CN107149602B

CN107149602B - Application of indole compounds and derivatives thereof in preparation of anti-HIV drugs

Info

Publication number: CN107149602B
Application number: CN201610136144.9A
Authority: CN
Inventors: 石建功; 郭颖; 徐成博; 陈勍; 陈明华; 霸明宇; 朱承根; 唐克; 蒋建东; 郭庆兰; 林生; 杨永春
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: 2020-10-09
Anticipated expiration: 2036-03-10
Also published as: CN107149602A

Abstract

The invention discloses indole compounds extracted from isatis roots and derivatives thereof as shown in a general formula (I), and application of pharmaceutically acceptable salts of the indole compounds and the derivatives thereof in preparation of anti-HIV drugs; also discloses a preparation method of the compound and application of a pharmaceutical composition containing the compound in preparing anti-HIV drugs.

Description

Application of indole compounds and derivatives thereof in preparation of anti-HIV drugs

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 two nucleoside reverse transcriptase inhibitors are used in combination with a non-nucleoside reverse transcriptase inhibitor or egg yolk antibody The protease inhibitor is a conventional administration scheme^[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 consisting of a p66 subunit and a p51 subunit, and p66 is a 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.

The non-nucleoside reverse transcriptase inhibitor isAn important component of highly effective antiretroviral therapy is usually combined 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 protein 1, PB 1; Polymerase basic protein 2, PB 2; Polymerase acidic protein 3, PA), Nucleoprotein (NP), Matrix protein (Matrix protein 1, M1; Matrix protein 2, M2), nonstructural protein (Non-structural protein 1, 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 the isatis root mainly focuses on the aspects of the activity evaluation of water or alcohol extract of the isatis root, injection prepared from the isatis root and separated parts, and related research results show that the isatis root injection is used for treating thyroxineThe influenza virus, Japanese encephalitis virus and mumps virus have the functions of inhibiting infection and proliferation, and have obvious virus killing 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 (HBeA g), 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. In addition, the isatis root ethanol extract and the separation part thereof have the inhibition effect on staphylococcus aureus and pseudomonas aeruginosa, have the obvious inhibition effect on mouse auricle swelling caused by xylene and foot swelling caused by carrageenan, and have the effect equivalent to that of a positive control medicament 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 inhibition of 5-Activity of lipoxygenase or Effect of decreasing 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-methoxy-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 foundHas anti-HIV and anti-influenza virus activity.

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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.

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,

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;

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 fromSubstituted 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 (IA1) and pharmaceutically acceptable salts thereof

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;

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;

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 (IA1b) 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 (IA1c) 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_1-6Alkoxy radical；

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

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 (IA1g) 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, trifluoromethylRadical, 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 (IA1h) 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 (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 monosubstitution is selected from ortho-position, meta-position and para-position monosubstitution(ii) a 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 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;

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

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 radical 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;

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

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;

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 (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

Wherein R is mono-or polysubstituted and is selected fromHydrogen, 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 (IA3) and pharmaceutically acceptable salts thereof

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;

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

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 benzeneA formyl 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;

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 (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 of the water, the ethanol, the isopropanol and the propylene glycol 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 can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for 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 the use of the indole derivatives and pharmaceutically acceptable salts thereof in the pharmaceutical field, in particular the use of the indole derivatives and pharmaceutically acceptable salts thereof in preparing medicaments for resisting viruses, and the indole derivatives and pharmaceutically acceptable salts thereof in preparing medicaments 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 of the present invention or the composition of the present invention are used for treating the above-mentioned diseases, the dosage thereof can be referred to the dosage when the indole derivative is used for treatment.

The inventor carries out a large number of drug experiments and proves that the indole derivative has the effects of inhibiting the replication of HIV and influenza virus and has good treatment effect on diseases caused by the HIV and the influenza virus.

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.

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.

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.

As referred to herein, the term "alkyl" refers to an alkyl group having the indicated number of carbon atoms, which may be straight or branched, such as the reference to "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. representA subrange of groups, and preferred specific groups such as 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. IC of compound with highest HIV virus inhibiting activity ₅₀The 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.

And thirdly, 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) in 5min, reacting at 15-20 ℃ for 1H after dropwise adding, adding dichloromethane (200mL) and water (200mL), quickly stirring for 10min, carrying out phase separation, extracting a water phase with dichloromethane (100mL × 2), combining organic phases, washing the organic phases with saturated saline solution (200mL), carrying out phase separation, carrying out column chromatography on the organic phases, and eluting with ethyl acetate-petroleum ether (1:5) to obtain a brown colloid 2- (1-hydroxy-1H-indol-3-yl) -N-phenylacetamide (0.64 g).¹HNMR(400MHz,acetone-d₆):10.26(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):170.7(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 of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) in 5min, reacting at 15-20 ℃ for 1H, adding dichloromethane (200mL) and water (200mL), quickly stirring for 10min, carrying out phase separation, extracting a water phase with dichloromethane (100mL × 2), combining organic phases, adding saturated saline water (200mL) to the organic phases, washing and carrying out phase separation, carrying out column chromatography separation on the organic phases, and eluting with ethyl acetate-petroleum ether (1:5) to obtain brown colloid ethyl-2- [2- (1-hydroxy-1H-indol-3-yl) acetamide ]Benzoate (0.71 g).¹H NMR(400MHz,acetone-d₆):10.99(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):170.8(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 deg.C, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) in 5min, reacting at 15-20 deg.C for 1h, adding dichloromethane (200mL) and water (200mL), stirring rapidly for 10min, separating phases, extracting water phase with dichloromethane (100mL × 2), mixing organic phases, washing organic phase with saturated saline solution (200mL), separating organic phase by column chromatography, and separating with ethyl acetate-stoneOil ether (1:5) elution gave methyl-3- [2- (1-hydroxy-1H-indol-3-yl) acetamide as a brown gum]-4-methylbenzoate (0.69 g).¹H NMR(400MHz,acetone-d₆):10.27(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):170.8(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) in 5min, reacting at 15-20 ℃ for 1H after dropwise adding, adding dichloromethane (200mL) and water (200mL), rapidly stirring for 10min, carrying out phase separation, extracting a water phase with dichloromethane (100mL × 2), combining organic phases, washing the organic phases with saturated saline solution (200mL), carrying out phase separation, carrying out column chromatography on the organic phases, and eluting with ethyl acetate-petroleum ether (1:5) to obtain a brown colloid 2- (1-hydroxy-1H-indol-3-yl) -N- (4-methoxy-2-methylphenyl) acetamide (0.8 g). ¹H NMR(400MHz,CD₃OD-d₄):7.57(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):173.7(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.

and thirdly, 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) in 5min, reacting at 15-20 ℃ for 1H, adding dichloromethane (200mL) and water (200mL), quickly stirring for 10min, carrying out phase separation, extracting an aqueous phase with dichloromethane (100mL × 2), combining organic phases, washing the organic phases with saturated saline solution (200mL), carrying out phase separation, carrying out column chromatography on the organic phases, and eluting with ethyl acetate-petroleum ether (1:5) to obtain brown colloid N- (2-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide (0.76 g). ¹H NMR(400MHz,acetone-d₆):8.44(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):170.2(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.

and thirdly, 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) in 5min, reacting at 15-20 ℃ for 1H, adding dichloromethane (200mL) and water (200mL), quickly stirring for 10min, carrying out phase separation, extracting an aqueous phase with dichloromethane (100mL × 2), combining organic phases, washing the organic phases with saturated salt water (200mL), carrying out phase separation, carrying out column chromatography on the organic phases, and eluting with ethyl acetate-petroleum ether (1:5) to obtain a white-like solid N- (4-chlorphenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide (0.79 g). ¹H NMR(300MHz,acetone-d₆):10.09(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):170.8(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.

and thirdly, 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) in 5min, reacting at 15-20 ℃ for 1H, adding dichloromethane (200mL) and water (200mL), quickly stirring for 10min, carrying out phase separation, extracting an aqueous phase with dichloromethane (100mL × 2), combining organic phases, washing the organic phase with saturated saline solution (200mL), carrying out phase separation, carrying out column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:3) to obtain brown colloid 2- (1-hydroxy-1H-indol-3-yl) -N- (4-nitrophenyl) acetamide (0.72 g). ¹H NMR(400MHz,acetone-d₆):10.15(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):171.1(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 of methanol, cooling to 15-20 deg.C, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) within 5min, reacting at 15-20 deg.C for 1h, adding dichloromethane (200mL) and water (200mL), stirring rapidly for 10min, separating phases, extracting water phase with dichloromethane (100mL × 2), mixing organic phases, adding saturated salt water (200mL) into organic phase, washing, separating phases, and collecting organic phaseSeparating 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):10.97(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):171.7(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 of methanol, cooling to 15-20 ℃, stirring, adding sodium tungstate dihydrate (0.3g), dropwise adding 30% hydrogen peroxide (10mL) in 5min, reacting at 15-20 ℃ for 1H, adding dichloromethane (200mL) and water (200mL), quickly stirring for 10min, carrying out phase separation, extracting a water phase with dichloromethane (100mL × 2), combining organic phases, adding saturated saline water (200mL) to the organic phases, washing and carrying out phase separation, carrying out column chromatography separation on the organic phases, and eluting with ethyl acetate-petroleum ether (1:5) to obtain brown colloid methyl-2- [4- (1-hydroxy-1H-indol-3-yl) butyramide ]Benzoate (0.67 g).¹H NMR(400MHz,acetone-d₆):10.97(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):172.2(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):9.16(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):169.9(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):10.92(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):170.7(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):9.37(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):170.2(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):9.52(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):170.5(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.

The fourth step, the one obtained in the third step Adding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the organic phase, and reacting for 24h 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):11.00(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):170.7(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):8.47(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):170.0(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):8.43(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):169.5(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; chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:5) gave 2- (1-methoxy-1H-indol-3-yl) -N- (3-methoxyphenyl) acetamide as a pale brown gum (643 mg).¹H NMR(400MHz,acetone-d₆):9.30(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):169.9(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):9.02(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):169.5(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):8.28(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):169.7(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):8.46(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):169.9(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):9.33(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):170.3(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):9.30(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):170.1(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):9.11(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):169.7(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):8.99(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):169.6(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):9.00(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):169.7(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):8.33(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):169.7(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):8.20(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):169.8(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):8.83(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):170.1(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):8.32(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):169.9(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):8.17(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):169.9(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):9.76(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):170.8(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):9.19(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):170.0(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; separating by silica gel column chromatographyElution 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):9.12(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):169.8(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.

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-3-yl) acetamide (156mg) as a dark brown solid.¹H NMR(400MHz,acetone-d₆):9.42(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):170.5(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):9.59(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):171.0(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 at room temperature in a dark place for 24 h; 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):9.36(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):170.5(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.

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-chloropyridin-4-yl) -2- (1-methoxy-1H-indol-3-yl) acetamide (340mg) as a brown solid.¹H NMR(400MHz,acetone-d₆):8.69(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):170.9(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):8.51(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):170.8(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.

The fourth step, the organic matter obtained in the third stepAdding 2N trimethylsilane diazomethane N-hexane solution (10mL) into the mixture, and reacting the mixture 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):10.95(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):171.6(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):10.97(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):172.0(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) acetylAmines as pesticides]Benzoate (40 mg).¹H NMR(400MHz,acetone-d₆):10.94(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):170.8(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.

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; 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):8.45(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):170.0(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), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline solution (50mL), quickly stirring for 10min, separating phases, separating the organic phases by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain a light pink gum-like methyl-2- [2- (1-ethoxy-1H-indol-3-yl) acetamide]Benzoate (510 mg);¹H NMR(400MHz,acetone-d₆):10.93(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):170.2(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.

step four, 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), stirring at room temperature for reaction for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out chromatographic separation on the organic phase, and eluting with ethyl acetate-petroleum ether (1:5) to obtain a pink solid N- (2-chlorphenyl) -2- (1-ethoxy-1H-indol-3-yl) acetamide (498 mg). ¹H NMR(400MHz,acetone-d₆):8.44(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):169.9(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), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline solution (50mL), quickly stirring for 10min, separating phases, separating the organic phases by 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):10.92(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):170.8(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/z 367.1664[M+H]⁺(calcd for C₂₁H₂₃N₂O₄,367.1652)。

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

step four, 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), stirring at room temperature for reaction for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out chromatographic separation on the organic phase through a silica gel column, and eluting with ethyl acetate-petroleum ether (1:5) to obtain a pink solid N- (2-chlorphenyl) -2- (1-propoxy-1H-indol-3-yl) acetamide (511 mg). ¹H NMR(400MHz,acetone-d₆):8.44(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):169.9(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), stirring at room temperature for reacting for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline solution (50mL), quickly stirring for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:5) to obtain white solid N- (3-chloropyridin-4-yl) -2- (1-propoxy-1H-indol-3-yl) acetamide (445 mg).¹H NMR(400MHz,acetone-d₆):8.66(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):170.9(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.

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 bromopropane (1.1g), stirring at room temperature for reacting for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline solution (50mL), quickly stirring for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:3) to obtain a reddish brown solid N- (3-fluoropyridin-4-yl) -2- (1-propoxy-1H-indol-3-yl) acetamide (203 mg). ¹H NMR(400MHz,acetone-d₆):9.29(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):171.1(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), stirring at room temperature for reacting for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:5) to obtain a white-like solid N- (2-chloro-5-methylphenyl) -2- (1-propoxy-1H-indol-3-yl)Acetamide (519 mg).¹H NMR(400MHz,acetone-d₆):8.37(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):169.9(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), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline (50mL), quickly stirring for 10min, separating phases, separating the organic phase by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain a light purple solid 2- (1-propoxy-1H-indol-3-yl) -N- [2- (trifluoromethyl) phenyl]Acetamide (95 mg).¹H NMR(400MHz,acetone-d₆):8.30(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):170.2(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/z 377.1477[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.

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 NCS (86mg) was added, and the reaction was stirred at room temperature for 2 hours, and subjected to silica gel column chromatography, eluting 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):8.46(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):168.6(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 (20)0mg), dichloromethane (10mL) was added and the mixture was dissolved with stirring at room temperature and 25 ℃ and NCS (86mg) was added and the reaction was stirred at room temperature for 2 hours, followed by silica gel column chromatography and elution 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):8.74(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):169.6(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):8.40(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):168.6(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 dry DMF (8mL) into 2- (5-chloro-1-hydroxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropane (1.65g), stirring at room temperature for reaction for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline (50mL), quickly stirring for 10min, separating phases, separating the organic phases by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain a light brown solid 2- (5-chloro-1-propoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide (102 mg). ¹H NMR(400MHz,acetone-d₆):8.76(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):170.7(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 dry DMF (8mL) into 2- (4-methoxy-1-hydroxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and bromopropane (1.65g), stirring at room temperature for reaction for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, carrying out phase separation, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline (50mL), quickly stirring for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:5) to obtain a light brown solid 2- (4-methoxy-1-propoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide (110 mg).¹H NMR(400MHz,acetone-d₆):8.65(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):171.4(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), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline solution (50mL), quickly stirring for 10min, separating phases, separating the organic phases by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain purple jelly methyl-2- [2- (1-isopropoxy-1H-indol-3-yl) acetamide]Benzoate (495 mg).¹H NMR(400MHz,acetone-d₆):10.93(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):170.8(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), stirring at room temperature for reacting for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline solution (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography separation on the organic phase, and eluting with ethyl acetate-petroleum ether (1:5) to obtain a light pink solid N- (2-chlorphenyl) -2- (1-isopropoxy-1H-indol-3-yl) acetamide (480 mg). ¹H NMR(400MHz,acetone-d₆):8.42(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):170.0(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

Step four, adding dry DMF (5mL) into N- (2-chlorophenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and N-bromobutane (1.23g), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, separating the phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline (50mL), stirring rapidly for 10min, separating the phases, separating the organic phases by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5), and obtaining N- (2-chlorophenyl) -2- (1-butoxy-1H-indol-3-yl) acetamide (560mg) as a purple solid.¹H NMR(400MHz,acetone-d₆):8.43(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):169.9(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

Step four, 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), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, separating the phases, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline (50mL), stirring rapidly for 10min, separating the phases, separating the organic phases by silica gel column chromatography and eluting with ethyl acetate-petroleum ether (1:5) to obtain light yellow gum 2- (1-butoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide (440 mg). ¹H NMR(400MHz,acetone-d6):8.66(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):170.9(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), stirring at room temperature for reacting for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline solution (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:8) to obtain a purple colloid N- (2-chlorphenyl) -2- (1-pentoxy-1H-indol-3-yl) acetamide (549 mg).¹H NMR(400MHz,acetone-d₆):8.43(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):169.9(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

Step four, 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), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, separating the phases, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline (50mL), stirring rapidly for 10min, separating the phases, separating the organic phases by silica gel column chromatography and eluting with ethyl acetate-petroleum ether (1:5) to obtain a light yellow gum, namely 2- (1-pentoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide (450 mg). ¹H NMR(400MHz,acetone-d6):8.66(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):170.9(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

Step four, adding dry DMF (8mL) into N- (2-chlorophenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and N-bromohexane (1.48g), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, carrying out phase separation, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:8) to obtain a light brown colloid N- (2-chlorophenyl) -2- (1-hexyloxy-1H-indol-3-yl) acetamide (530 mg).¹H NMR(400MHz,acetone-d₆):8.43(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):169.9(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

Step four, adding dry DMF (8mL) into N- (2-chlorophenyl) -2- (1-hydroxy-1H-indol-3-yl) acetamide, stirring at room temperature, adding anhydrous potassium carbonate (1.66g) and N-bromoheptane (1.6g), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, separating the phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline (50mL), stirring rapidly for 10min, separating the phases, separating the organic phases with silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:8), and obtaining light brown colloid N- (2-chlorophenyl) -2- (1-heptyloxy-1H-indol-3-yl) acetamide (580 mg). ¹H NMR(400MHz,acetone-d₆):8.43(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):169.9(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

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-bromooctane (1.72g), stirring at room temperature for reacting for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:10) to obtain a light brown colloid N- (2-chlorphenyl) -2- (1-octyloxy-1H-indol-3-yl) acetamide (602 mg).¹H NMR(400MHz,acetone-d₆):8.43(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):169.9(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

Step four, 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), stirring at room temperature for 2 hours, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:5) to obtain a light yellow solid N- (2-chlorphenyl) -2- (1-nonoxy-1H-indol-3-yl) acetamide (660 mg). ¹H NMR(400MHz,acetone-d₆):8.43(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):169.9(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), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out chromatographic separation on the organic phase by using a silica gel column, and eluting with ethyl acetate-petroleum ether (1:10) to obtain a light purple gum N- (2-chlorphenyl) -2- (1-decyloxy-1H-indol-3-yl) acetamide (689 mg).¹H NMR(400MHz,acetone-d₆):8.42(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):169.9(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/z 441.2309[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), stirring at room temperature for reacting for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline (50mL), stirring rapidly Splitting the phases for 10 min; 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):8.42(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):169.3(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), stirring at room temperature for 2 hours, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline solution (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:10) to obtain brown solid N- (2-chlorphenyl) -2- (1-hexadecyloxy-1H-indol-3-yl) acetamide (717 mg). ¹H NMR(400MHz,acetone-d₆):8.43(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):169.3(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), stirring at room temperature for 2 hours, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, eluting with ethyl acetate-petroleum ether (1:5) to obtain a yellow solid 2- [1- (secondary butoxy) -1H-indol-3-yl]-N- (2-chlorophenyl) acetamide (515 mg).¹H NMR(400MHz,acetone-d₆):8.41(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):170.0(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), stirring at room temperature for 2 hours, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2) and combining organic phases, adding saturated saline solution (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:5) to obtain yellow solid N- (2-chlorphenyl) -2- (1-isobutoxy-1H-indol-3-yl) acetamide (552 mg). ¹H NMR(400MHz,acetone-d₆):8.43(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):169.9(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), stirring at room temperature for reacting for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, quickly stirring for 10min, carrying out phase separation, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline solution (50mL), quickly stirring for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:5) to obtain a light yellow gum 2- (1-isobutoxy-1H-indol-3-yl) -N- (3-chloropyridin-4-yl) acetamide (435 mg).¹H NMR(400MHz,acetone-d6):8.67(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):170.9(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), stirring at room temperature for 2 hours, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline solution (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, eluting with ethyl acetate-petroleum ether (1:5), and obtaining a light brown colloid N- (2-chlorphenyl) -2- [1- (2-pentoxy) -1H-indol-3-yl ]Acetamide (610 mg).¹H NMR(400MHz,acetone-d₆):8.43(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):170.0(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

Step four, 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-methyl bromobutane (1.36g), stirring at room temperature for reacting for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring quickly for 10min, separating the phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline (50mL), stirring quickly for 10min, separating the phases, separating the organic phases by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain a pale yellow gum N- (3-chloropyridin-4-yl) -2- (1-isopentyloxy-1H-indol-3-yl) acetamide (480 mg). ¹H NMR(400MHz,acetone-d6):8.66(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):170.9(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), stirring at room temperature for reaction for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline solution (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:5) to obtain light brown solid N- (2-chlorphenyl) -2- (1-cyclopentanyloxy-1H-indol-3-yl) acetamide (429 mg).¹H NMR(400MHz,acetone-d₆):8.41(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):170.0(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

The fourth step, 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 bromocyclopentane (1.4g), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, separating the phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline (50mL), stirring rapidly for 10min, separating the phases, separating the organic phases by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain a pale yellow gum N- (3-chloropyridin-4-yl) -2- (1-cyclopentyloxy-1H-indol-3-yl) acetamide (405 mg). ¹H NMR(400MHz,acetone-d6):8.64(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):171.0(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

Step four, 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), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, separating the phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated brine (50mL), stirring rapidly for 10min, separating the phases, separating the organic phases 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-methylbutoxy-1H-indol-3-yl) acetamide (610 mg).¹H NMR(500MHz,acetone-d6):8.65(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):170.9(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

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, 3-dimethylbutane (1.5g), stirring at room temperature for reaction for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, carrying out phase separation, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline (50mL), quickly stirring for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, eluting with ethyl acetate-petroleum ether (1:3) to obtain a light yellow solid N- (3-chloropyridin-4-yl) -2- [1- (3, 3-dimethylbutoxy) -1H-indol-3-yl ]Acetamide (480 mg).¹H NMR(400MHz,acetone-d6):8.67(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):170.9(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

Step four, 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), stirring at room temperature for reaction for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, separating the phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated brine (50mL), stirring rapidly for 10min, separating the phases, separating the organic phases 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-ethylbutoxy-1H-indol-3-yl) acetamide (615 mg). ¹H NMR(500MHz,acetone-d6):8.66(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):170.9(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

Step four, 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 propylene iodide (1.5g), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline (50mL), stirring rapidly for 10min, separating phases, separating the organic phases by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:5) to obtain light brown solid N- (2-chlorphenyl) -2- (1-allyloxy-1H-indol-3-yl) acetamide (395 mg).¹H NMR(400MHz,acetone-d₆):8.42(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):169.9(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), stirring at room temperature for 2 hours to react, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, quickly stirring for 10min, carrying out phase separation, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline solution (50mL), quickly stirring for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:3) to obtain a reddish brown solid 2- [1- (allyloxy) -1-hydro-indol-3-yl ]-N- (3-fluoropyridin-4-yl) acetamide (224 mg).¹H NMR(400MHz,acetone-d₆):9.25(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):171.1(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), stirring at room temperature for reaction for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated brine (50mL), quickly stirring for 10min, separating phases, separating the organic phases by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain light yellow solid 2- [1- (alkene butoxy) -1-hydro-indol-3-yl ]-N- (3-chloropyridin-4-yl) acetamide (520 mg).¹H NMR(400MHz,acetone-d6):8.67(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):170.9(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), stirring at room temperature for reaction for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, carrying out phase separation, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated brine (50mL), quickly stirring for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phases, and eluting with ethyl acetate-petroleum ether (1:3) to obtain a light yellow colloidal N- (3-chloropyridin-4-yl) -2- [1- (2-pentyl-4-en-1-yloxy) -1H-indol-3-yl) -2- [ 1H-indol-3-yl ] acetamide ]Acetamide (540 mg).¹H NMR(400MHz,acetone-d6):8.66(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):170.9(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), stirring at room temperature for reaction for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, carrying out phase separation, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated brine (50mL), quickly stirring for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phases, and eluting with ethyl acetate-petroleum ether (1:3) to obtain a light yellow colloidal N- (3-chloropyridin-4-yl) -2- [1- (2-hexyl-5-en-1-yloxy) -1H-indol-3-yl) -2 ]Acetamide (580 mg).¹H NMR(400MHz,acetone-d6):8.69(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):170.9(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), stirring at room temperature for reaction for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline (50mL), quickly stirring for 10min, separating the phases, and passing the organic phase through siliconSeparating with gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain light yellow gum 2- [1- (butyl-3-alkyne-1-yloxy) -1-hydrogen-indol-3-yl ]-N- (3-chloropyridin-4-yl) acetamide (490 mg).¹H NMR(400MHz,acetone-d6):8.69(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):170.9(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), stirring at room temperature for reaction for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, carrying out phase separation, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline solution (50mL), quickly stirring for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:3) to obtain a light yellow colloid 2- [1- (butyl-2-yn-1-yloxy) -1-hydro-indol-3-yl ]-N- (3-chloropyridin-4-yl) acetamide (416 mg).¹H NMR(400MHz,acetone-d6):8.69(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):170.9(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), stirring at room temperature for reacting for 2 hours, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography separation on the organic phase, and using ethyl acetate as an organic solventPetroleum ether (1:5) elution gave N- (2-chlorophenyl) -2- [1- (3-chloropropyloxy) -1H-indol-3-yl as a brown gum]Acetamide (450 mg).¹H NMR(400MHz,acetone-d₆):8.47(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):169.9(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 for C₁₉H₁₉Cl₂N₂O₂,377.0818)。

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), stirring at room temperature for reaction for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, carrying out phase separation, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline solution (50mL), quickly stirring for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:3) to obtain a light yellow colloid 2- [1- (3-chloropropyloxy) -1-hydro-indol-3-yl) ]-N- (3-chloropyridin-4-yl) acetamide (452 mg).¹H NMR(400MHz,acetone-d6):8.69(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):170.8(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), stirring at room temperature for reaction for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the aqueous phasesAdding saturated salt water (50mL) into the organic phase, rapidly stirring for 10min, and separating 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):8.70(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):170.9(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), stirring at room temperature for reacting for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:5) to obtain a light brown solid N- (2-chlorphenyl) -2- (1-cyanomethoxy-1H-indol-3-yl) acetamide (315 mg).¹H NMR(400MHz,acetone-d₆):8.56(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):169.6(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), stirring at room temperature for 2 hours, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10 minutes, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline (50mL), and reacting rapidly Stirring for 10min, and separating 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):8.80(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):170.6(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), stirring at room temperature for 2 hours, adding ethyl acetate (50mL) and water (50mL) into reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline water (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography separation on the organic phase, eluting with ethyl acetate-petroleum ether (1:5), and obtaining a light brown colloid N- (2-chlorphenyl) -2- [1- (3-hydroxy propoxy) -1H-indol-3-yl ]Acetamide (340 mg).¹H NMR(400MHz,acetone-d₆):8.49(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):170.0(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), stirring at room temperature for 2 hours to react, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, quickly stirring for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2), combining the organic phases, adding saturated saline (50mL), quickly stirring for 10min, separating phases(ii) a 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):8.70(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):170.9(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), stirring at room temperature for reacting for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline solution (50mL), stirring rapidly for 10min, separating phases, separating the organic phases by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain a reddish brown solid N- (3-fluoropyridin-4-yl) -2- [1- (3-hydroxypropoxy) -1H-indol-3-yl ] acetamide ]Acetamide (120 mg).¹H NMR(400MHz,acetone-d₆):9.31(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):171.1(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 bromomethyl cyclopropane (1.2g), stirring at room temperature for 2 hours, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10 minutes, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phasesAdding saturated salt water (50mL), rapidly stirring for 10min, and separating 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):8.62(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):171.3(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), stirring at room temperature for reacting for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline solution (50mL), quickly stirring for 10min, separating phases, separating the organic phases by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain a reddish brown solid N- (3-fluoropyridin-4-yl) -2- [1- (cyclopropylmethoxy) -1H-indol-3-yl ] acetamide ]Acetamide (650 mg).¹H NMR(400MHz,acetone-d₆):9.28(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):171.1(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

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 1-bromo-4-butanenitrile (1.2g) were added and stirred at room temperatureStirring for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, rapidly stirring for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline (50mL), rapidly stirring for 10min, separating phases, separating the organic phases by silica gel column chromatography, eluting with ethyl acetate-petroleum ether (1:3) to obtain a light yellow gum N- (3-chloropyridin-4-yl) -2- [1- (3-cyanopropoxy) -1H-indol-3-yl ] -2- [1- (3-cyanopropoxy) -1H-indol-3-yl ]Acetamide (170 mg).¹H NMR(400MHz,acetone-d6):8.70(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):170.8(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):10.97(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):170.2(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):8.52(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):169.7(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):11.04(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):169.6(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):8.60(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):169.7(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), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, quickly stirring for 10min, separating phases, extracting the aqueous phase with ethyl acetate (25mL × 2) and combining the organic phases, adding saturated saline solution (50mL), quickly stirring for 10min, separating phases, separating the organic phases 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 a yellow solid ]Benzoate (521 mg).¹H NMR(400MHz,acetone-d₆):10.93(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):170.7(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), stirring at room temperature for reacting for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:5) to obtain a light pink solid N- (2-chlorphenyl) -2- (1-benzyloxy-1H-indol-3-yl) acetamide (537 mg).¹H NMR(300MHz,acetone-d₆):8.43(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):169.9(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

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-methoxy benzyl bromide (1.8g), stirring at room temperature for 2 hours, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2) and combining organic phases, adding saturated saline (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, eluting with ethyl acetate-petroleum ether (1:5) to obtain a light red solid N- (2-chlorphenyl) -2- {1- [ (4-methoxybenzyl) oxy) ethyl acetate ]-1H-indol-3-yl } acetamide (728 mg).¹H NMR(400MHz,acetone-d₆):8.39(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):169.9(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), stirring at room temperature for 2 hours, adding ethyl acetate (50mL) and water (50mL) into the reaction liquid, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2) and combining organic phases, adding saturated saline solution (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography separation on the organic phase, eluting with ethyl acetate-petroleum ether (1:5) to obtain a yellowish solid N- (2-chlorphenyl) -2- {1- [ (4-methylbenzyl) oxy]-1H-indol-3-yl } acetamide (605 mg).¹H NMR(400MHz,acetone-d₆):8.38(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):169.3(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

Step four, 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), stirring at room temperature for 2H, adding ethyl acetate (50mL) and water (50mL) into the reaction solution, stirring rapidly for 10min, carrying out phase separation, extracting an aqueous phase with ethyl acetate (25mL × 2), combining organic phases, adding saturated saline (50mL), stirring rapidly for 10min, carrying out phase separation, carrying out silica gel column chromatography on the organic phase, and eluting with ethyl acetate-petroleum ether (1:5) to obtain a purple gum N- (2-chlorphenyl) -2- (1-phenethyl-1H-indol-3-yl) acetamide (566 mg). ¹H NMR(400MHz,acetone-d₆):8.43(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):169.9(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 5 × 10 cells number 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 the example compounds 1-105, and the results show that 57 compounds have stronger activity of inhibiting wild HIV-1 (half inhibition concentration is 10 nM-20 muM, table 1), 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 compounds for anti-influenza effects, we prepared human influenzaA virus A/Puerto Rico/8/1934(H1N1), A/lake Beizhongshan/50/2005 (H1N1), A/Jingfang 262/95(H1N1), A/Jingfang/359/95 (H3N2), A/Jifang/15/90 (H3N2) and B/Jiangxi new construction/BV/39/2008 are prepared by the following steps: 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 method ₅₀)。

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

3 × 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 method ₅₀)。

(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

1. An application of indole compounds and pharmaceutically acceptable salts thereof in preparing medicines for preventing, relieving and/or treating HIV is characterized in that the compounds are shown as formula (IA2)

x is selected from substituted or unsubstituted C₁Alkyl radical, C₅A cycloalkyl group; wherein said substituents are optionally substituted with: 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. Use according to claim 1, characterized in that said compound is of formula (IA2a)

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

3. Use according to claim 1, characterized in that said compound is of formula (IA2b)

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

4. Use according to claim 1, characterized in that said compound is of formula (IA2c)

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

5. Use according to claim 1, characterized in that said compound is of formula (IA2d)

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

6. Use according to claim 1, characterized in that said compound is of formula (IA2e)

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

7. An application of indole compounds and pharmaceutically acceptable salts thereof in preparing medicines for preventing, relieving and/or treating HIV is characterized in that the compounds are selected from the following:

8. use of a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 7, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier for the manufacture of a medicament for the prevention, alleviation and/or treatment of HIV.