBeAg), hepatitis B virus core antigen (HBcAg) and HBV-DNA^[9](ii) a The radix Isatidis extract or separated part has effects of inhibiting human herpes simplex virus HSV-I and HSV-II type virus, and inhibiting TK gene transcription^[10,^11]Inhibiting HSV-I infection of Hep-2 cell, inactivating HSV-I^[12]Inhibiting replication of dog kidney cell (MDCK) inoculated human influenza A1 virus PR8 strain (A/PR/8/34, H1N1)^[13,^14]Inhibiting human cytomegalovirus HCMV^[15]Inhibiting Hela cell line from transfecting mumps virus^[16]And inhibiting porcine kidney cell infection with pseudorabies virus pre-and post-cytopathic effect^[17]And the like. And in some evaluations showed that the activity of isatis root extract was comparable to or stronger than that of positive control acyclovir (Aciclovir), Zidovudine (AZT) or polyinosinic. Additionally, radix Isatidis ethanol extractionThe product and its separation part have inhibiting effect on Staphylococcus aureus and Pseudomonas aeruginosa, and on mouse ear swelling caused by xylene and foot swelling caused by carrageenan, and the effect is equivalent to that of positive control drug indometacin^[18,19]. Therefore, the antiviral effect of the isatis root extract is definite.

From the 80 s of the last century, researchers at home and abroad have also conducted continuous research on chemical components of isatis root and its leaves, and nearly 80 compounds with various structures, including alkaloid, lignan, ceramide and flavone, as well as epigoitrin and 2-hydroxy-3-butenyl thiocyanic acid, have been isolated and identified. Although the research also finds that the indole alkaloid components such as indirubin derivatives, tryptanthrin, 2,4(1H,3H) -quinazoledione, adenosine and the like respectively have certain pharmacological activities such as anti-tumor, antibacterial and antiviral activities^[20～22]The syringic acid, salicylic acid, anthranilic acid, benzoic acid, 4(3H) -quinazolinone and other components have obvious effects of resisting endotoxin, inhibiting TNF α and NO release and the like^[23-30]And the effect of inhibiting the activity of 5-lipoxygenase or reducing the level of leukotriene B (4) secretion from cells^[31～33]. However, due to the limitations of sample size and pharmacological evaluation models, most compounds have not been evaluated for activity determination, and in particular, the content, activity intensity, etc. of the reported compounds are difficult to correspond to the strong activity against various viruses exhibited by the extract and isolated fraction of isatis root. It follows that the antiviral active ingredients in the isatis root extract are not yet fully understood at present.

Based on the above background, combined with the situation that most of the previous radix Isatidis chemical component researches are extracted by ethanol or methanol, while the traditional application and pharmacological evaluation of radix Isatidis are mainly decocted in water, we have developed the research of radix Isatidis water decoction extract, and have conducted systematic and deep research from the aspects of chemical component separation, antiviral activity evaluation, structural transformation association and derivatization, and structure-activity relationship^[34～36]. In the research, an N-alkoxy indole derivative, methyl-2- [2- (1-methoxy-1H-indol-3-yl) acetamide, with remarkable HIV-1 replication inhibition activity is found]Benzoate { Methyl 2- [2- (1-met)hoxy-1H-indol-3-yl)acetamido]benzoate, 1 }. Therefore, the inventive result of the invention is obtained by taking the compound as a lead structure and optimizing the structure modification.

Indole derivatives are not only widely found in plants, but also many clinically used drugs contain indole-forming units, and they have a wide variety of biological activities, such as anti-inflammatory, anti-tumor, anti-viral, anti-bacterial, etc. Meanwhile, some indole derivatives with good anti-HIV-1 activity are reported in the literature^[37,38]. However, the compounds shown in these documents are not only unsubstituted derivatives of indole N, but also have significant differences between the overall structure and the structure of the compounds of the present invention.

In addition, there are reports on derivatives with complex structure in which indole nitrogen atom is substituted by alkoxy and cytotoxic activity thereof^[39]However, they were not found to have anti-HIV as well as anti-influenza activity.

Reference documents:

1)Douek D C,Roederer M,Koup R A.Emerging concepts in theimmunopathogenesis of AIDS[J].Annual review of medicine,2009,60:471-81.

2)Levy J A.HIV pathogenesis and long-term survival[J].Aids,1993,7:1401-1410.

3)Engelman A,Cherepanov P.The structural biology of HIV-1:mechanisticand therapeutic insights[J].Nature Reviews Microbiology,2012,10(4):279-290.

4)Jonckheere H,AnnéJ,De Clercq E.The HIV-1reverse transcription(RT)process as target for RT inhibitors[J].Medicinal research reviews,2000,20:129-154.

5)Sarafianos S G,Marchand B,Das K,et al.Structure and function ofHIV-1reverse transcriptase:molecular mechanisms of polymerization andinhibition[J].Journal of molecular biology,2009,385:693-713.

6)Ren J,Stammers D K.Structural basis for drug resistance mechanismsfor non-nucleoside inhibitors of HIV reverse transcriptase[J].Virus research,2008,134:157-170.

7) jiangsu New medical college, Chinese medicine dictionary, Shanghai, science and technology Press, 1986, 1250-.

8) The State administration of Traditional Chinese Medicine (TCM) is "China materia Medica" ed committee, China materia Medica, Shanghai: Shanghai science and technology Press, 1999: 709-.

9) The comparison of 50 Chinese herbal medicines for treating hepatitis and preparations for inhibiting HBA g activity in vitro, modern applied medicine 1992,9,208 and 211.

10) He Li Wei, Li Xiang, Chen Jian Wei, etc. screening the antiviral effective parts of isatis root, and Chinese pharmacy 2008,19(3): 2565-.

11) Dongwei, Zhang Jun Feng, He Li Wei, etc. research on the molecular mechanism of active components of radix Isatidis against herpes simplex virus type 1, Shizhen Chinese medicines 2011,22,396 + 398.

12) The formula is Jian nationality, Tangjie, Yang Zhang Qiu, etc. the in vitro anti-herpes simplex virus I effect of radix isatidis, Chinese herbal medicine, 2005,36,242 and 244.

13) Liu Sheng, Chen Wan Sheng, Qiao Zhuo, Isatis indigotica of different germplasm and dyers woad leaf have the effect of resisting influenza A virus, and second Legionnaire university bulletin 2000,26,204 and 206.

14) The primary screening research of active substances of isatis root for resisting influenza A1 virus, the university of traditional Chinese medicine of Guangzhou, 2011,28,419 and 422.

15) Sun Guanglian, HUZHILI, MANHONG, MTT method for detecting anti-cytomegalovirus effect of radix Isatidis, Shandong college of traditional Chinese medicine 2000,24, 137-one 139.

16) Zhao Yan Ling, Xiao He, Hu Yan. the biological thermodynamic method compares the antiviral action of different extraction parts of isatis root, and liberates the military pharmaceutical science bulletin 2005,21, 410-.

17)S.L.Hsuan,S.C.Chan g,S.Y.Wan g,et al.The cytotoxicity to leukemiacells and antiviral effects of Isatis indi gotica extracts on pseudorabiesvirus,J.Ethnopharm.,2009,123,61-67.

18) Jie, spring Yang, break, etc. evaluation of the bacteriostatic and anti-inflammatory active components of isatis root, the pharmaceutical journal 2003,2 in China Hospital: 327-.

19)Ho Y.L.Chan g Y.S.Studies on the antinociceptive,anti-inflammatoryand antipyretic effects of Isatis indi gotica root,Phytomedicine,2002,9,419-424.

20) "Shousanshan" in Shang, jin Yu, Sun Yuqing, the research progress of chemical composition, pharmacology and quality control of Isatis root, Shenyang pharmaceutical university report 2003,20, 455-.

21) The institute of medicine, institute of Chinese medicine and sciences, modern research on Chinese herbal medicine, Beijing, Press of Chinese synergetic medical university, volume I, 1994, 227.

22) Liangyonghong, Houhuaxin, Lithostrong, Isatis root diketone B in vitro anticancer activity research, Chinese herbal medicine 2000,31,531-533.

23) Isatis root chloroform extract and components thereof have a comparative effect on resisting endotoxin, namely Liuyun, Linaihua, Ding level, etc., and the pharmaceutical journal 2001,21, 326-charge 328 of Chinese hospitals.

24) The research on the anti-endotoxin activity of the F022 part of the isatis root, China journal 2002,27,439 and 442.

25)J.g.Fan g,Y.H.Liu,W.Q.Wan g,et al.The anti-endotoxic effect of o-aminobenzoic acid from radix Isatidis,Acta Pharm.Sini 2005,26,593-597.

26)g.W.Qin,R.S.Xu，Recent advances on bioactive natural products fromChinese medicinal plants,Med.Res.Rev.1998,18,375-382.

27)Fan g J.g.,Liu Y.H.,Wan g W.Q.,et al.Anti-endotoxic effects ofsyrin gic acid of radix Isatidis,J Huazhon g Univ.Sci.Tech.[Med.Sci.]2003,23,206-208.

28) Liuyun Hai, Fangjian, Gongxue Wu, etc. the anti-endotoxin effect of syringic acid in radix Isatidis, Chinese herbal medicines 2003,31,926 and 928.

29) Lijing, Liuyun Hai, Tangjie, etc. the anti-endotoxin effect of salicylic acid in radix Isatidis, in the journal of pharmacy 2007,27, 1349-one 1352 in China.

30) The antiendotoxin effect of 4(3H) -quinazolinone in isatis root, Lijing, Liuyun Hai, Huangming Sheng, etc., Huaxi pharmaceutical journal 2008,23,07-09.

31)H.Danz,S.Stoyanova,M.Hambur ger,Identification and isolation ofthe cyclooxy genase-2inhibitory principle in Isatis tinctoria,PlantaMed.2001,67,411-416.

32)C.Oberthur,R.Ja g gi,M.Hambur ger,HPLC based activity profilin gfor 5-lipoxy genase inhibitory activity in Isatis tinctoria leaf extracts,Fitoterapia 2005,76,324-332.

33)P.Molina,A.Tárra ga,A.gonzalez-Tejero,et al.Inhibition ofleukocyte functions by the alkaloid isaindi gotone from Isatis indi goticaand some new synthetic derivatives,J.Nat.Prod.2001,64,1297–1300.

34)M.H.Chen,L.S.gan,S.Lin,X.L.Wan g,L.Li,Y.H.Li,C.g.Zhu,Y.N.Wan g,B.Y.Jian g,J.D.Jian g,Y.C.Yan g,J.g.Shi,Alkoloids from the root of Isatisindi gotica J.Nat.Prod.2012,75,1167–1176.

35)M.H.Chen,S.Lin,L.Li,C.g.Zhu,X.L.Wan g,Y.N.Wan g,B.Y.Jian g,S.J.Wang,Y.H.Li,J.D.Jian g,J.g.Shi,Alkoloids from the root of Isatis indi gotica,Org.Lett.2012,22,5668–5671.

36) Wangxiang, Chenming Hua, Wang Fang, Bopeng Bing, Linsheng, Zhucheng Gen, Liyuhuan, Jiandong, Shijiagong, research on chemical components of radix Isatidis water extract, Chinese journal of TCM 2013,38,1172 and 1182.

37) Wu-uncle Wen, Zhou Hai Bing, Tianbo, Dongchun' e, Ouyangjie, Hanxin, CN 103113285A.

38)T.Wan g,Z.Yin,Z.Zhan g,J.A.Bender,Z.Yan g,g.Johnson,Z.Yan g,L.M.Zadjura,C.J.D’Arienzo,D.D.Parker,C.gesenber g,g.A.Yamanaka,Y.-F.gon g,H.-T.Ho,H.Fan g,N.Zhou,B.V.McAuliffe,B.J.E g gers,L.Fan,B.Nowicka-Sans,I.B.Dicker,Q.gao,R.J.Colonno,P.-F.Lin,N.A.Meanwell and J.F.Kadow,Inhibitorsof human immunodeficiency virus type 1(HIV-1)attachment.5.an evolution fromindole to azaindoles leadin g to the discovery of 1-(4-benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)ethane-1,2-dione(BMS-488043),a dru g candidate that demonstrates antiviral activity in HIV-1infected subjects,J.Med.Chem.,2009,52(23),7778–7787

39)S.A.Lakatosh,J.Balzarini,g.Andrei,R.Snoeck,E.De Clercq,M.N.Preobrazhenskaya,Synthesis,and cytotoxic activity of Nind-alkoxyderivatives of antibiotic arcyriarubin and dechloro-rebeccamycin a glycon,TheJournal of Antibiotics,2002,8,768-773

Disclosure of Invention

The technical problem to be solved by the invention is to provide indole compounds and pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition and application of the indole compounds in preparation of anti-HIV or anti-influenza virus drugs or health care products.

The first aspect of the technical scheme of the invention provides indole compounds and pharmaceutically acceptable salts thereof, wherein the structural formula of the indole compounds is shown as a general formula (I):

wherein the content of the first and second substances,

n is an integer selected from 1,2, 3 and 4;

r is mono-or polysubstituted and is selected from hydrogen, halogen, C_1-6Alkyl or C_1-6An alkoxy group;

x is selected from hydrogen, substituted or unsubstituted C_1-16Alkyl radical, C_3-6Cycloalkyl radical, C_1-6Alkanoyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzoyl; wherein said substituents are optionally substituted with: OH, C_1-6Alkyl radical, C_1-6Alkoxy, halogen, NH₂、NO₂Cyano, carboxyl, phenyl, C_1-6Unsaturated alkyl radical, C_3-6Cycloalkyl radical, C_1-6An alkoxyacyl group;

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

z is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; wherein said substituents are optionally substituted with: halogen, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxyl, C_1-6An alkoxyacyl group.

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA) and pharmaceutically acceptable salts thereof

Wherein R is mono-substituted or multi-substituted and is selected from hydrogen, halogen and C_1-6Alkyl or C_1-6An alkoxy group;

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA1) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

R₁is mono-or polysubstituted and is selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxyl, C_1-6An alkoxyacyl group; wherein the mono-substitution is selected from ortho-position, meta-position and para-position mono-substitution; the polysubstitution is selected from disubstituted, trisubstituted, tetrasubstituted and pentasubstituted.

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA1a) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA1b) and pharmaceutically acceptable salts thereof

Wherein R is mono-or polysubstituted and is selected from hydrogen,halogen, C_1-6Alkyl or C_1-6An alkoxy group;

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA1c) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA1d) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl,C_1-6an alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA1e) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA1f) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA1g) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA1h) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

R₁is mono-or polysubstituted and is selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxyl, C_1-6An alkoxyacyl group; whereinThe single substitution is selected from ortho-position, meta-position and para-position single substitution; the polysubstitution is selected from disubstituted, trisubstituted, tetrasubstituted and pentasubstituted.

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA1I) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

R₁is mono-or polysubstituted and is selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxyl, C_1-6An alkoxyacyl group; wherein the mono-substitution is selected from ortho-position, meta-position and para-position mono-substitution; the polysubstitution is selected from disubstituted, trisubstituted, tetrasubstituted and pentasubstituted;

R₁' is selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6An alkoxy group.

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA1j) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

R₁is mono-or polysubstituted and is selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxyl, C_1-6An alkoxyacyl group; wherein said sheetThe substitution is selected from ortho-position, meta-position and para-position monosubstitution; the polysubstitution is selected from disubstituted, trisubstituted, tetrasubstituted and pentasubstituted;

R₁is selected from C_1-6Alkyl, phenyl.

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA2) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

R₂is mono-or polysubstituted and is selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxyl, C_1-6An alkoxyacyl group; wherein the monosubstitution is selected from ortho-position and meta-position monosubstitution of amide group; the polysubstitution is selected from disubstituted, trisubstituted and tetrasubstituted.

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA 2') and pharmaceutically acceptable salts thereof

Wherein R is mono-substituted or poly-substitutedIs selected from hydrogen, halogen, C_1-6Alkyl or C_1-6An alkoxy group;

x is selected from substituted or unsubstituted C_1-6An alkyl group; wherein said substituents are optionally substituted with: OH, C_1-6Alkyl radical, C_1-6Alkoxy, halogen, NH₂、NO₂Cyano, carboxyl, phenyl, C_1-6Unsaturated alkyl radical, C_3-6Cycloalkyl radical, C_1-6An alkoxyacyl group;

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA2a) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA2b) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA2c) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA2d) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA2e) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA3) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

R₂is mono-or polysubstituted and is selected from hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxyl, C_1-6An alkoxyacyl group; wherein the monosubstitution is selected from ortho-position, meta-position and para-position monosubstitution of amide group; the polysubstitution is selected from disubstituted, trisubstituted and tetrasubstituted.

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IA4) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IB) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

Preferred compounds of formula (I) and pharmaceutically acceptable salts thereof include, but are not limited to, compounds of formula (IC) and pharmaceutically acceptable salts thereof

y is selected from hydrogen, halogen, cyano, carboxyl, C_1-6An alkyl group;

In a second aspect of the present invention, there is provided a process for preparing a compound of the first aspect, which can be synthesized by the following steps and methods:

wherein R, n, Y, Z are as defined in the first aspect of the invention

Carrying out amidation reaction on substituted 3-indole carboxylic acid (formula 1) and various amines to obtain a formula 2, and reducing the formula 2 to obtain an intermediate formula 3; reacting substituted indole (formula 4) with acyl chloride to obtain formula 5, performing amidation reaction with different amines to obtain formula 6, and reducing to obtain formula 7; the intermediate formula 3 and the intermediate formula 7 are oxidized and N-substituted to obtain a target compound formula 8, and then indole 2-position substitution is carried out to obtain a target compound formula 9.

In a third aspect of the present invention, there is provided a pharmaceutical composition containing the compound of the first aspect and its pharmaceutically acceptable salt, wherein the pharmaceutical composition contains a therapeutically effective amount of the indole derivatives and its pharmaceutically acceptable salt of the present invention, and optionally a pharmaceutically acceptable carrier. Wherein the medicinal carrier refers to a medicinal carrier commonly used in the field of pharmacy; the pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention and its pharmaceutically acceptable salt in its pharmaceutical composition is usually 0.1 to 95% by weight.

The compounds of the present invention and their pharmaceutically acceptable salts or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like.

The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.

The compound and the pharmaceutically acceptable salt thereof can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.

For tableting the compounds of the present invention and pharmaceutically acceptable salts thereof, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.

The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.

In order to encapsulate the administration unit, the active ingredient of the compound of the present invention and a pharmaceutically acceptable salt thereof may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. Or the effective component of the compound and the pharmaceutically acceptable salt thereof can be prepared into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compounds of the present invention and their pharmaceutically acceptable salt tablets may also be used to prepare capsules of the compounds of the present invention and their pharmaceutically acceptable salts.

In order to prepare the compound and the pharmaceutically acceptable salt thereof into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field are added, wherein the solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl- β -cyclodextrin and the like, the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide and the like, the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate and the like, and mannitol, glucose and the like can be added as a propping agent for preparing freeze-dried powder injection.

In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.

For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

Therefore, another object of the present invention is to provide applications of the indole derivatives and the pharmaceutically acceptable salts thereof in the fields of pharmaceuticals and health care products, in particular applications of the indole derivatives and the pharmaceutically acceptable salts thereof in preparing antiviral drugs, and the indole derivatives and the pharmaceutically acceptable salts thereof can be used for preparing drugs and health care products for treating diseases caused by viruses, in particular anti-HIV viruses and anti-influenza viruses.

When the indole derivative and the pharmaceutically acceptable salt thereof or the composition of the invention are used for treating the diseases, the dosage of the indole derivative and the pharmaceutically acceptable salt thereof or the composition of the invention can be referred to the dosage of the indole derivative for treatment; when the indole derivative of the present invention or the composition of the present invention is used as a health product or added to a health product, the amount thereof should be less than the usual therapeutic amount.

The inventor carries out a large number of pharmaceutical experiments, and proves that the indole derivative has the effects of inhibiting the replication of HIV and influenza virus, has good treatment effect on diseases caused by the HIV and the influenza virus, can be used as or added into health-care products, and is beneficial to improving physical conditions and enhancing immunity.

The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is from 0.001 to 150mg/Kg body weight, preferably from 0.1 to 100mg/Kg body weight, more preferably from 1 to 60mg/Kg body weight, and most preferably from 2 to 30mg/Kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.

The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.

The fourth aspect of the technical scheme of the invention is to provide the compound of the first aspect and the pharmaceutically acceptable salt thereof and the application of the pharmaceutical composition of the third aspect in preparing anti-HIV drugs or health products.

The fifth aspect of the technical scheme of the invention is to provide the compound and the pharmaceutically acceptable salt thereof in the first aspect and the application of the pharmaceutical composition in the third aspect in preparing anti-influenza virus medicines or health care products.

Detailed description of the invention:

various aspects and features of the disclosure are described further below.

All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure. The following are definitions of various terms used herein, which apply to the terms used throughout the specification of the present application unless otherwise specified in specific instances.

As referred to herein, the terms "halo", "halogen atom", "halo", and the like, denote fluorine, chlorine, bromine, or iodine, preferably chlorine or bromine.

Definitions for various groups of the compounds of the present invention are provided below and, unless otherwise defined, are used uniformly throughout the specification and claims.

According to the inventionAs mentioned, the term "alkyl" refers to an alkyl group having the specified number of carbon atoms, which may be straight or branched, such as the mentioned "C_1-6When the alkyl group "is used, it means an alkyl group having 1,2, 3,4,5 or 6 carbon atoms and may include C_1-5Alkyl radical, C_1-4Alkyl radical, C_2-5Alkyl radical, C_2-4Alkyl radical, C_2-3Alkyl radical, C_3-5Alkyl, etc., and preferred specific groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl; as referred to herein, the term "C_1-16Alkyl "which refers to an alkyl group having 1,2, 3,4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 carbon atoms and may include C_1-10Alkyl radical, C_1-6Alkyl radical, C_2-10Alkyl radical, C_2-6Alkyl radical, C_3-4Alkyl, etc., and preferred specific groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl;

as referred to herein, the term "C_3-6Cycloalkyl "refers to a cycloalkyl group having 3,4,5, 6 carbon atoms, and may include C_3-5Cycloalkyl radical, C_3-4Cycloalkyl radical, C_4-6Cycloalkyl radical, C_4-5Cycloalkyl radical, C_5-6Cycloalkyl, etc., and preferred specific groups are, for example, cyclopropane, cyclopentane, and cyclohexane.

As referred to herein, the term "C_1-6Alkoxy "which means an alkoxy group having 1,2, 3,4,5, 6 carbon atoms and may include C_1-5Alkoxy radical, C_1-3Alkoxy radical, C_2-5Alkoxy radical, C_2-3Alkoxy radical, C_3-4Alkoxy, and the like, and preferred specific groups are, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy;

as referred to herein, the term "C_1-6Alkanoyl "refers to an alkanoyl group having 1,2, 3,4,5, 6 carbon atoms and may include C_1-5Alkanoyl radical, C_1-3Alkanoyl radical, C_2-4Alkanoyl radical, C_2-3Alkanoyl radical, C_3-4Alkanoyl and the like, and preferred specific groups such as formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, sec-butyryl, tert-butyryl;

as referred to herein, the term "C_1-6Alkoxyacyl group "which means an alkoxyacyl group having 1,2, 3,4,5, 6 carbon atoms and may include C_1-5Alcoxyl acyl radical, C_1-3Alcoxyl acyl radical, C_2-5Alcoxyl acyl radical, C_2-3Alcoxyl acyl radical, C_3-4A sub-range of groups represented by alkoxyacyl group and the like, and preferred specific groups such as methoxyacyl group, ethoxyacyl group;

as referred to herein, the term "C_1-6Unsaturated alkyl "which means an unsaturated alkyl group having 1,2, 3,4,5, 6 carbon atoms and may include C_1-5Unsaturated alkyl of C_1-4Unsaturated alkyl of C_2-5Unsaturated alkyl of C_2-4Unsaturated alkyl group of (b), etc., and preferred specific groups such as vinyl, ethynyl, isopropenyl, isobutenyl, isopentenyl, 1, 4-dibutenyl;

as mentioned in the present invention, the pyridyl group is linked to the mother nucleus in the 2,3, 4 positions, preferably in the 4 position.

The beneficial technical effects are as follows:

in the process of researching the active ingredients of the traditional Chinese medicine isatis root, the inventor of the invention separates methyl-2- [2- (1-methoxy-1H-indol-3-yl) acetamide with remarkable anti-HIV (human immunodeficiency virus) and anti-influenza virus effects from isatis root by an activity tracking method]Benzoic acid esters. On the basis of the above-mentioned amino acid, methyl-2- [2- (1-methoxy-1H-indol-3-yl) acetamide is prepared]The synthesis and derivatization modification of benzoate, and the further evaluation of the antiviral activity of the compounds confirm the anti-HIV and anti-influenza effects of the compounds, and the compounds have strong inhibitory activity on wild and drug-resistant HIV viruses and influenza viruses. Wherein the HIV virus is treatedIC of Compounds with the highest inhibitory Activity₅₀The value can reach 0.01 mu M, and the compound has better activity on Nevirapine and Efavirenz drug-resistant HIV virus; IC of Compounds having the highest inhibitory Activity against influenza A/Puerto Rico/8/1934(H1N1)₅₀The value can reach 1.9 mu M, is superior to the clinical first-line medicament ribavirin, and is superior to the clinical first-line medicament tamiflu in the infection activity of resisting influenza A virus A/Hubei Hongshan/50/2005 (H1N1), A/Jing prevention 262/95(H1N1), A/Jing prevention/359/95 (H3N2) and B/Jiangxi new construction/BV/39/2008.

Detailed Description

The following examples further illustrate the invention but are not intended to limit the invention in any way.

Example 1: preparation of 2- (1-hydroxy-1H-indol-3-yl) -N-phenylacetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; aniline (0.62g) and DMAP (0.15g) are added, and the mixture is stirred at room temperature and reacts for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude 2- (1H-indol-3-yl) -N-phenylacetamide as a pale reddish brown oil.

Secondly, dissolving 2- (1H-indol-3-yl) -N-phenylacetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude 2- (indolin-3-yl) -N-phenylacetamide as a dark brown oil.

Thirdly, dissolving 2- (indolin-3-yl) -N-phenylacetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g) and 5miDropwise adding 30% hydrogen peroxide (10mL) into the n, and reacting for 1h at 15-20 ℃ after dropwise adding; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the organic phase was subjected to column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to give 2- (1-hydroxy-1H-indol-3-yl) -N-phenylacetamide (0.64g) as a brown gum.¹HNMR(400MHz,acetone-d₆):δ10.26(1H,s,N-H),9.31(1H,s,N-OH),7.69(3H,m,H-4,2’,6’),7.50(1H,d,J＝8.0Hz,H-7),7.41(1H,s,H-2),7.28(3H,m,H-6,3’,5’),7.11(2H,m,H-5,4’),3.87(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.7(C-9),139.9(C-1’),134.9(C-7a),129.41(C-3’),129.37(C-5’),125.3(C-2),124.5(C-3a),124.3(C-6),122.6(C-4’),120.3(C-2’),120.2(C-6’),119.8(C-5),119.6(C-4),109.1(C-7),104.9(C-3),34.6(C-8)；(+)-HR-ESIMS m/z 267.1136[M+H]⁺(calcd for C₁₆H₁₄N₂O₂,267.1089)。

Example 2: preparation of ethyl-2- [2- (1-hydroxy-1H-indol-3-yl) acetamide ] benzoate

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding ethyl anthranilate (1.09g) and DMAP (0.15g), and stirring at room temperature for reacting for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude ethyl-2- [2- (1H-indol-3-yl) acetamide ] benzoate as a pale reddish brown oil.

Secondly, dissolving ethyl-2- [2- (1H-indol-3-yl) acetamide ] benzoate in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was stripped of solvent under reduced pressure at 50 ℃ to give crude ethyl-2- [2- (indolin-3-yl) acetamide ] benzoate as a dark brown oil.

In the third step, ethyl-2- [2- (indolin-3-yl) acetamide]Dissolving benzoate in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; separating the organic phase by column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain brown gum ethyl-2- [2- (1-hydroxy-1H-indol-3-yl) acetamide]Benzoate (0.71 g).¹H NMR(400MHz,acetone-d₆):δ10.99(1H,brs,N-H),10.21(1H,s,N-OH),8.71(1H,d,J＝8.4Hz,H-3’),7.95(1H,d,J＝8.0Hz,H-6’),7.59(1H,d,J＝8.0Hz,H-4),7.53(1H,t,J＝7.6Hz,H-4’),7.48(1H,s,H-2),7.42(1H,d,J＝8.0Hz,H-7),7.17(1H,t,J＝7.6Hz,H-6),7.05(2H,m,H-5,5’),4.22(2H,q,H-8’),3.86(2H,s,H-8),1.28(3H,t,H-9’)；¹³C NMR(400MHz,acetone-d₆):δ170.8(C-9),168.2(C-7’),142.4(C-2’),134.9(C-4’,7a),131.5(C-6’),125.8(C-2),124.7(C-3a),123.1(C-6),122.8(C-4’),120.7(C-5),120.0(C-3’),119.6(C-4),116.4(C-1’),109.2(C-7),104.2(C-3),61.9(C-8’),35.8(C-8),14.3(C-9’)；(+)-HR-ESIMS m/z 339.1353[M+H]⁺(calcd for C₁₉H₁₈N₂O₄,339.1300)。

Example 3: preparation of methyl-3- [2- (1-hydroxy-1H-indol-3-yl) acetamide ] -4-methylbenzoate

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; 4-methyl-3-amino-benzoic acid methyl ester (1.09g) and DMAP (0.15g) are added, and the mixture is stirred and reacted for 3 hours at room temperature; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude methyl-3- [2- (1H-indol-3-yl) acetamide ] -4-methylbenzoate as a pale reddish brown oil.

Secondly, methyl-3- [2- (1H-indol-3-yl) acetamide ] -4-methylbenzoate is dissolved in trifluoroacetic acid (10mL), triethylsilane (1.74g) is added, and the mixture is refluxed for reaction for 3 hours at 60 ℃; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was stripped of solvent under reduced pressure at 50 ℃ to give crude methyl-3- [2- (indolin-3-yl) acetamide ] -4-methylbenzoate as a dark brown oil.

In the third step, methyl-3- [2- (indolin-3-yl) acetamide]Dissolving 4-methyl benzoate in 50mL of methanol, cooling to 15-20 ℃, stirring, adding 0.3g of sodium tungstate dihydrate, dropwise adding 10mL of 30% hydrogen peroxide within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; separating the organic phase by column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain brown gum-like methyl-3- [2- (1-hydroxy-1H-indol-3-yl) acetamide]-4-methylbenzoate (0.69 g).¹H NMR(400MHz,acetone-d₆):δ10.27(1H,brs,N-H),8.53(1H,s,N-OH),8.34(1H,s,H-2’),7.63(2H,m,H-4,5’),7.41(2H,m,H-2,7),7.18(2H,m,H-6,6’),7.04(1H,t,J＝7.2Hz,H-5),3.85(2H,s,H-8),3.82(3H,s,H-8’),2.04(3H,s,H-9’)；¹³C NMR(400MHz,acetone-d₆):δ170.8(C-9),166.9(C-7’),137.4(C-3’),136.8(C-4’),135.0(C-7a),131.2(C-6’),129.1(C-1’),126.5(C-5’),125.6(C-2’),125.3(C-2),124.4(C-3a),122.8(C-6),120.0(C-5),119.6(C-4),109.2(C-7),104.7(C-3),52.2(C-8’),34.1(C-8),17.9(C-9’)；(+)-HR-ESIMS m/z 339.1353[M+H]⁺(calcd for C₁₉H₁₈N₂O₄,339.1300)。

Example 4: preparation of 2- (1-hydroxy-1H-indol-3-yl) -N- (4-methoxy-2-methylphenyl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding 3-methyl-4-aminoanisole (0.9g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude 2- (1H-indol-3-yl) -N- (4-methoxy-2-methylphenyl) acetamide as a red-brown oil.

Secondly, dissolving 2- (1H-indol-3-yl) -N- (4-methoxy-2-methylphenyl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude 2- (indolin-3-yl) -N- (4-methoxy-2-methylphenyl) acetamide as a dark brown oil.

Dissolving 2- (indolin-3-yl) -N- (4-methoxy-2-methylphenyl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the organic phase was subjected to column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to give 2- (1-hydroxy-1H-indol-3-yl) -N- (4-methoxy-2-methylphenyl) acetamide (0.8g) as a brown gum.¹H NMR(400MHz,CD₃OD-d₄):δ7.57(1H,d,J＝7.6Hz,H-6’),7.34(1H,d,J＝8.0Hz,H-4),7.25(1H,s,H-2),7.11(2H,m,H-5,6’),7.00(1H,t,J＝7.6Hz,H-6),6.64(2H,m,H-3’,5’),3.73(2H,s,H-8),3.66(3H,s,H-7’),1.96(3H,s,H-8’)；¹³C NMR(400MHz,CD₃OD-d₄):δ173.7(C-9),159.4(C-4’),136.1(C-1’),135.6(C-7a),129.7(C-2’),128.2(C-2),125.7(C-6’),124.8(C-3a),123.0(C-6),120.1(C-5),119.6(C-4),116.6(C-5’),112.4(C-3’),109.4(C-7),104.8(C-3),55.7(C-8’),34.0(C-8),18.1(C-7’)；(+)-HR-ESIMS m/z 311.1401[M+H]⁺(calcd for C₁₈H₁₈N₂O₃,311.1351)。

Example 5: preparation of N- (2-chlorophenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; o-chloroaniline (0.84g) and DMAP (0.15g) are added, and the mixture is stirred and reacted for 3 hours at room temperature; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was freed from the solvent under reduced pressure at 40 ℃ to give the crude N- (2-chlorophenyl) -2- (1H-indol-3-yl) acetamide as a pale reddish brown oil.

Secondly, dissolving N- (2-chlorphenyl) -2- (1H-indol-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude N- (2-chlorophenyl) -2- (indolin-3-yl) acetamide as a dark brown oil.

Dissolving N- (2-chlorphenyl) -2- (indolin-3-yl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane(200mL) and water (200mL) are quickly stirred for 10min, and phase separation is carried out; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the organic phase was subjected to column chromatography, eluting with ethyl acetate-petroleum ether (1:5), to give N- (2-chlorophenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide (0.76g) as a brown gum.¹H NMR(400MHz,acetone-d₆):δ8.44(1H,brs,N-H),8.28(1H,d,J＝8.4Hz,H-6’),7.64(1H,d,J＝8.0Hz,H-3’),7.51(1H,s,H-2),7.44(1H,d,J＝8.0Hz,H-4),7.32(1H,d,J＝8.0Hz,H-7),7.23(2H,m,H-4’,5’),7.05(2H,m,H-5,6),3.91(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.2(C-9),136.1(C-1’),135.1(C-7a),129.8(C-3’),128.3(C-5’),125.8(C-4’),125.5(C-2),124.5(C-3a),123.9(C-2’),123.0(C-6),122.8(C-6’),120.2(C-5),119.6(C-4),109.3(C-7),104.4(C-3),34.6(C-8)；(+)-HR-ESIMS m/z301.0746[M+H]⁺(calcd for C₁₆H₁₃ClN₂O₂,302.0636)。

Example 6: preparation of N- (4-chlorophenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding parachloroaniline (0.84g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude N- (4-chlorophenyl) -2- (1H-indol-3-yl) acetamide as a pale reddish brown oil.

Secondly, dissolving N- (4-chlorphenyl) -2- (1H-indol-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude N- (4-chlorophenyl) -2- (indolin-3-yl) acetamide as a dark brown oil.

Dissolving N- (4-chlorphenyl) -2- (indolin-3-yl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the organic phase was subjected to column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to give N- (4-chlorophenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide (0.79g) as an off-white solid.¹H NMR(300MHz,acetone-d₆):δ10.09(1H,brs,N-H),9.24(1H,s,N-OH),7.59(3H,m,H-4,3’,5’),7.34(2H,m,H-2,7),7.23(2H,d,J＝8.7Hz,H-2’,6’),7.13(1H,t,J＝7.5Hz,H-6),6.98(1H,t,J＝7.5Hz,H-5),3.75(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.8(C-9),138.8(C-1’),134.9(C-7a),129.3(C-2’,6’),128.5(C-4’),125.3(C-6),124.5(C-3a),122.6(C-2),121.7(C-3’,5’),119.8(C-5),119.6(C-4),109.1(C-7),104.6(C-3),34.5(C-8)；(+)-HR-ESIMS m/z301.0746[M+H]⁺(calcd for C₁₆H₁₃ClN₂O₂,302.0636)。

Example 7: preparation of 2- (1-hydroxy-1H-indol-3-yl) -N- (4-nitrophenyl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding p-nitroaniline (0.91g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was freed of the solvent under reduced pressure at 40 ℃ to give crude 2- (1H-indol-3-yl) -N- (4-nitrophenyl) acetamide as a brown oil.

Secondly, dissolving 2- (1H-indol-3-yl) -N- (4-nitrophenyl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude 2- (indolin-3-yl) -N- (4-nitrophenyl) acetamide as a dark brown oil.

Dissolving 2- (indolin-3-yl) -N- (4-nitrophenyl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding is finished; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the organic phase was subjected to column chromatography eluting with ethyl acetate-petroleum ether (1:3) to give 2- (1-hydroxy-1H-indol-3-yl) -N- (4-nitrophenyl) acetamide as a brown gum (0.72 g).¹H NMR(400MHz,acetone-d₆):δ10.15(1H,brs,N-H),9.74(1H,s,N-OH),8.16(2H,d,J＝8.8Hz,H-3’,5’),7.87(2H,d,J＝9.2Hz,H-2’,6’),7.61(1H,d,J＝8.0Hz,H-4),7.39(2H,m,H-2,7),7.17(1H,t,J＝7.6Hz,H-5),3.87(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ171.1(C-9),146.2(C-4’),143.7(C-1’),135.0(C-7a),125.5(C-3’,5’),125.4(C-3a),124.6(C-2),122.8(C-6),119.9(C-4),119.7(C-2’,6’),119.6(C-5),109.1(C-7),104.4(C-3),34.8(C-8)；(+)-HR-ESIMS m/z 312.0993[M+H]⁺(calcd forC₁₆H₁₃N₃O₄,312.0940)。

Example 8: preparation of methyl-2- [3- (1-hydroxy-1H-indol-3-yl) propanamide ] benzoate

Firstly, weighing indole propionic acid (1.13g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolving; adding methyl anthranilate (1g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was freed of the solvent under reduced pressure at 40 ℃ to give the crude methyl-2- [3- (1H-indol-3-yl) propionamide ] benzoate as a pale reddish brown oil.

Secondly, methyl-2- [3- (1H-indol-3-yl) propionamide ] benzoate is dissolved in trifluoroacetic acid (10mL), triethylsilane (1.74g) is added, and reflux reaction is carried out at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed of the solvent under reduced pressure at 50 ℃ to give the crude methyl-2- [3- (indolin-3-yl) propanamide ] benzoate as a dark brown oil.

In the third step, methyl-2- [3- (indolin-3-yl) propanamide]Dissolving benzoate in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; separating the organic phase by column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain brown gum-like methyl-2- [3- (1-hydroxy-1H-indol-3-yl) propionamide]Benzoate (0.62 g).¹H NMR(400MHz,acetone-d₆):δ10.97(1H,brs,N-H),9.99(1H,s,N-OH),8.72(1H,d,J＝8.4Hz,H-3’),8.00(1H,d,J＝8.0Hz,H-6’),7.59(2H,m,H-4,4’),7.36(1H,d,J＝8.0Hz,H-7),7.24(1H,s,H-2),7.13(2H,m,H-5,6),7.01(1H,t,J＝7.6Hz,H-5’),3.89(3H,s,H-8’),3.15(2H,t,J＝7.2Hz,H-8a),2.82(2H,t,J＝7.2Hz,H-8)；¹³C NMR(400MHz,acetone-d₆):δ171.7(C-9),169.1(C-7’),142.5(C-2’),135.2(C-4’),131.6(C-6’),124.4(C-3a),124.0(C-2,7a),123.1(C-5’),122.5(C-5),120.9(C-3’),119.5(C-6),119.4(C-4),115.9(C-1’),110.5(C-3),109.0(C-7),52.8(C-8’),39.7(C-8),21.3(C-8a)；(+)-HR-ESIMS m/z 339.1346[M+H]⁺(calcd for C₁₉H₁₈N₂O₄,339.1300)。

Example 9: preparation of methyl-2- [4- (1-hydroxy-1H-indol-3-yl) butanamide ] benzoate

Firstly, weighing indolebutyric acid (1.22g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding methyl anthranilate (1g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude methyl-2- [4- (1H-indol-3-yl) butanamide ] benzoate as a pale reddish brown oil.

Secondly, methyl-2- [4- (1H-indol-3-yl) butanamide ] benzoate is dissolved in trifluoroacetic acid (10mL), triethylsilane (1.74g) is added, and the mixture is refluxed for reaction for 3 hours at 60 ℃; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was stripped of solvent under reduced pressure at 50 ℃ to give crude methyl-2- [4- (indolin-3-yl) butanamide ] benzoate as a dark brown oil.

In the third step, methyl-2- [4- (indolin-3-yl) butanamide]Dissolving benzoate in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; separating the organic phase by column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain methyl-2- [4- (1-hydroxy-1H-indol-3-yl) butanamide as brown gum]Benzoate (0.67 g).¹H NMR(400MHz,acetone-d₆):δ10.97(1H,brs,N-H),10.00(1H,s,N-OH),8.72(1H,d,J＝8.4Hz,H-3’),8.01(1H,d,J＝8.0Hz,H-6’),7.57(2H,m,H-4,4’),7.38(1H,d,J＝8.0Hz,H-7),7.22(1H,s,H-2),7.13(2H,m,H-6,5’),7.01(1H,t,J＝7.2Hz,H-5),3.90(3H,s,H-8’),2.83(2H,s,H-8b),2.51(2H,t,J＝7.6Hz,H-8),2.10(2H,m,H-8a)；¹³C NMR(400MHz,acetone-d₆):δ172.2(C-9),169.2(C-7’),142.6(C-2’),135.3(C-7a),135.2(C-4’),131.6(C-6’),124.7(C-3a),124.0(C-2),123.0(C-5’),122.5(C-5),120.8(C-3’),119.6(C-6),119.4(C-4),115.8(C-3),111.2(C-1’),109.0(C-7),52.8(C-8’),38.3(C-8),26.8(C-8b),24.9(C-8a)；(+)-HR-ESIMS m/z 353.1508[M+H]⁺(calcd forC₂₀H₂₀N₂O₄,353.1457)。

Example 10: preparation of 2- (1-methoxy-1H-indol-3-yl) -N-phenylacetamide

Dissolving 2- (indolin-3-yl) -N-phenylacetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing 2- (1-hydroxy-1H-indole-3-yl) -N-phenylacetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave 2- (1-methoxy-1H-indol-3-yl) -N-phenylacetamide (498mg) as a brown solid.¹H NMR(400MHz,acetone-d₆):δ9.16(1H,brs,NH-1),7.64(3H,m,H-4,2’,6’),7.46(1H,s,H-2),7.42(1H,d,J＝8.4Hz,H-7),7.23(3H,m,H-6,3’,5’),7.04(2H,m,H-5,4’),4.05(3H,s,OMe-10),3.79(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),140.4(C-1’),133.4(C-7a),129.4(C-3’,5’),124.9(C-3a),124.1(C-2),123.4(C-6),123.2(C-4’),120.4(C-5),120.2(C-2’,6’),120.1(C-4),109.0(C-7),106.6(C-3),66.1(C-10),34.6(C-8)；(+)-HR-ESIMS m/z 281.1287[M+H]⁺(calcdfor C₁₇H₁₇N₂O₂,281.1285)。

Example 11: preparation of methyl 2- [2- (1-methoxy-1H-indol-3-yl) acetamide ] benzoate

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding methyl anthranilate (1g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude methyl-2- [2- (1H-indol-3-yl) acetamide ] benzoate as a pale reddish brown oil.

Secondly, methyl-2- [2- (1H-indol-3-yl) acetamide ] benzoate is dissolved in trifluoroacetic acid (10mL), triethylsilane (1.74g) is added, and the mixture is refluxed and reacted for 3 hours at the temperature of 60 ℃; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was stripped of solvent under reduced pressure at 50 ℃ to give crude methyl-2- [2- (indolin-3-yl) acetamide ] benzoate as a dark brown oil.

Dissolving methyl-2- [2- (indolin-3-yl) acetamide ] benzoate in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing methyl-2- [2- (1-hydroxy-1H-indole-3-yl) acetamide ] benzoate is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; separating with silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain pale yellow crystal methyl-2- [2- (1-methoxy-1H-indol-3-yl) acetamide]Benzoate (406 mg).¹H NMR(400MHz,acetone-d₆):δ10.92(1H,brs,NH-1),8.75(1H,d,J＝8.8Hz,H-3’),7.90(1H,d,J＝8.4Hz,H-6’),7.56(3H,m,H-2,4,4’),7.46(1H,d,J＝8.4Hz,H-7),7.21(1H,t,J＝7.6Hz,H-6),7.06(2H,m,H-5,5’),4.19(3H,s,H-10),3.87(2H,s,H-8),3.72(3H,s,H-8’)；¹³C NMR(400MHz,acetone-d₆):δ170.7(C-9),168.7(C-7’),142.3(C-2’),135.0(C-4’),133.4(C-7a),131.5(C-6’),124.8(C-2),124.2(C-3a),123.3(C-5’),123.1(C-6),120.6(C-4,3’),119.8(C-5),116.0(C-1’),109.0(C-7),105.1(C-3),66.4(C-10),52.5(C-8’),35.6(C-8)；(+)-HR-ESIMS m/z339.1342[M+H]⁺(calcd for C₁₉H₁₉N₂O₄,339.1339)。

Example 12: preparation of methyl 3- [2- (1-methoxy-1H-indol-3-yl) acetamide ] benzoate

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding methyl m-aminobenzoate (1g) and DMAP (0.15g), and stirring at room temperature for reacting for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude methyl-3- [2- (1H-indol-3-yl) acetamide ] benzoate as a pale reddish brown oil.

Secondly, methyl-3- [2- (1H-indol-3-yl) acetamide ] benzoate is dissolved in trifluoroacetic acid (10mL), triethylsilane (1.74g) is added, and the mixture is refluxed and reacted for 3 hours at the temperature of 60 ℃; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was stripped of solvent under reduced pressure at 50 ℃ to give crude methyl-3- [2- (indolin-3-yl) acetamide ] benzoate as a dark brown oil.

Dissolving methyl-3- [2- (indolin-3-yl) acetamide ] benzoate in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing methyl-3- [2- (1-hydroxy-1H-indole-3-yl) acetamide ] benzoate is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; separating by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain light brown solid methyl-3- [2- (1-methoxy-1H-indol-3-yl) acetamide]Benzoate (435 mg).¹H NMR(400MHz,acetone-d₆):δ9.37(1H,brs,NH-1),8.29(1H,s,H-2’),7.89(1H,d,J＝8.0Hz,H-4’),7.67(2H,d,J＝7.6Hz,H-4,6’),7.48(1H,s,H-2),7.40(2H,m,H-7,5’),7.21(1H,t,J＝7.6Hz,H-6),7.06(1H,t,J＝7.6Hz,H-5),4.09(3H,s,OMe-10),3.84(3H,s,OMe-8’),3.83(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.2(C-9),167.0(C-7’),140.6(C-3’),133.4(C-7a),131.6(C-1’),129.7(C-2’),124.9(C-6’),124.86(C-3a),124.4(C-2),123.5(C-6),123.2(C-5’),120.9(C-4’),120.5(C-5),120.1(C-4),109.0(C-7),106.3(C-3),66.2(C-10),52.3(C-8’),34.6(C-8)；(+)-HR-ESIMS m/z 339.1347[M+H]⁺(calcd for C₁₉H₁₉N₂O₄,339.1339)。

Example 13: preparation of methyl 4- [2- (1-methoxy-1H-indol-3-yl) acetamide ] benzoate

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding methyl p-aminobenzoate (1g) and DMAP (0.15g), and stirring at room temperature for reacting for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was freed of the solvent under reduced pressure at 40 ℃ to give the crude methyl-4- [2- (1H-indol-3-yl) acetamide ] benzoate as a pale reddish brown oil.

Secondly, methyl-4- [2- (1H-indol-3-yl) acetamide ] benzoate is dissolved in trifluoroacetic acid (10mL), triethylsilane (1.74g) is added, and the mixture is refluxed and reacted for 3 hours at the temperature of 60 ℃; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude methyl-4- [2- (indolin-3-yl) acetamide ] benzoate as a dark brown oil.

Dissolving methyl-4- [2- (indolin-3-yl) acetamide ] methyl benzoate in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing methyl-4- [2- (1-hydroxy-1H-indole-3-yl) acetamide ] benzoate is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; separating with silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain pale yellow solid methyl-4- [2- (1-methoxy-1H-indol-3-yl) acetamide]Benzoic acid methyl ester (500 mg).¹H NMR(400MHz,acetone-d₆):δ9.52(1H,brs,NH-1),7.92(2H,d,J＝8.4Hz,H-3’,5’),7.76(2H,d,J＝8.4Hz,H-2’,6’),7.65(1H,d,J＝8.0Hz,H-4),7.46(1H,s,H-2),7.41(1H,d,J＝8.0Hz,H-7),7.21(1H,t,J＝7.6Hz,H-6),7.07(1H,t,J＝7.6,H-5),4.06(3H,s,OMe-10),3.84(2H,s,H-8),3.83(3H,s,OMe-8’)；¹³C NMR(400MHz,acetone-d₆):δ170.5(C-9),166.7(C-7’),144.5(C-4’),133.3(C-7a),131.1(C-3’,5’),125.6(C-1’),124.8(C-3a),123.5(C-2),123.2(C-6),120.5(C-5),120.1(C-4),119.3(C-2’,6’),109.0(C-7),106.1(C-3),66.1(C-10),52.0(C-8’),34.7(C-8)；(+)-HR-ESIMS m/z 339.1344[M+H]⁺(calcd for C₁₉H₁₉N₂O₄,339.1339)。

Example 14: preparation of ethyl 2- [2- (1-methoxy-1H-indol-3-yl) acetamide ] benzoate

Dissolving ethyl-2- [2- (indolin-3-yl) acetamide ] benzoate in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing ethyl-2- [2- (1-hydroxy-1H-indole-3-yl) acetamide ] benzoate is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; separating by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain light brown solid ethyl-2- [2- (1-methoxy-1H-indol-3-yl) acetamide]Benzoate (423 mg).¹H NMR(400MHz,acetone-d₆):δ11.00(1H,brs,NH-1),8.76(1H,d,J＝8.4Hz,H-3’),7.92(1H,d,J＝8.0Hz,H-6’),7.60(1H,s,H-2),7.59(1H,d,J＝9.2Hz,H-4),7.53(1H,t,J＝8.0Hz,H-4’),7.46(1H,d,J＝8.0Hz,H-7),7.21(1H,t,J＝7.6Hz,H-6),7.06(2H,t,J＝7.2Hz,H-5,5’),4.18(5H,t,J＝10.0Hz,OMe-10,OCH₂CH₃-8’),3.87(2H,s,H-8),1.25(3H,t,J＝6.8Hz,OCH₂CH₃-9’)；¹³C NMR(400MHz,acetone-d₆):δ170.7(C-9),168.2(C-7’),142.4(C-2’),134.9(C-4’),133.3(C-7a),131.5(C-6’),124.8(C-3a),124.2(C-2),123.3(C-6),123.0(C-4’),120.6(C-5),120.5(C-3’),119.8(C-4),116.2(C-1’),109.0(C-7),105.1(C-3),66.4(C-10),61.9(C-8’),35.7(C-8),14.3(C-9’)；(+)-HR-ESIMS m/z 353.1504[M+H]⁺(calcd for C₂₀H₂₁N₂O₄,353.1496)。

Example 15: preparation of methyl 3- [2- (1-methoxy-1H-indol-3-yl) acetamide ] -4-methylbenzoate

Dissolving methyl-3- [2- (indolin-3-yl) acetamide ] -4-methylbenzoate in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding is finished; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing methyl-3- [2- (1-hydroxy-1H-indole-3-yl) acetamide ] -4-methylbenzoate is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; separating by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain white solid methyl-3- [2- (1-methoxy-1H-indol-3-yl) acetamide]-4-methylbenzoate (500 mg).¹H NMR(400MHz,acetone-d₆):δ8.47(1H,brs,NH-1),8.39(1H,s,H-2’),7.68(1H,d,J＝8.0Hz,H-5’),7.64(1H,d,J＝7.6Hz,H-4),7.55(1H,s,H-2),7.45(1H,d,J＝8.0Hz,H-7),7.23(2H,t,J＝7.6Hz,H-6,6’),7.09(1H,t,J＝7.6Hz,H-5),4.11(3H,s,OMe-10),3.87(2H,s,H-8),3.83(3H,s,H-8’),2.11(3H,s,H-9’)；¹³C NMR(400MHz,acetone-d₆):δ170.0(C-9),167.0(C-7’),137.8(C-3’),136.5(C-4’),133.4(C-7a),131.2(C-6’),129.3(C-5’),126.3(C-2’),125.1(C-1’),124.8(C-3a),123.7(C-2),123.4(C-6),120.6(C-5),120.1(C-4),109.1(C-7),106.4(C-3),66.2(C-10),52.2(C-8’),34.2(C-8),17.9(C-9’)；(+)-HR-ESIMS m/z353.1503[M+H]⁺(calcd for C₂₀H₂₁N₂O₄,353.1496)。

Example 16: preparation of 2- (1-methoxy-1H-indol-3-yl) -N- (2-methoxyphenyl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding o-aminoanisole (0.81g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude 2- (1H-indol-3-yl) -N- (2-methoxyphenyl) acetamide as a pale reddish brown oil.

Secondly, dissolving 2- (1H-indol-3-yl) -N- (2-methoxyphenyl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude 2- (indolin-3-yl) -N- (2-methoxyphenyl) acetamide as a dark brown oil.

Dissolving 2- (indolin-3-yl) -N- (2-methoxyphenyl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing 2- (1-hydroxy-1H-indole-3-yl) -N- (2-methoxyphenyl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave 2- (1-methoxy-1H-indol-3-yl) -N- (2-methoxyphenyl) acetamide (654mg) as an orange gum.¹H NMR(400MHz,acetone-d₆):δ8.43(1H,brs,NH-1),8.33(1H,d,J＝7.6Hz,H-6’),7.67(1H,d,J＝7.6Hz,H-3’),7.56(1H,s,H-2),7.47(1H,d,J＝8.0Hz,H-4),7.24(1H,t,J＝7.6Hz,H-5’),7.10(1H,t,J＝7.6Hz,H-4’),6.96(1H,t,J＝8.0Hz,H-6),6.87(2H,m,H-5,7),4.13(3H,s,OMe-10),3.86(2H,s,H-8),3.64(3H,s,OMe-7’)；¹³C NMR(400MHz,acetone-d₆):δ169.5(C-9),149.1(C-2’),133.4(C-7a),129.1(C-1’),124.7(C-3a),124.2(C-2),123.7(C-6’),123.4(C-6),121.3(C-3’),120.7(C-5),120.13(C-5’),120.09(C-4),111.2(C-4’),109.1(C-7),106.4(C-3),66.3(C-10),56.0(C-7’),34.8(C-8)；(+)-HR-ESIMS m/z 311.1397[M+H]⁺(calcd for C₁₈H₁₉N₂O₃,311.1396)。

Example 17: preparation of 2- (1-methoxy-1H-indol-3-yl) -N- (3-methoxyphenyl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding m-anisidine (0.81g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude 2- (1H-indol-3-yl) -N- (3-methoxyphenyl) acetamide as a pale reddish brown oil.

Secondly, dissolving 2- (1H-indol-3-yl) -N- (3-methoxyphenyl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude 2- (indolin-3-yl) -N- (3-methoxyphenyl) acetamide as a dark brown oil.

Dissolving 2- (indolin-3-yl) -N- (3-methoxyphenyl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing 2- (1-hydroxy-1H-indole-3-yl) -N- (3-methoxyphenyl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; separating by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5),this gave 2- (1-methoxy-1H-indol-3-yl) -N- (3-methoxyphenyl) acetamide as a pale brown gum (643 mg).¹H NMR(400MHz,acetone-d₆):δ9.30(1H,brs,NH-1),7.66(1H,d,J＝8.0Hz,H-6’),7.46(1H,s,H-2),7.41(2H,d,J＝6.8Hz,H-4,7),7.20(1H,t,J＝7.6Hz,H-6),7.13(2H,m,H-2’,5’),7.06(1H,t,J＝7.6Hz,H-5),6.59(1H,d,J＝6.8Hz,H-4’),4.08(3H,s,OMe-10),3.78(2H,s,H-8),3.72(3H,s,OMe-7’)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),160.9(C-3’),141.6(C-1’),133.3(C-7a),130.1(C-6’),124.9(C-3a),123.4(C-6),123.1(C-2),120.4(C-5),120.2(C-4),112.3(C-5’),109.5(C-7),108.9(C-4’),106.6(C-2’),105.9(C-3),66.1(C-10),55.4(C-7’),34.6(C-8)；(+)-HR-ESIMS m/z 311.1399[M+H]⁺(calcd for C₁₈H₁₉N₂O₃,311.1396)。

Example 18: preparation of 2- (1-methoxy-1H-indol-3-yl) -N- (4-methoxyphenyl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding p-anisidine (0.81g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude 2- (1H-indol-3-yl) -N- (4-methoxyphenyl) acetamide as a pale reddish brown oil.

Secondly, dissolving 2- (1H-indol-3-yl) -N- (4-methoxyphenyl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude 2- (indolin-3-yl) -N- (4-methoxyphenyl) acetamide as a dark brown oil.

Dissolving 2- (indolin-3-yl) -N- (4-methoxyphenyl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing 2- (1-hydroxy-1H-indole-3-yl) -N- (4-methoxyphenyl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave 2- (1-methoxy-1H-indol-3-yl) -N- (4-methoxyphenyl) acetamide (612mg) as a pale yellow solid.¹H NMR(400MHz,acetone-d₆):δ9.02(1H,brs,NH-1),7.66(1H,d,J＝8.0Hz,H-4),7.52(2H,d,J＝8.8Hz,H-2’,6’),7.45(1H,s,H-2),7.41(1H,d,J＝8.0Hz,H-7),7.20(1H,t,J＝7.6Hz,H-6),7.06(1H,t,J＝7.6Hz,H-5),6.82(2H,d,J＝8.8Hz,H-3’,5’),4.08(3H,s,OMe-10),3.75(2H,s,H-8),3.73(3H,s,OMe-4’)；¹³C NMR(400MHz,acetone-d₆):δ169.5(C-9),156.7(C-4’),133.5(C-1’),133.4(C-7a),124.9(C-3a),123.4(C-2),123.2(C-6),121.7(C-2’,6’),120.4(C-5),120.2(C-4),114.5(C-3’,5’),108.9(C-7),106.7(C-3),66.1(C-10),55.6(C-7’),34.5(C-8)；(+)-HR-ESIMS m/z 311.1398[M+H]⁺(calcd for C₁₈H₁₉N₂O₃,311.1396)。

Example 19: preparation of 2- (1-methoxy-1H-indol-3-yl) -N- (4-methoxy-2-methylphenyl) acetamide

Dissolving 2- (indolin-3-yl) -N- (4-methoxy-2-methylphenyl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing 2- (1-hydroxy-1H-indole-3-yl) -N- (4-methoxy-2-methylphenyl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave 2- (1-methoxy-1H-indol-3-yl) -N- (4-methoxy-2-methylphenyl) acetamide (408mg) as an off-white solid.¹H NMR(400MHz,acetone-d₆):δ8.28(1H,brs,NH-1),7.69(1H,d,J＝6.8Hz,H-6’),7.53(1H,s,H-2),7.44(2H,s,H-4,7),7.24(1H,s,H-6),7.10(1H,s,H-5),6.71(2H,s,H-3’,5’),4.11(3H,s,OMe-10),3.81(2H,s,H-8),3.73(3H,s,H-7’),2.04(3H,s,H-8’)；¹³C NMR(400MHz,acetone-d₆):δ169.7(C-9),157.9(C-4’),133.7(C-1’),133.4(C-7a),130.5(C-2’),126.5(C-2),124.8(C-3a),123.6(C-6’),123.3(C-6),120.5(C-5),120.2(C-4),116.2(C-5’),111.8(C-3’),109.0(C-7),106.8(C-3),66.2(C-10),55.5(C-8’),34.1(C-8),18.1(C-7’)；(+)-HR-ESIMSm/z 325.1554[M+H]⁺(calcd for C₁₉H₂₁N₂O₃,325.1547)。

Example 20: preparation of N- (2-chlorophenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide

Dissolving N- (2-chlorphenyl) -2- (indolin-3-yl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing N- (2-chlorphenyl) -2- (1-hydroxy-1H-indole-3-yl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; silica gel column chromatography eluting with ethyl acetate-petroleum ether (1:5) gave N- (2-chlorophenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide (414mg) as an off-white solid.¹H NMR(400MHz,acetone-d₆):δ8.46(1H,brs,NH-1),8.29(1H,d,J＝8.0Hz,H-6’),7.67(1H,d,J＝8.0Hz,H-3’),7.61(1H,s,H-2),7.47(1H,d,J＝8.0Hz,H-4),7.33(1H,d,J＝8.0Hz,H-7),7.26(2H,m,H-4’,5’),7.10(1H,t,J＝7.6Hz,H-6),7.05(1H,t,J＝8.0Hz,H-5),4.12(3H,s,OMe-10),3.925(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.4(C-7a),129.9(C-3’),128.3(C-5’),125.5(C-4’),124.7(C-3a),123.9(C-2),123.5(C-6),122.9(C-2’,6’),120.8(C-5),120.0(C-4),109.1(C-7),105.8(C-3),66.3(C-10),34.5(C-8)；(+)-HR-ESIMSm/z 315.0905[M+H]⁺(calcd for C₁₇H₁₆ClN₂O₂,315.0895)。

Example 21: preparation of N- (3-chlorophenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding m-chloroaniline (0.84g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was freed from the solvent under reduced pressure at 40 ℃ to give the crude N- (3-chlorophenyl) -2- (1H-indol-3-yl) acetamide as a pale reddish brown oil.

Secondly, dissolving N- (3-chlorphenyl) -2- (1H-indol-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude N- (3-chlorophenyl) -2- (indolin-3-yl) acetamide as a dark brown oil.

Dissolving N- (3-chlorphenyl) -2- (indolin-3-yl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing N- (3-chlorphenyl) -2- (1-hydroxy-1H-indole-3-yl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on a silica gel column eluting with ethyl acetate-petroleum ether (1:5) gave N- (3-chlorophenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide (436mg) as an orange gum.¹H NMR(400MHz,acetone-d₆):δ9.33(1H,brs,NH-1),7.89(1H,s,H-2’),7.64(1H,d,J＝8.0Hz,H-6’),7.44(3H,m,H-2,4,7),7.26(1H,t,J＝8.0Hz,H-6),7.21(1H,t,J＝8.0Hz,H-5’),7.06(2H,m,H-5,4’),4.09(3H,s,OMe-10),3.80(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.3(C-9),141.7(C-1’),134.6(C-3’),133.3(C-7a),130.9(C-2’),124.8(C-3a),123.9(C-2),123.5(C-6’),123.2(C-6),120.5(C-5),120.1(C-5’),119.9(C-4’),118.3(C-4),109.0(C-7),106.2(C-3),66.2(C-10),34.6(C-8)；(+)-HR-ESIMS m/z 315.0897[M+H]⁺(calcd for C₁₇H₁₆ClN₂O₂,315.0895)。

Example 22: preparation of N- (4-chlorophenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide

Dissolving N- (4-chlorphenyl) -2- (indolin-3-yl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing N- (4-chlorphenyl) -2- (1-hydroxy-1H-indole-3-yl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave N- (4-chlorophenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide (384mg) as a pale yellow solid.¹H NMR(400MHz,acetone-d₆):δ9.30(1H,brs,NH-1),7.65(3H,d,J＝8.4Hz,H-4,3’,5’),7.46(1H,s,H-2),7.41(1H,d,J＝8.4Hz,H-7),7.27(2H,d,J＝8.4Hz,H-2’,6’),7.21(1H,t,J＝7.6Hz,H-6),7.06(1H,t,J＝7.6Hz,H-5),4.08(3H,s,OMe-10),3.79(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.1(C-9),139.2(C-1’),133.3(C-7a),129.3(C-2’,6’),128.4(C-4’),124.8(C-3a),123.5(C-6),123.2(C-2),121.6(C-3’,5’),120.5(C-5),120.1(C-4),109.0(C-7),106.3(C-3),66.2(C-10),34.6(C-8)；(+)-HR-ESIMS m/z315.0905[M+H]⁺(calcd for C₁₇H₁₆ClN₂O₂,315.0895)。

Example 23: preparation of 2- (1-methoxy-1H-indol-3-yl) -N-p-methylphenyl acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; 4-methylaniline (0.71g) and DMAP (0.15g) are added, and the mixture is stirred and reacted for 3 hours at room temperature; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude 2- (1H-indol-3-yl) -N-p-methylphenyl acetamide as a yellow oil.

Secondly, dissolving 2- (1H-indol-3-yl) -N-p-methylphenyl acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude 2- (indolin-3-yl) -N-p-methylphenyl acetamide as a dark brown oil.

Dissolving 2- (indolin-3-yl) -N-p-methylphenyl acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing 2- (1-hydroxy-1H-indole-3-yl) -N-p-methylphenyl acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave 2- (1-methoxy-1H-indol-3-yl) -N-p-methylphenyl acetamide (490mg) as a yellow solid.¹H NMR(400MHz,acetone-d₆):δ9.11(1H,brs,NH-1),7.66(1H,d,J＝8.0Hz,H-4),7.51(2H,d,J＝8.4Hz,H-2’,6’),7.44(1H,s,H-2),7.41(1H,d,J＝8.4Hz,H-7),7.21(1H,t,J＝8.0Hz,H-6),7.06(3H,t,H-5,3’,5’),4.06(3H,s,OMe-10),3.77(2H,s,H-8),2.24(3H,s,H-7’)；¹³C NMR(400MHz,acetone-d₆):δ169.7(C-9),137.8(C-7a),133.3(C-1’),129.8(C-2’,6’),124.9(C-3a),123.4(C-6),123.1(C-4’),120.4(C-5),120.2(C-3’,5’),108.9(C-7),106.7(C-3),66.1(C-10),34.6(C-8),20.7(C-7’)；(+)-HR-ESIMS m/z 295.245[M+H]⁺(calcd for C₁₈H₁₉N₂O₂,295.1441)。

Example 24: preparation of N- (3, 4-dimethylphenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding 3, 4-dimethylaniline (0.8g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude N- (3, 4-dimethylphenyl) -2- (1H-indol-3-yl) acetamide as a yellow oil.

Secondly, dissolving N- (3, 4-dimethylphenyl) -2- (1H-indol-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude N- (3, 4-dimethylphenyl) -2- (indolin-3-yl) acetamide as a dark brown oil.

Dissolving N- (3, 4-dimethylphenyl) -2- (indolin-3-yl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing N- (3, 4-dimethylphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave N- (3, 4-dimethylphenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide (497mg) as a pale brown gum.¹H NMR(400MHz,acetone-d₆):δ8.99(1H,brs,NH-1),7.66(1H,d,J＝8.0Hz,H-4),7.45(1H,s,H-2),7.41(1H,d,J＝8.0Hz,H-7),7.38(1H,s,H-2’),7.35(1H,d,J＝8.0Hz,H-6’),7.20(1H,t,J＝7.6Hz,H-6),7.06(1H,t,J＝7.6Hz,H-5),6.99(1H,d,J＝8.0Hz,H-5’),4.08(3H,s,OMe-10),3.76(2H,s,H-8),2.16(3H,s,H-7’),2.15(3H,s,H-8’)；¹³C NMR(400MHz,acetone-d₆):δ169.6(C-9),138.1(C-1’),137.3(C-3’),133.4(C-7a),132.0(C-4’),130.4(C-5’),124.9(C-3a),123.4(C-2),123.2(C-6),121.4(C-2’),120.4(C-5),120.2(C-6’),117.7(C-4),108.9(C-7),106.7(C-3),66.1(C-10),34.6(C-8),19.9(C-7’),19.1(C-8’)；(+)-HR-ESIMSm/z 309.1601[M+H]⁺(calcd for C₁₉H₂₀N₂O₂,309.1598)。

Example 25: preparation of N- (3, 5-dimethylphenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding 3, 5-dimethylaniline (0.8g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude N- (3, 5-dimethylphenyl) -2- (1H-indol-3-yl) acetamide as a yellow oil.

Secondly, dissolving N- (3, 5-dimethylphenyl) -2- (1H-indol-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude N- (3, 5-dimethylphenyl) -2- (indolin-3-yl) acetamide as a dark brown oil.

Dissolving N- (3, 5-dimethylphenyl) -2- (indolin-3-yl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing N- (3, 5-dimethylphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide is obtained and is placed for later use.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; silica gel column chromatography eluting with ethyl acetate-petroleum ether (1:5) gave off-white solid N- (3, 5-dimethylphenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide (553 mg).¹H NMR(400MHz,acetone-d₆):δ9.00(1H,brs,NH-1),7.66(1H,d,J＝8.0Hz,H-4),7.46(1H,s,H-2),7.41(1H,d,J＝8.0Hz,H-7),7.25(2H,s,H-2’,6’),7.20(1H,t,J＝7.6Hz,H-6),7.06(1H,t,J＝7.6Hz,H-5),6.66(1H,s,H-4’),4.08(3H,s,OMe-10),3.77(2H,s,H-8),2.20(6H,s,H-7’,8’)；¹³C NMR(400MHz,acetone-d₆):δ169.7(C-9),140.2(C-1’),138.8(C-3’,5’),133.4(C-7a),125.7(C-2),124.9(C-3a),123.4(C-5),123.2(C-4’),120.4(C-5),120.2(C-4),117.9(C-2’,6’),108.9(C-7),106.7(C-3),66.1(C-10),34.7(C-8),21.4(C-7’,8’)；(+)-HR-ESIMS m/z309.1608[M+H]⁺(calcd for C₁₉H₂₀N₂O₂,309.1598)。

Example 26: preparation of 2- (1-methoxy-1H-indol-3-yl) -N-o-methylphenyl acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding 2-methylaniline (0.71g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude 2- (1H-indol-3-yl) -N-o-methylphenyl acetamide as a yellow oil.

Secondly, dissolving 2- (1H-indol-3-yl) -N-o-methylphenyl acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude 2- (indolin-3-yl) -N-o-methylphenylacetamide as a dark brown oil.

Dissolving 2- (indolin-3-yl) -N-o-methylphenyl acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing 2- (1-hydroxy-1H-indole-3-yl) -N-o-methylphenyl acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave 2- (1-methoxy-1H-indol-3-yl) -N-o-methylphenyl acetamide (354mg) as a white solid.¹H NMR(400MHz,acetone-d₆):δ8.33(1H,brs,NH-1),7.72(1H,d,J＝8.0Hz,H-6’),7.68(1H,d,J＝8.0Hz,H-4),7.54(1H,s,H-2),7.45(1H,d,J＝7.6Hz,H-7),7.24(1H,t,J＝7.6Hz,H-6),7.10(3H,m,H-3’,4’,5’),6.99(1H,t,J＝7.6Hz,H-5),4.10(3H,s,OMe-10),3.84(2H,s,H-8),2.01(3H,s,H-7’)；¹³C NMR(400MHz,acetone-d₆):δ169.7(C-9),137.6(C-1’),133.4(C-7a),131.0(C-6’),130.7(C-2’),126.9(C-3’),125.4(C-5’),124.8(C-3a),124.1(C-2),123.6(C-4’),123.3(C-6),120.6(C-5),120.1(C-4),109.0(C-7),106.6(C-3),66.2(C-10),34.3(C-8),17.7(C-7’)；(+)-HR-ESIMS m/z 295.1447[M+H]⁺(calcd for C₁₈H₁₉N₂O₂,295.1441)。

Example 27: preparation of 2- (1-methoxy-1H-indol-3-yl) -N-o-ethylphenylacetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding 2-ethylaniline (0.8g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was freed of the solvent under reduced pressure at 40 ℃ to give crude 2- (1H-indol-3-yl) -N-o-ethylphenylacetamide as a yellow oil.

Secondly, dissolving 2- (1H-indol-3-yl) -N-o-ethylphenylacetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude 2- (indolin-3-yl) -N-o-ethylphenylacetamide as a dark brown oil.

Dissolving 2- (indolin-3-yl) -N-o-ethylphenylacetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing 2- (1-hydroxy-1H-indole-3-yl) -N-o-ethyl phenyl acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave 2- (1-methoxy-1H-indol-3-yl) -N-o-ethylphenylacetamide (513mg) as an off-white solid.¹H NMR(400MHz,acetone-d₆):δ8.20(1H,brs,NH-1),7.76(1H,d,J＝8.0Hz,H-6’),7.68(1H,d,J＝8.0Hz,H-4),7.57(1H,s,H-2),7.46(1H,d,J＝7.6Hz,H-7),7.25(1H,t,J＝7.6Hz,H-6),7.11(3H,m,H-3’,4’,5’),7.03(1H,t,J＝6.8Hz,H-5),4.12(3H,s,OMe-10),3.84(2H,s,H-8),2.33(2H,q,J＝7.6Hz,H-7’),0.85(3H,t,J＝7.6Hz,H-8’)；¹³C NMR(400MHz,acetone-d₆):δ169.8(C-9),136.8(C-1’),136.4(C-2’),133.4(C-7a),129.4(C-5’),126.9(C-3’),125.7(C-4’),124.7(C-3a),124.4(C-2),123.7(C-6’),123.5(C-6),120.7(C-5),120.1(C-4),109.1(C-7),106.5(C-3),66.3(C-10),34.4(C-8),24.7(C-7’),14.3(C-8’)；(+)-HR-ESIMS m/z 309.1601[M+H]⁺(calcd for C₁₉H₂₀N₂O₂,309.1598)。

Example 28: preparation of N- (2-fluorophenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding o-fluoroaniline (0.73g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was freed of the solvent under reduced pressure at 40 ℃ to give the crude N- (2-fluorophenyl) -2- (1H-indol-3-yl) acetamide as a reddish brown oil.

Secondly, dissolving N- (2-fluorophenyl) -2- (1H-indol-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed of the solvent under reduced pressure at 50 ℃ to give the crude N- (2-fluorophenyl) -2- (indolin-3-yl) acetamide as a dark brown oil.

Dissolving N- (2-fluorophenyl) -2- (indolin-3-yl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing N- (2-fluorophenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; silica gel column chromatography eluting with ethyl acetate-petroleum ether (1:5) gave off-white crystalline N- (2-fluorophenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide (330 mg).¹H NMR(400MHz,acetone-d₆):δ8.83(1H,brs,NH-1),8.22(1H,t,J＝8.0Hz,H-5’),7.68(1H,d,J＝8.0Hz,H-3’),7.52(1H,s,H-2),7.44(1H,d,J＝8.0Hz,H-4),7.22(1H,t,J＝7.6Hz,H-6),7.09(4H,m,H-7,4’,5’,6’),4.09(3H,s,OMe-10),3.91(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.1(C-9),133.4(C-7a),125.2(C-1’),125.14(C-3’),125.09(C-2’),124.8(C-3a),123.5(C-2),123.4(C-5’),123.3(C-6),120.5(C-5),120.1(C-4),115.8(C-4’),115.6(C-6’),109.0(C-7),106.3(C-3),66.2(C-10),34.3(C-8)；(+)-HR-ESIMS m/z 299.1193[M+H]⁺(calcd forC₁₇H₁₆FN₂O₂,299.119)。

Example 29: preparation of N- (2-bromophenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; o-bromoaniline (1.2g) and DMAP (0.15g) are added, and the mixture is stirred at room temperature and reacts for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was removed under reduced pressure at 40 ℃ to give crude N- (2-bromophenyl) -2- (1H-indol-3-yl) acetamide as a red-brown oil.

Secondly, dissolving N- (2-bromophenyl) -2- (1H-indol-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was removed under reduced pressure at 50 ℃ to give crude N- (2-bromophenyl) -2- (indolin-3-yl) acetamide as a dark brown oil.

Dissolving N- (2-bromophenyl) -2- (indolin-3-yl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing N- (2-bromophenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave N- (2-bromophenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide (240mg) as a yellow solid.¹H NMR(400MHz,acetone-d₆):δ8.32(1H,brs,NH-1),8.27(1H,d,J＝8.0Hz,H-6’),7.66(1H,d,J＝8.0Hz,H-3’),7.64(1H,s,H-2),7.49(1H,d,J＝7.6Hz,H-4),7.47(1H,d,J＝8.0Hz,H-7),7.32(1H,t,J＝8.0Hz,H-6),7.25(1H,t,J＝7.6Hz,H-5’),7.10(1H,t,J＝7.6Hz,H-4’),6.99(1H,t,J＝8.0Hz,H-5),4.13(3H,s,OMe-10),3.91(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),137.2(C-1’),133.4(C-7a),133.2(C-5’),129.0(C-3’),126.0(C-6’),124.7(C-3a),124.0(C-2),123.6(C-6),122.9(C-4’),120.9(C-5),120.0(C-4),114.2(C-2’),109.1(C-7),105.6(C-3),66.4(C-10),34.6(C-8)；(+)-HR-ESIMS m/z359.0403[M+H]⁺(calcd forC₁₇H₁₅BrN₂O₂,359.039)。

Example 30: preparation of N- (2-iodophenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding o-iodoaniline (1.45g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was removed under reduced pressure at 40 ℃ to give crude N- (2-iodophenyl) -2- (1H-indol-3-yl) acetamide as a brown oil.

Secondly, dissolving N- (2-iodophenyl) -2- (1H-indol-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was stripped of solvent under reduced pressure at 50 deg.C to give crude N- (2-iodophenyl) -2- (indolin-3-yl) acetamide as a dark brown oil.

Dissolving N- (2-iodophenyl) -2- (indolin-3-yl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing N- (2-iodophenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; silica gel column chromatography eluting with ethyl acetate-petroleum ether (1:5) gave N- (2-iodophenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide (252mg) as a pale brown solid.¹H NMR(400MHz,acetone-d₆):δ8.17(1H,d,J＝8.4Hz,H-6’),8.13(1H,brs,NH-1),7.72(1H,d,J＝7.6Hz,H-3’),7.65(2H,d,J＝8.0Hz,H-2,4),7.47(1H,d,J＝8.4Hz,H-7),7.33(1H,t,J＝8.0Hz,H-4’),7.25(1H,t,J＝8.0Hz,H-5’),7.10(1H,t,J＝7.6Hz,H-6),6.83(1H,t,J＝7.6Hz,H-5),4.14(3H,s,OMe-10),3.89(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),139.8(C-1’,5’),133.5(C-7a),129.7(C-3’),126.7(C-4’),124.7(C-3a),124.2(C-2),123.6(C-6),122.7(C-2’,6’),120.9(C-5),120.1(C-4),109.2(C-7),105.4(C-3),66.5(C-10),34.6(C-8)；(+)-HR-ESIMS m/z 407.0269[M+H]⁺(calcd for C₁₇H₁₆IN₂O₂,407.0251)。

Example 31: preparation of 2- (1-methoxy-1H-indol-3-yl) -N- (4-nitrophenyl) acetamide

Dissolving 2- (indolin-3-yl) -N- (4-nitrophenyl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding is finished; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing 2- (1-hydroxy-1H-indole-3-yl) -N- (4-nitrophenyl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave 2- (1-methoxy-1H-indol-3-yl) -N- (4-nitrophenyl) acetamide (506mg) as a yellow solid.¹H NMR(400MHz,acetone-d₆):δ9.76(1H,brs,NH-1),8.17(2H,d,J＝9.2Hz,H-3’,5’),7.88(2H,d,J＝8.8Hz,H-2’,6’),7.64(1H,d,J＝7.6Hz,H-4),7.49(1H,s,H-2),7.42(1H,d,J＝8.0Hz,H-7),7.21(1H,t,J＝7.6Hz,H-6),7.07(1H,t,J＝7.2Hz,H-5),4.09(3H,s,OMe-10),3.88(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.8(C-9),146.3(C-4’),143.8(C-1’),133.3(C-7a),125.5(C-3’,5’),124.8(C-3a),123.6(C-2),123.3(C-6),120.5(C-5),120.1(C-4),119.7(C-2’,6’),109.0(C-7),105.8(C-3),66.2(C-10),34.7(C-8)；(+)-HR-ESIMS m/z 326.1144[M+H]⁺(calcd for C₁₇H₁₆N₃O₄,326.1135)。

Example 32: preparation of N- (3, 5-dimethoxyphenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding 3, 5-dimethoxyaniline (1g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was removed under reduced pressure at 40 ℃ to give crude N- (3, 5-dimethoxyphenyl) -2- (1H-indol-3-yl) acetamide as a pale reddish brown oil.

Secondly, dissolving N- (3, 5-dimethoxyphenyl) -2- (1H-indol-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was removed under reduced pressure at 50 ℃ to give crude N- (3, 5-dimethoxyphenyl) -2- (indolin-3-yl) acetamide as a dark brown oil.

Dissolving N- (3, 5-dimethoxyphenyl) -2- (indolin-3-yl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing N- (3, 5-dimethoxyphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; silica gel column chromatography eluting with ethyl acetate-petroleum ether (1:5) gave off-white solid N- (3, 5-dimethoxyphenyl) -2- (1-methoxy-1H-indol-3-yl) acetamide (497 mg).¹H NMR(400MHz,acetone-d₆):δ9.19(1H,brs,NH-1),7.65(1H,d,J＝8.0Hz,H-4),7.44(1H,s,H-2),7.41(1H,d,J＝8.0Hz,H-7),7.21(1H,t,J＝7.6Hz,H-5),7.06(1H,t,J＝7.6Hz,H-4),6.92(2H,d,J＝1.2Hz,H-2’,6’),6.20(1H,s,H-4’),4.07(3H,s,OMe-10),3.78(2H,s,H-8),3.70(6H,s,H-7’,8’)；¹³C NMR(400MHz,acetone-d₆):δ170.0(C-9),161.9(C-3’,5’),141.9(C-1’),133.3(C-7a),124.8(C-3a),123.4(C-6),123.2(C-2),120.4(C-5),120.2(C-4),108.9(C-7),106.5(C-3),98.4(C-2’,6’),96.2(C-4’),66.1(C-10),55.4(C-7’,8’),34.7(C-8)；(+)-HR-ESIMS m/z 341.1506[M+H]⁺(calcd for C₁₉H₂₁N₂O₄,341.1496)。

Example 33: preparation of 2- (1-methoxy-1H-indol-3-yl) -N- (3,4, 5-trimethoxyphenyl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding 3,4, 5-trimethoxyaniline (1.21g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude 2- (1H-indol-3-yl) -N- (3,4, 5-trimethoxyphenyl) acetamide as a pale reddish brown oil.

Secondly, dissolving 2- (1H-indol-3-yl) -N- (3,4, 5-trimethoxyphenyl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude 2- (indolin-3-yl) -N- (3,4, 5-trimethoxyphenyl) acetamide as a dark brown oil.

Dissolving 2- (indolin-3-yl) -N- (3,4, 5-trimethoxyphenyl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding is finished; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing 2- (1-hydroxy-1H-indole-3-yl) -N- (3,4, 5-trimethoxyphenyl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; silica gel column chromatography eluting with ethyl acetate-petroleum ether (1:5) gave 2- (1-methoxy-1H-indol-3-yl) -N- (3,4, 5-trimethoxyphenyl) acetamide (230mg) as an off-white solid.¹H NMR(400MHz,acetone-d₆):δ9.12(1H,brs,NH-1),7.65(1H,d,J＝8.0Hz,H-7),7.45(1H,s,H-2),7.42(1H,d,J＝8.0Hz,H-4),7.21(1H,t,J＝7.6Hz,H-6),7.06(1H,t,J＝7.6Hz,H-5),7.03(2H,s,H-2’,6’),4.09(3H,s,OMe-10),3.78(2H,s,H-8),3.72(6H,s,H-7’,9’),3.65(3H,s,H-8’)；¹³C NMR(400MHz,acetone-d₆):δ169.8(C-9),154.2(C-3’,5’),136.4(C-4’),133.4(C-7a),124.9(C-3a),123.4(C-2),123.2(C-6),120.4(C-4),120.2(C-5),109.0(C-7),106.6(C-3),98.0(C-2’,6’),66.2(C-10),60.5(C-8’),56.2(C-7’,9’),34.7(C-8)；(+)-HR-ESIMS m/z 371.1613[M+H]⁺(calcd for C₂₀H₂₃N₂O₅,371.1601)。

Example 34: preparation of 2- (1-methoxy-1H-indol-3-yl) -N- (pyridin-3-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding 3-aminopyridine (0.62g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude 2- (1H-indol-3-yl) -N- (pyridin-3-yl) acetamide as a brown oil.

Secondly, dissolving 2- (1H-indol-3-yl) -N- (pyridin-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude 2- (indolin-3-yl) -N- (pyridin-3-yl) acetamide as a dark brown oil.

Dissolving 2- (indolin-3-yl) -N- (pyridine-3-yl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing 2- (1-hydroxy-1H-indole-3-yl) -N- (pyridine-3-yl) acetamide is obtained and is placed for standby.

The fourth step, adding 2N trimethylsilane to the organic phase obtained in the third stepReacting a N-hexane solution (10mL) of the azomethane at room temperature in a dark place for 24 hours; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:3) gave 2- (1-methoxy-1H-indol-3-yl) -N- (pyridin-3-yl) acetamide (156mg) as a dark brown solid.¹H NMR(400MHz,acetone-d₆):δ9.42(1H,brs,NH-1),8.73(1H,s,H-2’),8.24(1H,d,J＝4.4Hz,H-6’),8.12(1H,d,J＝8.4Hz,H-4’),7.65(1H,d,J＝8.0Hz,H-4),7.48(1H,s,H-2),7.42(1H,d,J＝8.0Hz,H-7),7.26(1H,dd,J＝8.4,4.8Hz,H-5’),7.21(1H,t,7.6Hz,H-6),7.07(1H,t,7.6Hz,H-5),4.08(3H,s,OMe-10),3.84(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.5(C-9),145.2(C-2’),141.9(C-6’),136.9(C-3’),133.3(C-7a),127.0(C-4’),124.8(C-3a),124.2(C-2),123.5(C-5’),123.2(C-3),120.5(C-5),120.1(C-4),109.0(C-7),106.1(C-3),66.2(C-10),34.4(C-8)；(+)-HR-ESIMS m/z 282.1242[M+H]⁺(calcd for C₁₆H₁₆N₃O₂,282.1237)。

Example 35: preparation of 2- (1-methoxy-1H-indol-3-yl) -N- (pyridin-4-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; 4-aminopyridine (0.62g) and DMAP (0.15g) were added, and the mixture was stirred at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude 2- (1H-indol-3-yl) -N- (pyridin-4-yl) acetamide as a brown oil.

Secondly, dissolving 2- (1H-indol-3-yl) -N- (pyridin-4-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude 2- (indolin-3-yl) -N- (pyridin-4-yl) acetamide as a dark brown oil.

Dissolving 2- (indolin-3-yl) -N- (pyridine-4-yl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing 2- (1-hydroxy-1H-indole-3-yl) -N- (pyridine-4-yl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:3) gave 2- (1-methoxy-1H-indol-3-yl) -N- (pyridin-4-yl) acetamide (169mg) as a dark brown solid.¹H NMR(400MHz,acetone-d₆):δ9.59(1H,brs,NH-1),8.39(2H,d,J＝5.6Hz,H-2’,6’),7.63(1H,d,J＝8.0Hz,H-4),7.59(2H,d,J＝5.6Hz,H-3’,5’),7.47(1H,s,H-2),7.42(1H,d,J＝8.0Hz,H-7),7.21(1H,t,J＝7.6Hz,H-6),7.06(1H,t,J＝7.6Hz,H-5),4.09(3H,s,OMe-10),3.84(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ171.0(C-9),151.2(C-2’,6’),146.9(C-4’),133.3(C-7a),124.8(C-3a),123.5(C-2),123.2(C-6),120.5(C-5),120.1(C-4),114.1(C-3’,5’),109.0(C-7),105.8(C-3),66.2(C-10),34.7(C-8)；(+)-HR-ESIMS m/z 282.1243[M+H]⁺(calcd forC₁₆H₁₆N₃O₂,282.1237)。

Example 36: preparation of 2- (1-methoxy-1H-indol-3-yl) -N- (pyridin-2-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding 2-aminopyridine (0.62g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude 2- (1H-indol-3-yl) -N- (pyridin-2-yl) acetamide as a brown oil.

Secondly, dissolving 2- (1H-indol-3-yl) -N- (pyridin-2-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude 2- (indolin-3-yl) -N- (pyridin-2-yl) acetamide as a dark brown oil.

Dissolving 2- (indolin-3-yl) -N- (pyridine-2-yl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing 2- (1-hydroxy-1H-indole-3-yl) -N- (pyridine-2-yl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:3) gave 2- (1-methoxy-1H-indol-3-yl) -N- (pyridin-2-yl) acetamide (173mg) as a dark brown solid.¹H NMR(300MHz,acetone-d₆):δ9.36(1H,brs,NH-1),8.22(2H,m,H-3’,6’),7.70(2H,m,H-4,4’),7.52(1H,s,H-2),7.43(1H,d,J＝7.8Hz,H-7),7.22(1H,t,J＝7.5Hz,H-6),7.08(1H,t,J＝7.5Hz,H-5),7.01(1H,dd,J＝7.2,4.5Hz,H-5’),4.07(3H,s,OMe-10),3.93(2H,s,H-8)；¹³C NMR(300MHz,acetone-d₆):δ170.5(C-9),153.1(C-2’),148.7(C-6’),138.7(C-3’),133.3(C-7a),124.8(C-3a),123.6(C-2),123.3(C-6),120.5(C-5),120.2(C-4’),120.1(C-4),114.1(C-5’),109.0(C-7),106.1(C-3),66.2(C-10),34.5(C-8)；(+)-HR-ESIMS m/z 282.1239[M+H]⁺(calcd forC₁₆H₁₆N₃O₂,282.1237)。

Example 37: preparation of N- (3-chloropyridin-4-yl) -2- (1-methoxy-1H-indol-3-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding 3-chloro-4-aminopyridine (0.85g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 h; adding deionized water (20mL), rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude N- (3-chloropyridin-4-yl) -2- (1H-indol-3-yl) acetamide as a pale reddish brown oil.

Secondly, dissolving N- (3-chloropyridin-4-yl) -2- (1H-indol-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was stripped of solvent under reduced pressure at 50 ℃ to give crude N- (3-chloropyridin-4-yl) -2- (indolin-3-yl) acetamide as a dark brown oil.

Dissolving N- (3-chloropyridine-4-yl) -2- (indolin-3-yl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide is obtained and is placed for standby.

The fourth stepAdding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave N- (3-chloropyridin-4-yl) -2- (1-methoxy-1H-indol-3-yl) acetamide (340mg) as a brown solid.¹H NMR(400MHz,acetone-d₆):δ8.69(1H,brs,NH-1),8.42(1H,s,H-2’),8.36(2H,m,H-5’,6’),7.66(1H,d,J＝8.0Hz,H-4),7.63(1H,s,H-2),7.47(1H,d,J＝8.0Hz,H-7),7.25(1H,t,J＝7.6Hz,H-6),7.10(1H,t,J＝7.6Hz,H-5),4.12(3H,s,H-10),4.01(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.3(C-7a),124.5(C-3a),123.9(C-2),123.6(C-3),120.9(C-5),120.2(C-3’),119.9(C-4),115.1(C-5’),109.2(C-7),105.2(C-3),66.4(C-10),34.6(C-8)；(+)-HR-ESIMS m/z316.086[M+H]⁺(calcd for C₁₆H₁₅ClN₃O₂,316.0847)。

Example 38: preparation of N- (3-bromopyridin-4-yl) -2- (1-methoxy-1H-indol-3-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding 3-bromo-4-aminopyridine (1.14g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 h; adding deionized water (20mL), rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude N- (3-bromopyridin-4-yl) -2- (1H-indol-3-yl) acetamide as a red-brown oil.

Secondly, dissolving N- (3-bromopyridine-4-yl) -2- (1H-indole-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was stripped of solvent under reduced pressure at 50 ℃ to give crude N- (3-bromopyridin-4-yl) -2- (indolin-3-yl) acetamide as a dark brown oil.

Dissolving N- (3-bromopyridine-4-yl) -2- (indolin-3-yl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding is finished; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing N- (3-bromopyridine-4-yl) -2- (1-hydroxy-1H-indole-3-yl) acetamide is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave N- (3-bromopyridin-4-yl) -2- (1-methoxy-1H-indol-3-yl) acetamide (319mg) as a brown solid.¹H NMR(400MHz,acetone-d₆):δ8.51(1H,brs,NH-1),8.38(1H,d,J＝5.6Hz,H-6’),8.33(1H,d,J＝5.6Hz,H-5’),7.65(2H,d,J＝9.2Hz,H-2,4),7.48(1H,d,J＝8.0Hz,H-7),7.26(1H,t,J＝7.6Hz,H-6),7.11(1H,t,J＝7.6Hz,H-5),4.14(3H,s,OMe-10),3.99(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ170.8(C-9),152.5(C-2’),150.3(C-6’),143.5(C-4’),133.4(C-7a),124.5(C-3a),124.1(C-2),123.7(C-3),121.0(C-5),119.9(C-3’),115.3(C-4),110.9(C-5’),109.2(C-7),104.9(C-3),66.5(C-10),34.7(C-8)；(+)-HR-ESIMS m/z 360.0345[M+H]⁺(calcd forC₁₆H₁₅BrN₃O₂,360.0342)。

Example 39: preparation of methyl 2- [3- (1-methoxy-1H-indol-3-yl) propanamide ] benzoate

Dissolving methyl-2- [3- (indolin-3-yl) propionamide ] benzoate in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing methyl-2- [3- (1-hydroxy-1H-indole-3-yl) propionamide ] benzoate is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; separating by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain methyl-2- [3- (1-methoxy-1H-indol-3-yl) propionamide as orange gum]Benzoate (147 mg).¹H NMR(400MHz,acetone-d₆):δ10.95(1H,brs,NH-1),8.72(1H,d,J＝8.8Hz,H-3’),7.99(1H,d,J＝8.0Hz,H-6’),7.64(1H,d,J＝7.6Hz,H-4),7.58(1H,t,J＝7.6Hz,H-4’),7.38(1H,d,J＝8.4Hz,H-7),7.35(1H,s,H-2),7.19(1H,t,J＝7.6Hz,H-6),7.11(1H,t,J＝7.6Hz,H-5),7.05(1H,t,J＝7.6Hz,H-5’),4.03(3H,s,OMe-10),3.89(3H,s,OMe-8’),3.15(2H,t,J＝7.6Hz,H-8a),2.83(2H,t,J＝7.6Hz,H-8)；¹³C NMR(400MHz,acetone-d₆):δ171.6(C-9),169.1(C-7’),142.5(C-2’),135.2(C-4’),133.6(C-7a),131.6(C-6’),124.7(C-3a),123.1(C-2,5’),122.1(C-5),120.9(C-3’),120.2(C-6),119.8(C-4),115.9(C-1’),111.9(C-3),109.0(C-7),65.9(C-10),52.8(C-8’),39.5(C-8),21.4(C-8a)；(+)-HR-ESIMS m/z353.1513[M+H]⁺(calcd forC₂₀H₂₁N₂O₄,353.1496)。

Example 40: preparation of methyl 2- [4- (1-methoxy-1H-indol-3-yl) butanamide ] benzoate

Dissolving methyl-2- [4- (indolin-3-yl) butanamide ] benzoate in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing methyl-2- [4- (1-hydroxy-1H-indole-3-yl) butanamide ] benzoate is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; separating by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain brown gum-like methyl-2- [4- (1-methoxy-1H-indol-3-yl) butanamide]Benzoate (102 mg).¹H NMR(400MHz,acetone-d₆):δ10.97(1H,brs,NH-1),8.73(1H,d,J＝8.4Hz,H-3’),8.01(1H,d,J＝8.0Hz,H-6’),7.59(2H,m,H-4,4’),7.39(1H,d,J＝8.0Hz,H-7),7.33(1H,s,H-2),7.18(1H,t,J＝7.6Hz,H-6),7.12(1H,t,J＝7.6Hz,H-5’),7.04(1H,t,J＝7.6Hz,H-5),4.06(3H,s,OMe-10),3.91(3H,s,OMe-8’),2.83(2H,t,J＝6.0Hz,H-8b),2.52(2H,t,J＝7.6Hz,H-8),2.11(2H,m,H-8a)；¹³C NMR(400MHz,acetone-d₆):δ172.0(C-9),169.2(C-7’),142.6(C-2’),135.2(C-4’),133.7(C-7a),131.6(C-6’),124.9(C-3a),123.0(C-2,5’),122.0(C-5),120.8(C-3’),120.1(C-6),120.0(C-4),115.8(C-1’),112.5(C-3),109.0(C-7),65.8(C-10),52.8(C-8’),38.2(C-8),26.6(C-8b),24.9(C-8a)；(+)-HR-ESIMS m/z 367.166[M+H]⁺(calcd for C₂₁H₂₃N₂O₄,367.1652)。

Example 41: preparation of methyl 2- [2- (1, 5-dimethoxy-1H-indol-3-yl) acetamide ] benzoate

Firstly, weighing 5-methoxyindole acetic acid (0.5g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (0.52g) at room temperature, and stirring for dissolving; methyl anthranilate (0.41g) and DMAP (0.1g) are added, and the mixture is stirred and reacted for 3 hours at room temperature; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude methyl-2- [2- (5-methoxy-1H-indol-3-yl) acetamide ] benzoate as a yellow oil.

Secondly, methyl-2- [2- (5-methoxy-1H-indol-3-yl) acetamide ] benzoate is dissolved in trifluoroacetic acid (10mL), triethylsilane (0.7g) is added, and the mixture is refluxed and reacted for 3 hours at the temperature of 60 ℃; recovering solvent from the reaction solution, adding ethyl acetate (20mL) and saturated sodium bicarbonate aqueous solution (20mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (20mL), and separating the phases; mixing the organic phases, adding saturated saline (20mL), stirring for 10min, and separating the phases; the organic phase was stripped of solvent under reduced pressure at 50 ℃ to give crude methyl-2- [2- (5-methoxyindolin-3-yl) acetamide ] benzoate as a dark brown oil.

Dissolving methyl-2- [2- (5-methoxyindolin-3-yl) acetamide ] benzoate in (25mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.15g), dropwise adding 30% hydrogen peroxide (5mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding; adding dichloromethane (100mL) and water (100mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (50 mL. times.2) and the organic phases were combined; adding saturated saline solution (100mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing methyl-2- [2- (1-hydroxy-5-methoxy-1H-indole-3-yl) acetamide ] benzoate is obtained and is placed for standby.

Fourthly, adding 2N trimethylsilane diazomethane N-hexane solution (5mL) into the organic phase obtained in the third step, and reacting for 24 hours at room temperature in a dark place; separating by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain methyl-2- [2- (1, 5-dimethoxy-1H-indol-3-yl) acetamide as light brown gum]Benzoate (40 mg).¹H NMR(400MHz,acetone-d₆):δ10.94(1H,brs,NH-1),8.75(1H,d,J＝8.4Hz,H-3’),7.92(1H,d,J＝7.6Hz,H-6’),7.55(2H,m,H-2,4’),7.36(1H,d,J＝8.8Hz,H-7),7.09(2H,m,H-4,5’),6.87(1H,dd,J＝8.8,2.0Hz,H-6),4.18(3H,s,OMe-10),3.83(2H,s,H-8),3.77(3H,s,OMe-5a),3.74(3H,s,H-7’)；¹³C NMR(400MHz,acetone-d₆):δ170.8(C-9),168.7(C-7’),155,6(C-5),142.3(C-2’),135.1(C-4’),131.6(C-6’),128.7(C-7a),125.4(C-2),124.8(C-3a),123.1(C-6),120.7(C-3’),116.1(C-1’),113.7(C-4),110.0(C-7),104.6(C-3),101.5(C-5’),66.4(C-10),55.9(C-5a),52.6(C-8’),35.7(C-8)；(+)-HR-ESIMS m/z 369.1453[M+H]⁺(calcd forC₂₀H₂₀N₂O₅,369.1445)。

Example 42: preparation of N- (2-chlorophenyl) -2- (1, 5-dimethoxy-1H-indol-3-yl) acetamide

Firstly, weighing 5-methoxyindole acetic acid (0.5g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (0.52g) at room temperature, and stirring for dissolving; o-chloroaniline (0.41g) and DMAP (0.1g) were added, and the mixture was stirred at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 deg.C to give crude N- (2-chlorophenyl) -2- (5-methoxy-1H-indol-3-yl) acetamide as a yellow oil.

Secondly, dissolving N- (2-chlorphenyl) -2- (5-methoxy-1H-indol-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (0.7g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (20mL) and saturated sodium bicarbonate aqueous solution (20mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (20mL), and separating the phases; mixing the organic phases, adding saturated saline (20mL), stirring for 10min, and separating the phases; the organic phase was freed from the solvent under reduced pressure at 50 ℃ to give the crude N- (2-chlorophenyl) -2- (5-methoxyindolin-3-yl) acetamide as a dark brown oil.

Dissolving N- (2-chlorphenyl) -2- (5-methoxyindolin-3-yl) acetamide in (25mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.15g), dropwise adding 30% hydrogen peroxide (5mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding is finished; adding dichloromethane (100mL) and water (100mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (50 mL. times.2) and the organic phases were combined; adding saturated saline solution (100mL) into the organic phase for washing, and separating phases; the dichloromethane phase containing N- (2-chlorphenyl) -2- (1-hydroxy-5-methoxy-1H-indole-3-yl) acetamide is obtained and is placed for standby.

Fourth step, organic addition obtained in the third stepAdding 2N trimethylsilane diazomethane N-hexane solution (5mL), and reacting for 24h at room temperature in a dark place; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave N- (2-chlorophenyl) -2- (1, 5-dimethoxy-1H-indol-3-yl) acetamide (88mg) as a pale brown solid.¹H NMR(400MHz,acetone-d₆):δ8.45(1H,brs,NH-1),8.29(1H,d,J＝8.4Hz,H-6’),7.56(1H,s,H-2),7.37(1H,d,J＝8.8Hz,H-3’),7.34(1H,d,J＝8.0Hz,H-7),7.28(1H,t,J＝8.0Hz,H-4’),7.20(1H,d,J＝1.2Hz,H-4),7.05(1H,t,J＝7.6Hz,H-5’),6.90(1H,dd,J＝8.8,1.6Hz,H-6),4.09(3H,s,OMe-10),3.88(2H,s,H-8),3.77(3H,s,OMe-5a)；¹³C NMR(400MHz,acetone-d₆):δ170.0(C-9),155.7(C-5),136.1(C-7a),129.9(C-6’),128.8(C-1’),128.4(C-6),125.5(C-3’),125.3(C-3a),124.5(C-2),122.8(C-4’),113.9(C-4),110.6(C-2’),110.1(C-7),105.3(C-3),101.7(C-5’),66.3(C-10),55.9(C-5a),34.6(C-8)；(+)-HR-ESIMS m/z 345.1003[M+H]⁺(calcd forC₁₈H₁₈ClN₂O₃,345.1)。

Example 43: preparation of methyl 2- [2- (1-ethoxy-1H-indol-3-yl) acetamide ] benzoate

Dissolving methyl-2- [2- (indolin-3-yl) acetamide ] benzoate in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; and removing the solvent by organic phase under reduced pressure to obtain a crude product of methyl-2- [2- (1-hydroxy-1H-indol-3-yl) acetamide ] benzoate.

In the fourth step, methyl-2- [2- (1-hydroxy-1H-indol-3-yl) acetamide]Adding dry DMF (5mL) into benzoate, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromoethane (0.98g), and stirring at room temperature for reacting for 2 h; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain methyl-2- [2- (1-ethoxy-1H-indol-3-yl) acetamide as a pale pink gum]Benzoate (510 mg);¹H NMR(400MHz,acetone-d₆):δ10.93(1H,brs,NH-1),8.75(1H,d,J＝8.4Hz,H-3’),7.90(1H,d,J＝8.4Hz,H-6’),7.56(3H,m,H-2,4,4’),7.46(1H,d,J＝8.4Hz,H-7),7.21(1H,t,J＝7.6Hz,H-6),7.06(2H,m,H-5,5’),4.43(2H,q,J＝6.8Hz,H-1”),3.87(2H,s,H-8),3.71(3H,s,H-8’),1.43(3H,t,J＝6.8Hz,H-2”)；¹³C NMR(400MHz,acetone-d₆):δ170.2(C-9),168.0(C-7’),141.7(C-2’),134.4(C-4’),133.5(C-7a),130.9(C-6’),124.4(C-2),124.1(C-3a),122.6(C-5’),122.5(C-6),120.0(C-3’),119.9(C-4),119.1(C-5),115.4(C-1’),108.7(C-7),104.2(C-3),74.3(C-1”),51.9(C-8’),35.1(C-8),13.6(C-2”)；(+)-HR-ESIMS m/z 353.1502[M+H]⁺(calcd for C₂₀H₂₁N₂O₄,353.1496)。

example 44: preparation of N- (2-chlorophenyl) -2- (1-ethoxy-1H-indol-3-yl) acetamide

Dissolving N- (2-chlorphenyl) -2- (indolin-3-yl) acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the organic phase is decompressed and the solvent is removed, thus obtaining the crude product of N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide.

Fourthly, adding dry DMF (5mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromoethane (0.98g), and stirring at room temperature for reaction for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; water (W)Extracting the phases with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- (1-ethoxy-1H-indol-3-yl) acetamide (498mg) as a pink solid.¹H NMR(400MHz,acetone-d₆):δ8.44(1H,brs,NH-1),8.30(1H,d,J＝8.4Hz,H-6’),7.67(1H,d,J＝8.0Hz,H-3’),7.60(1H,s,H-2),7.47(1H,d,J＝8.0Hz,H-4),7.32(1H,d,J＝8.0Hz,H-7),7.25(2H,m,H-4’,5’),7.09(1H,t,J＝7.6Hz,H-6),7.04(1H,t,J＝7.6Hz,H-5),4.35(2H,q,J＝7.2Hz,H-1”),3.93(2H,s,H-8),1.38(3H,t,H-2”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.0(C-1’),134.0(C-7a),129.8(C-5’),125.5(C-3’),124.7(C-2),124.5(C-3a),123.4(C-6,4’),122.8(C-2’,6’),120.7(C-5),119.9(C-4),109.3(C-7),105.4(C-3),74.7(C-1”),34.5(C-8),14.1(C-2”)；(+)-HR-ESIMS m/z 329.106[M+H]⁺(calcd for C₁₈H₁₈ClN₂O₂,329.1051)。

Example 45: preparation of methyl 2- [2- (1-propoxy-1H-indol-3-yl) acetamide ] benzoate

In the fourth step, methyl-2- [2- (1-hydroxy-1H-indol-3-yl) acetamide]Adding dry DMF (5mL) into benzoate, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropane (1.1g), and stirring at room temperature for reacting for 2 h; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase with silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain light pink solid methyl-2- [2- (1-propoxy-1H-indol-3-yl) acetamide]Benzoate ester (523 mg).¹H NMR(400MHz,acetone-d₆):δ10.92(1H,brs,NH-1),8.75(1H,d,J＝8.4Hz,H-3’),7.90(1H,d,J＝8.4Hz,H-6’),7.56(3H,m,H-2,4,4’),7.46(1H,d,J＝8.0Hz,H-7),7.21(1H,t,J＝7.6Hz,H-6),7.06(2H,m,H-5,5’),4.34(2H,t,J＝6.4Hz,H-1”),3.87(2H,s,H-8),3.72(3H,s,H-8’),1.86(2H,m,H-2”),1.10(3H,t,J＝7.6Hz,H-3”)；¹³C NMR(400MHz,acetone-d₆):δ170.8(C-9),168.6(C-7’),142.3(C-2’),135.0(C-4’),133.9(C-7a),131.5(C-6’),124.9(C-2),124.7(C-3a),123.2(C-5’),123.1(C-6),120.6(C-3’),120.5(C-4),119.7(C-5),116.0(C-1’),109.2(C-7),104.9(C-3),80.8(C-1”),52.5(C-8’),35.7(C-8),22.3(C-2”),10.6(C-3”)；(+)-HR-ESIMS m/z367.1664[M+H]⁺(calcd for C₂₁H₂₃N₂O₄,367.1652)。

Example 46: preparation of N- (2-chlorophenyl) -2- (1-propoxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropane (1.1g), and stirring at room temperature for reaction for 2 hours; ethyl acetate (50) was added to the reaction mixturemL) and water (50mL) are quickly stirred for 10min, and phase separation is carried out; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- (1-propoxy-1H-indol-3-yl) acetamide (511mg) as a pink solid.¹H NMR(400MHz,acetone-d₆):δ8.44(1H,brs,NH-1),8.30(1H,d,J＝8.4Hz,H-6’),7.67(1H,d,J＝8.0Hz,H-3’),7.61(1H,s,H-2),7.47(1H,d,J＝8.0Hz,H-4),7.33(1H,d,J＝8.0Hz,H-7),7.26(2H,m,H-4’,5’),7.09(1H,t,J＝7.6Hz,H-6),7.04(1H,t,J＝7.6Hz,H-5),4.26(2H,t,J＝6.8Hz,H-1”),3.92(2H,s,H-8),1.81(2H,m,H-2”),1.07(3H,t,J＝7.6Hz,H-3”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.9(C-7a),129.9(C-5’),128.3(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6,2’),122.8(C-6’),120.7(C-5),119.9(C-4),109.3(C-7),105.5(C-3),80.7(C-1”),34.6(C-8),22.3(C-2”),10.5(C-3”)；(+)-HR-ESIMS m/z 343.1221[M+H]⁺(calcd for C₁₉H₂₀ClN₂O₂,343.1208)。

Example 47: preparation of N- (3-chloropyridin-4-yl) -2- (1-propoxy-1H-indol-3-yl) acetamide

Dissolving N- (3-chloropyridine-4-yl) -2- (indolin-3-yl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the organic phase is decompressed and the solvent is removed, thus obtaining the crude product of N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide.

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropane (1.1g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to give N- (3-chloropyridin-4-yl) -2- (1-propoxy-1H-indol-3-yl) acetamide (445mg) as a white solid.¹H NMR(400MHz,acetone-d₆):δ8.66(1H,brs,NH-1),8.42(1H,s,H-2’),8.36(2H,m,H-5’,6’),7.65(1H,d,J＝8.0Hz,H-4),7.63(1H,s,H-2),7.47(1H,d,J＝8.0Hz,H-7),7.24(1H,t,J＝7.6Hz,H-6),7.10(1H,t,J＝7.6Hz,H-5),4.26(2H,t,J＝6.8Hz,H-1”),4.00(2H,s,H-8),1.81(2H,m,H-2”),1.08(3H,t,H-3”)；¹³C NMR(400MHz,acetone-d₆):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.8(C-7a),124.7(C-2),124.5(C-3a),123.5(C-6),120.8(C-5),119.9(C-4),115.0(C-5’),114.9(C-3’),109.3(C-7),104.9(C-3),80.8(C-1”),34.7(C-8),22.3(C-2”),10.5(C-3”)；(+)-HR-ESIMS m/z 344.1166[M+H]⁺(calcd for C₁₈H₁₉ClN₃O₂,344.116)。

Example 48: preparation of N- (3-fluoropyridin-4-yl) -2- (1-propoxy-1H-indol-3-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding 3-fluoro-4-aminopyridine (0.9g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 h; adding water (10mL), rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was stripped of solvent under reduced pressure at 40 ℃ to give crude N- (3-fluoropyridin-4-yl) -2- (1H-indol-3-yl) acetamide as a pale reddish brown oil.

Secondly, dissolving N- (3-fluoropyridin-4-yl) -2- (1H-indol-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was stripped of solvent under reduced pressure at 50 ℃ to give crude N- (3-fluoropyridin-4-yl) -2- (indolin-3-yl) acetamide as a dark brown oil.

Dissolving N- (3-fluoropyridin-4-yl) -2- (indolin-3-yl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting at 15-20 ℃ for 1h after dropwise adding; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the organic phase was depressurized to remove the solvent to give crude N- (3-fluoropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide.

In the fourth step, N- (3-fluoropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide was added to dry DMF (5mL), stirred at room temperature and anhydrous potassium carbonate (1)66g), bromopropane (1.1g), stirred at room temperature for 2 h; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:3) to give N- (3-fluoropyridin-4-yl) -2- (1-propoxy-1H-indol-3-yl) acetamide (203mg) as a red brown solid.¹H NMR(400MHz,acetone-d₆):δ9.29(1H,brs,NH-1),8.36(2H,m,H-2’,6’),8.28(1H,d,J＝6.4Hz,H-5’),7.65(1H,d,J＝8.0Hz,H-4),7.52(1H,s,H-2),7.43(1H,d,J＝7.6Hz,H-7),7.21(1H,t,J＝7.6Hz,H-6),7.07(1H,t,J＝7.6Hz,H-5),4.24(2H,t,J＝6.4Hz,H-1”),3.98(2H,s,H-8),1.79(2H,m,H-2”),1.07(3H,t,H-3”)；¹³C NMR(400MHz,acetone-d₆):δ171.1(C-9),147.45(C-2’),147.39(C-6’),138.0(C-3’),137.8(C-3’),133.8(C-4’),124.7(C-7a),124.3(C-2),123.3(C-6),120.5(C-5),120.0(C-4),115.6(C-5’),110.6(C-3a),109.2(C-7),105.4(C-3),80.6(C-1”),34.4(C-8),22.3(C-2”),10.5(C-3”)；(+)-HR-ESIMS m/z 327.1386[M+H]⁺(calcd for C₁₈H₁₈FN₃O₂,327.1383)。

Example 49: preparation of N- (2-chloro-5-methylphenyl) -2- (1-propoxy-1H-indol-3-yl) acetamide

Firstly, weighing indoleacetic acid (1.05g), adding dichloromethane (20mL) for suspension stirring, adding EDCI (1.27g) at room temperature, and stirring for dissolution; adding 5-methyl-2-chloroaniline (0.93g) and DMAP (0.15g), and stirring at room temperature for reaction for 3 hours; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was removed under reduced pressure at 40 ℃ to give crude N- (2-chloro-5-methylphenyl) -2- (1H-indol-3-yl) acetamide as a pale reddish brown oil.

Secondly, dissolving N- (2-chloro-5-methylphenyl) -2- (1H-indol-3-yl) acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was stripped of solvent under reduced pressure at 50 deg.C to give crude N- (2-chloro-5-methylphenyl) -2- (indolin-3-yl) acetamide as a dark brown oil.

Dissolving N- (2-chloro-5-methylphenyl) -2- (indolin-3-yl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃ after dropwise adding; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the organic phase was removed under reduced pressure to give crude N- (2-chloro-5-methylphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide.

Fourthly, adding dry DMF (5mL) into N- (2-chloro-5-methylphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropane (1.1g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to give N- (2-chloro-5-methylphenyl) -2- (1-propoxy-1H-indol-3-yl) acetamide (519mg) as an off-white solid.¹H NMR(400MHz,acetone-d₆):δ8.37(1H,brs,NH-1),8.14(1H,s,H-6’),7.66(1H,d,J＝8.0Hz,H-3’),7.60(1H,s,H-2),7.46(1H,d,J＝8.4Hz,H-4’),7.24(1H,t,J＝7.6Hz,H-6),7.18(1H,d,J＝8.0Hz,H-4),7.09(1H,t,J＝7.6Hz,H-5),6.85(1H,d,J＝8.0Hz,H-7),4.25(2H,t,J＝6.8Hz,H-1”),3.91(2H,s,H-8),2.27(3H,s,H-7’),1.81(2H,m,H-2”),1.07(3H,t,J＝7.6Hz,H-3”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),138.4(C-1’),135.6(C-5’),133.9(C-7a),129.4(C-3’),126.1(C-4’),124.6(C-3a),124.5(C-6’),123.4(C-6),123.2(C-2’),120.7(C-5),119.9(C-4),109.2(C-7),105.5(C-3),80.7(C-1”),34.6(C-8),22.3(C-7’),21.2(C-2”),10.5(C-3”)；(+)-HR-ESIMS m/z 357.1365[M+H]⁺(calcd for C₂₀H₂₁ClN₂O₂,357.1364)。

Example 50: preparation of 2- (1-propoxy-1H-indol-3-yl) -N- [2- (trifluoromethyl) phenyl ] acetamide

Firstly, weighing indoleacetic acid (1.05g), adding the weighed indoleacetic acid into dichloromethane (20mL), suspending and stirring, cooling to 0-5 ℃, and stirring; oxalyl chloride (1.15g) is added within 5min, a drop of DMF is added dropwise, and the mixture is slowly heated to room temperature to react for 1 h; the reaction mixture was removed under reduced pressure at 25 ℃ to give 2- (1H-indol-3-yl) acetyl chloride.

Secondly, adding dichloromethane (20mL) into 2- (1H-indol-3-yl) acetyl chloride, stirring for dissolving, cooling to 0-5 ℃, and stirring; adding 2-trifluoromethylaniline (0.97g) and triethylamine (1.2g), slowly raising the temperature to room temperature for reaction for 1 h; adding 2N hydrochloric acid (20mL), rapidly stirring for 10min, and separating phases; adding saturated salt water (10mL) into the organic phase, stirring for 10min, and separating phases; the organic phase was freed from the solvent under reduced pressure at 40 ℃ to give the crude 2- (1H-indol-3-yl) -N- [2- (trifluoromethyl) phenyl ] acetamide as a pale reddish brown oil.

Thirdly, dissolving 2- (1H-indol-3-yl) -N- [2- (trifluoromethyl) phenyl ] acetamide in trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was freed of the solvent under reduced pressure at 50 ℃ to give the crude 2- (indolin-3-yl) -N- [2- (trifluoromethyl) phenyl ] acetamide as a dark brown oil.

Fourthly, dissolving 2- (indolin-3-yl) -N- [2- (trifluoromethyl) phenyl ] acetamide in (50mL) methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the organic phase was stripped of the solvent under reduced pressure to give crude 2- (1-hydroxy-1H-indol-3-yl) -N- [2- (trifluoromethyl) phenyl ] acetamide.

In the fifth step, 2- (1-hydroxy-1H-indol-3-yl) -N- [2- (trifluoromethyl) phenyl]Adding dry DMF (5mL) into acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropane (1.1g), and stirring at room temperature for reaction for 2 h; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain light purple solid 2- (1-propoxy-1H-indol-3-yl) -N- [2- (trifluoromethyl) phenyl]Acetamide (95 mg).¹H NMR(400MHz,acetone-d₆):δ8.30(1H,brs,NH-1),8.11(1H,d,J＝8.4Hz,H-6’),7.61(4H,m,H-2,4,3’,5’),7.46(1H,d,J＝8.4Hz,H-7),7.29(1H,t,J＝7.6Hz,H-4’),7.24(1H,t,J＝7.6Hz,H-6),7.09(1H,t,J＝7.6Hz,H-5),4.26(2H,t,J＝6.8Hz,H-1”),3.90(2H,s,H-8),1.83(2H,m,H-2”),1.08(3H,t,J＝7.6Hz,H-3”)；¹³C NMR(600MHz,acetone-d₆):δ170.2(C-9),136.8(C-1’),133.9(C-7a),133.7(C-5’),126.8(q,C-7’),126.2(C-3’),125.7(C-2’),125.6(C-5’),125.5(C-6’),124.6(C-2),123.9(C-3a),123.4(C-6),120.7(C-5),119.8(C-4),109.2(C-7),105.2(C-3),80.8(C-1”),34.3(C-8),22.3(C-2”),10.5(C-3”)；(+)-HR-ESIMS m/z377.1477[M+H]⁺(calcd for C₂₀H₂₀F₃N₂O₂,377.1473)。

Example 51: preparation of 2- (2-chloro-1-propoxy-1H-indol-3-yl) -N- (2-chlorophenyl) acetamide

Fourthly, adding dry DMF (5mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropane (1.1g), and stirring at room temperature for reaction for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- (1-propoxy-1H-indol-3-yl) acetamide (570mg) as a white solid.

The fifth step, N- (2-chlorophenyl) -2- (1-propoxy-1H-indol-3-yl) acetamide(200mg), dichloromethane (10mL) was added and the mixture was dissolved with stirring at room temperature and 25 ℃ C, NCS (86mg) was added and the reaction was stirred at room temperature for 2 hours, and the mixture was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to give 2- (2-chloro-1-propoxy-1H-indol-3-yl) -N- (2-chlorophenyl) acetamide (150mg) as a yellow solid.¹H NMR(400MHz,acetone-d₆):δ8.46(1H,brs,NH-1),8.22(1H,d,J＝8.0Hz,H-6’),7.68(1H,d,J＝7.6Hz,H-4),7.48(1H,d,J＝8.0Hz,H-3’),7.37(1H,d,J＝8.0Hz,H-7),7.28(2H,t,7.6Hz,H-4’,5’),7.15(1H,t,J＝7.6Hz,H-6),7.08(1H,t,J＝7.6Hz,H-5),4.29(2H,t,J＝6.4Hz,H-1”),3.94(2H,s,H-8),1.89(2H,m,H-2”),1.12(3H,t,J＝7.2Hz,H-3”)；¹³C NMR(400MHz,acetone-d₆):δ168.6(C-9),136.0(C-1’),133.9(C-7a),129.9(C-5’),128.4(C-3’),125.8(C-3a,4’),124.1(C-6),124.0(C-2’),123.6(C-2),123.4(C-6’),121.9(C-5),119.7(C-4),109.5(C-7),104.2(C-3),80.9(C-1”),33.2(C-8),22.3(C-2”),10.6(C-3”)；(+)-HR-ESIMS m/z 377.0816[M+H]⁺(calcd for C₁₉H₁₉Cl₂N₂O₂,377.0818)。

Example 52: preparation of 2- (2-chloro-1-propoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropane (1.1g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:3) to give N- (3-chloropyridin-4-yl) -2- (1-propoxy-1H-indol-3-yl) acetamide (445mg) as a white solid.

In the fifth step, N- (3-chloropyridin-4-yl) -2- (1-propoxy-1H-indol-3-yl) acetamide (200mg) was dissolved by adding methylene chloride (10mL) and stirring at room temperature and 25 ℃ under stirring, NCS (86mg) was added and the reaction was stirred at room temperature for 2 hours, and the mixture was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:3) to give 2- (2-chloro-1-propoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide (102mg) as a yellow solid.¹H NMR(400MHz,acetone-d₆):δ8.74(1H,brs,NH-1),8.47(1H,s,H-2’),8.37(1H,d,J＝5.6Hz,H-6’),8.31(1H,d,J＝5.6Hz,H-5’),7.66(1H,d,J＝8.0Hz,H-4),7.48(1H,d,J＝8.0Hz,H-7),7.29(1H,t,J＝7.6Hz,H-6),7.16(1H,t,J＝7.6Hz,H-5),4.30(2H,t,J＝6.4Hz,H-1”),4.04(2H,s,H-8),1.89(2H,m,H-2”),1.12(3H,t,H-3”)；¹³C NMR(400MHz,acetone-d₆):δ169.6(C-9),150.0(C-2’),149.8(C-6’),142.5(C-4’),133.8(C-7a),124.1(C-6),123.9(C-2),121.9(C-5),119.6(C-4),115.4(C-5’),109.5(C-7),103.6(C-3),80.9(C-1”),33.3(C-8),22.2(C-2”),10.6(C-3”)；(+)-HR-ESIMS m/z377.0712[M+H]⁺(calcd for C₁₈H₁₈Cl₂N₃O₂,377.0698)。

Example 53: preparation of 2- (2-bromo-1-propoxy-1H-indol-3-yl) -N- (2-chlorophenyl) acetamide

Fourthly, adding dry DMF (5mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropane (1.1g), and stirring at room temperature for reaction for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- (1-propoxy-1H-indol-3-yl) acetamide (570mg) as a white solid;

in the fifth step, N- (2-chlorophenyl) -2- (1-propoxy-1H-indol-3-yl) acetamide (200mg) was dissolved by adding methylene chloride (10mL) with stirring, stirred at 25 ℃ and NBS (115mg) was added, and the reaction was stirred at room temperature for 2 hours, and subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to give 2- (2-bromo-1-propoxy-1H-indol-3-yl) -N- (2-chlorophenyl) acetamide (192mg) as a pale yellow solid.¹H NMR(300MHz,acetone-d₆):δ8.40(1H,brs,NH-1),8.25(1H,d,J＝8.1Hz,H-6’),7.69(1H,d,J＝7.8Hz,H-4),7.49(1H,d,J＝8.1Hz,H-3’),7.36(1H,dd,J＝8.1,1.5Hz,H-7),7.27(2H,m,H-4’,5’),7.10(2H,m,H-5,6),4.29(2H,t,J＝6.6Hz,H-1”),3.93(2H,s,H-2),1.90(2H,m,H-2”),1.13(3H,t,J＝7.5Hz,H-3”)；¹³C NMR(300MHz,acetone-d₆):δ168.6(C-9),135.9(C-1’),134.7(C-7a),129.9(C-5’),128.4(C-3’),125.8(C-3a,4’),124.7(C-2),124.0(C-6),123.1(C-6’),121.7(C-5),119.6(C-4),112.3(C-2’),109.5(C-7),107.1(C-3),80.8(C-1”),34.3(C-8),22.3(C-2”),10.7(C-3”)；(+)-HR-ESIMS m/z 421.0308[M+H]⁺(calcd for C₁₉H₁₈BrClN₂O₂,421.0313)。

Example 54: preparation of 2- (5-chloro-1-propoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide

Firstly, weighing 5-chloroindole (1.51g), adding anhydrous ether (30mL), stirring for dissolving, cooling to 0-5 ℃, stirring, dropwise adding oxalyl chloride (1.9g) within 5min, heating to room temperature of 20-25 ℃ after dropwise adding, and stirring for reacting for 2 h. The reaction mixture was subjected to removal of the solvent under reduced pressure at 25 ℃ to give 2- (5-chloro-1H-indol-3-yl) -2-carbonylacetyl chloride as a brown oil.

And secondly, adding dichloromethane (20mL) into the 2- (5-chloro-1H-indol-3-yl) -2-carbonyl acetyl chloride, stirring and dissolving, cooling to 0-5 ℃, and stirring. 3-chloro-4-aminopyridine (1.28g) and triethylamine (1.5g) were added and the reaction was allowed to warm to room temperature slowly for 2 h. Cooling to 0-5 ℃, stirring for 30min, filtering, and washing a filter cake with dichloromethane (5 mL); forced air drying at 40 ℃ gave 2- (5-chloro-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) -2-carbonylacetamide (2.0g) as a pale yellow solid.

And thirdly, adding methanol (20mL) into the 2- (5-chloro-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) -2-carbonyl acetamide, stirring and dissolving, cooling to 10-15 ℃, stirring, adding sodium borohydride (1g), slowly heating to room temperature, and reacting for 30 min. Removing solvent at 30 deg.C under reduced pressure, adding ethyl acetate (20mL) and water (20mL), rapidly stirring for 5min, and separating phases; extracting the water phase with ethyl acetate (20mL), and separating the phases; mixing ethyl acetate phases, adding saturated saline (20mL), rapidly stirring for 5min, and separating phases; the ethyl acetate phase was removed under reduced pressure at 45 ℃ to give crude 2- (5-chloro-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) -2-hydroxyacetamide as a pale yellow oil.

Fourthly, dissolving the 2- (5-chloro-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) -2-hydroxyacetamide obtained in the third step into trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was stripped of solvent under reduced pressure at 50 ℃ to give crude 2- (5-chloro-indolin-3-yl) -N- (3-chloropyridin-4-yl) acetamide as a dark brown oil.

Fifthly, dissolving 2- (5-chloro-indolin-3-yl) -N- (3-chloropyridine-4-yl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the organic phase was stripped of solvent under reduced pressure to give crude 2- (5-chloro-1-hydroxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide.

Sixthly, adding the 2- (5-chloro-1-hydroxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide into dry DMF (8mL), stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropane (1.65g), and stirring at room temperature for reacting for 2H; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to give 2- (5-chloro-1-propoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide (102mg) as a pale brown solid.¹H NMR(400MHz,acetone-d₆):δ8.76(1H,brs,NH-1),8.45(1H,s,H-2’),8.38(1H,d,J＝5.6Hz,H-6’),8.33(1H,d,J＝5.2Hz,H-5’),7.72(1H,s,H-4),7.68(1H,s,H-2),7.48(1H,d,J＝8.4Hz,H-7),7.22(1H,d,J＝8.8Hz,H-6),4.28(2H,t,J＝6.8Hz,H-1”),4.02(2H,s,H-8),1.81(2H,m,H-2”),1.07(3H,t,J＝6.4Hz,H-3”)；¹³C NMR(600MHz,acetone-d₆):δ170.7(C-9),150.0(C-6’),149.8(C-5’),142.6(C-4’),132.2(C-7a),126.16(C-2),125.6(C-3a),123.6(C-6),120.4(C-5),119.6(C-4),115.36(C-2’),115.29(C-3’),110.8(C-7),105.0(C-3),81.1(C-1”),34.3(C-8),22.3(C-2”),10.5(C-3”)；(+)-HR-ESIMS m/z 378.0784[M+H]⁺(calcd for C₁₈H₁₈Cl₂N₃O₂,378.0771)。

Example 55: preparation of N- (3-chloropyridin-4-yl) -2- (4-methoxy-1-propoxy-1H-indol-3-yl) acetamide

Firstly, weighing 4-methoxyindole (1.47g), adding anhydrous ether (30mL), stirring for dissolving, cooling to 0-5 ℃, stirring, dropwise adding oxalyl chloride (1.9g) within 5min, heating to room temperature of 20-25 ℃, and stirring for reacting for 2 h. The reaction mixture was subjected to removal of the solvent under reduced pressure at 25 ℃ to give 2- (4-methoxy-1H-indol-3-yl) -2-carbonyl acetyl chloride as a brown oil.

And secondly, adding dichloromethane (20mL) into 2- (4-methoxy-1H-indol-3-yl) -2-carbonyl acetyl chloride, stirring for dissolving, cooling to 0-5 ℃, and stirring. 3-chloro-4-aminopyridine (1.28g) and triethylamine (1.5g) were added and the reaction was allowed to warm to room temperature slowly for 2 h. Cooling to 0-5 ℃, stirring for 30min, filtering, and washing a filter cake with dichloromethane (5 mL); forced air drying at 40 ℃ gave 2- (4-methoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) -2-carbonylacetamide as a pale yellow solid (2.0 g).

And thirdly, adding methanol (20mL) into the 2- (4-methoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) -2-carbonyl acetamide, stirring and dissolving, cooling to 10-15 ℃, stirring, adding sodium borohydride (1g), slowly heating to room temperature, and reacting for 30 min. Removing solvent at 30 deg.C under reduced pressure, adding ethyl acetate (20mL) and water (20mL), rapidly stirring for 5min, and separating phases; extracting the water phase with ethyl acetate (20mL), and separating the phases; mixing ethyl acetate phases, adding saturated saline (20mL), rapidly stirring for 5min, and separating phases; the ethyl acetate phase was removed under reduced pressure at 45 ℃ to give crude 2- (4-methoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) -2-hydroxyacetamide as a pale yellow oil.

Fourthly, dissolving the 2- (4-methoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) -2-hydroxyacetamide obtained in the third step into trifluoroacetic acid (10mL), adding triethylsilane (1.74g), and carrying out reflux reaction at 60 ℃ for 3H; recovering solvent from the reaction solution, adding ethyl acetate (30mL) and saturated sodium bicarbonate aqueous solution (30mL), rapidly stirring for 15min, and separating phases; extracting the water phase with ethyl acetate (30mL), and separating the phases; mixing the organic phases, adding saturated saline (30mL), stirring for 10min, and separating the phases; the organic phase was stripped of solvent under reduced pressure at 50 ℃ to give crude 2- (4-methoxy-indolin-3-yl) -N- (3-chloropyridin-4-yl) acetamide as a dark brown oil.

Fifthly, dissolving 2- (4-methoxy-indolin-3-yl) -N- (3-chloropyridine-4-yl) acetamide in 50mL of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, and reacting for 1h at 15-20 ℃; adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, and separating phases; the aqueous phase was extracted with dichloromethane (100 mL. times.2) and the organic phases were combined; adding saturated saline solution (200mL) into the organic phase for washing, and separating phases; the organic phase was stripped of solvent under reduced pressure to give crude 2- (5-chloro-1-hydroxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide.

Sixthly, adding the 2- (4-methoxy-1-hydroxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide into dry DMF (8mL), stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropane (1.65g), and stirring at room temperature for reacting for 2H; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:5) to give 2- (4-methoxy-1-propoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide (110mg) as a pale brown solid.¹H NMR(400MHz,acetone-d₆):δ8.65(1H,brs,NH-1),8.37(3H,m,H-2’,5’,6’),7.45(1H,s,H-2),7.15(1H,t,J＝8.0Hz,H-6),7.06(1H,d,J＝8.4Hz,H-7),6.59(1H,d,J＝6.8Hz,H-1”),4.00(2H,s,H-1”),3.91(3H,s,H-4a),1.79(2H,m,H-2”),1.06(3H,t,J＝7.6Hz,H-3”)；¹³C NMR(400MHz,acetone-d₆):δ171.4(C-9),155.1(C-4),149.9(C-2’),149.8(C-6’),142.7(C-4’),135.5(C-7a),124.8(C-2),123.5(C-6),114.8(C-5),114.7(C-3a),114.0(C-3’),104.4(C-3a),102.8(C-5’),101.1(C-7),80.8(C-1”),55.9(C-4a),36.7(C-8),22.2(C-2”),10.5(C-3”)；(+)-HR-ESIMS m/z 373.12[M+H]⁺(calcd for C₁₉H₂₀ClN₃O₃,373.1193)。

Example 56: preparation of methyl 2- [2- (1-isopropoxy-1H-indol-3-yl) acetamide ] benzoate

In the fourth step, methyl-2- [2- (1-hydroxy-1H-indol-3-yl) acetamide]Adding dry DMF (5mL) into benzoate, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromoisopropane (1.1g), and stirring at room temperature for reacting for 2 h; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and purified with ethyl acetate-petroleum ether (1:5) eluting to obtain purple gum methyl-2- [2- (1-isopropoxy-1H-indol-3-yl) acetamide]Benzoate (495 mg).¹H NMR(400MHz,acetone-d₆):δ10.93(1H,brs,NH-1),8.75(1H,d,J＝8.4Hz,H-3’),7.91(1H,d,J＝8.0Hz,H-6’),7.55(3H,m,H-2,4,4’),7.45(1H,d,J＝8.0Hz,H-7),7.20(1H,t,J＝7.6Hz,H-5’),7.06(2H,m,H-5,6),4.71(1H,m,H-1”),3.99(2H,s,H-8),3.71(3H,s,H-8’),1.42(3H,s,H-2”),1.40(3H,s,H-3”)；¹³C NMR(400MHz,acetone-d₆):δ170.8(C-9),168.6(C-7’),142.4(C-2),135.0(C-4’),134.8(C-7a),131.5(C-6’),125.9(C-2),124.7(C-3a),123.2(C-6),123.1(C-5’),120.6(C-5),120.4(C-3’),119.6(C-4),116.0(C-1’),109.6(C-7),104.7(C-3),81.2(C-1”),52.6(C-8’),35.8(C-8),21.4(C-2”,3”)；(+)-HR-ESIMS m/z 367.1656[M+H]⁺(calcd for C₂₁H₂₃N₂O₄,367.1652)。

Example 57: preparation of N- (2-chlorophenyl) -2- (1-isopropoxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromoisopropane (1.1g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- (1-isopropoxy-1H-indol-3-yl) acetamide (480mg) as a pale pink solid.¹H NMR(400MHz,acetone-d₆):δ8.42(1H,brs,NH-1),8.32(1H,d,J＝8.0Hz,H-6’),7.66(1H,d,J＝8.0Hz,H-3’),7.58(1H,s,H-2),7.46(1H,d,J＝8.0Hz,H-4),7.27(3H,m,H-7,4’,5’),7.09(1H,t,J＝7.6Hz,H-6),7.04(1H,t,J＝7.6Hz,H-5),4.61(1H,m,H-1”),3.93(2H,s,H-8),1.36(3H,s,H-2”),1.35(3H,s,H-3”)；¹³C NMR(400MHz,acetone-d₆):δ170.0(C-9),136.0(C-1’),134.7(C-7a),129.8(C-3’),128.3(C-5’),125.5(C-4’),125.4(C-3),124.5(C-3a),123.4(C-2),122.7(C-2’,6’),120.6(C-5),119.8(C-4),109.7(C-7),105.2(C-3),81.1(C-1”),34.6(C-8),21.2(C-2”,3”)；(+)-HR-ESIMS m/z 343.1227[M+H]⁺(calcd for C₁₉H₂₀ClN₂O₂,343.1208)。

Example 58: preparation of N- (2-chlorophenyl) -2- (1-butoxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and N-bromobutane (1.23g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating organic phase with silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtainTo a purple solid, N- (2-chlorophenyl) -2- (1-butoxy-1H-indol-3-yl) acetamide (560 mg).¹H NMR(400MHz,acetone-d₆):δ8.43(1H,brs,NH-1),8.30(1H,d,J＝8.4Hz,H-6’),7.66(1H,d,J＝8.0Hz,H-4),7.61(1H,s,H-2),7.46(1H,d,J＝8.0Hz,H-3’),7.33(1H,d,J＝8.0Hz,H-7),7.26(2H,m,H-4’,5’),7.09(1H,t,J＝7.6Hz,H-6),7.04(1H,t,J＝7.6Hz,H-5),4.30(2H,t,J＝6.4Hz,H-1”),3.92(2H,s,H-8),1.78(2H,m,H-2”),1.56(2H,m,H-3”),0.98(3H,t,J＝7.2Hz,H-4”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.9(C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6,2’),122.8(C-6’),120.7(C-5),120.0(C-4),109.2(C-7),105.5(C-3),79.0(C-1”),34.6(C-8),31.0(C-2”),19.7(C-3”),14.1(C-4”)；(+)-HR-ESIMS m/z 357.1373[M+H]⁺(calcd forC₂₀H₂₂ClN₂O₂,357.1364)。

Example 59: preparation of 2- (1-butoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromobutane (1.2g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to give 2- (1-butoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide (440mg) as a pale yellow gum.¹H NMR(400MHz,acetone-d6):δ8.66(1H,brs,N-H),8.42(1H,s,H-2’),8.36(2H,m,H-5’,6’),7.64(2H,m,H-2,4),7.47(1H,d,J＝8.4Hz,H-7),7.25(1H,t,J＝7.6Hz,H-6),7.10(1H,t,J＝7.6Hz,H-5),4.31(2H,t,J＝7.2Hz,H-1”),4.00(2H,s,H-8),1.78(2H,s,H-2”),1.54(2H,m,H-3”),0.98(3H,t,J＝7.6Hz,H-4”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.9(C-7a),124.7(C-2),124.5(C-3’),123.6(C-6),120.8(C-5’),119.9(C-4),115.03(C-3a),114.96(C-5),109.3(C-7),104.9(C-3),79.1(C-1”),34.7(C-8),31.0(C-2”),19.7(C-3”),14.1(C-4”)；(+)-HR-ESIMSm/z 357.1249[M+H]⁺(calcd for C₁₉H₂₁ClN₃O₂,357.1244)。

Example 60: preparation of N- (2-chlorophenyl) -2- (1-pentoxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and N-bromopentane (1.36g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; organic phase processColumn chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:8) gave N- (2-chlorophenyl) -2- (1-pentoxy-1H-indol-3-yl) acetamide (549mg) as a violet gum.¹H NMR(400MHz,acetone-d₆):δ8.43(1H,brs,NH-1),8.30(1H,d,J＝8.4Hz,H-6’),7.66(1H,d,J＝8.0Hz,H-4),7.61(1H,s,H-2),7.46(1H,d,J＝8.0Hz,H-3’),7.33(1H,d,J＝8.0Hz,H-7),7.26(2H,m,H-4’,5’),7.07(2H,m,H-5,6),4.30(2H,t,J＝6.4Hz,H-1”),3.92(2H,s,H-8),1.80(2H,m,H-2”),1.51(2H,m,H-3”),1.41(2H,m,H-4”),0.93(3H,t,J＝7.2Hz,H-5”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.9(C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6,2’),122.8(C-6’),120.7(C-5),120.0(C-4),109.3(C-7),105.5(C-3),79.3(C-1”),34.6(C-8),28.70(C-2”),28.68(C-3”),23.1(C-4”),14,2(C-5”)；(+)-HR-ESIMS m/z 371.1528[M+H]⁺(calcd forC₂₁H₂₄ClN₂O₂,371.1521)。

Example 61: preparation of N- (3-chloropyridin-4-yl) -2- [1- (pentyloxy) -1H-indol-3-yl ] acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopentane (1.2g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:5) to give 2- (1-pentyloxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide (450mg) as a pale yellow gum.¹H NMR(400MHz,acetone-d6):δ8.66(1H,brs,N-H),8.42(1H,s,H-2’),8.36(2H,m,H-5’,6’),7.64(2H,m,H-2,4),7.47(1H,d,J＝8.4Hz,H-7),7.25(1H,t,J＝7.6Hz,H-6),7.10(1H,t,J＝7.6Hz,H-5),4.31(2H,t,J＝7.2Hz,H-1”),4.00(2H,s,H-8),1.81(2H,s,H-2”),1.45(2H,m,H-3”,4”),0.93(3H,t,J＝7.2Hz,H-5”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.9(C-7a),124.7(C-2),124.5(C-3’),123.6(C-6),120.8(C-5’),119.9(C-4),115.0(C-3a),109.3(C-7),104.9(C-3),79.4(C-1”),34.7(C-8),28.69(C-2”),28.68(C-3”),23.1(C-4”),14.2(C-5”)；(+)-HR-ESIMS m/z 371.141[M+H]⁺(calcd for C₂₀H₂₃ClN₃O₂,371.1401)。

Example 62: preparation of N- (2-chlorophenyl) -2- (1-hexyloxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (8mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and N-bromohexane (1.48g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; the aqueous phase was extracted with ethyl acetate (25 mL. times.2), and the organic phases were combinedAdding saturated salt solution (50mL), rapidly stirring for 10min, and separating phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:8) to give N- (2-chlorophenyl) -2- (1-hexyloxy-1H-indol-3-yl) acetamide as a pale brown gum (530 mg).¹H NMR(400MHz,acetone-d₆):δ8.43(1H,brs,NH-1),8.30(1H,d,J＝8.4Hz,H-6’),7.66(1H,d,J＝8.0Hz,H-4),7.61(1H,s,H-2),7.46(1H,d,J＝8.0Hz,H-3’),7.33(1H,d,J＝8.0Hz,H-7),7.26(2H,m,H-4’,5’),7.09(1H,t,J＝7.6Hz,H-6),7.04(1H,t,J＝7.6Hz,H-5),4.30(2H,t,J＝6.4Hz,H-1”),3.92(2H,s,H-8),1.80(2H,m,H-2”),1.53(2H,m,H-3”),1.35(4H,m,H-4”,5”),0.90(3H,t,J＝6.4Hz,H-6”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.9(C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6,2’),122.8(C-6’),120.7(C-5),120.0(C-4),109.3(C-7),105.5(C-3),79.3(C-1”),34.6(C-8),32.3(C-2”),29.0(C-3”),26.2(C-4”),23.2(C-5”),14.2(C-6”)；(+)-HR-ESIMS m/z 385.1678[M+H]⁺(calcd for C₂₂H₂₆ClN₂O₂,385.1677)。

Example 63: preparation of N- (2-chlorophenyl) -2- (1-heptyloxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (8mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and N-bromoheptane (1.6g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:8) to give N- (2-chlorophenyl) -2- (1-heptyloxy-1H-indol-3-yl) acetamide as a pale brown gum (580 mg).¹H NMR(400MHz,acetone-d₆):δ8.43(1H,brs,NH-1),8.30(1H,d,J＝8.4Hz,H-6’),7.66(1H,d,J＝8.0Hz,H-4),7.61(1H,s,H-2),7.46(1H,d,J＝8.0Hz,H-3’),7.33(1H,d,J＝8.0Hz,H-7),7.26(2H,m,H-4’,5’),7.07(2H,m,H-5,6),4.30(2H,t,J＝6.4Hz,H-1”),3.92(2H,s,H-8),1.81(2H,m,H-2”),1.53(2H,m,H-3”),1.34(6H,m,H-4”,5”,6”),0.88(3H,t,J＝6.0Hz,H-7”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.9(C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6,2’),122.8(C-6’),120.7(C-5),120.0(C-4),109.3(C-7),105.5(C-3),79.3(C-1”),34.6(C-8),32.4(C-2”),29.8(C-3”),29.0(C-4”),26.5(C-5”),23.2(C-6”),14.3(C-7”)；(+)-HR-ESIMS m/z399.184[M+H]⁺(calcd for C₂₃H₂₈ClN₂O₂,399.1834)。

Example 64: preparation of N- (2-chlorophenyl) -2- (1-octyloxy-1H-indol-3-yl) acetamide

In the fourth step, N- (2-chlorophenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide was added to dry DMF (8mL), stirred at room temperature, and anhydrous potassium carbonate (1.66g), N-bromooctane(1.72g), and the reaction is stirred at room temperature for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:10) to give N- (2-chlorophenyl) -2- (1-octyloxy-1H-indol-3-yl) acetamide as a pale brown gum (602 mg).¹H NMR(400MHz,acetone-d₆):δ8.43(1H,brs,NH-1),8.30(1H,d,J＝8.4Hz,H-6’),7.66(1H,d,J＝8.0Hz,H-4),7.61(1H,s,H-2),7.46(1H,d,J＝8.0Hz,H-3’),7.33(1H,d,J＝8.0Hz,H-7),7.26(2H,m,H-4’,5’),7.07(2H,m,H-5,6),4.31(2H,t,J＝6.4Hz,H-1”),3.92(2H,s,H-8),1.81(2H,m,H-2”),1.53(2H,m,H-3”),1.32(8H,m,H-4”,5”,6”,7”),0.88(3H,t,J＝6.4Hz,H-8”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.9(C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6,2’),122.8(C-6’),120.7(C-5),120.0(C-4),109.3(C-7),105.5(C-3),79.3(C-1”),34.6(C-8),32.5(C-2”),30.1(C-3”),29.9(C-4”),29.0(C-5”),26.5(C-6”),23.3(C-7”),14.3(C-8”)；(+)-HR-ESIMS m/z 413.1996[M+H]⁺(calcd for C₂₄H₃₀ClN₂O₂,413.199)。

Example 65: preparation of N- (2-chlorophenyl) -2- (1-nonyloxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (8mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and N-bromononane (1.84g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- (1-nonanyloxy-1H-indol-3-yl) acetamide (660mg) as a pale yellow solid.¹H NMR(400MHz,acetone-d₆):δ8.43(1H,brs,NH-1),8.30(1H,d,J＝8.4Hz,H-6’),7.66(1H,d,J＝8.0Hz,H-4),7.61(1H,s,H-2),7.46(1H,d,J＝8.0Hz,H-3’),7.33(1H,d,J＝8.0Hz,H-7),7.26(2H,m,H-4’,5’),7.09(1H,t,J＝7.6Hz,H-6),7.05(1H,t,J＝7.6Hz,H-5),4.30(2H,t,J＝6.4Hz,H-1”),3.92(2H,s,H-8),1.80(2H,m,H-2”),1.53(2H,m,H-3”),1.33(10H,m,H-4”,5”,6”,7”,8”),0.87(3H,t,J＝6.4Hz,H-9”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.9(C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6,2’),122.7(C-6’),120.7(C-5),120.0(C-4),109.3(C-7),105.5(C-3),79.3(C-1”),34.6(C-8),32.5(C-2”),30.2(C-3”),30.1(C-4”),29.9(C-5”),29.0(C-6”),26.5(C-7”),23.3(C-8”),14.3(C-9”)；(+)-HR-ESIMS m/z 427.2158[M+H]⁺(calcd for C₂₅H₃₂ClN₂O₂,427.2147)。

Example 66: preparation of N- (2-chlorophenyl) -2- (1-decyloxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (10mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and N-bromodecane (2g), and stirring at room temperature for reaction for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:10) to give N- (2-chlorophenyl) -2- (1-decyloxy-1H-indol-3-yl) acetamide as a pale purple gum (689 mg).¹H NMR(400MHz,acetone-d₆):δ8.42(1H,brs,NH-1),8.30(1H,d,J＝8.4Hz,H-6’),7.66(1H,d,J＝8.0Hz,H-4),7.61(1H,s,H-2),7.46(1H,d,J＝8.0Hz,H-3’),7.33(1H,d,J＝8.0Hz,H-7),7.26(2H,m,H-4’,5’),7.07(2H,m,H-5,6),4.30(2H,t,J＝6.4Hz,H-1”),3.92(2H,s,H-8),1.81(2H,m,H-2”),1.53(2H,m,H-3”),1.32(12H,m,H-4”,5”,6”,7”,8”,9”),0.87(3H,t,J＝6.4Hz,H-10”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.9(C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6,2’),122.7(C-6’),120.7(C-5),120.0(C-4),109.3(C-7),105.5(C-3),79.3(C-1”),34.6(C-8),32.6(C-2”),30.2(C-3”,4”),30.1(C-5”),30.0(C-6”),29.0(C-7”),26.5(C-8”),23.3(C-9”),14.3(C-10”)；(+)-HR-ESIMS m/z441.2309[M+H]⁺(calcd for C₂₆H₃₄ClN₂O₂,441.2303)。

Example 67: preparation of N- (2-chlorophenyl) -2- (1-tetradecyloxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (10mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromotetradecane (2.5g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:10) to give N- (2-chlorophenyl) -2- (1-tetradecyloxy-1H-indol-3-yl) acetamide (690mg) as a pale brown solid.¹H NMR(400MHz,acetone-d₆):δ8.42(1H,brs,NH-1),8.30(1H,d,J＝8.4Hz,H-6’),7.66(1H,d,J＝8.0Hz,H-4),7.61(1H,s,H-2),7.46(1H,d,J＝8.0Hz,H-3’),7.33(1H,d,J＝8.0Hz,H-7),7.26(2H,m,H-4’,5’),7.07(2H,m,H-5,6),4.30(2H,t,J＝6.4Hz,H-1”),3.92(2H,s,H-8),1.81(2H,m,H-2”),1.53(2H,m,H-3”),1.35(20H,m,H-4”,5”,6”,7”,8”,9”,10”,11”,12”,13”),0.87(3H,t,J＝6.4Hz,H-14”)；¹³C NMR(400MHz,acetone-d₆):δ169.3(C-9),135.5(C-1’),133.3(C-7a),129.2(C-5’),127.8(C-3’),124.9(C-3a,4),124.0(C-2),122.8(C-6,2’),122.1(C-6’),120.1(C-5),119.3(C-4),108.7(C-7),104.9(C-3),78.7(C-1”),33.9(C-8),32.0(C-2”),29.8(C-3”,4”),29.71(C-5”),29.65(C-6”),29.6(C-7”),29.5(C-8”),29.4(C-9”,10”),28.4(C-11”),25.9(C-12”),22.7(C-13”),13.7(C-14”)；(+)-HR-ESIMS m/z 497.2944[M+H]⁺(calcd for C₃₀H₄₂ClN₂O₂,497.2929)。

Example 68: preparation of N- (2-chlorophenyl) -2- (1-hexadecyloxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (10mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromohexadecane (2.5g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:10) to give N- (2-chlorophenyl) -2- (1-hexadecyloxy-1H-indol-3-yl) acetamide (717mg) as a brown solid.¹H NMR(400MHz,acetone-d₆):δ8.43(1H,brs,NH-1),8.32(1H,d,J＝8.4Hz,H-6’),7.67(1H,d,J＝8.0Hz,H-4),7.62(1H,s,H-2),7.47(1H,d,J＝8.0Hz,H-3’),7.34(1H,d,J＝8.0Hz,H-7),7.27(2H,m,H-4’,5’),7.10(1H,t,J＝7.6Hz,H-6),7.06(1H,t,J＝7.6Hz,H-5),4.31(2H,t,J＝6.4Hz,H-1”),3.93(2H,s,H-8),1.82(2H,m,H-2”),1.54(2H,m,H-3”),1.36(24H,m,H-4”,5”,6”,7”,8”,9”,10”,11”,12”,13”,14”,15”),0.88(3H,t,J＝6.4Hz,H-16”)；¹³C NMR(300MHz,acetone-d₆):δ169.3(C-9),135.5(C-1’),133.3(C-7a),129.2(C-5’),127.7(C-3’),124.8(C-3a,4),124.0(C-2),122.8(C-6,2’),122.1(C-6’),120.1(C-5),119.3(C-4),108.6(C-7),104.9(C-3),78.7(C-1”),34.0(C-8),32.0(C-2”),29.8(C-3”,4”,5”,6”,7”,8”),29.6(C-9”),29.4(C-10”,11”,12”),28.4(C-13”),25.9(C-14”),22.7(C-15”),13.7(C-16”)；(+)-HR-ESIMS m/z525.3255[M+H]⁺(calcd for C₃₂H₄₆ClN₂O₂,525.3242)。

Example 69: preparation of 2- [1- (secondary butoxy) -1H-indol-3-yl ] -N- (2-chlorophenyl) acetamide

Fourthly, adding dry DMF (5mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 2-bromobutane (1.24g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; the aqueous phase was extracted with ethyl acetate (25 mL. times.2), the organic phases were combined, saturated brine (50mL) was added, and the mixture was stirred rapidlyStirring for 10min, and separating phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:5) to give 2- [1- (secondary butoxy) -1H-indol-3-yl as a yellow solid]-N- (2-chlorophenyl) acetamide (515 mg).¹H NMR(400MHz,acetone-d₆):δ8.41(1H,brs,NH-1),8.29(1H,d,J＝9.4Hz,H-6’),7.65(1H,d,J＝8.0Hz,H-4),7.59(1H,s,H-2),7.46(1H,d,J＝8.0Hz,H-3’),7.33(1H,d,J＝8.0Hz,H-7),7.28(1H,t,J＝7.6Hz,H-4’),7.23(1H,t,J＝7.6Hz,H-5’),7.07(2H,m,H-5,6),4.43(1H,m,H-1”),3.92(2H,s,H-8),1.76(3H,m,H-2”),1.32(2H,d,J＝6.4Hz,H-4”),1.07(3H,t,J＝2.6Hz,H-3”)；¹³C NMR(400MHz,acetone-d₆):δ170.0(C-9),136.1(C-1’),134.8(C-7a),129.9(C-5’),128.4(C-3’),125.6(C-4),125.5(C-3a),124.6(C-2),123.4(C-6,2’),122.7(C-6’),120.6(C-5),119.9(C-4),109.7(C-7),105.3(C-3),86.0(C-1”),34.6(C-8),28.5(C-4”),18.8(C-2”),9.9(C-3”)；(+)-HR-ESIMS m/z 357.1376[M+H]⁺(calcd for C₂₀H₂₁ClN₂O₂,357.1364)。

Example 70: preparation of N- (2-chlorophenyl) -2- (1-isobutoxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 2-methyl bromopropane (1.24g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- (1-isobutoxy-1H-indol-3-yl) acetamide (552mg) as a yellow solid.¹H NMR(400MHz,acetone-d₆):δ8.43(1H,brs,NH-1),8.29(1H,d,J＝9.4Hz,H-6’),7.66(1H,d,J＝8.0Hz,H-4),7.62(1H,s,H-2),7.46(1H,d,J＝8.0Hz,H-3’),7.34(1H,d,J＝8.0Hz,H-7),7.26(2H,m,H-4’,5’),7.08(2H,m,H-5,6),4.09(2H,t,J＝6.8Hz,H-1”),3.92(2H,s,H-8),2.15(1H,m,H-2”),1.14(6H,d,J＝6.8Hz,H-3”,4”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),133.7(C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2’),124.5(C-2),123.5(C-6),122.8(C-6’),120.7(C-5),120.0(C-4),109.2(C-7),105.6(C-3),85.5(C-1”),34.6(C-8),28.3(C-2”),19.3(C-3”,4”)；(+)-HR-ESIMSm/z 357.1369[M+H]⁺(calcd for C₂₀H₂₂ClN₂O₂,357.1364)。

Example 71: preparation of N- (3-chloropyridin-4-yl) -2- (1-isobutoxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromoisobutane (1.2g), and stirring at room temperature for reacting for 2 hours; ethyl acetate (50mL) and water (50mL) were added to the reaction mixture, and the mixture was stirred rapidlyStirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:5) to give 2- (1-isobutoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide as a pale yellow gum (435 mg).¹H NMR(400MHz,acetone-d6):δ8.67(1H,brs,N-H),8.42(1H,s,H-2’),8.36(2H,m,H-5’,6’),7.65(2H,m,H-2,4),7.47(1H,d,J＝8.4Hz,H-7),7.25(1H,t,J＝7.6Hz,H-6),7.10(1H,t,J＝7.6Hz,H-5),4.08(2H,t,J＝6.8Hz,H-1”),4.00(2H,s,H-8),2.13(1H,m,H-2”),1.09(6H,d,J＝6.8Hz,H-3”,4”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.7(C-7a),124.6(C-2),124.5(C-3a),123.6(C-6),120.8(C-5),119.9(C-4),115.0(C-5’),109.3(C-7),105.0(C-3),85.5(C-1”),34.6(C-8),28.3(C-2”),19.3(C-3”,4”)；(+)-HR-ESIMS m/z 357.1245[M+H]⁺(calcdfor C₁₉H₂₁ClN₃O₂,357.1244)。

Example 72: preparation of N- (2-chlorophenyl) -2- [1- (2-pentyloxy) -1H-indol-3-yl ] acetamide

Fourthly, adding dry DMF (5mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 3-methyl bromobutane (1.36g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- [1- (2-pentyloxy) -1H-indol-3-yl as a pale brown gum]Acetamide (610 mg).¹H NMR(400MHz,acetone-d₆):δ8.43(1H,brs,NH-1),8.29(1H,d,J＝9.4Hz,H-6’),7.66(1H,d,J＝8.0Hz,H-4),7.62(1H,s,H-2),7.46(1H,d,J＝8.0Hz,H-3’),7.33(1H,d,J＝8.0Hz,H-7),7.26(2H,m,H-4’,5’),7.07(2H,m,H-5,6),4.35(2H,t,J＝6.8Hz,H-1”),3.92(2H,s,H-8),1.89(1H,m,H-3”),1.72(2H,q,J＝13.6,6.8Hz,H-2”),0.98(6H,d,J＝6.8Hz,H-4”,5”)；¹³C NMR(400MHz,acetone-d₆):δ170.0(C-9),136.1(C-1’),133.9(C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),124.6(C-2),123.5(C-6’),122.8(C-6,2’),120.7(C-5),120.0(C-4),109.3(C-7),105.6(C-3),77.9(C-1”),37.7(C-8),34.6(C-3”),25.8(C-2”),22.8(C-4”,5”)；(+)-HR-ESIMS m/z 371.1534[M+H]⁺(calcd forC₂₁H₂₄ClN₂O₂,371.1521)。

Example 73: preparation of N- (3-chloropyridin-4-yl) -2- (1-isopentyloxy-1H-indol-3-yl) acetamide

In the fourth step, N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide was added to dry DMF (5mL) and stirred at room temperature, anhydrous potassium carbonate (1.66g) and 3-methylbromobutane (1.36g) were added and the reaction was stirred at room temperature for 2 hours(ii) a Adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:3) to give N- (3-chloropyridin-4-yl) -2- (1-isopentyloxy-1H-indol-3-yl) acetamide (480mg) as a pale yellow gum.¹H NMR(400MHz,acetone-d6):δ8.66(1H,brs,N-H),8.42(1H,s,H-2’),8.36(2H,m,H-5’,6’),7.65(2H,m,H-2,4),7.47(1H,d,J＝8.0Hz,H-7),7.25(1H,t,J＝7.6Hz,H-6),7.10(1H,t,J＝7.6Hz,H-5),4.35(2H,t,J＝6.8Hz,H-1”),4.00(2H,s,H-8),1.89(1H,m,H-3”),1.72(2H,m,H-2”),0.98(6H,d,J＝6.8Hz,H-4”,5”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.8(C-7a),124.7(C-2),124.5(C-3’),123.6(C-6),120.8(C-5’),119.9(C-5),115.0(C-4),109.3(C-7),105.0(C-3),77.9(C-1”),37.7(C-3”),34.7(C-8),25.7(C-2”),22.8(C-4”,5”)；(+)-HR-ESIMS m/z 371.1406[M+H]⁺(calcd for C₂₀H₂₃ClN₃O₂,371.1401)。

Example 74: preparation of N- (2-chlorophenyl) -2- (1-cyclopentanyloxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromocyclopentane (1.4g), and stirring at room temperature for reaction for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- (1-cyclopentyloxy-1H-indol-3-yl) acetamide (429mg) as a pale brown solid.¹H NMR(400MHz,acetone-d₆):δ8.41(1H,brs,NH-1),8.30(1H,d,J＝8.4Hz,H-6’),7.65(1H,d,J＝8.0Hz,H-4),7.63(1H,s,H-2),7.45(1H,d,J＝8.4Hz,H-3’),7.33(1H,d,J＝8.0Hz,H-7),7.28(1H,t,J＝7.6Hz,H-4’),7.23(1H,t,J＝7.6Hz,H-5’),7.07(2H,m,H-5,6),5.00(1H,m,H-1”),3.92(2H,s,H-8),1.83(8H,m,H-2”,3”,4”,5”)；¹³C NMR(400MHz,acetone-d₆):δ170.0(C-9),136.1(C-1’),134.5(C-7a),129.9(C-5’),128.4(C-3’),125.5(C-3a,4),125.2(C-2),124.5(C-2’),123.5(C-6),122.7(C-6’),120.7(C-5),119.9(C-4),109.5(C-7),105.3(C-3),90.9(C-1”),34.6(C-8),31.9(C-2”,5”),24.1(C-3”,4”)；(+)-HR-ESIMS m/z 369.1363[M+H]⁺(calcd for C₂₁H₂₂ClN₂O₂,369.1364)。

Example 75: preparation of N- (3-chloropyridin-4-yl) -2- (1-cyclopentyloxy-1H-indol-3-yl) acetamide

In the fourth step, N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide was added to dry DMF (5mL), stirred at room temperature and added with anhydrous carbonic acidPotassium (1.66g) and bromocyclopentane (1.4g) are stirred and reacted for 2 hours at room temperature; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:3) to give N- (3-chloropyridin-4-yl) -2- (1-cyclopentyloxy-1H-indol-3-yl) acetamide (405mg) as a pale yellow gum.¹H NMR(400MHz,acetone-d6):δ8.64(1H,brs,N-H),8.41(1H,s,H-2’),8.36(2H,m,H-5’,6’),7.64(2H,m,H-2,4),7.46(1H,d,J＝8.0Hz,H-7),7.24(1H,t,J＝7.6Hz,H-6),7.09(1H,t,J＝7.6Hz,H-5),5.01(1H,m,H-1”),4.00(2H,s,H-8),1.83(8H,m,H-2”,3”,4”,5”)；¹³C NMR(400MHz,acetone-d6):δ171.0(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),134.5(C-7a),125.3(C-2),124.4(C-3’),123.6(C-6),120.8(C-5’),119.8(C-4),115.0(C-3a),109.5(C-7),104.7(C-3),90.9(C-1”),34.7(C-8),31.9(C-2”,5”),24.1(C-3”,4”)；(+)-HR-ESIMS m/z369.1249[M+H]⁺(calcd for C₂₀H₂₁ClN₃O₂,369.1244)。

Example 76: preparation of N- (3-chloropyridin-4-yl) -2- (1-methylbutoxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 2-methylbutane (1.4g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:3) to give N- (3-chloropyridin-4-yl) -2- (1-methylbutoxy-1H-indol-3-yl) acetamide (610mg) as a pale yellow solid.¹H NMR(500MHz,acetone-d6):δ8.65(1H,brs,N-H),8.41(1H,s,H-2’),8.35(2H,m,H-5’,6’),7.64(2H,m,H-2,4),7.46(1H,d,J＝8.0Hz,H-7),7.25(1H,t,J＝7.5Hz,H-6),7.10(1H,t,J＝7.5Hz,H-5),4.15(2H,m,H-1”),4.00(2H,s,H-8),1.93(1H,m,H-2”),1.64(1H,m,H-3”),1.33(1H,m,H-3”),1.09(3H,d,J＝7.0Hz,H-5”),0.97(3H,t,J＝7.0Hz,H-4”)；¹³C NMR(500MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.7(C-7a),124.5(C-2),123.6(C-6),120.8(C-3a),119.9(C-5),115.0(C-4),109.3(C-7),107.7(C-3),84.1(C-1”),34.8(C-8),34.7(C-2”),26.6(C-3”),16.6(C-5”),11.5(C-4”)；(+)-HR-ESIMS m/z 371.14[M+H]⁺(calcd for C₂₀H₂₂ClN₃O₂,371.1401)。

Example 77: preparation of N- (3-chloropyridin-4-yl) -2- [1- (3, 3-dimethylbutoxy) -1H-indol-3-yl ] acetamide

The fourth step, N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamideAdding dry DMF (5mL), stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 3, 3-dimethylbutane (1.5g), and stirring at room temperature for reaction for 2 h; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:3) to give N- (3-chloropyridin-4-yl) -2- [1- (3, 3-dimethylbutoxy) -1H-indol-3-yl as a pale yellow solid]Acetamide (480 mg).¹H NMR(400MHz,acetone-d6):δ8.67(1H,brs,N-H),8.42(1H,s,H-2’),8.36(2H,m,H-5’,6’),7.66(2H,m,H-2,4),7.47(1H,d,J＝8.4Hz,H-7),7.25(1H,t,J＝7.6Hz,H-6),7.10(1H,t,J＝7.6Hz,H-5),4.39(2H,t,J＝7.2Hz,H-1”),4.00(2H,s,H-8),1.80(2H,t,J＝7.2Hz,H-2”),0.99(9H,s,H-4”,5”,6”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.8(C-7a),124.7(C-2),124.5(C-6),123.6(C-5),120.8(C-4),119.9(C-3a),115.0(C-5’),109.4(C-7),104.9(C-3),77.0(C-1”),42.0(C-2”),34.7(C-8),29.9(C-4”,5”,6”)；(+)-HR-ESIMS m/z385.1554[M+H]⁺(calcd for C₂₁H₂₄ClN₃O₂,385.1557)。

Example 78: preparation of N- (3-chloropyridin-4-yl) -2- [1- (2-ethylbutoxy) -1H-indol-3-yl ] acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 2-ethylbutane (1.5g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:3) to give N- (3-chloropyridin-4-yl) -2- (1-ethylbutoxy-1H-indol-3-yl) acetamide (615mg) as a pale yellow solid.¹H NMR(500MHz,acetone-d6):δ8.66(1H,brs,N-H),8.36(3H,m,H-2’,5’,6’),7.65(2H,m,H-2,4),7.46(1H,d,J＝8.0Hz,H-7),7.25(1H,t,J＝7.5Hz,H-6),7.10(1H,t,J＝7.5Hz,H-5),4.22(2H,m,H-1”),4.00(2H,s,H-8),1.71(1H,m,H-2”),1.57(4H,m,H-3”,5”),0.98(6H,m,H-4”,6”)；¹³C NMR(500MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.7(C-7a),124.53(C-2),124.47(C-6),123.6(C-5),120.8(C-4),119.9(C-3a),115.0(C-4),109.2(C-7),105.0(C-3),81.6(C-1”),41.1(C-2”),34.7(C-8),23.9(C-3”,5”),11.4(C-4”,6”)；(+)-HR-ESIMS m/z 385.1562[M+H]⁺(calcd for C₂₁H₂₄ClN₃O₂,385.1557)。

Example 79: preparation of N- (2-chlorophenyl) -2- (1-allyloxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide(5mL), stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and propylene iodide (1.5g), and stirring at room temperature for reaction for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- (1-allyloxy-1H-indol-3-yl) acetamide (395mg) as a pale brown solid.¹H NMR(400MHz,acetone-d₆):δ8.42(1H,brs,NH-1),8.29(1H,d,J＝8.0Hz,H-6’),7.66(1H,d,J＝8.0Hz,H-4),7.60(1H,s,H-2),7.47(1H,d,J＝8.0Hz,H-3’),7.33(1H,d,J＝8.0Hz,H-7),7.26(2H,m,H-4’,5’),7.07(2H,m,H-5,6),6.19(1H,m,H-2”),5.36(2H,m,H-3”),4.80(2H,d,J＝6.8Hz,H-1”),3.91(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.1(C-1’),134.1(C-7a),133.1(C-2”),129.9(C-5’),128.3(C-3’),125.5(C-3a,4),124.9(C-2),124.6(C-2’),123.5(C-6),122.8(C-6’),121.5(C-3”),120.8(C-5),119.9(C-4),109.5(C-7),105.5(C-3),79.8(C-1”),34.6(C-8)；(+)-HR-ESIMS m/z 341.1051[M+H]⁺(calcd for C₁₉H₁₈ClN₂O₂,341.1051)。

Example 80: preparation of 2- [1- (allyloxy) -1-hydro-indol-3-yl ] -N- (3-fluoropyridin-4-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (3-fluoropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropylene (1.1g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain 2- [1- (allyloxy) -1-hydrogen-indol-3-yl ] as a red brown solid]-N- (3-fluoropyridin-4-yl) acetamide (224 mg).¹H NMR(400MHz,acetone-d₆):δ9.25(1H,brs,NH-1),8.35(2H,m,H-2’,6’),8.27(1H,d,J＝6.4Hz,H-5’),7.65(1H,d,J＝8.0Hz,H-4),7.52(1H,s,H-2),7.44(1H,d,J＝8.4Hz,H-7),7.22(1H,t,J＝7.6Hz,H-6),7.08(1H,t,J＝7.6Hz,H-5),6.18(1H,m,H-2”),5.34(2H,m,H-3”),4.78(2H,d,J＝6.8Hz,H-1”),3.97(2H,s,H-8)；¹³C NMR(400MHz,acetone-d₆):δ171.1(C-9),147.41(C-2’),147.36(C-6’),137.9(C-3’),137.8(C-3’),133.8(C-4’),133.0(C-2”),124.6(C-7a),124.5(C-2),123.3(C-6),121.5(C-4),120.5(C-5),120.0(C-3”),115.43(C-5’),115.35(C-3a),109.3(C-7),105.3(C-3),79.7(C-1”),34.3(C-8)；(+)-HR-ESIMS m/z 325.1229[M+H]⁺(calcd for C₁₈H₁₇FN₃O₂,325.1227)。

Example 81: preparation of 2- [1- (Enebutoxy) -1-hydro-indol-3-yl ] -N- (3-chloropyridin-4-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 1-bromo-3-butene (1.3g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:3) to give 2- [1- (en-butoxy) -1-hydro-indol-3-yl as a pale yellow solid]-N- (3-chloropyridin-4-yl) acetamide (520 mg).¹H NMR(400MHz,acetone-d6):δ8.67(1H,brs,N-H),8.42(1H,s,H-2’),8.35(2H,m,H-5’,6’),7.65(2H,m,H-2,4),7.48(1H,d,J＝8.0Hz,H-7),7.25(1H,t,J＝7.6Hz,H-6),7.10(1H,t,J＝7.6Hz,H-5),5.96(1H,m,H-3”),5.19(2H,m,H-4”),4.37(2H,t,J＝6.4Hz,H-1”),4.00(2H,s,H-8),2.57(2H,m,H-2”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),135.0(C-3”),133.9(C-7a),124.7(C-2),124.5(C-4”),123.6(C-6),120.9(C-3a),119.9(C-5),117.8(C-4),115.0(C-5’),109.4(C-7),105.1(C-3),78.2(C-1”),34.7(C-8),34.3(C-2”)；(+)-HR-ESIMS m/z355.1096[M+H]⁺(calcd for C₁₉H₁₉ClN₃O₂,355.1088)。

Example 82: preparation of N- (3-chloropyridin-4-yl) -2- [1- (2-pentyl-4-en-1-yloxy) -1H-indol-3-yl ] acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 1-bromo-4-pentene (1.4g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:3) to give N- (3-chloropyridin-4-yl) -2- [1- (2-pentyl-4-en-1-yloxy) -1H-indol-3-yl as a pale yellow gum]Acetamide (540 mg).¹H NMR(400MHz,acetone-d6):δ8.66(1H,brs,N-H),8.42(1H,s,H-2’),8.35(2H,m,H-5’,6’),7.64(2H,m,H-2,4),7.48(1H,d,J＝8.0Hz,H-7),7.25(1H,t,J＝7.6Hz,H-6),7.10(1H,t,J＝7.6Hz,H-5),5.88(1H,m,H-4”),5.05(2H,m,H-5”),4.32(2H,t,J＝6.8Hz,H-1”),4.00(2H,s,H-8),2.30(2H,m,H-3”),1.90(2H,m,H-2”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),138.6(C-4”),133.8(C-7a),124.6(C-2),124.5(C-5”),123.6(C-6),120.8(C-3a),119.9(C-5),115.7(C-4),115.0(C-5’),109.3(C-7),105.0(C-3),78.6(C-1”),34.7(C-8),30.6(C-3”),28.2(C-2”)；(+)-HR-ESIMS m/z 369.1259[M+H]⁺(calcd for C₂₀H₂₀ClN₃O₂,369.1244)。

Example 83: preparation of N- (3-chloropyridin-4-yl) -2- [1- (2-hexyl-5-en-1-yloxy) -1H-indol-3-yl ] acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 1-bromo-5-hexene (1.6g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:3) to give N- (3-chloropyridin-4-yl) -2- [1- (2-hexyl-5-en-1-yloxy) -1H-indol-3-yl as a pale yellow gum]Acetamide (580 mg).¹H NMR(400MHz,acetone-d6):δ8.69(1H,brs,N-H),8.42(1H,s,H-2’),8.36(2H,m,H-5’,6’),7.65(2H,m,H-2,4),7.47(1H,d,J＝8.0Hz,H-7),7.25(1H,t,J＝7.6Hz,H-6),7.10(1H,t,J＝7.6Hz,H-5),5.84(1H,m,H-5”),4.98(2H,m,H-6”),4.31(2H,t,J＝6.4Hz,H-1”),4.00(2H,s,H-8),2.13(2H,m,H-4”),1.81(2H,m,H-2”),1.62(2H,m,H-3”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),139.2(C-2),133.7(C-7a),124.6(C-6”),124.4(C-3a),123.5(C-6),120.8(C-5),120.1(C-3’),119.9(C-4),115.2(C-5”),115.0(C-5’),109.3(C-7),104.9(C-3),79.1(C-1”),34.6(C-8),34.1(C-4”),28.4(C-2”),25.8(C-3”)；(+)-HR-ESIMS m/z383.1406[M+H]⁺(calcd for C₂₁H₂₃ClN₃O₂,383.1401)。

Example 84: preparation of 2- [1- (butyl-3-yn-1-yloxy) -1-hydro-indol-3-yl ] -N- (3-chloropyridin-4-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 1-bromo-3-butyne (1.2g), and stirring at room temperature for reaction for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain 2- [1- (butyl-3-alkyne-1-yloxy) -1-hydrogen-indol-3-yl ] as pale yellow gum]-N- (3-chloropyridin-4-yl) acetamide (490 mg).¹H NMR(400MHz,acetone-d6):δ8.69(1H,brs,N-H),8.42(1H,s,H-2’),8.35(2H,m,H-5’,6’),7.66(2H,m,H-2,4),7.58(1H,d,J＝8.0Hz,H-7),7.26(1H,t,J＝7.6Hz,H-6),7.11(1H,t,J＝7.6Hz,H-5),4.42(2H,t,J＝6.4Hz,H-1”),4.01(2H,s,H-8),2.70(2H,m,H-2”),2.56(1H,m,H-4”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),150.0(C-2’),149.8(C-6’),142.5(C-4’),134.2(C-7a),124.8(C-2),124.6(C-3’),123.7(C-6),121.0(C-5’),119.9(C-4),115.1(C-3a),109.5(C-7),105.5(C-3),81.1(C-3”),76.9(C-1),71.7(C-4”),34.6(C-8),19.0(C-2”)；(+)-HR-ESIMS m/z353.0935[M+H]⁺(calcd for C₁₉H₁₇ClN₃O₂,353.0931)。

Example 85: preparation of 2- [1- (butyl-2-yn-1-yloxy) -1-hydro-indol-3-yl ] -N- (3-chloropyridin-4-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 1-bromo-2-butyne (1.2g), and stirring at room temperature for reaction for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain 2- [1- (butyl-2-alkyne-1-yloxy) -1-hydrogen-indol-3-yl ] as pale yellow gum]-N- (3-chloropyridin-4-yl) acetamide (416 mg).¹H NMR(400MHz,acetone-d6):δ8.69(1H,brs,N-H),8.43(1H,s,H-2’),8.36(2H,m,H-5’,6’),7.65(2H,m,H-2,4),7.52(1H,d,J＝8.0Hz,H-7),7.25(1H,t,J＝7.6Hz,H-6),7.10(1H,t,J＝7.6Hz,H-5),4.90(2H,s,H-1”),4.00(2H,s,H-8),1.79(3H,s,H-4”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),150.0(C-2’),149.8(C-6’),142.6(C-4’),134.3(C-7a),125.2(C-2),124.5(C-3’),123.6(C-6),121.0(C-5’),120.3(C-5),119.8(C-4),115.0(C-3a),109.8(C-7),105.2(C-3),86.9(C-2”),74.2(C-3”),68.9(C-1”),34.6(C-8),3.4(C-4”)；(+)-HR-ESIMS m/z 353.0942[M+H]⁺(calcd forC₁₉H₁₆ClN₃O₂,353.0931)。

Example 86: preparation of N- (2-chlorophenyl) -2- [1- (3-chloropropoxy) -1H-indol-3-yl ] acetamide

Fourthly, adding dry DMF (5mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 3-chlorobromopropane (1.4g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain brown gum N- (2-chlorophenyl) -2- [1- (3-chloropropoxy) -1H-indol-3-yl]Acetamide (450 mg).¹H NMR(400MHz,acetone-d₆):δ8.47(1H,brs,NH-1),8.29(1H,d,J＝8.4Hz,H-6’),7.68(1H,d,J＝8.0Hz,H-4),7.62(1H,s,H-2),7.50(1H,d,J＝8.0Hz,H-3’),7.33(1H,d,J＝8.0Hz,H-7),7.26(2H,m,H-4’,5’),7.11(1H,t,J＝7.6Hz,H-6),7.04(1H,t,J＝7.6Hz,H-5),4.46(2H,t,J＝6.0Hz,H-1”),3.93(2H,s,H-8),3.88(2H,t,J＝6.4Hz,H-3”),2.28(2H,m,H-2”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),136.0(C-1’),133.8(C-7a),129.8(C-5’),128.3(C-3’),125.5(C-3a,4),124.6(C-2’),124.5(C-2),123.6(C-6),122.9(C-6’),120.8(C-5),120.0(C-4),109.2(C-7),105.9(C-3),75.8(C-1”),42.0(C-3”),34.5(C-8),31.9(C-2”)；(+)-HR-ESIMS m/z 377.0824[M+H]⁺(calcd forC₁₉H₁₉Cl₂N₂O₂,377.0818)。

Example 87: preparation of 2- [1- (3-chloropropyloxy) -1-hydro-indol-3-yl ] -N- (3-chloropyridin-4-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 3-chloro-1-bromopropane (1.3g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain light yellow gum 2- [1- (3-chloropropoxy) -1-hydrogen-indol-3-yl]-N- (3-chloropyridin-4-yl) acetamide (452 mg).¹H NMR(400MHz,acetone-d6):δ8.69(1H,brs,N-H),8.42(1H,s,H-2’),8.35(2H,m,H-5’,6’),7.65(2H,m,H-2,4),7.51(1H,d,J＝8.4Hz,H-7),7.26(1H,t,J＝7.6Hz,H-6),7.11(1H,t,J＝7.6Hz,H-5),4.47(2H,t,J＝6.4Hz,H-1”),4.01(2H,s,H-8),3.88(2H,t,J＝6.4Hz,H-3”),2.28(2H,m,H-2”)；¹³C NMR(400MHz,acetone-d6):δ170.8(C-9),149.9(C-2’),149.7(C-6’),142.4(C-4’),133.8(C-7a),124.5(C-2),123.7(C-6),120.9(C-5’),120.2(C-3a),119.9(C-5),115.1(C-4),109.3(C-7),105.2(C-3),75.8(C-1”),42.0(C-8),34.6(C-3”),31.9(C-2”)；(+)-HR-ESIMS m/z 377.0707[M+H]⁺(calcd for C₁₈H₁₈Cl₂N₃O₂,377.0698)。

Example 88: preparation of 2- [1- (4-chlorobutoxy) -1-hydro-indol-3-yl ] -N- (3-chloropyridin-4-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 4-chloro-1-bromobutane (1.4g), and stirring at room temperature for reaction for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain light yellow gum 2- [1- (4-chlorobutoxy) -1-hydro-indol-3-yl]-N- (3-chloropyridin-4-yl) acetamide (465 mg).¹H NMR(400MHz,acetone-d6):δ8.70(1H,brs,N-H),8.43(1H,s,H-2’),8.36(2H,m,H-5’,6’),7.67(2H,m,H-2,4),7.49(1H,d,J＝8.4Hz,H-7),7.27(1H,t,J＝7.6Hz,H-6),7.11(1H,t,J＝7.6Hz,H-5),4.38(2H,t,J＝6.4Hz,H-1”),4.02(2H,s,H-8),3.73(2H,t,J＝6.4Hz,H-4”),2.02(4H,m,H-2”,3”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.8(C-7a),124.7(C-2),124.5(C-3’),123.6(C-6),120.9(C-5’),120.3(C-5),119.9(C-4),115.1(C-3a),109.3(C-7),105.1(C-3),78.6(C-1”),45.5(C-4”),34.6(C-8),29.9(C-2”),26.5(C-3”)；(+)-HR-ESIMSm/z 391.0858[M+H]⁺(calcd for C₁₉H₁₉Cl₂N₃O₂,391.0854)。

Example 89: preparation of N- (2-chlorophenyl) -2- (1-cyanomethoxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and chloroacetonitrile (0.68g), and stirring at room temperature for reaction for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was subjected to silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- (1-cyanomethoxy-1H-indol-3-yl) acetamide (315mg) as a pale brown solid.¹H NMR(400MHz,acetone-d₆):δ8.56(1H,brs,NH-1),8.24(1H,d,J＝8.4Hz,H-6’),7.70(2H,d,J＝6.8Hz,H-2,4),7.57(1H,d,J＝8.0Hz,H-3’),7.35(1H,d,J＝8.4Hz,H-7),7.28(2H,m,H-4’,5’),7.16(1H,t,J＝7.6Hz,H-5),5.33(2H,s,H-10),3.96(2H,s,H-2)；¹³CNMR(400MHz,acetone-d₆):δ169.6(C-9),136.0(C-1’),135.0(C-7a),129.9(C-5’),128.3(C-3’),125.7(C-4’),125.2(C-3a),125.1(C-2),124.2(C-6,2’),123.3(C-11),121.7(C-6’),120.2(C-5),116.4(C-4),109.8(C-7),108.1(C-3),63.5(C-10),34.3(C-8)；(+)-HR-ESIMS m/z 340.0844[M+H]⁺(calcd for C₁₈H₁₅ClN₃O₂,340.0847)。

Example 90: preparation of N- (3-chloropyridin-4-yl) -2- [1- (cyanomethoxy) -1H-indol-3-yl ] acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromoacetonitrile (0.9g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain light yellow solid N- (3-chloropyridin-4-yl) -2- [1- (cyanomethoxy) -1H-indol-3-yl]Acetamide (670 mg).¹H NMR(400MHz,acetone-d6):δ8.80(1H,brs,N-H),8.44(1H,s,H-2’),8.35(2H,m,H-5’,6’),7.72(1H,s,H-2),7.69(1H,d,J＝8.0Hz,H-4),7.57(1H,d,J＝8,4Hz,H-7),7.30(1H,t,J＝7.6Hz,H-6),7.16(1H,t,J＝7.6Hz,H-5),5.35(2H,s,H-1”),4.05(2H,s,H-8)；¹³C NMR(400MHz,acetone-d6):δ170.6(C-9),150.0(C-2’),149.7(C-6’),142.5(C-4’),134.9(C-7a),125.2(C-2),125.1(C-2”),124.2(C-6),121.8(C-5),120.2(C-4),116.4(C-3’),115.3(C-5’),109.9(C-7),107.4(C-3),63.6(C-1”),34.4(C-8)；(+)-HR-ESIMS m/z 340.0731[M+H]⁺(calcd for C₁₇H₁₄ClN₄O₂,340.0727)。

Example 91: preparation of N- (2-chlorophenyl) -2- [1- (3-hydroxypropoxy) -1H-indol-3-yl ] acetamide

Fourthly, adding dry DMF (8mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 3-hydroxy bromopropane (1.25g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- [1- (3-hydroxypropoxy) -1H-indol-3-yl as a pale brown gum]Acetamide (340 mg).¹H NMR(400MHz,acetone-d₆):δ8.49(1H,brs,NH-1),8.32(1H,d,J＝8.4Hz,H-6’),7.70(1H,d,J＝8.0Hz,H-4),7.65(1H,s,H-2),7.53(1H,d,J＝8.4Hz,H-3’),7.37(1H,d,J＝8.0Hz,H-7),7.29(2H,m,H-4’,5’),7.13(1H,t,J＝7.6Hz,H-6),7.08(1H,t,J＝7.6Hz,H-5),4.47(2H,t,J＝6.8Hz,H-1”),3.96(2H,s,H-8),3.83(3H,H-3”,-OH),2.04(2H,m,H-2”)；¹³C NMR(400MHz,acetone-d₆):δ170.0(C-9),136.0(C-1’),133.9(C-7a),129.9(C-5’),128.3(C-3’),125.5(C-3a,4’),124.6(C-2),123.5(C-6’),122.9(C-6,2’),120.7(C-5),119.9(C-4),109.3(C-7),105.5(C-3),76.4(C-1”),58.7(C-3”),34.5(C-8),32.3(C-2”)；(+)-HR-ESIMS m/z 359.1165[M+H]⁺(calcd for C₁₉H₂₀ClN₂O₃,359.1157)。

Example 92: preparation of N- (3-chloropyridin-4-yl) -2- [1- (3-hydroxypropoxy) -1H-indol-3-yl ] acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 3-bromopropanol (1.0g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:3) to give N- (3-chloropyridin-4-yl) -2- [1- (3-hydroxypropoxy) -1H-indol-3-yl) as a pale yellow gum]Acetamide (150 mg).¹H NMR(400MHz,acetone-d6):δ8.70(1H,brs,N-H),8.42(1H,s,H-2’),8.36(2H,m,H-5’,6’),7.65(2H,m,H-2,4),7.51(1H,d,J＝8.0Hz,H-7),7.24(1H,t,J＝7.6Hz,H-6),7.10(1H,t,J＝7.6Hz,H-5),4.44(2H,t,J＝6.4Hz,H-1”),4.01(2H,s,H-8),3.79(2H,t,H-3”),2.00(2H,m,H-2”)；¹³C NMR(400MHz,acetone-d6):δ170.9(C-9),149.9(C-2’),149.8(C-6’),142.3(C-4’),133.7(C-7a),124.6(C-2),124.4(C-3a),123.5(C-6),120.7(C-5),119.8(C-4),115.0(C-3’),114.9(C-5’),109.3(C-7),104.8(C-3),76.4(C-1”),58.4(C-3”),34.6(C-8),32.1(C-2”)；(+)-HR-ESIMS m/z 359.104[M+H]⁺(calcd for C₁₈H₁₉ClN₃O₃,359.1037)。

Example 93: preparation of N- (3-fluoropyridin-4-yl) -2- [1- (3-hydroxypropoxy) -1H-indol-3-yl ] acetamide

Fourthly, adding dry DMF (5mL) into N- (3-fluoropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropanol (1.2g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain a red brown solid N- (3-fluoropyridin-4-yl) -2- [1- (3-hydroxypropoxy) -1H-indol-3-yl]Acetamide (120 mg).¹H NMR(400MHz,acetone-d₆):δ9.31(1H,brs,NH-1),8.35(2H,m,H-2’,6’),8.27(1H,d,J＝5.2Hz,H-5’),7.65(1H,d,J＝8.0Hz,H-4),7.53(1H,s,H-2),7.46(1H,d,J＝8.0Hz,H-7),7.21(1H,t,J＝7.6Hz,H-6),7.07(1H,t,J＝7.6Hz,H-5),4.41(2H,t,J＝6.0Hz,H-1”),3.98(2H,s,H-8),3.79(3H,m,H-3”,H-OH),1.99(2H,m,H-2”)；¹³C NMR(400MHz,acetone-d₆):δ171.1(C-9),147.42(C-2’),147.37(C-6’),138.0(C-3’),137.8(C-3’),133.8(C-4’),124.7(C-7a),124.3(C-2),123.2(C-6),120.5(C-4),120.0(C-5),115.6(C-5’),109.3(C-7),105.4(C-3),76.3(C-1”),58.7(C-3”),34.4(C-8),32.3(C-2”)；(+)-HR-ESIMS m/z 343.133[M+H]⁺(calcd for C₁₈H₁₉FN₃O₃,343.1332)。

Example 94: preparation of N- (3-chloropyridin-4-yl) -2- [1- (cyclopropylmethoxy) -1H-indol-3-yl ] acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromomethylcyclopropane (1.2g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:5) to give N- (3-chloropyridin-4-yl) -2- [1- (cyclopropylmethoxy) -1H-indol-3-yl) as a pale yellow gum]Acetamide (105 mg).¹H NMR(300MHz,acetone-d₆):δ8.62(1H,brs,NH-1),8.39(1H,s,H-2’),8.36(2H,s,H-5’,6’),7.63(1H,d,J＝8.1Hz,H-4),7.54(1H,s,H-2),7.51(1H,d,J＝8.4Hz,H-7),7.20(1H,t,J＝7.8Hz,H-6),7.07(1H,t,J＝8.1Hz,H-5),4.11(2H,d,J＝6.9Hz,H-1”),4.00(2H,s,H-8),0.87(1H,m,H-2”),0.58(2H,m,H-3”),0.44(2H,m,H-4”)；¹³C NMR(600MHz,acetone-d₆):δ171.3(C-9),149.9(C-5’,6’),142.5(C-4’),137.8(C-7a),128.62(C-2’),128.57(C-3’),122.7(C-2),120.1(C-6),119.5(C-5),114.73(C-4),114.66(C-3a),110.8(C-7),107.6(C-3),50.9(C-1”),35.0(C-8),12.2(C-2”),4.2(C-3”,4”)；(+)-HR-ESIMS m/z 356.1156[M+H]⁺(calcd for C₁₉H₁₉ClN₃O₂,356.116)。

Example 95: preparation of N- (3-fluoropyridin-4-yl) -2- [1- (cyclopropylmethoxy) -1H-indol-3-yl ] acetamide

Fourthly, adding dry DMF (5mL) into N- (3-fluoropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropanol (1.2g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase with silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain a red brown solid N- (3-fluoropyridin-4-yl) -2- [1- (cyclopropylmethoxy) -1H-indol-3-yl]Acetamide (650 mg).¹H NMR(400MHz,acetone-d₆):δ9.28(1H,brs,NH-1),8.35(2H,m,H-2’,6’),8.28(1H,d,J＝5.2Hz,H-5’),7.65(1H,d,J＝8.0Hz,H-4),7.53(1H,s,H-2),7.46(1H,d,J＝8.0Hz,H-7),7.20(1H,t,J＝7.6Hz,H-6),7.06(1H,t,J＝7.6Hz,H-5),4.08(2H,d,J＝7.2Hz,H-1”),3.98(2H,s,H-8),1.20(1H,m,H-2”),0.57(2H,m,H-3”),0.28(2H,m,H-4”)；¹³C NMR(400MHz,acetone-d₆):δ171.1(C-9),147.44(C-2’),147.39(C-6’),138.0(C-3’),137.8(C-3’),133.9(C-4’),124.64(C-7a),124.58(C-2),123.2(C-6),120.4(C-5),119.9(C-4),115.6(C-5’),109.4(C-7),105.4(C-3),83.5(C-1”),34.4(C-8),10.2(C-2”),3.6(C-3”,4”)；(+)-HR-ESIMS m/z339.1384[M+H]⁺(calcd for C₁₉H₁₉FN₃O₂,339.1383)。

Example 96: preparation of N- (3-chloropyridin-4-yl) -2- [1- (3-cyanopropoxy) -1H-indol-3-yl ] acetamide

Fourthly, adding dry DMF (5mL) into N- (3-chloropyridin-4-yl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and 1-bromo-4-butyronitrile (1.2g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase with silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain light yellow gum N- (3-chloropyrazine)Pyridin-4-yl) -2- [1- (3-cyanopropoxy) -1H-indol-3-yl]Acetamide (170 mg).¹H NMR(400MHz,acetone-d6):δ8.70(1H,brs,N-H),8.42(1H,s,H-2’),8.35(2H,m,H-5’,6’),7.67(2H,m,H-2,4),7.52(1H,d,J＝8,4Hz,H-7),7.26(1H,t,J＝7.6Hz,H-6),7.11(1H,t,J＝7.6Hz,H-5),4.45(2H,t,J＝6.0Hz,H-1”),4.01(2H,s,H-8),2.78(2H,m,H-3”),2.19(2H,m,H-2”)；¹³C NMR(400MHz,acetone-d6):δ170.8(C-9),149.9(C-2’),149.8(C-6’),142.5(C-4’),133.8(C-7a),124.6(C-2),123.7(C-6),121.0(C-3a),120.3(C-3’),120.04(C-4”),119.96(C-5),115.1(C-4),109.3(C-7),105.4(C-3),77.2(C-1”),34.6(C-8),25.1(C-3”),14.2(C-2”)；(+)-HR-ESIMS m/z 368.1044[M+H]⁺(calcd for C₁₉H₁₈ClN₄O₂,368.104)。

Example 97: preparation of methyl 2- [2- (1-acetoxy-1H-indol-3-yl) acetamido ] benzoate

In the fourth step, methyl-2- [2- (1-hydroxy-1H-indol-3-yl) acetamide]Adding dry dichloromethane (20mL) into benzoate, stirring at 0-5 ℃, adding acetyl chloride (0.94g) and triethylamine (1.2g), and stirring at 0-5 ℃ for reacting for 1 h; separating by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:4) to obtain methyl-2- [2- (1-acetoxyl-1H-indol-3-yl) acetamide as yellow solid]Benzoate (410 mg).¹H NMR(400MHz,acetone-d₆):δ10.97(1H,brs,NH-1),8.71(1H,d,J＝8.8Hz,H-3’),7.94(1H,d,J＝8.0Hz,H-6’),7.67(1H,d,J＝8.4Hz,H-4),7.55(1H,t,J＝7.6Hz,H-4’),7.49(1H,s,H-2),7.33(1H,d,J＝8.0Hz,H-7),7.22(1H,t,J＝7.6Hz,H-5’),7.10(2H,m,H-5,6),3.90(2H,s,H-8),3.73(3H,s,H-11),2.43(3H,s,H-8’)；¹³C NMR(400MHz,acetone-d₆):δ170.2(C-9),169.4(C-7’),168.7(C-10),142.2(C-2’),135.5(C-7a),135.0(C-4’),131.6(C-6’),125.9(C-2),125.3(C-3a),123.9(C-5’),123.2(C-6),121.2(C-5),120.8(C-4),120.0(C-3’),116.3(C-1’),109.4(C-7),107.3(C-3),52.6(C-11),35.6(C-8),18.0(C-8’)；(+)-HR-ESIMS m/z 367.1287[M+H]⁺(calcd forC₂₀H₁₉N₂O₅,367.1288)。

Example 98: preparation of N- (2-chlorophenyl) -2- (1-acetoxy-1H-indol-3-yl) acetamide

Fourthly, adding dry dichloromethane (20mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at 0-5 ℃, adding acetyl chloride (0.94g) and triethylamine (1.2g), and stirring at 0-5 ℃ for reacting for 1H; separating by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:4) to obtain light yellow solid 3- {2- [ (2-chlorophenyl) amino]-2-acetoxy } -1H-indol-1-yl acetamide (480 mg).¹H NMR(400MHz,acetone-d₆):δ8.52(1H,brs,NH-1),8.28(1H,d,J＝8.0Hz,H-6’),7.69(1H,d,J＝8.4Hz,H-3’),7.51(1H,s,H-2),7.34(2H,d,J＝8.4Hz,H-4,7),7.26(2H,m,H-4’,5’),7.14(1H,t,J＝7.6Hz,H-6),7.06(1H,t,J＝7.6Hz,H-5),3.95(2H,s,H-8),2.42(3H,s,H-11)；¹³C NMR(400MHz,acetone-d₆):δ169.7(C-9),169.4(C-10),136.1(C-1’),135.3(C-7a),129.9(C-5’),128.3(C-3’),125.8(C-4’),125.6(C-2),125.1(C-3a),124.0(C-6),123.0(C-2’),121.3(C-6’),120.3(C-4),109.4(C-7),107.4(C-3),34.4(C-8),18.0(C-11)；(+)-HR-ESIMS m/z 343.0845[M+H]⁺(calcd forC₁₈H₁₆ClN₂O₃,343.0849)。

Example 99: preparation of methyl 2- [2- (1-benzoyloxy-1H-indol-3-yl) acetamide ] benzoate

In the fourth step, methyl-2- [2- (1-hydroxy-1H-indol-3-yl) acetamide]Adding dry dichloromethane (20mL) into benzoate, stirring at 0-5 ℃, adding benzoyl chloride (1.36g) and triethylamine (1.2g), and stirring at 0-5 ℃ for reacting for 1 h; separating with silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain orange yellow crystal methyl-2- [2- (1-benzoyloxy-1H-indol-3-yl) acetamide]Benzoate (568 mg).¹H NMR(400MHz,acetone-d₆):δ11.04(1H,brs,NH-1),8.73(1H,d,J＝8.8Hz,H-3’),8.25(2H,d,J＝8.0Hz,H-2”,6”),7.96(1H,d,J＝7.6Hz,H-6’),7.82(1H,t,J＝7.6Hz,H-4”),7.73(1H,d,J＝8.0Hz,H-4),7.67(3H,m,H-2,3”,5”),7.57(1H,t,J＝7.6Hz,H-4’),7.39(1H,d,J＝8.4Hz,H-7),7.26(1H,t,J＝7.6Hz,H-5’),7.17(1H,t,J＝7.6Hz,H-6),7.11(1H,t,J＝7.6Hz,H-5),3.97(2H,s,H-8),3.81(3H,s,H-8’)；¹³C NMR(400MHz,acetone-d₆):δ169.6(C-9),168.1(C-7’),164.6(C-10),141.6(C-2’),135.4(C-7a),134.9(C-4’),134.4(C-4”),131.0(C-6’),130.3(C-3”,5”),129.4(C-2”,6”),126.8(C-1”),125.9(C-2),125.0(C-3a),123.5(C-6),122.6(C-5’),120.9(C-5),120.2(C-3’),119.6(C-4),115.7(C-1’),109.0(C-7),107.3(C-3),52.0(C-8’),35.0(C-8)；(+)-HR-ESIMS m/z 429.1452[M+H]⁺(calcd for C₂₅H₂₀N₂O₅,429.1445)。

Example 100: preparation of N- (2-chlorophenyl) -2- (1-benzoyloxy-1H-indol-3-yl) acetamide

Fourthly, adding dry dichloromethane (20mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at 0-5 ℃, adding benzoyl chloride (1.36g) and triethylamine (1.2g), and stirring at 0-5 ℃ for reacting for 1H; separating by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:4) to obtain yellow crystal 3- {2- [ (2-chlorophenyl) amino group]-2-oxyethyl } -1H-indole-1-benzoic acid ester (530 mg).¹H NMR(400MHz,acetone-d₆):δ8.60(1H,brs,NH-1),8.29(1H,d,J＝8.0Hz,H-6’),8.240(2H,d,J＝7.6Hz,H-2”,6”),7.81(1H,t,J＝7.2Hz,H-4”),7.75(1H,d,J＝8.0Hz,H-3’),7.66(3H,m,H-2,3”,5”),7.38(2H,m,H-4,7),7.28(2H,m,H-4’,5’),7.18(1H,t,J＝7.6Hz,H-6),7.07(1H,t,J＝7.6Hz,H-5),4.01(2H,s,H-8)；¹³CNMR(400MHz,acetone-d₆):δ169.7(C-9),165.3(C-10),136.1(C-1’),135.8(C-7a),135.6(C-4”),130.9(C-2”,6”),130.0(C-3”,5”),129.9(C-5’),128.3(C-3’),127.4(C-1”),126.3(C-4’),125.6(C-2),125.4(C-3a),124.2(C-6),123.1(C-2’,6’),121.6(C-5),120.2(C-4),109.6(C-7),108.0(C-3),34.4(C-8)；(+)-HR-ESIMS m/z405.1010[M+H]⁺(calcdfor C₂₃H₁₈ClN₂O₃,405.1006)。

Example 101: preparation of methyl 2- [2- (1-benzyloxy-1H-indol-3-yl) acetamide ] benzoate

In the fourth step, methyl-2- [2- (1-hydroxy-1H-indol-3-yl) acetamide]Adding dry DMF (5mL) into benzoate, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and benzyl bromide (1.5g), and stirring at room temperature for reacting for 2 h; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain methyl-2- [2- (1-benzyloxy-1H-indol-3-yl) acetamide as yellow solid]Benzoate (521 mg).¹H NMR(400MHz,acetone-d₆):δ10.93(1H,brs,NH-1),8.76(1H,d,J＝8.4Hz,H-3’),7.91(1H,d,J＝8.0Hz,H-6’),7.56(5H,m,H-2,4,4’,3”,5”),7.41(4H,m,H-7,2”,4”,6”),7.19(1H,t,J＝7.6Hz,H-6),7.06(2H,m,H-5,5’),5.36(2H,s,H-10),3.86(2H,s,H-8),3.70(3H,s,H-8’)；¹³C NMR(400MHz,acetone-d₆):δ170.7(C-9),168.7(C-7’),142.3(C-2’),136.0(C-1”),135.0(C-4’),134.0(C-7a),131.5(C-6’),130.6(C-3”,5”),129.8(C-4”),129.4(C-2”,6”),125.0(C-2),124.8(C-3a),123.3(C-5’),123.1(C-6),120.6(C-1’,3’),119.7(C-5),116.0(C-1’),109.4(C-7),105.1(C-3),81.2(C-10),52.6(C-8),35.7(C-8’)；(+)-HR-ESIMS m/z 415.1666[M+H]⁺(calcd for C₂₅H₂₃N₂O₄,415.1652)。

Example 102: preparation of N- (2-chlorophenyl) -2- (1-benzyloxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (5mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and benzyl bromide (1.5g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- (1-benzyloxy-1H-indol-3-yl) acetamide (537mg) as a pale pink solid.¹H NMR(300MHz,acetone-d₆):δ8.43(1H,brs,NH-1),8.31(1H,dd,J＝8.4,1.2Hz,H-6’),7.35(1H,m,H-2,4,7,3’,4’,5’),7.07(2H,m,H-5,6),5.28(2H,s,H-10),3.90(2H,s,H-8)；¹³C NMR(300MHz,acetone-d₆):δ169.9(C-9),136.0(C-1’),135.8(C-1”),134.0(C-7a),130.5(C-2”,6”),129.81(C-6’),129.78(C-4”),129.7(C-3’),129.3(C-3”,5”),128.3(C-5’),125.5(C-4’),124.8(C-2),124.5(C-3a),123.4(C-6),122.9(C-2’),120.7(C-5),119.9(C-4),109.4(C-7),105.5(C-3),80.9(C-10),34.5(C-8)；(+)-HR-ESIMS m/z391.1215[M+H]⁺(calcd for C₂₃H₂₀ClN₂O₂,391.1208)。

Example 103: preparation of N- (2-chlorophenyl) -2- {1- [ (4-methoxybenzyl) oxy ] -1H-indol-3-yl } acetamide

The fourth step, N- (2-chlorophenyl) -2- (1-hydroxy-1H-indol-3-yl) Adding dry DMF (8mL) into acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and p-methoxy benzyl bromide (1.8g), and stirring at room temperature for reaction for 2 h; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- {1- [ (4-methoxybenzyl) oxy ] p-toluenesulfonate as a pale red solid]-1H-indol-3-yl } acetamide (728 mg).¹H NMR(400MHz,acetone-d₆):δ8.39(1H,brs,NH-1),8.28(1H,d,J＝8.0Hz,H-6’),7.65(1H,d,J＝8.0Hz,H-4),7.42(4H,m,H-2,3’,2”,6”),7.34(1H,d,J＝8.0Hz,H-7),7.28(1H,t,J＝8.0Hz,H-4’),7.20(1H,t,J＝7.6Hz,H-5’),7.07(2H,m,H-5,6),6.91(2H,d,J＝8.4Hz,H-3”,5”),5.22(2H,s,H-10),3.88(2H,s,H-8),3.76(3H,s,OMe-7”)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),161.3(C-4”),136.1(C-1’),134.0(C-7a),132.3(C-3”,5”),129.9(C-5’),128.3(C-3’),127.9(C-1”),125.5(C-3a),125.0(C-4’),124.6(C-6,2’),123.4(C-2),122.9(C-6’),120.7(C-5),119.9(C-4),114.7(C-2”,6”),109.5(C-7),105.4(C-3),80.6(C-10),55.5(C-7”),34.5(C-8)；(+)-HR-ESIMS m/z421.1312[M+H]⁺(calcd for C₂₄H₂₂ClN₂O₃,421.1313)。

Example 104: preparation of N- (2-chlorophenyl) -2- {1- [ (4-methylbenzyl) oxy ] -1H-indol-3-yl } acetamide

Fourthly, adding dry DMF (8mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and p-methylbenzyl bromide (1.67g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; separating the organic phase by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain N- (2-chlorophenyl) -2- {1- [ (4-methylbenzyl) oxy ] benzene as a yellowish solid]-1H-indol-3-yl } acetamide (605 mg).¹H NMR(400MHz,acetone-d₆):δ8.38(1H,brs,NH-1),8.28(1H,d,J＝8.0Hz,H-6’),7.65(1H,d,J＝8.0Hz,H-4),7.39(5H,m,H-2,7,3’,2”,6”),7.28(1H,t,J＝8.0Hz,H-4’),7.20(3H,m,H-5’,3”,5”),7.07(2H,m,H-5,6),5.25(2H,s,H-10),3.88(2H,s,H-8),2.31(3H,s,H-7”)；¹³C NMR(400MHz,acetone-d₆):δ169.3(C-9),139.1(C-4”),135.5(C-1’),133.4(C-7a),132.3(C-1”),130.1(C-3”,5”),129.4(C-2”,6”),129.3(C-5’),127.7(C-3’),124.9(C-4’),124.3(C-2),124.0(C-3a),122.8(C-6’),122.3(C-6,2’),120.1(C-5),119.3(C-4),108.9(C-7),104.9(C-3),80.2(C-10),33.9(C-8),20.6(C-7”)；(+)-HR-ESIMS m/z 405.1359[M+H]⁺(calcd for C₂₄H₂₂ClN₂O₂,405.1364)。

Example 105: preparation of N- (2-chlorophenyl) -2- (1-phenethyloxy-1H-indol-3-yl) acetamide

Fourthly, adding dry DMF (8mL) into N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromoethylbenzene (1.65g), and stirring at room temperature for reacting for 2 hours; adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, and separating phases; extracting the water phase with ethyl acetate (25mL × 2), mixing the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, and separating the phases; the organic phase was chromatographed on silica gel eluting with ethyl acetate-petroleum ether (1:5) to give N- (2-chlorophenyl) -2- (1-phenethyloxy-1H-indol-3-yl) acetamide (566mg) as a purple gum.¹H NMR(400MHz,acetone-d₆):δ8.43(1H,brs,NH-1),8.28(1H,d,J＝8.4Hz,H-6’),7.65(1H,d,J＝8.0Hz,H-4),7.57(1H,s,H-2),7.31(8H,m,7,3’,4’2”,3”,4”,5”,6”),7.18(1H,t,H-5’),7.06(2H,m,H-5,6),4.54(2H,t,J＝6.8Hz,H-10),3.91(2H,s,H-8),3.14(2H,t,J＝6.8Hz,H-11)；¹³C NMR(400MHz,acetone-d₆):δ169.9(C-9),138.8(C-1’),136.1(C-1”),133.9(C-7a),129.9(C-3”,5”),129.8(C-4”),129.3(C-2”,6”),128.4(C-5’),127.4(C-3’),125.5(C-4’),124.61(C-2),124.58(C-6’),123.5(C-3a),122.9(C-2’6),120.8(C-5),119.9(C-4),109.3(C-7),105.7(C-3),79.7(C-10),35.3(C-11),34.5(C-8)；(+)-HR-ESIMS m/z 405.1345[M+H]⁺(calcd for C₂₄H₂₂ClN₂O₂,405.1364)。

Pharmacological experiments

Experimental example 1 anti-HIV Virus Activity

(1) Principle of recombinant virus screening

The model applies VSV G/HIV recombinant virus model technology to co-transfect plasmid expressing Vesicular stomatis virus coat protein (VSV-G) and plasmid expressing HIV-1 core gene (pNL4-3, which can be wild strain or drug-resistant strain containing mutation site) to 293T cells, and the VSV-G and HIV-1 core expressed by the cells can be assembled into recombinant virus. The recombinant virus is characterized in that env, vpr and nef genes in an HIV genome are knocked out, so that recombinant virus particles can only infect cells once and can be replicated in the cells, the recombinant virus does not have the capacity of repackaging and reproduction, and the operation can be carried out in a conventional laboratory; the luciferase gene is introduced into the nef gene and the expression of the reporter gene is measured to reflect the replication level of HIV [ Caogeli Guo & applied to the research of HIV-1 replication inhibitor by the pseudovirus technology, pharmaceutical science, 2008, 43: 253-.

(2) Experimental methods

The day before infection, 293T cells were counted at 5X 10⁴Perwell were seeded into 24-well plates. The compound or positive drug (nevirapine or efavirenz) in this example was dissolved in DMSO. The test compound/positive drug (final DMSO concentration is 0.1%) is added 15 minutes before infection, DMSO is used as a solvent control, and nevirapine and efavirenz are used as positive controls. An additional 0.5mL of recombinant virus solution was added (virus stock was diluted to 0.1-0.5 ng p24/mL based on p24 concentration). 48h after infection, removing the culture medium, adding 50 mu L of cell lysate (Prome ga) into each well for lysis, adding 20 mu L of cell lysate into 30 mu L of luciferase substrate, mixing uniformly, measuring the relative activity of luciferase in the cells by using an FB12 fluorescence detector, wherein the activity reflects the intensity of HIV replication level, DMSO is used as a control, and the result is shown in tables 1 and 2.

(3) Results of the experiment

1) Evaluation of wild type HIV replication Activity

The invention researches the anti-HIV-1 activity of example compounds 1-105, and finds that 57 compounds have stronger activity (half inhibitory concentration is 10 nM-20 muM, table 1) for inhibiting wild HIV-1, wherein the activity of examples 69, 81, 97 and 105 is equivalent to that of a first-line clinical non-nucleoside reverse transcriptase inhibiting drug nevirapine, the activity of examples 74, 93, 95, 98, 99, 104 and 110 is superior to that of nevirapine, and the results are shown in tables 1 and 2.

TABLE 1 evaluation of the Activity of some Compounds to inhibit wild HIV-1 replication in vitro

2) Evaluation results of drug-resistant HIV-1 replication Activity

HIV-1 is an RNA virus, the replication fidelity of the virus is low due to the lack of a correction function of reverse transcriptase, mutant drug-resistant strains can survive under the selective pressure of drugs, and wild types are inhibited, so that the drug-resistant strains are massively proliferated, a drug-resistant phenomenon is generated, and the difficulty in treating AIDS is caused. The anti-AIDS non-nucleoside reverse transcriptase inhibitors Nevirapine (NVP), Delavirdine (DLV) and Efavirenz (EFV) have been clinically applied for more than ten years, and drug-resistant strains exist in patients. ETR and RPV were approved for marketing in 2009 and 2011, respectively. Clinical studies have shown that 48 weeks after administration of the drug, resistant viruses to both drugs appear in vivo. Therefore, the continuous research and development of the medicines aiming at the drug-resistant HIV-1 strain are still important subjects in the research and development field of the antiviral medicines, and the invention determines the 17 target compounds of two non-nucleoside reverse transcriptase inhibitor drug-resistant mutant strains HIV-1 with the highest clinical occurrence probability_RT-K103N(occurrence probability 11%) and HIV-1_RT-Y181C(occurrence probability is 3%) of inhibitory activity [ Caogeli, Lisinomenia, Chenhong, Guogue ] non-nucleoside reverse transcriptase inhibitor drug-resistant HIV-1 pharmacological evaluation system establishment, pharmaceutical science report, 2009, 44: 355-reservoir 361.]The results show that the inhibition activity and the drug resistance multiple of 14 compounds on two drug-resistant strains are superior to those of nevirapine (table 2).

TABLE 2 evaluation results of HIV-1 replication inhibition in vitro for some compounds

Experimental example 2 anti-influenza Virus Activity

(1) Preparation of influenza virus:

to test the anti-influenza effect of the compounds, human influenza viruses A/Puerto Rico/8/1934(H1N1), A/Hubei Hongshan/50/2005 (H1N1) and A/Jingfang 262 were preparedThe preparation methods of the components are as follows, wherein the components are selected from a group consisting of/95 (H1N1), A/Jingfang/359/95 (H3N2), A/Jifang/15/90 (H3N2) and B/Jiangxi new construction/BV/39/2008: inoculating virus stock solution into allantoic cavity and amnion cavity of 9-day-old chick embryo, culturing chick embryo at 35 deg.C for 2-3 days, collecting virus in allantoic fluid and amniotic fluid, centrifuging, packaging, and storing at-70 deg.C. Selecting sensitive cell strain MDCK cell (canine kidney cell) suitable for influenza virus growth as virus infected cell, DMEM + 0.2% BSA +2 mug/ml TPCK as virus maintaining liquid, diluting the virus liquid by 10 times of gradient, inoculating the diluted virus liquid to MDCK cell, setting 3 multiple holes on each gradient, culturing at 37 deg.C for 3 days, observing cytopathic effect, and calculating half infection quantity (TCID) of virus according to Reed-Muench method₅₀)。

(2) Compounds for inhibiting cytopathic effects of influenza virus infected host cells

3X 10 per well one day before infection⁴Cell Density MDCK cells were seeded in 96-well plates in DMEM + 10% FBS (GIBCO) under cell culture conditions of 37 ℃ and 5% CO₂. On the day of infection, MDCK cells were grown to 90-100% confluence and the cell culture medium was discarded, and the cells were washed 2 times with PBS solution (ph7.4) and 1 time with serum-free DMEM medium (excluding interference of serum with influenza virus infected host cells). Influenza virus A/Puerto Rico/8/1934(H1N1), A/lake Bei Hongshan/50/2005 (H1N1), A/Jing Fang 262/95(H1N1), A/Ji Fang/15/90 (H3N2) and B/Jiangxi new construction/BV/39/2008 are respectively diluted to 100TCID₅₀、316TCID₅₀、100TCID₅₀、100TCID₅₀And 43TCID₅₀Adding into cell well, setting normal cell control group without adding virus and virus control group with only adding virus and without compound, incubating at 37 deg.C for 2 hr, discarding virus solution, washing 2 times with PBS solution (pH7.4), and washing 1 time with serum-free DMEM medium. Diluting the compound with virus-maintaining solution, each well is 100 μ l, each group has 4 multiple wells, 37 deg.C, 5% CO₂Cytopathic effect (CPE) was observed after 3 days of culture, and the half Inhibitory Concentration (IC) of the compound against viral infection was calculated according to the Reed-Muench method₅₀)。

(3) Results of the experiment

The invention researches the anti-influenza virus activity of example compounds 1-105, and finds that 65 compounds have stronger A/Puerto Rico/8/1934(H1N1) infection inhibition activity (half inhibition concentration is 1.7-77 mu M, table 3), wherein the activity of example compounds 35 and 47 is better than that of a first-line clinical drug ribavirin. The inventor also determines the anti-influenza A virus A/Hubei Hongshan/50/2005 (H1N1), A/Jing prevention 262/95(H1N1), A/Jing prevention/359/95 (H3N2), A/Ji prevention/15/90 (H3N2) and B/Jiangxi new construction/BV/39/2008 infection activities of the 2 compounds, and the results show that the activities of the 2 compounds are superior to those of a first-line clinical medicament tamiflu (Table 4). The results show that the compound not only has good inhibition effect on influenza A virus, but also has better blocking effect on influenza B virus replication than the existing medicines, namely the compound has broad-spectrum anti-influenza effect.

TABLE 3 evaluation results of Activity of Compounds against influenza A/Puerto Rico/8/1934(H1N1) infection

Evaluation results of infection activity of compounds in Table 4 against influenza virus A/Hubei Hongshan/50/2005 (H1N1), A/Jing Fang 262/95(H1N1), A/Jing Fang/359/95 (H3N2), A/Ji Fang/15/90 (H3N2) and B/Jiangxi new construction/BV/39/2008

ND:Not detect.

Claims

(IA2) and pharmaceutically acceptable salts thereof,

wherein R is mono-substituted or poly-substitutedIs selected from hydrogen, halogen, C_1-6Alkyl or C_1-6An alkoxy group;

x is selected from substituted or unsubstituted C₁Alkyl radical, C₅A cycloalkyl group; wherein the substituents are: OH, C_1-6Alkyl, halogen, cyano, C_1-6Unsaturated alkyl radical, C₃A cycloalkyl group;

y is selected from hydrogen, halogen, C₁An alkyl group;

R₂is monosubstituted, selected from halogen, C₁An alkoxyacyl group; wherein the mono-substitution is selected from the ortho mono-substitutions of an amide group.
2. The compound of claim 1, wherein said compound is represented by formula (IA2a), and pharmaceutically acceptable salts thereof

Wherein R is mono-substituted or multi-substituted and is selected from hydrogen, halogen and C_1-6Alkyl or C_1-6An alkoxy group;

y is selected from hydrogen, halogen, C₁An alkyl group;

R₂is monosubstituted, selected from halogen, C₁An alkoxyacyl group; wherein the mono-substitution is selected from the ortho mono-substitutions of an amide group.
3. The compound of claim 1, wherein said compound is represented by formula (IA2b), and pharmaceutically acceptable salts thereof

Wherein R is mono-substituted or multi-substituted and is selected from hydrogen, halogen and C_1-6Alkyl or C_1-6An alkoxy group;

y is selected from hydrogen, halogen, C₁An alkyl group;

R₂is monosubstituted, selected from halogen, C₁An alkoxyacyl group; whereinThe monosubstitution is selected from ortho monosubstitution of amide group.
4. The compound of claim 1, wherein said compound is represented by formula (IA2c), and pharmaceutically acceptable salts thereof

Wherein R is mono-substituted or multi-substituted and is selected from hydrogen, halogen and C_1-6Alkyl or C_1-6An alkoxy group;

y is selected from hydrogen, halogen, C₁An alkyl group;

R₂is monosubstituted, selected from halogen, C₁An alkoxyacyl group; wherein the mono-substitution is selected from the ortho mono-substitutions of an amide group.
5. The compound of claim 1, wherein said compound is represented by formula (IA2d), and pharmaceutically acceptable salts thereof

Wherein R is mono-substituted or multi-substituted and is selected from hydrogen, halogen and C_1-6Alkyl or C_1-6An alkoxy group;

y is selected from hydrogen, halogen, C₁An alkyl group;

R₂is monosubstituted, selected from halogen, C₁An alkoxyacyl group; wherein the mono-substitution is selected from the ortho mono-substitutions of an amide group.
6. The compound of claim 1, wherein said compound is represented by formula (IA2e), and pharmaceutically acceptable salts thereof

Wherein R is mono-substituted or multi-substituted and is selected from hydrogen, halogen and C_1-6Alkyl or C_1-6An alkoxy group;

y is selected from hydrogen, halogen, C₁An alkyl group;

R₂is monosubstituted, selected from halogen, C₁An alkoxyacyl group; wherein the mono-substitution is selected from the ortho mono-substitutions of an amide group.
7. The following compounds and pharmaceutically acceptable salts thereof:
8. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 7, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.