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

Abstract

The present invention discloses an indole compound extracted from Radix isatidis represented by general formula (I) and derivatives thereof, as well as pharmaceutically acceptable salts thereof, as well as a preparation method of the compound and a pharmaceutical combination thereof thing. The compounds have obvious anti-HIV activity and anti-influenza virus activity, and can be used for preparing anti-HIV or anti-influenza virus medicines or health care products.

Description

A class of indole compounds with antiviral activity in Radix isatidis and their derivatives

technical field

The present invention relates to an indole derivative and a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and the application of the compound in anti-HIV virus and anti-influenza virus. field of medical technology.

Background technique

Human immunodeficiency virus (Human Immunodeficiency Virus, HIV) infects human immune cells and destroys the human immune system, so that patients eventually die from complications such as severe infection or secondary tumors. The disease caused by this virus is called Acquired Immunodeficiency Syndrome, or AIDS ^[1] .

According to the United Nations Programme on HIV/AIDS (UNAIDS), as of the end of 2012, the number of people living with HIV worldwide was 35 million [32.2-38.8 million], including 3.3 million children [3.0-3.7 million]. In 2012, there were 2.3 million [1.9 million-2.7 million] new HIV infections globally and 1.6 million [1.4 million-1.9 million] deaths in the year [http://www.actoronto.org/home.nsf/pages/hivaidsstatsworld HIV and AIDS Statistics–Worldwide]. Statistics in 2012 show that my country has reported a total of 434,000 HIV-infected and AIDS patients and 88,000 deaths. By the end of 2011, it is estimated that there are 154,000 AIDS patients alive in my country [http://www.avert.org/hiv-aids-china.htm]. The report also shows that the number of people infected with AIDS in my country is increasing year by year, and the epidemic situation is serious in some areas. Therefore, the prevention and treatment of AIDS still needs to be carried out in depth.

HIV belongs to the retroviral family lentivirus and belongs to the human lentivirus group, which is divided into type I human immunodeficiency virus (HIV-1) and type II human immunodeficiency virus (HIV-2). Caused by viral infection, HIV-2 is mainly distributed in West Africa ^[2] . There is no cure for AIDS, and there is no preventive vaccine. At this stage, highly active anti-retroviral therapy (HAART) is mainly used, that is, taking several (usually 3 or 4) antiretroviral drugs at the same time, in which two nucleosides are used in combination Reverse transcriptase inhibitors and a non-nucleoside reverse transcriptase inhibitor or protease inhibitor are routine regimens ^[3] . As of the end of 2013, 26 drugs have been approved for the treatment of AIDS. These drugs are divided into 6 categories according to their mechanism of action: 7 nucleoside reverse transcriptase inhibitors; 5 non-nucleoside reverse transcriptase inhibitors (Non- Nucleoside Reverse Transcriptase Inhibitors, NNRTIs); 10 protease inhibitors; 2 integrase inhibitors; 1 fusion inhibitor; 1 CCR5 inhibitor. The combined drug can effectively reduce the virus replication speed, restore the patient's immune function, and achieve the purpose of prolonging the patient's life. However, due to the inability to completely remove the virus and the need for patients to take medicine for life, drug-resistant viruses will inevitably arise, resulting in a significant decrease in the efficacy of HAART treatment. Therefore, the development of new drugs with high efficacy against drug-resistant HIV-1 virus is an important topic in the field of AIDS treatment.

HIV-1 reverse transcriptase (RT) is a functional group necessary to complete the reverse transcription of single-stranded RNA into double-stranded DNA, and plays a crucial role in the life cycle of HIV-1, so RT has become a drug for the treatment of AIDS The classic target ^[4] . RT is a heterodimer composed of p66 subunit and p51 subunit. p66 is a functional subunit with RNA-dependent DNA polymerase activity, DNA-dependent DNA polymerase activity and ribonuclease H (RNase H) activity. The p66 subunit is divided into a polymerase active region and an RNase H active region. The sequence of the polymerase active region is highly conserved and resembles the human right hand, including "finger" (residues 1-85 and 118-155), "palm" (86 -117 residues), "thumb" (238-318 residues) and connecting region (319-426 residues), the polymerase activity center is located in the center of the "palm", which is a highly conserved region (including D110, D185 and D186). Non-nucleoside reverse transcriptase inhibitors act on the hydrophobic "pocket" (non-nucleoside inhibitor binding pocket, NNIBP) 1 nm away from the active center site of reverse transcriptase. The efficient conformation of the catalytically active region of reverse transcriptase, thereby inhibiting the binding of the enzyme to the substrate ^[5] . Currently listed non-nucleoside reverse transcriptase inhibitors are delavirdine, nevirapine, efavirenz, etravirine and rilpivirine.

Non-nucleoside reverse transcriptase inhibitors are an important part of high-efficiency antiretroviral therapy and are usually used in combination with nucleoside reverse transcriptase inhibitors. With the long-term and widespread use of HAART, drug-resistant viruses have emerged, and have the characteristics of multidrug resistance, resulting in treatment failure. According to statistics, there is a drug-resistant virus in at least 50% of clinical patients. After more than ten years of clinical application of nevirapine and efavirenz, stable drug-resistant strains have appeared ^[6] . Clinical studies have found that after taking etravirine and rilpivirine for 48 weeks, the body will produce resistant viruses against these two drugs. Therefore, the development of new non-nucleoside reverse transcriptase inhibitors is the focus of the anti-AIDS field.

Table 1: Common clinical NNRTIs drug resistance mutation sites, incidence rate and drug resistance multiple

Viral diseases are the main infectious diseases of human beings. Common diseases caused by viruses include: (1) epidemic diseases, such as influenza, measles, mumps, etc.; (2) chronic infectious diseases, such as AIDS, hepatitis B, etc. (3) Latent infectious diseases, such as herpetic keratitis, etc.; (4) Certain tumors, such as nasopharyngeal cancer, cervical cancer, etc. The prevention and treatment of viral diseases is an important research topic in the current medical and pharmaceutical fields. The research and invention of drugs for the treatment of viral diseases, especially the simultaneous treatment of multiple viral diseases, have important potential application value.

Influenza virus is the causative agent of influenza and one of the main causes of human death. Influenza virus belongs to the Orthomyxoviridae family, and is divided into three types: A (A), B (B), and C (C) according to the antigenicity of internal proteins. The influenza A virus is the most closely related to humans, and its genome consists of 8 single-stranded negative-stranded RNAs, encoding at least 10 proteins: hemagglutinin (HA), neuraminidase (NA), polymerase (Polymerase basic protein 1, PB1; Polymerase basic protein 2, PB2); Polymerase acidic protein 3, PA), nucleoprotein (NP), matrix protein (Matrix protein 1, M1; Matrix protein 2, M2), non-structural protein (Non-structural protein 1, NS1; Non-structural protein 2, NS2) ). There are many strains of influenza virus. According to the different antigenicity of the viral envelope protein hemagglutinin HA and neuraminidase NA, influenza A virus is divided into various subtypes. At present, 17 kinds of HA and 10 kinds of NA have been found. NA subtypes can form different combinations, such as H1N1, H2N2, H3N2, H5N1, H7N9 subtypes, etc.

The current clinical anti-influenza drugs are mainly divided into two categories according to their mechanism of action: one is amantadine and rimantadine that inhibit M2 ion channel protein; the other is neuraminidase inhibitors that inhibit the release of influenza virus , oseltamivir, zanamivir, and peramivir. Statistics show that all currently marketed anti-influenza drugs have drug-resistant virus strains. Because the drug resistance is too severe, the US Centers for Disease Control and Prevention has recommended that amantadine and rimantadine should not be used as clinical treatments. In addition to the above-mentioned anti-influenza drugs, a variety of single-flavor and compound traditional Chinese medicine preparations, such as Banlangen granules and Shuanghuanglian oral liquid, are also effective therapeutic drugs against influenza virus.

Radix Isatidis is the root of cruciferous plants Isatis tinctoria L. and I. indi goticaFort. It is cultivated all over the country and is rich in resources. It is also a traditional Chinese medicine commonly used in China. The efficacy of the pharynx is clinically used to treat influenza, mumps, hepatitis B, herpes simplex keratitis, pharyngitis, flat warts, pink eye, dacryocystitis, chickenpox, measles and other viral infections ^[7,8] . The 2010 edition of "Chinese Pharmacopoeia" clarifies that Radix isatidis has the functions of clearing away heat and detoxifying, cooling blood and soothing throat. In particular, Banlangen and its preparations have played an important role in the prevention and treatment of SARS and avian influenza, as one of the recommended emergency Chinese medicine varieties in my country.

In the past, pharmacological studies of Radix Isatidis mainly focused on its water or alcohol extract and its injections and the activity evaluation of the isolated parts. Mumps virus has the effect of inhibiting infection and proliferation, and has obvious virucidal effect on hemorrhagic fever virus and herpes simplex virus ^[7] . , Hepatitis B virus core antigen (HBcA g) and HBV-DNA have significant inhibitory effect ^[9] ; Radix isatidis extract or the isolated part can inhibit human herpes simplex virus HSV-I and HSV-II virus, inhibit TK Gene transcription ^[10 , ^11] , inhibition of HSV-I infection of Hep-2 cells, inactivation of HSV-I ^[12] , inhibition of dog kidney cells (MDCK) inoculated with human influenza A1 virus PR8 strain (A/PR/8 /34, H1N1) replication ^[13 , ^14] , inhibition of human cytomegalovirus HCMV ^[15] , inhibition of Hela cell line transfection of mumps virus ^[16] and inhibition of porcine kidney cells before and after pseudorabies virus infection disease ^[17] and so on. And in some evaluations, the activity of Radix Isatidis extract was shown to be comparable or stronger than that of the positive controls, acyclovir (Aciclovir), zidovudine (Zidovudine, AZT) or polymyocytes. In addition, the ethanol extract of Radix isatidis and its isolated parts have inhibitory effects on Staphylococcus aureus and Pseudomonas aeruginosa, and have significant inhibitory effects on xylene-induced auricle swelling and carrageenan-induced foot swelling in mice. The positive control drug indomethacin is comparable ^[18,19] . It can be seen that the antiviral effect of Radix Isatidis extract is definitely affirmed.

Since the 1980s, domestic and foreign scholars have also conducted continuous research on the chemical constituents of Radix isatidis and its leaves. Nearly 80 compounds with diverse structures such as -3-butenyl thiocyanate. Although indole alkaloids such as indirubin derivatives, tryptamines, 2,4(1H,3H)-quinazoledione, adenosine and other components have also been found to have certain anti-tumor and antibacterial properties in research. and antiviral pharmacological activities ^[20-22] ; syringic acid, salicylic acid, anthranilic acid, benzoic acid and 4(3H)-quinazolone have significant anti-endotoxin, inhibit TNFα and NO release, etc. ^[23-30] , as well as inhibiting the activity of 5-lipoxygenase or reducing the level of leukotriene B(4) secreted by cells ^[31-33] . However, due to the limitation of sample size and pharmacological evaluation model, most of the compounds have not been tested and evaluated for their activity. In particular, the content and activity intensity of the reported compounds are difficult to compare with the strong anti-virus properties of Radix isatidis extracts and isolated parts. activity corresponds. It can be seen that the antiviral active components in the extract of Radix Isatidis are not yet fully understood.

Based on the above background, combined with the previous studies on the chemical constituents of Radix isatidis, most of them were extracted with ethanol or methanol, while the traditional application and pharmacological evaluation of Radix isatidis were mainly based on water decocting. Systematic and in-depth studies have been carried out from the aspects of separation of chemical components, evaluation of antiviral activity, correlation of structural transformation and derivatization, and structure-activity relationship ^[34-36] . A N-alkoxyindole derivative, methyl-2-[2-(1-methoxy-1H-indol-3-yl), with significant inhibitory activity against HIV-1 replication was found in the study Acetamide]benzoate {Methyl 2-[2-(1-methoxy-1H-indol-3-yl)acetamido]benzoate, 1}. Therefore, taking this compound as the leading structure, the inventive result of the present invention is obtained through structural modification and optimization.

Indole derivatives not only exist widely in plants, but also many clinically used drugs contain indole resultant units, which have a wide variety of biological activities, such as anti-inflammatory, antitumor, antiviral, antibacterial and so on. At the same time, some indole derivatives have also been reported to have good anti-HIV-1 activity ^[37,38] . However, the compounds shown in these documents not only belong to the unsubstituted derivatives on indole N, but also the overall structure is significantly different from that of the compounds of the present invention.

In addition, some literatures have also reported complex structural derivatives of indole nitrogen atoms substituted with alkoxy groups and their cytotoxic activities ^[39] , but they have not been found to have anti-HIV and anti-influenza virus activities.

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SUMMARY OF THE INVENTION

The technical problem solved by the present invention is to provide a class of indole compounds and their pharmaceutically acceptable salts, as well as their preparation methods, pharmaceutical compositions and applications of such compounds in the preparation of anti-HIV or anti-influenza virus drugs or health care products .

The first aspect of the technical solution of the present invention is to provide a class of indole compounds and pharmaceutically acceptable salts thereof, whose structural formula is shown in general formula (I):

in,

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

R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

X is selected from hydrogen, substituted or unsubstituted C _1-16 alkyl, C _3-6 cycloalkyl, C _1-6 alkanoyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzoyl; wherein The substituents are optionally substituted by the following groups: OH, C _1-6 alkyl, C _1-6 alkoxy, halogen, NH ₂ , NO ₂ , cyano, carboxyl, phenyl, C _1-6 Unsaturated alkyl, C _3-6 cycloalkyl, C _1-6 alkoxyacyl;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

Z is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; wherein said substituent is optionally substituted by the following groups: halogen, C _1-6 alkyl, C _1-6 alkoxy, Cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _1-6 alkoxyacyl.

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 monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

X is selected from hydrogen, substituted or unsubstituted C _1-16 alkyl, C _3-6 cycloalkyl, C _1-6 alkanoyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzoyl; wherein The substituents are optionally substituted by the following groups: OH, C _1-6 alkyl, C _1-6 alkoxy, halogen, NH ₂ , NO ₂ , cyano, carboxyl, phenyl, C _1-6 Unsaturated alkyl, C _3-6 cycloalkyl, C _1-6 alkoxyacyl;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

Z is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; wherein said substituent is optionally substituted by the following groups: halogen, C _1-6 alkyl, C _1-6 alkoxy, Cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _1-6 alkoxyacyl.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

X is selected from hydrogen, substituted or unsubstituted C _1-16 alkyl, C _3-6 cycloalkyl, C _1-6 alkanoyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzoyl; wherein The substituents are optionally substituted by the following groups: OH, C _1-6 alkyl, C _1-6 alkoxy, halogen, NH ₂ , NO ₂ , cyano, carboxyl, phenyl, C _1-6 Unsaturated alkyl, C _3-6 cycloalkyl, C _1-6 alkoxyacyl;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₁ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from ortho-position, meta-position and para-position mono-substitution; the poly-substitution is selected from di-substitution, tri-substitution, tetra-substitution and penta-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₁ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from ortho-position, meta-position and para-position mono-substitution; the poly-substitution is selected from di-substitution, tri-substitution, tetra-substitution and penta-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₁ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from ortho-position, meta-position and para-position mono-substitution; the poly-substitution is selected from di-substitution, tri-substitution, tetra-substitution and penta-substitution.

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 monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₁ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from ortho-position, meta-position and para-position mono-substitution; the poly-substitution is selected from di-substitution, tri-substitution, tetra-substitution and penta-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₁ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from ortho-position, meta-position and para-position mono-substitution; the poly-substitution is selected from di-substitution, tri-substitution, tetra-substitution and penta-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₁ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from ortho-position, meta-position and para-position mono-substitution; the poly-substitution is selected from di-substitution, tri-substitution, tetra-substitution and penta-substitution.

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 monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₁ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from ortho-position, meta-position and para-position mono-substitution; the poly-substitution is selected from di-substitution, tri-substitution, tetra-substitution and penta-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₁ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from ortho-position, meta-position and para-position mono-substitution; the poly-substitution is selected from di-substitution, tri-substitution, tetra-substitution and penta-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₁ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from ortho-position, meta-position and para-position mono-substitution; the poly-substitution is selected from di-substitution, tri-substitution, tetra-substitution and penta-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₁ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from the ortho-position, meta-position, and the para-position mono-substitution; the multi-substitution is selected from the di-substitution, tri-substitution, tetra-substitution, and penta-substitution;

R ₁ ' is selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₁ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from the ortho-position, meta-position, and the para-position mono-substitution; the multi-substitution is selected from the di-substitution, tri-substitution, tetra-substitution, and penta-substitution;

R ₁ " is selected from C _1-6 alkyl, 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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

X is selected from hydrogen, substituted or unsubstituted C _1-16 alkyl, C _3-6 cycloalkyl, C _1-6 alkanoyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzoyl; wherein The substituents are optionally substituted by the following groups: OH, C _1-6 alkyl, C _1-6 alkoxy, halogen, NH ₂ , NO ₂ , cyano, carboxyl, phenyl, C _1-6 Unsaturated alkyl, C _3-6 cycloalkyl, C _1-6 alkoxyacyl;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₂ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from the ortho-position and meta-position mono-substitution of the amide group; the poly-substitution is selected from the di-substitution, tri-substitution, and tetra-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

X is selected from substituted or unsubstituted C _1-6 alkyl; wherein said substituent is optionally substituted by the following groups: OH, C _1-6 alkyl, C _1-6 alkoxy, halogen, NH ₂ , NO ₂ , cyano, carboxyl, phenyl, C _1-6 unsaturated alkyl, C _3-6 cycloalkyl, C _1-6 alkoxyacyl;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₂ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from the ortho-position and meta-position mono-substitution of the amide group; the poly-substitution is selected from the di-substitution, tri-substitution, and tetra-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₂ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from the ortho-position and meta-position mono-substitution of the amide group; the poly-substitution is selected from the di-substitution, tri-substitution, and tetra-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₂ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from the ortho-position and meta-position mono-substitution of the amide group; the poly-substitution is selected from the di-substitution, tri-substitution, and tetra-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₂ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from the ortho-position and meta-position mono-substitution of the amide group; the poly-substitution is selected from the di-substitution, tri-substitution, and tetra-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₂ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from the ortho-position and meta-position mono-substitution of the amide group; the poly-substitution is selected from the di-substitution, tri-substitution, and tetra-substitution.

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 monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₂ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from the ortho-position and meta-position mono-substitution of the amide group; the poly-substitution is selected from the di-substitution, tri-substitution, and tetra-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

X is selected from hydrogen, substituted or unsubstituted C _1-16 alkyl, C _3-6 cycloalkyl, C _1-6 alkanoyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzoyl; wherein The substituents are optionally substituted by the following groups: OH, C _1-6 alkyl, C _1-6 alkoxy, halogen, NH ₂ , NO ₂ , cyano, carboxyl, phenyl, C _1-6 Unsaturated alkyl, C _3-6 cycloalkyl, C _1-6 alkoxyacyl;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₂ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from the ortho, meta, and para-position mono-substitution of the amide group; the polysubstitution is selected from the di-substitution, tri-substitution, and tetra-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

X is selected from hydrogen, substituted or unsubstituted C _1-16 alkyl, C _3-6 cycloalkyl, C _1-6 alkanoyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzoyl; wherein The substituents are optionally substituted by the following groups: OH, C _1-6 alkyl, C _1-6 alkoxy, halogen, NH ₂ , NO ₂ , cyano, carboxyl, phenyl, C _1-6 Unsaturated alkyl, C _3-6 cycloalkyl, C _1-6 alkoxyacyl;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

R ₂ is mono- or poly-substituted, selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _{1- 6} alkoxyacyl group; wherein the mono-substitution is selected from the ortho, meta, and para-position mono-substitution of the amide group; the polysubstitution is selected from the di-substitution, tri-substitution, and tetra-substitution.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

X is selected from hydrogen, substituted or unsubstituted C _1-16 alkyl, C _3-6 cycloalkyl, C _1-6 alkanoyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzoyl; wherein The substituents are optionally substituted by the following groups: OH, C _1-6 alkyl, C _1-6 alkoxy, halogen, NH ₂ , NO ₂ , cyano, carboxyl, phenyl, C _1-6 Unsaturated alkyl, C _3-6 cycloalkyl, C _1-6 alkoxyacyl;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

Z is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; wherein said substituent is optionally substituted by the following groups: halogen, C _1-6 alkyl, C _1-6 alkoxy, Cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _1-6 alkoxyacyl.

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

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy;

X is selected from hydrogen, substituted or unsubstituted C _1-16 alkyl, C _3-6 cycloalkyl, C _1-6 alkanoyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzoyl; wherein The substituents are optionally substituted by the following groups: OH, C _1-6 alkyl, C _1-6 alkoxy, halogen, NH ₂ , NO ₂ , cyano, carboxyl, phenyl, C _1-6 Unsaturated alkyl, C _3-6 cycloalkyl, C _1-6 alkoxyacyl;

Y is selected from hydrogen, halogen, cyano, carboxyl, C _1-6 alkyl;

Z is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; wherein said substituent is optionally substituted by the following groups: halogen, C _1-6 alkyl, C _1-6 alkoxy, Cyano, trifluoromethyl, nitro, hydroxyl, amino, carboxyl, C _1-6 alkoxyacyl.

The second aspect of the technical solution of the present invention is to provide a preparation method of the compound described in the first aspect, which can be synthesized by the following steps and methods:

The definitions of R, n, Y and Z are as described in the first aspect of the present invention

Substituted 3-indole carboxylic acid (formula 1) is subjected to amidation reaction with various amines to obtain formula 2, and formula 2 is reduced to obtain intermediate formula 3; substituted indole (formula 4) is reacted with acid chloride to obtain formula 5, which is then combined with Different amines are amidated to obtain formula 6, and then reduced to obtain formula 7; intermediates of formula 3 and formula 7 are oxidized and N-substituted to obtain the target compound of formula 8, and then substituted by indole 2-position to obtain the target compound of formula 9.

The third aspect of the technical solution of the present invention is to provide a pharmaceutical composition containing the compound described in the first aspect and a pharmaceutically acceptable salt thereof, the pharmaceutical composition containing a therapeutically effective amount of the indole derivative of the present invention and its pharmacy acceptable salts of the above, optionally with a pharmaceutically acceptable carrier. The pharmaceutical carrier mentioned therein refers to a pharmaceutical carrier commonly used in the field of pharmacy; the pharmaceutical composition can be prepared according to a method known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compounds of the present invention and their pharmaceutically acceptable salts with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compounds of the present invention and their pharmaceutically acceptable salts in their pharmaceutical compositions is usually 0.1-95% by weight.

The compounds of the present invention and their pharmaceutically acceptable salts or pharmaceutical compositions containing them can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal , oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

The dosage form for administration can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o/w, w/o and double emulsion), suspensions, injections (including water injection, powder injection and infusion), eye drops solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, drop pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.; semi-solid dosage forms can be ointments, Gels, pastes, etc.

The compounds of the present invention and their pharmaceutically acceptable salts can be prepared into common preparations, as well as sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

In order to formulate the compounds of the present invention and their pharmaceutically acceptable salts into tablets, various excipients well known in the art can be widely used, including diluents, binders, wetting agents, disintegrating agents, lubricants, adjuvants flow agent. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; Propanol, etc.; the binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia mucilage, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polymer Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfonate, etc.; lubricants and flow aids The agent may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like.

The tablets can also be further prepared as coated tablets, such as sugar-coated, film-coated, enteric-coated, or bilayer and multi-layer tablets.

In order to make the dosage unit into capsules, the active ingredients of the compounds of the present invention and their pharmaceutically acceptable salts can be mixed with diluents and glidants, and the mixture can be directly placed in hard capsules or soft capsules. The compounds of the present invention and their pharmaceutically acceptable salts as active ingredients can also be prepared into granules or pellets with diluents, binders and disintegrating agents, and then placed in hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants, glidants used in the preparation of the compounds of the present invention and their pharmaceutically acceptable salt tablets can also be used in the preparation of the compounds of the present invention and their pharmaceutically acceptable salts. Capsules of salt.

In order to prepare the compounds of the present invention and their pharmaceutically acceptable salts into injections, water, ethanol, isopropanol, propylene glycol or their mixtures can be used as solvents and an appropriate amount of commonly used solubilizers, cosolvents, pH adjusters, Osmotic pressure regulator. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjuster can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure adjuster can be It is sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, in the preparation of freeze-dried powder injection, mannitol, glucose, etc. can also be added as proppant.

In addition, colorants, preservatives, fragrances, flavors, or other additives can also be added to the pharmaceutical preparations, if desired.

In order to achieve the purpose of medication and enhance the therapeutic effect, the medicament 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 application of the indole derivatives of the present invention and their pharmaceutically acceptable salts in the fields of pharmacy and health care products, especially the indole derivatives of the present invention and their pharmaceutically acceptable salts. The application of the accepted salt in the preparation of antiviral medicines, the indole derivatives of the present invention and their pharmaceutically acceptable salts can be used to prepare and treat diseases caused by viruses, especially anti-HIV virus and anti-influenza virus medicines and health products.

When the indole derivatives of the present invention and their pharmaceutically acceptable salts or the compositions of the present invention are used to treat the above-mentioned diseases, the dosage of the indole derivatives may refer to the dosage of the indole derivatives for treatment; When the indole derivatives of the present invention or the composition of the present invention are used as health care products, or added to health care products, the dosage should be less than the usual therapeutic amount.

The inventors have conducted a large number of drug experiments and proved that the indole derivatives of the present invention have the effect of inhibiting the replication of HIV virus and anti-influenza virus, and have a good therapeutic effect on diseases caused by HIV virus and anti-influenza virus, and It can be used as or added to health care products to improve physical condition and improve immunity.

The dosage of the pharmaceutical composition of the compound of the present invention may vary widely according to the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form. In general, a suitable daily dosage range of the compounds of the invention is 0.001-150 mg/Kg body weight, preferably 0.1-100 mg/Kg body weight, more preferably 1-60 mg/Kg body weight, and most preferably 2-30 mg/Kg body weight. The above doses may be administered in a single dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosing 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 drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.

The fourth aspect of the technical solution of the present invention is to provide the compounds and their pharmaceutically acceptable salts of the first aspect and the pharmaceutical composition of the third aspect in the preparation of anti-HIV drugs or health care products.

The fifth aspect of the technical solution of the present invention is to provide the compounds described in the first aspect and the pharmaceutically acceptable salts thereof and the pharmaceutical compositions described in the third aspect in the preparation of anti-influenza virus drugs or health care products.

Detailed description of the invention:

Various aspects and features of the present invention are further described below.

All documents cited in the present invention, their entire contents are incorporated herein by reference, and if the meaning expressed by these documents is inconsistent with the present invention, the expression of the present invention shall prevail. In addition, various terms and phrases used in the present invention have ordinary meanings known to those skilled in the art. Even so, the present invention still hopes to make more detailed descriptions and explanations for these terms and phrases. The terms and phrases mentioned are such as If there is any inconsistency with the known meaning, the meaning expressed in the present invention shall prevail. The following are definitions of various terms used in the present invention, and these definitions apply to the terms used throughout the specification of this application unless otherwise indicated in a specific case.

As referred to in the present invention, the terms "halo", "halogen", "halogen atom", "halo" and the like mean fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.

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

As referred to in the present invention, the term "alkyl" refers to an alkyl group having the specified number of carbon atoms, which may be straight-chain or branched, such as when referring to "C _1-6 alkyl" , which refers to an alkyl group with 1, 2, 3, 4, 5, and 6 carbon atoms, which can include C _1-5 alkyl, C _1-4 alkyl, C _2-5 alkyl, C _2-4 alkane groups of sub-ranges represented by radicals, _C2-3 alkyl, _C3-5 alkyl, etc., as well as preferred specific groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec Butyl, tert-butyl; as mentioned in the present invention, the term "C _1-16 alkyl", which refers to the number of carbon atoms is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16 alkyl, can include C _1-10 alkyl, C _1-6 alkyl, C _2-10 alkyl, C _2-6 alkyl, C _3-4 Sub-ranges of groups represented by alkyl, etc., and preferred specific groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl base;

As mentioned in the present invention, the term "C _3-6 cycloalkyl", which refers to a cycloalkyl group with 3, 4, 5, and 6 carbon atoms, may include C _3-5 cycloalkyl, C _{3- 4} cycloalkyl, C _4-6 cycloalkyl, C _4-5 cycloalkyl, C _5-6 cycloalkyl, etc. represent sub-range groups, and preferred specific groups such as cyclopropanyl, cyclo pentyl and cyclohexane.

As mentioned in the present invention, the term "C _1-6 alkoxy", which refers to alkoxy with carbon atoms of 1, 2, 3, 4, 5, 6, may include C _1-5 alkoxy , C _1-3 alkoxy, C _2-5 alkoxy, C _2-3 alkoxy, C _3-4 alkoxy, etc. represented by sub-range groups, and preferred specific groups such as methoxy group, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy;

As mentioned in the present invention, the term "C _1-6 alkanoyl", which refers to alkanoyl groups with carbon atoms of 1, 2, 3, 4, 5, and 6, may include C _1-5 alkanoyl, C _{1 -3} -alkanoyl, _C2-4alkanoyl , _C2-3alkanoyl , _C3-4alkanoyl , etc. represented by sub-range groups, and preferred specific groups such as formyl, acetyl, n-propionyl , isopropionyl, n-butyryl, sec-butyryl, tert-butyryl;

As mentioned in the present invention, the term "C _1-6 alkoxy acyl" refers to alkoxy acyl groups with carbon atoms of 1, 2, 3, 4, 5, 6, and may include C _1-5 alkoxy acyl groups , C _1-3 alkoxy acyl, C _2-5 alkoxy acyl, C _2-3 alkoxy acyl, C _3-4 alkoxy acyl, etc. represented by sub-range groups, and preferred specific groups such as methoxy Acyl, ethoxyacyl;

As mentioned in the present invention, the term "C _1-6 unsaturated alkyl", which refers to unsaturated alkyl groups with 1, 2, 3, 4, 5, 6 carbon atoms, may include C _1-5 Unsaturated alkyl, C _1-4 unsaturated alkyl, C _2-5 unsaturated alkyl, C _2-4 unsaturated alkyl, etc. represent sub-range groups, and preferred specific groups such as vinyl, ethynyl, isopropenyl, isopropynyl, isobutenyl, isopentenyl, 1,4-dibutenyl;

As referred to in the present invention, the pyridyl group is linked to the parent nucleus at the 2, 3, 4 positions, preferably at the 4 position.

Beneficial technical effects:

In the process of researching the active ingredients of the traditional Chinese medicine Radix Radix, the inventor of the present invention isolated methyl-2-[2-(1-methyl-2-[2-(1- Methoxy-1H-indol-3-yl)acetamide]benzoate. On this basis, the synthesis and derivatization of methyl-2-[2-(1-methoxy-1H-indol-3-yl)acetamide]benzoate were carried out. The antiviral activity was further evaluated to confirm their anti-HIV and anti-influenza effects, and the compounds have strong inhibitory activity against wild and drug-resistant HIV and influenza virus replication. The IC ₅₀ value of the compound with the highest inhibitory activity against HIV virus can reach 0.01 μM, and this compound also has good activity against nevirapine and efavirenz-resistant HIV virus; against influenza virus A/Puerto Rico/8/1934 The IC ₅₀ value of the compound with the highest inhibitory activity (H1N1) can reach 1.9 μM, which is better than that of the clinical first-line drug ribavirin. The anti-262/95 (H1N1), type A/Jingfang/359/95 (H3N2) and type B/Jiangxi Xinjian/BV/39/2008 infection activity is better than the clinical first-line drug Tamiflu.

Detailed ways

The following examples further illustrate the invention, but do not limit it in any way.

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; aniline (0.62g), DMAP (0.15g) were added, The reaction was stirred at room temperature for 3 h; 2N hydrochloric acid was added and rapidly stirred for 10 min, and the phases were separated; the organic phase was added with saturated brine (10 mL) and stirred for 10 min, and the phases were separated; -Indol-3-yl)-N-phenylacetamide.

In the second step, 2-(1H-indol-3-yl)-N-phenylacetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the reaction was refluxed at 60°C for 3 h; the reaction solution The solvent was recovered, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate solution (30 mL), stirred rapidly for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined, and saturated brine ( 30 mL) was stirred for 10 min, and the phases were separated; the solvent was removed from the organic phase under reduced pressure at 50° C. to obtain a dark brown oily crude product, 2-(indolin-3-yl)-N-phenylacetamide.

In the third step, 2-(indolin-3-yl)-N-phenylacetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate (0.3 g) was added, and the reaction time was 5 min. 30% hydrogen peroxide (10 mL) was added dropwise, the dropwise addition was completed, and the reaction was carried out at 15-20 °C for 1 h; dichloromethane (200 mL) and water (200 mL) were added, rapidly stirred for 10 min, and the phases were separated; dichloromethane (100 mL×2 ) extraction, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the organic phase was separated by column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a brown gum 2- (1-Hydroxy-1H-indol-3-yl)-N-phenylacetamide (0.64 g). ¹ HNMR (400MHz, acetone-d ₆ ): δ10.26(1H,s,NH), 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); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; ethyl anthranilate (1.09g) was added, DMAP (0.15g), stirred for 3h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; the organic phase was decompressed at 40°C to remove the solvent to obtain a light reddish-brown oil. Crude ethyl-2-[2-(1H-indol-3-yl)acetamide]benzoate.

In the second step, ethyl-2-[2-(1H-indol-3-yl)acetamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL), stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product, ethyl-2-[2-(indolin-3-yl)acetamide] Parabens.

In the third step, ethyl-2-[2-(indolin-3-yl)acetamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the organic phase was separated by column chromatography and eluted with ethyl acetate-petroleum ether (1:5), Ethyl-2-[2-(1-hydroxy-1H-indol-3-yl)acetamide]benzoate (0.71 g) was obtained as a brown gum. ¹ H NMR (400MHz, acetone-d ₆ ): δ 10.99 (1H, brs, NH), 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'); ¹³ C NMR (400MHz, acetone) -d ₆ ): δ170.8(C-9), 168.2(C-7'), 142.4(C-2'), 134.9(C-4', 7a), 131.5(C-6'), 125.8( C-2), 124.7(C-3a), 123.1(C-6), 122.8(C-4'), 120.7(C-5), 120.0(C-3'), 119.6(C-4), 116.4 (C-1'), 109.2(C-7), 104.2(C-3), 61.9(C-8'), 35.8(C-8), 14.3(C-9'); (+)-HR- ESIMS m/z 339.1353 [M+H] ⁺ (calcd for C ₁₉ H ₁₈ N ₂ O ₄ , 339.1300).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 4-methyl-3-amino-benzoic acid methyl was added Ester (1.09g), DMAP (0.15g), stirred and reacted at room temperature for 3h; 2N hydrochloric acid was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; to obtain crude methyl-3-[2-(1H-indol-3-yl)acetamide]-4-methylbenzoate as a light reddish-brown oil.

In the second step, methyl-3-[2-(1H-indol-3-yl)acetamide]-4-methylbenzoate was dissolved in trifluoroacetic acid (10 mL), and triethylsilane ( 1.74g), refluxed at 60°C for 3h; the solvent was recovered from the reaction solution, ethyl acetate (30mL) was added, saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30mL), The phases were separated; the organic phases were combined, saturated brine (30 mL) was added and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50°C to obtain a dark brown oily crude product methyl-3-[2-(indoline-3- yl)acetamide]-4-methylbenzoate.

In the third step, methyl-3-[2-(indolin-3-yl)acetamide]-4-methylbenzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and added with two Sodium tungstate (0.3g) was added dropwise to 30% hydrogen peroxide (10mL) in 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and then separated phase; the aqueous phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the organic phase was separated by column chromatography, and the organic phases were separated with ethyl acetate-petroleum ether (1: 5) Elution gave methyl-3-[2-(1-hydroxy-1H-indol-3-yl)acetamide]-4-methylbenzoate (0.69 g) as a brown gum. ¹ H NMR (400MHz, acetone-d ₆ ): δ 10.27 (1H, brs, NH), 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'); ¹³ C NMR (400MHz, acetone-d ₆ ): δ170.8(C-9), 166.9(C-7'), 137.4(C-3'), 136.8(C-4'), 135.0(C-7a), 131.2(C-6'), 129.1( C-1'), 126.5(C-5'), 125.6(C-2'), 125.3(C-2), 124.4(C-3a), 122.8(C-6), 120.0(C-5), 119.6(C-4), 109.2(C-7), 104.7(C-3), 52.2(C-8'), 34.1(C-8), 17.9(C-9'); (+)-HR- ESIMS m/z 339.1353 [M+H] ⁺ (calcd for C ₁₉ H ₁₈ N ₂ O ₄ , 339.1300).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-methyl-4-aminoanisole ( 0.9g), DMAP (0.15g), stirred for 3h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; the organic phase was removed under reduced pressure at 40°C to obtain a Crude 2-(1H-indol-3-yl)-N-(4-methoxy-2-methylphenyl)acetamide as reddish brown oil.

In the second step, 2-(1H-indol-3-yl)-N-(4-methoxy-2-methylphenyl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane was added (1.74g), refluxed at 60°C for 3h; the solvent was recovered from the reaction solution, ethyl acetate (30mL) was added, saturated aqueous sodium bicarbonate solution (30mL), stirred rapidly for 15min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30mL) , the phases were separated; the organic phases were combined, saturated brine (30 mL) was added and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product 2-(indolin-3-yl)-N- (4-Methoxy-2-methylphenyl)acetamide.

In the third step, 2-(indolin-3-yl)-N-(4-methoxy-2-methylphenyl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and added Sodium tungstate dihydrate (0.3g), 30% hydrogen peroxide (10mL) was added dropwise in 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, and the mixture was rapidly stirred for 10min. The phases were separated; the aqueous phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; :5) eluted to give 2-(1-hydroxy-1H-indol-3-yl)-N-(4-methoxy-2-methylphenyl)acetamide (0.8g) as a brown gum . ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ): δ 7.57 (1H, d, J=7.6 Hz, H-6'), 7.34 (1H, d, J=8.0 Hz, 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'); ¹³ C NMR (400MHz, CD ₃ OD- d ₄ ): δ173.7(C-9), 159.4(C-4'), 136.1(C-1'), 135.6(C-7a), 129.7(C-2'), 128.2(C-2) , 125.7(C-6'), 124.8(C-3a), 123.0(C-6), 120.1(C-5), 119.6(C-4), 116.6(C-5'), 112.4(C-3 '), 109.4(C-7), 104.8(C-3), 55.7(C-8'), 34.0(C-8), 18.1(C-7'); (+)-HR-ESIMS m/z 311.1401 [M+H] ⁺ (calcd for C ₁₈ H ₁₈ N ₂ O ₃ , 311.1351).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the organic phase was separated by column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain Brown gum N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide (0.76 g). ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.44 (1H, brs, NH), 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); ¹³ C NMR (400MHz, acetone-d ₆ ) : δ170.2(C-9), 136.1(C-1'), 135.1(C-7a), 129.8(C-3'), 128.3(C-5'), 125.8(C-4'), 125.5 (C-2), 124.5(C-3a), 123.9(C-2'), 123.0(C-6), 122.8(C-6'), 120.2(C-5), 119.6(C-4), 109.3(C-7), 104.4(C-3), 34.6(C-8); (+)-HR-ESIMS m/z 301.0746[M+H] ⁺ (calcd for C ₁₆ H ₁₃ ClN ₂ O ₂ , 302.0636).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; p-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (4-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(4-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(4-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(4-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the organic phase was separated by column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain Off-white solid N-(4-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide (0.79 g). ¹ H NMR (300MHz, acetone-d ₆ ): δ 10.09 (1H, brs, NH), 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); ¹³ C NMR (400MHz, acetone-d ₆ ): δ 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/z 301.0746 [M ₊ H] ⁺ ( _calcd for _C16H13ClN2O2 , _302.0636 ).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; p-nitroaniline (0.91g), DMAP (0.15g) were added. g), stirred at room temperature for 3 h; added 2N hydrochloric acid, quickly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40°C to obtain a brown oily crude product 2-( 1H-Indol-3-yl)-N-(4-nitrophenyl)acetamide.

In the second step, 2-(1H-indol-3-yl)-N-(4-nitrophenyl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; Phase, saturated brine (30 mL) was added and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product 2-(indolin-3-yl)-N-(4-nitrobenzene base) acetamide.

In the third step, 2-(indolin-3-yl)-N-(4-nitrophenyl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the organic phase was separated by column chromatography and eluted with ethyl acetate-petroleum ether (1:3), 2-(1-Hydroxy-1H-indol-3-yl)-N-(4-nitrophenyl)acetamide (0.72 g) was obtained as a brown gum. ¹ H NMR (400MHz, acetone-d ₆ ): δ 10.15 (1H, brs, NH), 9.74 (1H, s, N-OH), 8.16 (2H, d, J=8.8 Hz, 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); ¹³ C NMR (400MHz, acetone-d ₆ ): δ171.1 (C-9) ,146.2(C-4'),143.7(C-1'),135.0(C-7a),125.5(C-3',5'),125.4(C-3a),124.6(C-2),122.8 (C-6), 119.9 (C-4), 119.7 (C-2', 6'), 119.6 (C-5), 109.1 (C-7), 104.4 (C-3), 34.8 (C-8 ); (+)-HR-ESIMS m/z 312.0993 [M+H] ⁺ (calcd for C ₁₆ H ₁₃ N ₃ O ₄ , 312.0940).

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

In the first step, indole propionic acid (1.13 g) was weighed, added to dichloromethane (20 mL) for suspension and stirring, EDCI (1.27 g) was added at room temperature, stirred and dissolved; methyl anthranilate (1 g) was added, DMAP (0.15g), stirred for 3h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; the organic phase was decompressed at 40°C to remove the solvent to obtain a light reddish-brown oil. Crude methyl-2-[3-(1H-indol-3-yl)propanamide]benzoate.

In the second step, methyl-2-[3-(1H-indol-3-yl)propionamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL) and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product methyl-2-[3-(indolin-3-yl)propanamide] Parabens.

In the third step, methyl-2-[3-(indolin-3-yl)propionamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the organic phase was separated by column chromatography and eluted with ethyl acetate-petroleum ether (1:5), Methyl-2-[3-(1-hydroxy-1H-indol-3-yl)propanamide]benzoate (0.62 g) was obtained as a brown gum. ¹ H NMR (400MHz, acetone-d ₆ ): δ 10.97 (1H, brs, NH), 9.99 (1H, s, N-OH), 8.72 (1H, d, J=8.4 Hz, 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=7.2 Hz, H-8a), 2.82 (2H, t, J=7.2 Hz, H-8); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 C ₁₉ H ₁₈ N ₂ O ₄ , 339.1300).

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

In the first step, indolebutyric acid (1.22g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; methyl anthranilate (1g) was added, DMAP (0.15g), stirred for 3h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; the organic phase was decompressed at 40°C to remove the solvent to obtain a light reddish-brown oil. Crude methyl-2-[4-(1H-indol-3-yl)butanamide]benzoate.

In the second step, methyl-2-[4-(1H-indol-3-yl)butanamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL), stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product methyl-2-[4-(indolin-3-yl)butanamide] Parabens.

In the third step, methyl-2-[4-(indolin-3-yl)butanamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the organic phase was separated by column chromatography and eluted with ethyl acetate-petroleum ether (1:5), Methyl-2-[4-(1-hydroxy-1H-indol-3-yl)butanamide]benzoate (0.67 g) was obtained as a brown gum. ¹ H NMR (400MHz, acetone-d ₆ ): δ 10.97 (1H, brs, NH), 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=7.6 Hz, H-8), 2.10 (2H, m, H-8a); ¹³ C NMR (400 MHz, acetone-d ₆ ) : δ172.2(C-9), 169.2(C-7'), 142.6(C-2'), 135.3(C-7a), 135.2(C-4'), 131.6(C-6'), 124.7 (C-3a), 124.0(C-2), 123.0(C-5'), 122.5(C-5), 120.8(C-3'), 119.6(C-6), 119.4(C-4), 115.8(C-3), 111.2(C-1'), 109.0(C-7), 52.8(C-8'), 38.3(C-8), 26.8(C-8b), 24.9(C-8a) ; (+)-HR-ESIMS m/z 353.1508 [M+H] ⁺ (calcd for C ₂₀ H ₂₀ N ₂ O ₄ , 353.1457).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; aniline (0.62g), DMAP (0.15g) were added, The reaction was stirred at room temperature for 3 h; 2N hydrochloric acid was added and rapidly stirred for 10 min, and the phases were separated; the organic phase was added with saturated brine (10 mL) and stirred for 10 min, and the phases were separated; -Indol-3-yl)-N-phenylacetamide.

In the second step, 2-(1H-indol-3-yl)-N-phenylacetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the reaction was refluxed at 60°C for 3 h; the reaction solution The solvent was recovered, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate solution (30 mL), stirred rapidly for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined, and saturated brine ( 30 mL) was stirred for 10 min, and the phases were separated; the solvent was removed from the organic phase under reduced pressure at 50° C. to obtain a dark brown oily crude product, 2-(indolin-3-yl)-N-phenylacetamide.

In the third step, 2-(indolin-3-yl)-N-phenylacetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate (0.3 g) was added, and the reaction time was 5 min. 30% hydrogen peroxide (10 mL) was added dropwise, the dropwise addition was completed, and the reaction was carried out at 15-20 °C for 1 h; dichloromethane (200 mL) and water (200 mL) were added, rapidly stirred for 10 min, and the phases were separated; dichloromethane (100 mL×2 ) extraction, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the dichloromethane phase containing 2-(1-hydroxy-1H-indol-3-yl)-N-phenylacetamide was obtained Set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give 2-(1-methoxy-1H-indol-3-yl)-N-phenylacetamide (498 mg) as a brown solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 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); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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] ⁺ (calcd for C ₁₇ H ₁₇ N ₂ O ₂ , 281.1285).

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

The first step was to weigh indoleacetic acid (1.05g), add dichloromethane (20mL) to suspend and stir, add EDCI (1.27g) at room temperature, stir and dissolve; add methyl anthranilate (1g), DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude light reddish-brown oil Methyl-2-[2-(1H-indol-3-yl)acetamide]benzoate.

In the second step, methyl-2-[2-(1H-indol-3-yl)acetamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL) and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product methyl-2-[2-(indolin-3-yl)acetamide] Parabens.

In the third step, methyl-2-[2-(indolin-3-yl)acetamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain methyl-2-[2-(1-hydroxy-1H-indole-3- The dichloromethane phase of ethyl)acetamide]benzoate was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give methyl-2-[2-(1-methoxy-1H-indol-3-yl)acetamide]benzoate (406 mg) as pale yellow crystals. ¹ H NMR (400MHz, acetone-d ₆ ): δ 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=7.6 Hz,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'); ¹³ C NMR (400MHz, acetone-d ₆ ): δ 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/z 339.1342 [M+H] ⁺ (calcd for C ₁₉ H ₁₉ N ₂ O ₄ , 339.1339).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; methyl m-aminobenzoate (1g) was added, DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude light reddish-brown oil Methyl-3-[2-(1H-indol-3-yl)acetamide]benzoate.

In the second step, methyl-3-[2-(1H-indol-3-yl)acetamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL), stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product methyl-3-[2-(indolin-3-yl)acetamide] Parabens.

In the third step, methyl-3-[2-(indolin-3-yl)acetamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain methyl-3-[2-(1-hydroxy-1H-indole-3- The dichloromethane phase of ethyl)acetamide]benzoate was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give methyl-3-[2-(1-methoxy-1H-indol-3-yl)acetamide]benzoate (435 mg) as a light brown solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 9.37 (1H, brs, NH-1), 8.29 (1H, s, H-2'), 7.89 (1H, d, J=8.0 Hz, 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); ¹³ C NMR (400MHz, acetone-d ₆ ): δ 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 C ₁₉ H ₁₉ N ₂ O ₄ ,339.1339) .

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

In the first step, indole acetic acid (1.05 g) was weighed, added to dichloromethane (20 mL) for suspension and stirring, EDCI (1.27 g) was added at room temperature, and stirred to dissolve; methyl p-aminobenzoate (1 g) was added, DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude light reddish-brown oil Methyl-4-[2-(1H-indol-3-yl)acetamide]benzoic acid methyl ester.

In the second step, methyl-4-[2-(1H-indol-3-yl)acetamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL), stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product methyl-4-[2-(indolin-3-yl)acetamide] Methyl benzoate.

In the third step, methyl-4-[2-(indolin-3-yl)acetamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain methyl-4-[2-(1-hydroxy-1H-indole-3- The dichloromethane phase of methyl)acetamide]benzoate was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give methyl-4-[2-(1-methoxy-1H-indol-3-yl)acetamide]benzoate (500 mg) as a pale yellow solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 9.52 (1H, brs, NH-1), 7.92 (2H, d, J=8.4 Hz, 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'); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 C ₁₉ H ₁₉ N ₂ O ₄ , 339.1339).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; ethyl anthranilate (1.09g) was added, DMAP (0.15g), stirred for 3h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; the organic phase was decompressed at 40°C to remove the solvent to obtain a light reddish-brown oil. Crude ethyl-2-[2-(1H-indol-3-yl)acetamide]benzoate.

In the second step, ethyl-2-[2-(1H-indol-3-yl)acetamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL), stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product, ethyl-2-[2-(indolin-3-yl)acetamide] Parabens.

In the third step, ethyl-2-[2-(indolin-3-yl)acetamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; The dichloromethane phase of ethyl)acetamide]benzoate was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give ethyl-2-[2-(1-methoxy-1H-indol-3-yl)acetamide]benzoate (423 mg) as a light brown solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 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, OCH ₂ CH ₃ -8'), 3.87 (2H, s, H-8), 1.25 (3H, t, J=6.8Hz, OCH ₂ CH ₃ -9'); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 C ₂₀ H ₂₁ N ₂ O ₄ , 353.1496).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 4-methyl-3-amino-benzoic acid methyl was added Ester (1.09g), DMAP (0.15g), stirred and reacted at room temperature for 3h; 2N hydrochloric acid was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; to obtain crude methyl-3-[2-(1H-indol-3-yl)acetamide]-4-methylbenzoate as a light reddish-brown oil.

In the second step, methyl-3-[2-(1H-indol-3-yl)acetamide]-4-methylbenzoate was dissolved in trifluoroacetic acid (10 mL), and triethylsilane ( 1.74g), refluxed at 60°C for 3h; the solvent was recovered from the reaction solution, ethyl acetate (30mL) was added, saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30mL), The phases were separated; the organic phases were combined, saturated brine (30 mL) was added and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50°C to obtain a dark brown oily crude product methyl-3-[2-(indoline-3- yl)acetamide]-4-methylbenzoate.

In the third step, methyl-3-[2-(indolin-3-yl)acetamide]-4-methylbenzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and added with two Sodium tungstate (0.3g) was added dropwise to 30% hydrogen peroxide (10mL) in 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and then separated phase; the aqueous phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; The dichloromethane phase of indol-3-yl)acetamide]-4-methylbenzoate was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give methyl-3-[2-(1-methoxy-1H-indol-3-yl)acetamide]-4-methylbenzoate (500 mg) as a white solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.47 (1H, brs, NH-1), 8.39 (1H, s, H-2'), 7.68 (1H, d, J=8.0 Hz, 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'); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-anisole (0.81g) was added, DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude light reddish-brown oil 2-(1H-Indol-3-yl)-N-(2-methoxyphenyl)acetamide.

In the second step, 2-(1H-indol-3-yl)-N-(2-methoxyphenyl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, The reaction solution was refluxed at 60°C for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; To the organic phase, saturated brine (30 mL) was added and stirred for 10 min, and the phases were separated; the solvent was removed from the organic phase under reduced pressure at 50 °C to obtain a dark brown oily crude product 2-(indolin-3-yl)-N-(2-methoxy phenyl)acetamide.

In the third step, 2-(indolin-3-yl)-N-(2-methoxyphenyl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate was added. (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; the aqueous phase Extract with dichloromethane (100 mL×2), and combine the organic phases; add saturated brine (200 mL) to the organic phase to wash, and separate the phases; to obtain 2-(1-hydroxy-1H-indol-3-yl)-N- The dichloromethane phase of (2-methoxyphenyl)acetamide was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give 2-(1-methoxy-1H-indol-3-yl)-N-(2-methoxyphenyl)acetamide (654 mg) as an orange gum. ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.43 (1H, brs, NH-1), 8.33 (1H, d, J=7.6 Hz, 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'); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ169.5 (C -9), 149.1(C-2'), 133.4(C-7a), 129.1(C-1'), 124.7(C-3a), 124.2(C-2), 123.7(C-6'), 123.4 (C-6), 121.3(C-3'), 120.7(C-5), 120.13(C-5'), 120.09(C-4), 111.2(C-4'), 109.1(C-7) , 106.4(C-3), 66.3(C-10), 56.0(C-7'), 34.8(C-8); (+)-HR-ESIMS m/z 311.1397[M+H] ⁺ (calcd for C ₁₈ H ₁₉ N ₂ O ₃ , 311.1396).

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

In the first step, indole acetic acid (1.05 g) was weighed, added to dichloromethane (20 mL) for suspension and stirring, EDCI (1.27 g) was added at room temperature, stirred and dissolved; m-aminoanisole (0.81 g) was added, DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude light reddish-brown oil 2-(1H-Indol-3-yl)-N-(3-methoxyphenyl)acetamide.

In the second step, 2-(1H-indol-3-yl)-N-(3-methoxyphenyl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, The reaction solution was refluxed at 60°C for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; To the organic phase, saturated brine (30 mL) was added and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product 2-(indolin-3-yl)-N-(3-methoxy phenyl)acetamide.

In the third step, 2-(indolin-3-yl)-N-(3-methoxyphenyl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate was added. (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; the aqueous phase Extract with dichloromethane (100 mL×2), and combine the organic phases; add saturated brine (200 mL) to the organic phase to wash, and separate the phases; to obtain 2-(1-hydroxy-1H-indol-3-yl)-N- The dichloromethane phase of (3-methoxyphenyl)acetamide was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give 2-(1-methoxy-1H-indol-3-yl)-N-(3-methoxyphenyl)acetamide (643 mg) as a light brown gum. ¹ H NMR (400MHz, acetone-d ₆ ): δ 9.30 (1H, brs, NH-1), 7.66 (1H, d, J=8.0 Hz, 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'); ¹³ C NMR (400MHz, acetone-d ₆ ): δ 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 C ₁₈ H ₁₉ N ₂ O ₃ , 311.1396).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; p-aminoanisole (0.81g) was added, DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude light reddish-brown oil 2-(1H-Indol-3-yl)-N-(4-methoxyphenyl)acetamide.

In the second step, 2-(1H-indol-3-yl)-N-(4-methoxyphenyl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, The reaction solution was refluxed at 60°C for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; The organic phase was added with saturated brine (30 mL), stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product 2-(indolin-3-yl)-N-(4-methoxy phenyl)acetamide.

In the third step, 2-(indolin-3-yl)-N-(4-methoxyphenyl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate was added. (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; the aqueous phase Extract with dichloromethane (100 mL×2), and combine the organic phases; add saturated brine (200 mL) to the organic phase to wash, and separate the phases; to obtain 2-(1-hydroxy-1H-indol-3-yl)-N- The dichloromethane phase of (4-methoxyphenyl)acetamide was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give 2-(1-methoxy-1H-indol-3-yl)-N-(4-methoxyphenyl)acetamide (612 mg) as a pale yellow solid. ¹ H NMR (400 MHz, acetone-d ₆ ): δ 9.02 (1H, brs, NH-1), 7.66 (1H, d, J=8.0 Hz, H-4), 7.52 (2H, d, J=8.8 Hz,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'); ¹³ C NMR (400MHz, acetone-d ₆ ): δ 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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-methyl-4-aminoanisole ( 0.9g), DMAP (0.15g), stirred for 3h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; the organic phase was removed under reduced pressure at 40°C to obtain a Crude 2-(1H-indol-3-yl)-N-(4-methoxy-2-methylphenyl)acetamide as reddish brown oil.

In the second step, 2-(1H-indol-3-yl)-N-(4-methoxy-2-methylphenyl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane was added (1.74g), refluxed at 60°C for 3h; the solvent was recovered from the reaction solution, ethyl acetate (30mL) was added, saturated aqueous sodium bicarbonate solution (30mL), stirred rapidly for 15min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30mL) , the phases were separated; the organic phases were combined, saturated brine (30 mL) was added and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product 2-(indolin-3-yl)-N- (4-Methoxy-2-methylphenyl)acetamide.

In the third step, 2-(indolin-3-yl)-N-(4-methoxy-2-methylphenyl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and added Sodium tungstate dihydrate (0.3g), 30% hydrogen peroxide (10mL) was added dropwise in 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, and the mixture was rapidly stirred for 10min. Phase separation; the aqueous phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; yl)-N-(4-methoxy-2-methylphenyl)acetamide in dichloromethane was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give 2-(1-methoxy-1H-indol-3-yl)-N-(4-methoxy-2-methylphenyl)acetamide (408 mg) as an off-white solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 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'); ¹³ C NMR (400MHz, acetone-d ₆ ): δ169.7(C-9), 157.9(C-4'), 133.7(C-1'), 133.4(C-7a), 130.5(C-2') ,126.5(C-2),124.8(C-3a),123.6(C-6'),123.3(C-6),120.5(C-5),120.2(C-4),116.2(C-5' ), 111.8(C-3'), 109.0(C-7), 106.8(C-3), 66.2(C-10), 55.5(C-8'), 34.1(C-8), 18.1(C- 7'); (+)-HR-ESIMS m/z 325.1554 [M+H] ⁺ (calcd for C ₁₉ H ₂₁ N ₂ O ₃ , 325.1547).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain N-(2-chlorophenyl)-2-(1-hydroxy-1H-indole -3-yl)acetamide in dichloromethane was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give N-(2-chlorophenyl)-2-(1-methoxy-1H-indol-3-yl)acetamide (414 mg) as a tan solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.46 (1H, brs, NH-1), 8.29 (1H, d, J=8.0 Hz, 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); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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-ESIMS m/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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; m-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (3-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(3-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(3-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain N-(3-chlorophenyl)-2-(1-hydroxy-1H-indole -3-yl)acetamide in dichloromethane was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give N-(3-chlorophenyl)-2-(1-methoxy-1H-indol-3-yl)acetamide (436 mg) as an orange gum. ¹ H NMR (400MHz, acetone-d ₆ ): δ 9.33 (1H, brs, NH-1), 7.89 (1H, s, H-2'), 7.64 (1H, d, J=8.0 Hz, 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); ¹³ C NMR (400MHz, acetone-d ₆ ): δ170.3(C-9), 141.7(C-1'), 134.6(C-3'), 133.3(C-7a), 130.9(C-2'), 124.8(C-3a), 123.9(C -2), 123.5(C-6'), 123.2(C-6), 120.5(C-5), 120.1(C-5'), 119.9(C-4'), 118.3(C-4), 109.0 (C-7), 106.2(C-3), 66.2(C-10), 34.6(C-8); (+)-HR-ESIMS m/z 315.0897[M+H] ⁺ (calcd for C ₁₇ H _16ClN2O2 , _{315.0895 )} .

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; p-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (4-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(4-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(4-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(4-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain N-(4-chlorophenyl)-2-(1-hydroxy-1H-indole -3-yl)acetamide in dichloromethane was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give N-(4-chlorophenyl)-2-(1-methoxy-1H-indol-3-yl)acetamide (384 mg) as a pale yellow solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 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, ^13C NMR (400MHz, acetone-d ₆ ): δ170.1(C-9), 139.2(C-1'), 133.3(C-7a), 129.3(C-2', 6'), 128.4(C-4 '), 124.8(C-3a), 123.5(C-6), 123.2(C-2), 121.6(C-3', 5'), 120.5(C-5), 120.1(C-4), 109.0 (C-7), 106.3(C-3), 66.2(C-10), 34.6(C-8); (+)-HR-ESIMS m/z315.0905[M+H] ⁺ (calcd for C ₁₇ H ₁₆ ClN ₂ O ₂ , 315.0895).

Example 23: Preparation of 2-(1-methoxy-1H-indol-3-yl)-N-p-methylphenylacetamide

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 4-methylaniline (0.71g) was added, DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating the phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating the phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude yellow oil 2- (1H-Indol-3-yl)-N-p-methylphenylacetamide.

In the second step, 2-(1H-indol-3-yl)-N-p-methylphenylacetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the reaction was carried out at 60°C under reflux. 3h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined and added Saturated brine (30 mL) was stirred for 10 min, and the phases were separated; the solvent was removed from the organic phase under reduced pressure at 50° C. to obtain crude 2-(indolin-3-yl)-N-p-methylphenylacetamide as a dark brown oily product.

In the third step, 2-(indolin-3-yl)-N-p-methylphenylacetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g) was added. , 30% hydrogen peroxide (10mL) was added dropwise in 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; (100mL×2) extraction, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; The dichloromethane phase of acetamide was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give 2-(1-methoxy-1H-indol-3-yl)-N-p-methylphenylacetamide (490 mg) as a yellow solid. ¹ H NMR (400 MHz, acetone-d ₆ ): δ 9.11 (1H, brs, NH-1), 7.66 (1H, d, J=8.0 Hz, H-4), 7.51 (2H, d, J=8.4 Hz,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'); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 C ₁₈ H ₁₉ N ₂ O ₂ , 295.1441).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3,4-dimethylaniline (0.8g) was added , DMAP (0.15g), stirred at room temperature for 3 hours; added 2N hydrochloric acid, stirred rapidly for 10 minutes, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 minutes, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a yellow oil. Crude N-(3,4-Dimethylphenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(3,4-dimethylphenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added. ), refluxed at 60 °C for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated. ; Combine the organic phases, add saturated brine (30 mL), stir for 10 min, and separate the phases; the organic phase is 50 °C and the solvent is removed under reduced pressure to obtain a dark brown oily crude product N-(3,4-dimethylphenyl)-2-( indolin-3-yl)acetamide.

In the third step, N-(3,4-dimethylphenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungsten dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; methylene chloride (200mL) and water (200mL) were added, and the phases were rapidly stirred for 10min, and the phases were separated; The aqueous phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; The dichloromethane phase of 1-hydroxy-1H-indol-3-yl)acetamide was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give N-(3,4-dimethylphenyl)-2-(1-methoxy-1H-indol-3-yl)acetamide (497 mg) as a light brown gum. ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.99 (1H, brs, NH-1), 7.66 (1H, d, J=8.0 Hz, 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'); ¹³ C NMR (400MHz, acetone- d ₆ ): δ169.6(C-9), 138.1(C-1'), 137.3(C-3'), 133.4(C-7a), 132.0(C-4'), 130.4(C-5') ), 124.9(C-3a), 123.4(C-2), 123.2(C-6), 121.4(C-2'), 120.4(C-5), 120.2(C-6'), 117.7(C- 4), 108.9(C-7), 106.7(C-3), 66.1(C-10), 34.6(C-8), 19.9(C-7'), 19.1(C-8'); (+) -HR-ESIMS m/z 309.1601 [M+H] ⁺ (calcd for C ₁₉ H ₂₀ N ₂ O ₂ , 309.1598).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3,5-dimethylaniline (0.8g) was added , DMAP (0.15g), stirred at room temperature for 3 hours; added 2N hydrochloric acid, stirred rapidly for 10 minutes, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 minutes, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a yellow oil. Crude N-(3,5-Dimethylphenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(3,5-dimethylphenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added. ), refluxed at 60 °C for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated. ; Combine the organic phases, add saturated brine (30 mL), stir for 10 min, and separate the phases; the organic phase is 50 ° C and the solvent is removed under reduced pressure to obtain a dark brown oily crude product N-(3,5-dimethylphenyl)-2-( indolin-3-yl)acetamide.

In the third step, N-(3,5-dimethylphenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and tungsten dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; methylene chloride (200mL) and water (200mL) were added, and the phases were rapidly stirred for 10min, and the phases were separated; The aqueous phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain N-(3,5-dimethylphenyl)-2-( The dichloromethane phase of 1-hydroxy-1H-indol-3-yl)acetamide was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give N-(3,5-dimethylphenyl)-2-(1-methoxy-1H-indol-3-yl)acetamide (553 mg) as an off-white solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 9.00 (1H, brs, NH-1), 7.66 (1H, d, J=8.0 Hz, 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'); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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/z 309.1608 [M+H] ⁺ (calcd for C ₁₉ H ₂₀ N ₂ O ₂ , 309.1598).

Example 26: Preparation of 2-(1-methoxy-1H-indol-3-yl)-N-o-methylphenylacetamide

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 2-methylaniline (0.71g) was added, DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating the phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating the phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude yellow oil 2- (1H-Indol-3-yl)-N-o-methylphenylacetamide.

In the second step, 2-(1H-indol-3-yl)-N-o-methylphenylacetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the reaction was carried out at 60°C under reflux 3h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined and added Saturated brine (30 mL) was stirred for 10 min, and the phases were separated; the solvent was removed from the organic phase under reduced pressure at 50° C. to obtain crude 2-(indolin-3-yl)-N-o-methylphenylacetamide as a dark brown oily product.

In the third step, 2-(indolin-3-yl)-N-o-methylphenylacetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g) was added. , 30% hydrogen peroxide (10mL) was added dropwise in 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; (100mL×2) extraction, the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; to obtain 2-(1-hydroxy-1H-indol-3-yl)-N-o-toluene The dichloromethane phase of acetamide was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give 2-(1-methoxy-1H-indol-3-yl)-N-o-methylphenylacetamide (354 mg) as a white solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.33 (1H, brs, NH-1), 7.72 (1H, d, J=8.0 Hz, 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'); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 C ₁₈ H ₁₉ N ₂ O ₂ , 295.1441).

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

In the first step, indole acetic acid (1.05 g) was weighed, added to dichloromethane (20 mL) for suspension and stirring, EDCI (1.27 g) was added at room temperature, stirred and dissolved; 2-ethylaniline (0.8 g) was added, DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating the phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating the phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude yellow oil 2- (1H-Indol-3-yl)-N-o-ethylphenylacetamide.

In the second step, 2-(1H-indol-3-yl)-N-o-ethylphenylacetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the reaction was carried out at 60°C under reflux. 3h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined and added Saturated brine (30 mL) was stirred for 10 min, and the phases were separated; the solvent was removed from the organic phase under reduced pressure at 50° C. to obtain a dark brown oily crude product, 2-(indolin-3-yl)-N-o-ethylphenylacetamide.

In the third step, 2-(indolin-3-yl)-N-o-ethylphenylacetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate (0.3 g) was added. , 30% hydrogen peroxide (10mL) was added dropwise in 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; (100mL×2) extraction, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; to obtain 2-(1-hydroxy-1H-indol-3-yl)-N-o-ethylbenzene The dichloromethane phase of acetamide was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give 2-(1-methoxy-1H-indol-3-yl)-N-o-ethylphenylacetamide (513 mg) as an off-white solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.20 (1H, brs, NH-1), 7.76 (1H, d, J=8.0 Hz, 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'); ¹³ C NMR (400MHz, acetone-d ₆ ): δ169.8(C-9), 136.8(C-1'), 136.4(C-2'), 133.4(C-7a), 129.4(C-5'), 126.9(C-3') , 125.7(C-4'), 124.7(C-3a), 124.4(C-2), 123.7(C-6'), 123.5(C-6), 120.7(C-5), 120.1(C-4 ), 109.1(C-7), 106.5(C-3), 66.3(C-10), 34.4(C-8), 24.7(C-7'), 14.3(C-8'); (+)- HR-ESIMS m/z 309.1601 [ _{M +} H] ⁺ ( _calcd for _C19H20N2O2 , 309.1598).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-fluoroaniline (0.73g), DMAP (0.15g) were added. ), stirred at room temperature for 3 h; added 2N hydrochloric acid, quickly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a reddish brown oily crude product N-( 2-Fluorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-fluorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-fluorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-fluorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; -3-yl)acetamide in dichloromethane was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give N-(2-fluorophenyl)-2-(1-methoxy-1H-indol-3-yl)acetamide (330 mg) as off-white crystals. ¹ H NMR (400 MHz, acetone-d ₆ ): δ 8.83 (1H, brs, NH-1), 8.22 (1H, t, J=8.0 Hz, 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); ¹³ C NMR (400MHz, acetone-d ₆ ): δ170.1(C-9), 133.4(C-7a), 125.2(C-1'), 125.14(C-3'), 125.09(C-2'), 124.8(C- 3a), 123.5(C-2), 123.4(C-5'), 123.3(C-6), 120.5(C-5), 120.1(C-4), 115.8(C-4'), 115.6(C -6'), 109.0(C-7), 106.3(C-3), 66.2(C-10), 34.3(C-8); (+)-HR-ESIMS m/z 299.1193[M+H] ⁺ (calcd for C ₁₇ H ₁₆ FN ₂ O ₂ , 299.119).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-bromoaniline (1.2g), DMAP (0.15g) were added. ), stirred at room temperature for 3 h; added 2N hydrochloric acid, quickly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a reddish brown oily crude product N-( 2-Bromophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-bromophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-bromophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-bromophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated to obtain N-(2-bromophenyl)-2-(1-hydroxy-1H-indole) -3-yl)acetamide in dichloromethane was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give N-(2-bromophenyl)-2-(1-methoxy-1H-indol-3-yl)acetamide (240 mg) as a yellow solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.32 (1H, brs, NH-1), 8.27 (1H, d, J=8.0 Hz, 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); ¹³ C NMR (400MHz, acetone-d ₆ ): δ169.9(C-9), 137.2(C-1'), 133.4(C-7a), 133.2(C-5'), 129.0(C-3'), 126.0(C-6'), 124.7(C-3a), 124.0(C-2), 123.6(C-6), 122.9(C-4'), 120.9(C-5), 120.0(C-4), 114.2(C-2') , 109.1(C-7), 105.6(C-3), 66.4(C-10), 34.6(C-8); (+)-HR-ESIMS m/z359.0403[M+H] ⁺ (calcd forC _{17H15BrN2O2 , 359.039 )} .

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-iodoaniline (1.45g), DMAP (0.15g) were added. ), stirred at room temperature for 3 h; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a brown oily crude product N-(2 -iodophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-iodophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-iodophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-iodophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; -3-yl)acetamide in dichloromethane was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give N-(2-iodophenyl)-2-(1-methoxy-1H-indol-3-yl)acetamide (252 mg) as a light brown solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 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); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 C ₁₇ H ₁₆ IN ₂ O ₂ , 407.0251).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; p-nitroaniline (0.91g), DMAP (0.15g) were added. g), stirred at room temperature for 3 h; added 2N hydrochloric acid, quickly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40°C to obtain a brown oily crude product 2-( 1H-Indol-3-yl)-N-(4-nitrophenyl)acetamide.

In the second step, 2-(1H-indol-3-yl)-N-(4-nitrophenyl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; Phase, saturated brine (30 mL) was added and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product 2-(indolin-3-yl)-N-(4-nitrobenzene base) acetamide.

In the third step, 2-(indolin-3-yl)-N-(4-nitrophenyl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; The dichloromethane phase of 4-nitrophenyl)acetamide was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give 2-(1-methoxy-1H-indol-3-yl)-N-(4-nitrophenyl)acetamide (506 mg) as a yellow solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 9.76 (1H, brs, NH-1), 8.17 (2H, d, J=9.2 Hz, 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); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 C ₁₇ H ₁₆ N ₃ O ₄ , 326.1135).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3,5-dimethoxyaniline (1g) was added , DMAP (0.15g), stirred for 3h at room temperature; added 2N hydrochloric acid, quickly stirred for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; the organic phase was removed under reduced pressure at 40°C to obtain a light reddish brown Crude oil N-(3,5-dimethoxyphenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(3,5-dimethoxyphenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g g), refluxed for 3 h at 60 °C; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate solution (30 mL), stirred rapidly for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), separated The organic phases were combined, and saturated brine (30 mL) was added and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3,5-dimethoxyphenyl)-2 -(Indolin-3-yl)acetamide.

In the third step, N-(3,5-dimethoxyphenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and dihydrate was added. Sodium tungstate (0.3g) was added dropwise with 30% hydrogen peroxide (10mL) within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; methylene chloride (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated. The aqueous phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain N-(3,5-dimethoxyphenyl)-2 The dichloromethane phase of -(1-hydroxy-1H-indol-3-yl)acetamide was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give N-(3,5-dimethoxyphenyl)-2-(1-methoxy-1H-indol-3-yl)acetamide (497 mg) as an off-white solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 9.19 (1H, brs, NH-1), 7.65 (1H, d, J=8.0 Hz, 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'); ¹³ C NMR (400MHz, acetone-d ₆ ): δ 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 C ₁₉ H ₂₁ N ₂ O ₄ , 341.1496).

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

In the first step, indole acetic acid (1.05 g) was weighed, added to dichloromethane (20 mL) to suspend and stir, EDCI (1.27 g) was added at room temperature, and stirred to dissolve; 3,4,5-trimethoxyaniline (1.21 g) was added. g), DMAP (0.15g), stirred and reacted at room temperature for 3h; added 2N hydrochloric acid, rapidly stirred for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; Crude 2-(1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide as reddish brown oil.

In the second step, 2-(1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane ( 1.74g), refluxed at 60°C for 3h; the solvent was recovered from the reaction solution, ethyl acetate (30mL) was added, saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30mL), The phases were separated; the organic phases were combined, saturated brine (30 mL) was added and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50°C to obtain a dark brown oily crude product 2-(indolin-3-yl)-N-( 3,4,5-Trimethoxyphenyl)acetamide.

In the third step, 2-(indolin-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and added with two Sodium tungstate (0.3g) was added dropwise to 30% hydrogen peroxide (10mL) in 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and then separated phase; the aqueous phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain 2-(1-hydroxy-1H-indol-3-yl )-N-(3,4,5-trimethoxyphenyl)acetamide in dichloromethane was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give 2-(1-methoxy-1H-indol-3-yl)-N-(3,4,5-trimethoxyphenyl)acetamide (230 mg) as an off-white solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 9.12 (1H, brs, NH-1), 7.65 (1H, d, J=8.0 Hz, 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'); ¹³ C NMR (400MHz, acetone-d ₆ ): δ169.8 (C-9), 154.2 (C-3', 5'), 136.4 (C- 4'), 133.4(C-7a), 124.9(C-3a), 123.4(C-2), 123.2(C-6), 120.4(C-4), 120.2(C-5), 109.0(C- 7), 106.6(C-3), 98.0(C-2', 6'), 66.2(C-10), 60.5(C-8'), 56.2(C-7', 9'), 34.7(C -8); (+)-HR-ESIMS m/z _371.1613 [ _{M +} H] ⁺ (calcd for _C20H23N2O5 , 371.1601).

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

In the first step, indole acetic acid (1.05 g) was weighed, added to dichloromethane (20 mL) for suspension and stirring, EDCI (1.27 g) was added at room temperature, and stirred to dissolve; 3-aminopyridine (0.62 g), DMAP (0.15 g) were added. g), stirred at room temperature for 3 h; added 2N hydrochloric acid, quickly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40°C to obtain a brown oily crude product 2-( 1H-Indol-3-yl)-N-(pyridin-3-yl)acetamide.

In the second step, 2-(1H-indol-3-yl)-N-(pyridin-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product 2-(indolin-3-yl)-N-(pyridin-3-yl) Acetamide.

In the third step, 2-(indolin-3-yl)-N-(pyridin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain 2-(1-hydroxy-1H-indol-3-yl)-N-(pyridine -3-yl)acetamide in dichloromethane was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, and ethyl acetate-petroleum ether (1:3 ) to give 2-(1-methoxy-1H-indol-3-yl)-N-(pyridin-3-yl)acetamide (156 mg) as a dark brown solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 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); ¹³ C NMR (400MHz, acetone-d ₆ ): δ170.5 (C -9), 145.2(C-2'), 141.9(C-6'), 136.9(C-3'), 133.3(C-7a), 127.0(C-4'), 124.8(C-3a), 124.2(C-2), 123.5(C-5'), 123.2(C-3), 120.5(C-5), 120.1(C-4), 109.0(C-7), 106.1(C-3), 66.2 (C-10), 34.4 (C-8); (+)-HR-ESIMS m/z _282.1242 [ _M +H] ⁺ ( _calcd for C16H16N3O2, _282.1237 ).

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

In the first step, indole acetic acid (1.05 g) was weighed, added to dichloromethane (20 mL) for suspension and stirring, EDCI (1.27 g) was added at room temperature, and stirred to dissolve; 4-aminopyridine (0.62 g), DMAP (0.15 g) were added. g), stirred at room temperature for 3 h; added 2N hydrochloric acid, quickly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40°C to obtain a brown oily crude product 2-( 1H-Indol-3-yl)-N-(pyridin-4-yl)acetamide.

In the second step, 2-(1H-indol-3-yl)-N-(pyridin-4-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60°C The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product 2-(indolin-3-yl)-N-(pyridin-4-yl) Acetamide.

In the third step, 2-(indolin-3-yl)-N-(pyridin-4-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain 2-(1-hydroxy-1H-indol-3-yl)-N-(pyridine -4-yl)acetamide in dichloromethane was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, and ethyl acetate-petroleum ether (1:3 ) to give 2-(1-methoxy-1H-indol-3-yl)-N-(pyridin-4-yl)acetamide (169 mg) as a dark brown solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 9.59 (1H, brs, NH-1), 8.39 (2H, d, J=5.6 Hz, 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); ¹³ C NMR (400MHz, acetone-d ₆ ): δ 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 for C ₁₆ H ₁₆ N ₃ O ₂ , 282.1237).

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

In the first step, indole acetic acid (1.05 g) was weighed, added to dichloromethane (20 mL) for suspension and stirring, EDCI (1.27 g) was added at room temperature, and stirred to dissolve; 2-aminopyridine (0.62 g), DMAP (0.15 g) were added. g), stirred at room temperature for 3 h; added 2N hydrochloric acid, quickly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40°C to obtain a brown oily crude product 2-( 1H-Indol-3-yl)-N-(pyridin-2-yl)acetamide.

In the second step, 2-(1H-indol-3-yl)-N-(pyridin-2-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product 2-(indolin-3-yl)-N-(pyridin-2-yl) Acetamide.

In the third step, 2-(indolin-3-yl)-N-(pyridin-2-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain 2-(1-hydroxy-1H-indol-3-yl)-N-(pyridine -2-yl)acetamide in dichloromethane was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, and ethyl acetate-petroleum ether (1:3 ) to give 2-(1-methoxy-1H-indol-3-yl)-N-(pyridin-2-yl)acetamide (173 mg) as a dark brown solid. ¹ H NMR (300MHz, acetone-d ₆ ): δ 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); ¹³ C NMR (300 MHz, acetone-d ₆ ): δ 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 for C ₁₆ H ₁₆ N ₃ O ₂ , 282.1237).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phases were extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain N-(3-chloropyridin-4-yl)-2-(1- The dichloromethane phase of hydroxy-1H-indol-3-yl)acetamide was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give N-(3-chloropyridin-4-yl)-2-(1-methoxy-1H-indol-3-yl)acetamide (340 mg) as a brown solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 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); ¹³ C NMR (400MHz, acetone-d ₆ ): δ170.9(C-9), 149.9(C-2'), 149.8(C-6'), 142.5(C-4'), 133.3(C-7a) ,124.5(C-3a),123.9(C-2),123.6(C-3),120.9(C-5),120.2(C-3'),119.9(C-4),115.1(C-5' ), 109.2(C-7), 105.2(C-3), 66.4(C-10), 34.6(C-8); (+)-HR-ESIMS m/z316.086[M+H] ⁺ (calcd for C ₁₆ H ₁₅ ClN ₃ O ₂ , 316.0847).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-bromo-4-aminopyridine (1.14g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; The crude N-(3-bromopyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a reddish-brown oil.

In the second step, N-(3-bromopyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-bromopyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-bromopyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phases were extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; The dichloromethane phase of hydroxy-1H-indol-3-yl)acetamide was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give N-(3-bromopyridin-4-yl)-2-(1-methoxy-1H-indol-3-yl)acetamide (319 mg) as a brown solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 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-d ₆ ): δ170.8(C-9), 152.5(C-2'), 150.3(C-6'), 143.5(C-4'), 133.4(C-7a), 124.5 (C-3a), 124.1(C-2), 123.7(C-3), 121.0(C-5), 119.9(C-3'), 115.3(C-4), 110.9(C-5'), 109.2(C-7), 104.9(C-3), 66.5(C-10), 34.7(C-8); (+)-HR-ESIMS m/z 360.0345[M+H] ⁺ (calcd forC ₁₆ H _15BrN3O2 , _{360.0342 )} .

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

In the first step, indole propionic acid (1.13 g) was weighed, added to dichloromethane (20 mL) for suspension and stirring, EDCI (1.27 g) was added at room temperature, stirred and dissolved; methyl anthranilate (1 g) was added, DMAP (0.15g), stirred for 3h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; the organic phase was decompressed at 40°C to remove the solvent to obtain a light reddish-brown oil. Crude methyl-2-[3-(1H-indol-3-yl)propanamide]benzoate.

In the second step, methyl-2-[3-(1H-indol-3-yl)propionamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL) and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product methyl-2-[3-(indolin-3-yl)propanamide] Parabens.

In the third step, methyl-2-[3-(indolin-3-yl)propionamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain methyl-2-[3-(1-hydroxy-1H-indole-3- yl)propionamide]benzoate in dichloromethane was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give methyl-2-[3-(1-methoxy-1H-indol-3-yl)propanamide]benzoate (147 mg) as an orange gum. ¹ H NMR (400MHz, acetone-d ₆ ): δ 10.95 (1H, brs, NH-1), 8.72 (1H, d, J=8.8 Hz, 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=7.6 Hz, H-8a), 2.83 (2H, t, J=7.6 Hz, H-8); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 for C ₂₀ H ₂₁ N ₂ O ₄ , 353.1496).

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

In the first step, indolebutyric acid (1.22g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; methyl anthranilate (1g) was added, DMAP (0.15g), stirred for 3h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; the organic phase was decompressed at 40°C to remove the solvent to obtain a light reddish-brown oil. Crude methyl-2-[4-(1H-indol-3-yl)butanamide]benzoate.

In the second step, methyl-2-[4-(1H-indol-3-yl)butanamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL), stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product methyl-2-[4-(indolin-3-yl)butanamide] Parabens.

In the third step, methyl-2-[4-(indolin-3-yl)butanamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; to obtain methyl-2-[4-(1-hydroxy-1H-indole-3- The dichloromethane phase of benzoyl)butanamide]benzoate was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilane diazomethane n-hexane solution (10 mL), and the reaction was carried out in the dark at room temperature for 24 h; separated by silica gel column chromatography, using ethyl acetate-petroleum ether (1:5 ) to give methyl-2-[4-(1-methoxy-1H-indol-3-yl)butanamide]benzoate (102 mg) as a brown gum. ¹ H NMR (400MHz, acetone-d ₆ ): δ 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); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 C _21H23N2O4 , _{367.1652 ) .}

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

The first step is to weigh 5-methoxyindoleacetic acid (0.5g), add dichloromethane (20mL) to suspend and stir, add EDCI (0.52g) at room temperature, stir and dissolve; add methyl anthranilate ( 0.41g), DMAP (0.1g), stirred at room temperature for 3 hours; added 2N hydrochloric acid, rapidly stirred for 10 minutes, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 minutes, and separated the phases; the organic phase was removed under reduced pressure at 40° C. The solvent was obtained to obtain Crude methyl-2-[2-(5-methoxy-1H-indol-3-yl)acetamide]benzoate as a yellow oil.

In the second step, methyl-2-[2-(5-methoxy-1H-indol-3-yl)acetamide]benzoate was dissolved in trifluoroacetic acid (10 mL), and triethylsilane was added (0.7g), refluxed at 60°C for 3h; the solvent was recovered from the reaction solution, ethyl acetate (20mL) was added, saturated aqueous sodium bicarbonate solution (20mL), rapidly stirred for 15min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (20mL) , the phases were separated; the organic phases were combined, saturated brine (20 mL) was added and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product methyl-2-[2-(5-methoxyl) Indolin-3-yl)acetamide]benzoate.

In the third step, methyl-2-[2-(5-methoxyindolin-3-yl)acetamide]benzoate was dissolved in (25 mL) methanol, cooled to 15-20 °C, stirred, and added with two Sodium tungstate (0.15g) was added dropwise to 30% hydrogen peroxide (5mL) in 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (100mL) and water (100mL) were added, rapidly stirred for 10min, and then separated phase; the aqueous phase was extracted with dichloromethane (50 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (100 mL), and the phases were separated; to obtain methyl-2-[2-(1-hydroxy-5- The dichloromethane phase of methoxy-1H-indol-3-yl)acetamide]benzoate was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilanediazomethane n-hexane solution (5mL), and the reaction was carried out in the dark at room temperature for 24h; after separation by silica gel column chromatography, ethyl acetate-petroleum ether (1:5 ) to give methyl-2-[2-(1,5-dimethoxy-1H-indol-3-yl)acetamide]benzoate (40 mg) as a light brown gum. ¹ H NMR (400MHz, acetone-d ₆ ): δ 10.94 (1H, brs, NH-1), 8.75 (1H, d, J=8.4 Hz, 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'); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 forC _{20H20N2O5 , 369.1445 )} .

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

In the first step, 5-methoxyindoleacetic acid (0.5g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (0.52g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.41g) was added , DMAP (0.1 g), stirred at room temperature for 3 h; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a yellow oil. Crude N-(2-chlorophenyl)-2-(5-methoxy-1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(5-methoxy-1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane ( 0.7g), refluxed at 60°C for 3h; the reaction solution was recovered solvent, added with ethyl acetate (20mL), saturated aqueous sodium bicarbonate solution (20mL), rapidly stirred for 15min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (20mL), The phases were separated; the organic phases were combined, saturated brine (20 mL) was added and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(5- Methoxyindolin-3-yl)acetamide.

In the third step, N-(2-chlorophenyl)-2-(5-methoxyindolin-3-yl)acetamide was dissolved in (25 mL) methanol, cooled to 15-20 °C and stirred, and dihydrate was added. Sodium tungstate (0.15g) was added dropwise with 30% hydrogen peroxide (5mL) in 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (100mL) and water (100mL) were added, rapidly stirred for 10min, and the phases were separated. The aqueous phase was extracted with dichloromethane (50 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (100 mL), and the phases were separated; -5-Methoxy-1H-indol-3-yl)acetamide in dichloromethane was set aside for use.

In the fourth step, the organic phase obtained in the third step was added with 2N trimethylsilanediazomethane n-hexane solution (5mL), and the reaction was carried out in the dark at room temperature for 24h; after separation by silica gel column chromatography, ethyl acetate-petroleum ether (1:5 ) to give N-(2-chlorophenyl)-2-(1,5-dimethoxy-1H-indol-3-yl)acetamide (88 mg) as a light brown solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 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); ¹³ C NMR (400MHz, acetone-d ₆ ): δ170 .0(C-9), 155.7(C-5), 136.1(C-7a), 129.9(C-6'), 128.8(C-1'), 128.4(C-6), 125.5(C-3 '), 125.3(C-3a), 124.5(C-2), 122.8(C-4'), 113.9(C-4), 110.6(C-2'), 110.1(C-7), 105.3(C -3), 101.7(C-5'), 66.3(C-10), 55.9(C-5a), 34.6(C-8); (+)-HR-ESIMS m/z 345.1003[M+H] ⁺ ( _calcd for _C18H18ClN2O3 , _{345.1 )} .

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

The first step was to weigh indoleacetic acid (1.05g), add dichloromethane (20mL) to suspend and stir, add EDCI (1.27g) at room temperature, stir and dissolve; add methyl anthranilate (1g), DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude light reddish-brown oil Methyl-2-[2-(1H-indol-3-yl)acetamide]benzoate.

In the second step, methyl-2-[2-(1H-indol-3-yl)acetamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL) and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product methyl-2-[2-(indolin-3-yl)acetamide] Parabens.

In the third step, methyl-2-[2-(indolin-3-yl)acetamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain methyl-2-[2-(1-hydroxy-1H]. -Indol-3-yl)acetamide]benzoate crude.

The fourth step, methyl-2-[2-(1-hydroxy-1H-indol-3-yl)acetamide]benzoate was added to dry DMF (5mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g g), bromoethane (0.98g), stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), rapidly stirred for 10min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25mL×2) , combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a light pink gum yl-2-[2-(1-ethoxy-1H-indol-3-yl)acetamide]benzoate (510 mg); ¹ H NMR (400 MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (400MHz, acetone-d ₆ ): δ170.2(C-9), 168.0(C-7'), 141.7(C-2'), 134.4 (C-4'), 133.5(C-7a), 130.9(C-6'), 124.4(C-2), 124.1(C-3a), 122.6(C-5'), 122.5(C-6) ,120.0(C-3'),119.9(C-4),119.1(C-5),115.4(C-1'),108.7(C-7),104.2(C-3),74.3(C-1 ”), 51.9(C-8’), 35.1(C-8), 13.6(C-2”); (+)-HR-ESIMS m/z 353.1502[M+H] ⁺ (calcd for C ₂₀ H ₂₁ N ₂ O ₄ , 353.1496).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), ethyl bromide (0.98g), stirred for 2h at room temperature; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25mL×2), The organic phases were combined, saturated brine (50 mL) was added, rapidly stirred for 10 min, and the phases were separated; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a pink solid N-(2- Chlorophenyl)-2-(1-ethoxy-1H-indol-3-yl)acetamide (498 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (400MHz, acetone-d ₆ ) : δ169.9(C-9), 136.0(C-1'), 134.0(C-7a), 129.8(C-5'), 125.5(C-3'), 124.7(C-2), 124.5( C-3a), 123.4(C-6, 4'), 122.8(C-2', 6'), 120.7(C-5), 119.9(C-4), 109.3(C-7), 105.4(C -3), 74.7(C-1"), 34.5(C-8), 14.1(C-2"); (+)-HR-ESIMS m/z 329.106[M+H] ⁺ (calcd for C ₁₈ H _18ClN2O2 , _{329.1051 )} .

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

The first step was to weigh indoleacetic acid (1.05g), add dichloromethane (20mL) to suspend and stir, add EDCI (1.27g) at room temperature, stir and dissolve; add methyl anthranilate (1g), DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude light reddish-brown oil Methyl-2-[2-(1H-indol-3-yl)acetamide]benzoate.

In the second step, methyl-2-[2-(1H-indol-3-yl)acetamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL) and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product methyl-2-[2-(indolin-3-yl)acetamide] Parabens.

In the third step, methyl-2-[2-(indolin-3-yl)acetamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain methyl-2-[2-(1-hydroxy-1H]. -Indol-3-yl)acetamide]benzoate crude.

The fourth step, methyl-2-[2-(1-hydroxy-1H-indol-3-yl)acetamide]benzoate was added to dry DMF (5mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g g), bromopropane (1.1 g), stirred at room temperature for 2 h; added ethyl acetate (50 mL) and water (50 mL) to the reaction solution, stirred rapidly for 10 min, and separated the phases; the aqueous phase was extracted with ethyl acetate (25 mL×2), The organic phases were combined, saturated brine (50 mL) was added, rapidly stirred for 10 min, and the phases were separated; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain light pink solid methyl-2 -[2-(1-Propoxy-1H-indol-3-yl)acetamide]benzoate (523 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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=7.6 Hz,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=7.6 Hz, H-3"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ170.8(C-9), 168.6(C-7'), 142.3(C-2'), 135.0(C-4'), 133.9(C-7a), 131.5(C-6'), 124.9(C-2), 124.7(C-3a), 123.2(C-5'), 123.1(C-6), 120.6(C-3'), 120.5(C-4), 119.7(C-5) , 116.0(C-1'), 109.2(C-7), 104.9(C-3), 80.8(C-1"), 52.5(C-8'), 35.7(C-8), 22.3(C- 2"), 10.6 (C-3"); (+)-HR-ESIMS m/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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), bromopropane (1.1 g), and stirred at room temperature for 2 h; the reaction solution was added with ethyl acetate (50 mL) and water (50 mL), stirred rapidly for 10 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25 mL×2) and combined To the organic phase, saturated brine (50 mL) was added, rapidly stirred for 10 min, and the phases were separated; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a pink solid N-(2-chloro) Phenyl)-2-(1-propoxy-1H-indol-3-yl)acetamide (511 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (400MHz, acetone-d ₆ ): δ169.9(C-9), 136.1(C-1'), 133.9(C-7a), 129.9(C-5'), 128.3(C-3'), 125.5(C-3a,4), 124.6(C-2), 123.5(C-6,2'), 122.8(C-6'), 120.7(C-5), 119.9 (C-4), 109.3(C-7), 105.5(C-3), 80.7(C-1"), 34.6(C-8), 22.3(C-2"), 10.5(C-3") ; (+)-HR-ESIMS m/z 343.1221 [ _M +H] ⁺ ( _calcd for _C19H20ClN2O2 , _343.1208 ).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), bromopropane (1.1g), the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2) Extracted, combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a white solid N-( 3-Chloropyridin-4-yl)-2-(1-propoxy-1H-indol-3-yl)acetamide (445 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 C ₁₈ H _19ClN3O2 , _{344.116 )} .

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-fluoro-4-aminopyridine (0.9g) was added , DMAP (0.15g), stirred for 3h at room temperature; added water (10mL), stirred rapidly for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; Crude N-(3-fluoropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was a reddish brown oil.

In the second step, N-(3-fluoropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-fluoropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-fluoropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phases were extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain crude N-(3-fluoropyridin-4-yl) )-2-(1-hydroxy-1H-indol-3-yl)acetamide.

The fourth step, N-(3-fluoropyridin-4-yl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), bromopropane (1.1g), the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2) Extraction, combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; (3-Fluoropyridin-4-yl)-2-(1-propoxy-1H-indol-3-yl)acetamide (203 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 9.29 (1H, brs, NH-1), 8.36 (2H, m, H-2', 6'), 8.28 (1H, d, J=6.4 Hz ,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"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 C ₁₈ H ₁₈ FN ₃ O ₂ , 327.1383).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 5-methyl-2-chloroaniline (0.93g) was added. ), DMAP (0.15g), stirred and reacted at room temperature for 3h; added 2N hydrochloric acid, quickly stirred for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; the organic phase was removed under reduced pressure at 40°C to obtain a light red Brown oil crude N-(2-chloro-5-methylphenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chloro-5-methylphenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g g), refluxed for 3 h at 60 °C; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate solution (30 mL), stirred rapidly for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), separated The organic phases were combined, and saturated brine (30 mL) was added and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chloro-5-methylphenyl)-2 -(Indolin-3-yl)acetamide.

In the third step, N-(2-chloro-5-methylphenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and dihydrate was added. Sodium tungstate (0.3g) was added dropwise with 30% hydrogen peroxide (10mL) within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; methylene chloride (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated. The aqueous phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the organic phase was removed under reduced pressure to obtain the crude N-(2-chloro-5- methylphenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide.

The fourth step, N-(2-chloro-5-methylphenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous Potassium carbonate (1.66g) and bromopropane (1.1g) were stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL× 2) Extraction, combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain an off-white solid N-(2-Chloro-5-methylphenyl)-2-(1-propoxy-1H-indol-3-yl)acetamide (519 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.37 (1H, brs, NH-1), 8.14 (1H, s, H-6'), 7.66 (1H, d, J=8.0 Hz, 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=7.6 Hz, H-3"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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( (+)-HR-ESIMS m/z 357.1365[M+H] ⁺ (calcd for C ₂₀ H ₂₁ ClN ₂ O ₂ , 357.1364).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, cooled to 0-5°C and stirred; oxalyl chloride (1.15g) was added within 5min, a drop of DMF was added dropwise, and the The reaction was carried out at room temperature for 1 h; the reaction solution was removed under reduced pressure at 25° C. to obtain 2-(1H-indol-3-yl)acetyl chloride.

In the second step, 2-(1H-indol-3-yl)acetyl chloride was added to dichloromethane (20 mL), stirred to dissolve, cooled to 0-5 °C and stirred; 2-trifluoromethylaniline (0.97 g) was added, Triethylamine (1.2g) was slowly raised to room temperature and reacted for 1h; 2N hydrochloric acid (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase, stirred for 10min, and the phases were separated; the organic phase was removed under reduced pressure at 40°C solvent to give crude 2-(1H-indol-3-yl)-N-[2-(trifluoromethyl)phenyl]acetamide as a light reddish brown oil.

In the third step, 2-(1H-indol-3-yl)-N-[2-(trifluoromethyl)phenyl]acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g g), refluxed for 3 h at 60 °C; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate solution (30 mL), stirred rapidly for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), separated The organic phases were combined, and saturated brine (30 mL) was added and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product 2-(indolin-3-yl)-N-[2 -(trifluoromethyl)phenyl]acetamide.

In the fourth step, 2-(indolin-3-yl)-N-[2-(trifluoromethyl)phenyl]acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and dihydrate was added. Sodium tungstate (0.3g) was added dropwise with 30% hydrogen peroxide (10mL) within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; methylene chloride (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated. The aqueous phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; Indol-3-yl)-N-[2-(trifluoromethyl)phenyl]acetamide.

The fifth step, 2-(1-hydroxy-1H-indol-3-yl)-N-[2-(trifluoromethyl)phenyl]acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous Potassium carbonate (1.66g) and bromopropane (1.1g) were stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL× 2) Extraction, combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted 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). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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=7.6 Hz, H-3"); ¹³ C NMR (600 MHz, acetone-d ₆ ): δ 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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), bromopropane (1.1 g), and stirred at room temperature for 2 h; the reaction solution was added with ethyl acetate (50 mL) and water (50 mL), stirred rapidly for 10 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25 mL×2) and combined To the organic phase, saturated brine (50 mL) was added, rapidly stirred for 10 min, and the phases were separated; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a white solid N-(2-chloro) Phenyl)-2-(1-propoxy-1H-indol-3-yl)acetamide (570 mg).

The fifth step, N-(2-chlorophenyl)-2-(1-propoxy-1H-indol-3-yl)acetamide (200mg) was added with dichloromethane (10mL) and stirred to dissolve, and the room temperature was 25 Stir at °C, add NCS (86 mg), stir at room temperature for 2 h, separate by silica gel column chromatography, and elute with ethyl acetate-petroleum ether (1:5) to obtain 2-(2-chloro-1-propoxy) as a yellow solid -1H-Indol-3-yl)-N-(2-chlorophenyl)acetamide (150 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.46 (1H, brs, NH-1), 8.22 (1H, d, J=8.0 Hz, 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=6.4 ^13C NMR (400MHz, acetone-d ₆ ): δ168.6(C-9), 136.0(C-1'), 133.9(C-7a), 129.9(C-5'), 128.4(C-3'), 125.8(C-3a,4'), 124.1(C-6), 124.0(C-2'), 123.6(C-2), 123.4(C-6'), 121.9(C-5), 119.7(C -4), 109.5(C-7), 104.2(C-3), 80.9(C-1"), 33.2(C-8), 22.3(C-2"), 10.6(C-3");( +)-HR-ESIMS m/z _377.0816 [M ₊ H] ⁺ ( _calcd for _{C19H19Cl2N2O2} , _377.0818 ).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), bromopropane (1.1g), the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2) Extracted, combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:3) to obtain a white solid N-( 3-Chloropyridin-4-yl)-2-(1-propoxy-1H-indol-3-yl)acetamide (445 mg).

The fifth step, N-(3-chloropyridin-4-yl)-2-(1-propoxy-1H-indol-3-yl)acetamide (200mg) was added with dichloromethane (10mL) and stirred to dissolve , stirred at room temperature 25°C, added NCS (86 mg), stirred at room temperature for 2 h, separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:3) to obtain a yellow solid 2-(2-chloro-1- Propoxy-1H-indol-3-yl)-N-(3-chloropyridin-4-yl)acetamide (102 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (400MHz, acetone-d ₆ ): δ169 .6(C-9), 150.0(C-2'), 149.8(C-6'), 142.5(C-4'), 133.8(C-7a), 124.1(C-6), 123.9(C- 2), 121.9(C-5), 119.6(C-4), 115.4(C-5'), 109.5(C-7), 103.6(C-3), 80.9(C-1"), 33.3(C -8), 22.2(C-2"), 10.6(C-3"); (+)-HR-ESIMS m/z 377.0712[M+H] ⁺ (calcd for C ₁₈ H ₁₈ Cl ₂ N ₃ O _2,377.0698 ).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), bromopropane (1.1 g), and stirred at room temperature for 2 h; the reaction solution was added with ethyl acetate (50 mL) and water (50 mL), stirred rapidly for 10 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25 mL×2) and combined To the organic phase, saturated brine (50 mL) was added, rapidly stirred for 10 min, and the phases were separated; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a white solid N-(2-chloro) Phenyl)-2-(1-propoxy-1H-indol-3-yl)acetamide (570 mg);

The fifth step, N-(2-chlorophenyl)-2-(1-propoxy-1H-indol-3-yl)acetamide (200mg) was added with dichloromethane (10mL) and stirred to dissolve, and the room temperature was 25 Stir at °C, add NBS (115 mg), stir at room temperature for 2 h, separate by silica gel column chromatography, and elute with ethyl acetate-petroleum ether (1:5) to obtain 2-(2-bromo-1-propoxyl) as a light yellow solid yl-1H-indol-3-yl)-N-(2-chlorophenyl)acetamide (192 mg). ¹ H NMR (300MHz, acetone-d ₆ ): δ 8.40 (1H, brs, NH-1), 8.25 (1H, d, J=8.1 Hz, 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=7.5 Hz, H-3"); ¹³ C NMR (300 MHz, acetone-d ₆ ): δ 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( (+)-HR-ESIMS m/z 421.0308[M+H] ⁺ (calcd for C _{19H18BrClN2O2 , 421.0313 )} .

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

The first step is to weigh 5-chloroindole (1.51g), add anhydrous ether (30mL) and stir to dissolve, cool down to 0～5℃ and stir, add oxalyl chloride (1.9g) dropwise within 5min, complete the dropwise addition, liter The reaction was stirred at room temperature 20-25°C for 2h. The reaction solution was removed under reduced pressure at 25°C to obtain 2-(5-chloro-1H-indol-3-yl)-2-carbonylacetyl chloride as a brown oil.

In the second step, 2-(5-chloro-1H-indol-3-yl)-2-carbonylacetyl chloride was added to dichloromethane (20 mL) and stirred to dissolve, and the temperature was cooled to 0-5 °C and stirred. 3-Chloro-4-aminopyridine (1.28g) and triethylamine (1.5g) were added, and the mixture was slowly raised to room temperature for reaction for 2h. Cool to 0～5℃, stir for 30min, filter, wash the filter cake with dichloromethane (5mL); dry with air at 40℃ to obtain light yellow solid 2-(5-chloro-1H-indol-3-yl)-N- (3-Chloropyridin-4-yl)-2-carbonylacetamide (2.0 g).

The third step, 2-(5-chloro-1H-indol-3-yl)-N-(3-chloropyridin-4-yl)-2-carbonylacetamide was added with methanol (20 mL) and stirred to dissolve, and the temperature was lowered to 10 Stir at ~15°C, add sodium borohydride (1 g), slowly warm to room temperature and react for 30 min. The solvent was removed under reduced pressure at 30°C, ethyl acetate (20 mL) and water (20 mL) were added, rapidly stirred for 5 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (20 mL), and the phases were separated; the ethyl acetate phases were combined, and saturated common salt was added. Water (20 mL) was rapidly stirred for 5 min, and the phases were separated; the ethyl acetate phase was separated from the solvent under reduced pressure at 45°C to obtain a pale yellow oil crude product 2-(5-chloro-1H-indol-3-yl)-N-(3- chloropyridin-4-yl)-2-hydroxyacetamide.

The fourth step, the 2-(5-chloro-1H-indol-3-yl)-N-(3-chloropyridin-4-yl)-2-hydroxyacetamide obtained in the third step is dissolved in trifluoroacetic acid ( 10mL), triethylsilane (1.74g) was added, and the reaction was refluxed at 60°C for 3h; the solvent was recovered from the reaction solution, ethyl acetate (30mL) and saturated aqueous sodium bicarbonate solution (30mL) were added, and the phases were separated by rapid stirring for 15min; water The phases were extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined, saturated brine (30 mL) was added and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product 2-(5- Crude chloro-indolin-3-yl)-N-(3-chloropyridin-4-yl)acetamide.

The fifth step, 2-(5-chloro-indolin-3-yl)-N-(3-chloropyridin-4-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and added Sodium tungstate dihydrate (0.3g), 30% hydrogen peroxide (10mL) was added dropwise in 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, and the mixture was rapidly stirred for 10min. The phases were separated; the aqueous phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain 2-(5-chloro-1 -Hydroxy-1H-indol-3-yl)-N-(3-chloropyridin-4-yl)acetamide crude.

The sixth step, 2-(5-chloro-1-hydroxy-1H-indol-3-yl)-N-(3-chloropyridin-4-yl)acetamide was added to dry DMF (8 mL), stirred at room temperature, and added Anhydrous potassium carbonate (1.66g), bromopropane (1.65g) were stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate ( 25mL×2) extraction, combine the organic phases, add saturated brine (50mL), stir rapidly for 10min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a pale 2-(5-Chloro-1-propoxy-1H-indol-3-yl)-N-(3-chloropyridin-4-yl)acetamide (102 mg) as a brown solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (600MHz, acetone-d ₆ ): δ170.7 (C- 9), 150.0(C-6'), 149.8(C-5'), 142.6(C-4'), 132.2(C-7a), 126.16(C-2), 125.6(C-3a), 123.6( C-6), 120.4(C-5), 119.6(C-4), 115.36(C-2'), 115.29(C-3'), 110.8(C-7), 105.0(C-3), 81.1 (C-1”), 34.3(C-8), 22.3(C-2”), 10.5(C-3”); (+)-HR-ESIMS m/z 378.0784[M+H] ⁺ (calcd for _{C18H18Cl2N3O2 , 378.0771 ) .}

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

In the first step, 4-methoxyindole (1.47g) was weighed, anhydrous ether (30mL) was added and stirred to dissolve, cooled to 0～5°C and stirred, and oxalyl chloride (1.9g) was added dropwise within 5min, and the dropwise addition was completed. , warmed to room temperature 20 ~ 25 ℃ and stirred for 2 h. The solvent was removed from the reaction solution under reduced pressure at 25°C to obtain 2-(4-methoxy-1H-indol-3-yl)-2-carbonylacetyl chloride as a brown oil.

In the second step, 2-(4-methoxy-1H-indol-3-yl)-2-carbonylacetyl chloride was added to dichloromethane (20 mL) and stirred to dissolve, and the temperature was cooled to 0-5 °C and stirred. 3-Chloro-4-aminopyridine (1.28g) and triethylamine (1.5g) were added, and the mixture was slowly raised to room temperature for reaction for 2h. Cool to 0～5℃, stir for 30min, filter, wash the filter cake with dichloromethane (5mL); dry with air at 40℃ to obtain pale yellow solid 2-(4-methoxy-1H-indol-3-yl)- N-(3-Chloropyridin-4-yl)-2-carbonylacetamide (2.0 g).

In the third step, 2-(4-methoxy-1H-indol-3-yl)-N-(3-chloropyridin-4-yl)-2-carbonylacetamide was added with methanol (20 mL) and stirred to dissolve, and the temperature was lowered. Stir at 10-15 °C, add sodium borohydride (1 g), slowly raise to room temperature and react for 30 min. The solvent was removed under reduced pressure at 30°C, ethyl acetate (20 mL) and water (20 mL) were added, rapidly stirred for 5 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (20 mL), and the phases were separated; the ethyl acetate phases were combined, and saturated common salt was added. Water (20 mL) was rapidly stirred for 5 min, and the phases were separated; the ethyl acetate phase was removed under reduced pressure at 45 °C to obtain a pale yellow oil crude product 2-(4-methoxy-1H-indol-3-yl)-N-( 3-chloropyridin-4-yl)-2-hydroxyacetamide.

The fourth step, the 2-(4-methoxy-1H-indol-3-yl)-N-(3-chloropyridin-4-yl)-2-hydroxyacetamide obtained in the third step is dissolved in trifluoroacetamide In acetic acid (10 mL), triethylsilane (1.74 g) was added, and the reaction was refluxed at 60 °C for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min. The aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined, saturated brine (30 mL) was added and stirred for 10 min, and the phases were separated; Crude 4-methoxy-indolin-3-yl)-N-(3-chloropyridin-4-yl)acetamide.

The fifth step, 2-(4-methoxy-indolin-3-yl)-N-(3-chloropyridin-4-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15～20 ℃ and stirred , add sodium tungstate dihydrate (0.3g), dropwise add 30% hydrogen peroxide (10mL) in 5min, complete the dropwise addition, react at 15～20℃ for 1h; add dichloromethane (200mL), water (200mL), stir rapidly 10 min, phase separation; the aqueous phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain 2-(5-chloro) -1-Hydroxy-1H-indol-3-yl)-N-(3-chloropyridin-4-yl)acetamide crude.

The sixth step, 2-(4-methoxy-1-hydroxy-1H-indol-3-yl)-N-(3-chloropyridin-4-yl)acetamide was added to dry DMF (8 mL), and stirred at room temperature , anhydrous potassium carbonate (1.66g), bromopropane (1.65g) were added, and the reaction was stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), and rapidly stirred for 10min, and the phases were separated; the aqueous phase was treated with ethyl acetate Ester (25mL×2) was extracted, the organic phases were combined, saturated brine (50mL) was added, rapidly stirred for 10min, and the phases were separated; the organic phase was separated by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (1:5), 2-(4-Methoxy-1-propoxy-1H-indol-3-yl)-N-(3-chloropyridin-4-yl)acetamide (110 mg) was obtained as a light brown solid. ¹ H NMR (400MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 C ₁₉ H ₂₀ ClN ₃ O ₃ , 373.1193).

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

The first step was to weigh indoleacetic acid (1.05g), add dichloromethane (20mL) to suspend and stir, add EDCI (1.27g) at room temperature, stir and dissolve; add methyl anthranilate (1g), DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude light reddish-brown oil Methyl-2-[2-(1H-indol-3-yl)acetamide]benzoate.

In the second step, methyl-2-[2-(1H-indol-3-yl)acetamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL) and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product methyl-2-[2-(indolin-3-yl)acetamide] Parabens.

In the third step, methyl-2-[2-(indolin-3-yl)acetamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain methyl-2-[2-(1-hydroxy-1H]. -Indol-3-yl)acetamide]benzoate crude.

The fourth step, methyl-2-[2-(1-hydroxy-1H-indol-3-yl)acetamide]benzoate was added to dry DMF (5mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g g), bromoisopropane (1.1g), stirred for 2h at room temperature; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, rapidly stirred for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2) Extract, combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a purple gum yl-2-[2-(1-isopropoxy-1H-indol-3-yl)acetamide]benzoate (495 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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=7.6 Hz,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"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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( (+)- 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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), bromoisopropane (1.1g), stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), stirred rapidly for 10min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25mL×2) , the organic phases were combined, saturated brine (50 mL) was added, rapidly stirred for 10 min, and the phases were separated; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a light pink solid N-( 2-Chlorophenyl)-2-(1-isopropoxy-1H-indol-3-yl)acetamide (480 mg). ¹ H NMR (400 MHz, acetone-d ₆ ): δ 8.42 (1H, brs, NH-1), 8.32 (1H, d, J=8.0 Hz, 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"); ¹³ C NMR (400MHz, acetone-d ₆ ): δ170.0 (C- 9), 136.0(C-1'), 134.7(C-7a), 129.8(C-3'), 128.3(C-5'), 125.5(C-4'), 125.4(C-3), 124.5 (C-3a), 123.4(C-2), 122.7(C-2', 6'), 120.6(C-5), 119.8(C-4), 109.7(C-7), 105.2(C-3 ), 81.1(C-1”), 34.6(C-8), 21.2(C-2”, 3”); (+)-HR-ESIMS m/z 343.1227[M+H] ⁺ (calcd for C ₁₉ H ₂₀ ClN ₂ O ₂ , 343.1208).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), n-bromobutane (1.23g), stirred and reacted at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25mL×2) , combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a purple solid N-(2 -Chlorophenyl)-2-(1-butoxy-1H-indol-3-yl)acetamide (560 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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=7.2 Hz, H-4"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 for C ₂₀ H ₂₂ ClN ₂ O ₂ , 357.1364 ).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), bromobutane (1.2g), the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2 ) extraction, combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a light yellow gum Compound 2-(1-butoxy-1H-indol-3-yl)-N-(3-chloropyridin-4-yl)acetamide (440 mg). ¹ H NMR (400MHz, acetone-d6): δ 8.66 (1H, brs, NH), 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=7.6 Hz, H-4"); ¹³ C NMR (400 MHz, acetone-d6): δ 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-pentyloxy-1H-indol-3-yl)acetamide

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), n-bromopentane (1.36g), stirred and reacted at room temperature for 2h; added ethyl acetate (50mL) and water (50mL) to the reaction solution, stirred rapidly for 10min, and separated the phases; the aqueous phase was extracted with ethyl acetate (25mL×2) , combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:8) to obtain a purple gum N- (2-Chlorophenyl)-2-(1-pentyloxy-1H-indol-3-yl)acetamide (549 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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=7.2 Hz, H-5"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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( (+)-HR-ESIMS m/z 371.1528[M+H] ⁺ (calcd for C ₂₁ H ₂₄ ClN ₂ O _2,371.1521 ).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), bromopentane (1.2g), and the reaction was stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), stirred rapidly for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2 ) extraction, combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a light yellow gum Compound 2-(1-pentyloxy-1H-indol-3-yl)-N-(3-chloropyridin-4-yl)acetamide (450 mg). ¹ H NMR (400MHz, acetone-d6): δ 8.66 (1H, brs, NH), 8.42 (1H, s, H-2'), 8.36 (2H, m, H-5', 6'), 7.64 (2H,m,H-2,4),7.47(1H,d,J=8.4Hz,H-7),7.25(1H,t,J=7.6Hz,H-6),7.10(1H,t, J=7.6Hz,H-5),4.31(2H,t,J=7.2Hz,H-1"),4.00(2H,s,H-8),1.81(2H,s,H-2"), 1.45(2H,m,H-3",4"),0.93(3H,t,J=7.2Hz,H-5"); ^13C NMR(400MHz,acetone-d6):δ170.9(C-9 ), 149.9(C-2'), 149.8(C-6'), 142.5(C-4'), 133.9(C-7a), 124.7(C-2), 124.5(C-3'), 123.6( C-6), 120.8(C-5'), 119.9(C-4), 115.0(C-3a), 109.3(C-7), 104.9(C-3), 79.4(C-1"), 34.7 (C-8), 28.69(C-2”), 28.68(C-3”), 23.1(C-4”), 14.2(C-5”); (+)-HR-ESIMS m/z 371.141[ _M +H] ⁺ ( _calcd for _C20H23ClN3O2 , _371.1401 ).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (8 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), n-bromohexane (1.48g), stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), rapidly stirred for 10min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25mL×2) , combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:8) to obtain a light brown gum N -(2-Chlorophenyl)-2-(1-hexyloxy-1H-indol-3-yl)acetamide (530 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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=6.4 Hz, H-6"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (8 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), n-bromoheptane (1.6g), stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), rapidly stirred for 10min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25mL×2) , combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:8) to obtain a light brown gum N -(2-Chlorophenyl)-2-(1-heptyloxy-1H-indol-3-yl)acetamide (580 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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=6.0 Hz, H-7"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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/z 399.184 [M ₊ H] ⁺ ( _calcd for _C23H28ClN2O2 , _399.1834 ).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (8 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), n-bromooctane (1.72g), stirred and reacted at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), rapidly stirred for 10min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25mL×2) , the organic phases were combined, saturated brine (50 mL) was added, rapidly stirred for 10 min, and the phases were separated; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:10) to obtain a light brown gum N -(2-Chlorophenyl)-2-(1-octyloxy-1H-indol-3-yl)acetamide (602 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (8 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), n-bromononane (1.84g), and the reaction was stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), rapidly stirred for 10min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25mL×2) , combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain light yellow solid N-( 2-Chlorophenyl)-2-(1-nonyloxy-1H-indol-3-yl)acetamide (660 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (400MHz, acetone- d ₆ ): δ169.9(C-9), 136.1(C-1'), 133.9(C-7a), 129.9(C-5'), 128.4(C-3'), 125.5(C-3a, 4), 124.6(C-2), 123.5(C-6, 2'), 122.7(C-6'), 120.7(C-5), 120.0(C-4), 109.3(C-7), 105.5 (C-3), 79.3(C-1"), 34.6(C-8), 32.5(C-2"), 30.2(C-3"), 30.1(C-4"), 29.9(C-5 ”), 29.0(C-6”), 26.5(C-7”), 23.3(C-8”), 14.3(C-9”); (+)-HR-ESIMS m/z 427.2158 [M+H ] ⁺ ( _calcd for _C25H32ClN2O2 , _{427.2147 )} .

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

The fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (10 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g was added) ), n-bromodecane (2g), stirred for 2h at room temperature; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25mL×2), The organic phases were combined, saturated brine (50 mL) was added, rapidly stirred for 10 min, and the phases were separated; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:10) to obtain a light purple gum N- (2-Chlorophenyl)-2-(1-decyloxy-1H-indol-3-yl)acetamide (689 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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=6.4 Hz, H-10"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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( (+)-HR-ESIMS m/z 441.2309[M+H] ⁺ (calcd for C ₂₆ H ₃₄ ClN ₂ O _2,441.2303 ).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

The fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (10 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g was added) ), bromotetradecane (2.5g), and the reaction was stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), rapidly stirred for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2) Extract, combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; (2-Chlorophenyl)-2-(1-tetradecyloxy-1H-indol-3-yl)acetamide (690 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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=6.4 Hz, H-14"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ169.3(C-9), 135.5(C-1'), 133.3(C-7a), 129.2(C-5'), 127.8(C-3'), 124.9(C-3a,4), 124.0 (C-2), 122.8(C-6, 2'), 122.1(C-6'), 120.1(C-5), 119.3(C-4), 108.7(C-7), 104.9(C-3 ), 78.7(C-1”), 33.9(C-8), 32.0(C-2”), 29.8(C-3”, 4”), 29.71(C-5”), 29.65(C-6” ), 29.6(C-7"), 29.5(C-8"), 29.4(C-9", 10"), 28.4(C-11"), 25.9(C-12"), 22.7(C-13 "), 13.7 (C-14"); (+)-HR-ESIMS m/z 497.2944 [M ₊ H] ⁺ ( _calcd for _C30H42ClN2O2 , _497.2929 ).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

The fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (10 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g was added) ), bromohexadecane (2.5g), and the reaction was stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), rapidly stirred for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2) Extracted, combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:10) to obtain a brown solid N-( 2-Chlorophenyl)-2-(1-hexadecyloxy-1H-indol-3-yl)acetamide (717 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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=6.4 Hz, H-16"); ¹³ C NMR (300 MHz, acetone-d ₆ ): δ 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 C _{32 H46ClN2O2} , _{525.3242 )} .

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), 2-bromobutane (1.24g), stirred for 2h at room temperature; added ethyl acetate (50mL) and water (50mL) to the reaction solution, stirred rapidly for 10min, and separated the phases; the aqueous phase was mixed with ethyl acetate (25mL×2) Extract, combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted 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). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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=2.6 Hz, H-3"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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 C ₂₀ H _{21 ClN2O2} , _357.1364 ).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), 2-methylbromopropane (1.24g), and the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2 ) extraction, combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a yellow solid N- (2-Chlorophenyl)-2-(1-isobutoxy-1H-indol-3-yl)acetamide (552 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (400MHz, acetone-d ₆ ): δ169.9(C-9), 136.1(C-1'), 133.7(C-7a), 129.9(C-5'), 128.4(C-3'), 125.5(C-3a,4) ,124.6(C-2'),124.5(C-2),123.5(C-6),122.8(C-6'),120.7(C-5),120.0(C-4),109.2(C-7 ), 105.6(C-3), 85.5(C-1”), 34.6(C-8), 28.3(C-2”), 19.3(C-3”, 4”); (+)-HR-ESIMSm /z 357.1369 [ _M +H] ⁺ ( _calcd for _C20H22ClN2O2 , _357.1364 ).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), bromoisobutane (1.2g), and the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was washed with ethyl acetate (25mL× 2) Extraction, combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted 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). ¹ H NMR (400MHz, acetone-d6): δ 8.67 (1H, brs, NH), 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=6.8 Hz, H-3", 4"); ¹³ C NMR (400 MHz, acetone-d6): δ 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] ⁺ (calcd for C ₁₉ H ₂₁ ClN ₃ O ₂ , 357.1244).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), 3-methylbromobutane (1.36g), and the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL× 2) Extraction, combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a light brown gum Compound N-(2-chlorophenyl)-2-[1-(2-pentalkoxy)-1H-indol-3-yl]acetamide (610 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (400MHz, acetone-d ₆ ): δ 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 for _C21H24ClN2O2 , _371.1521 ).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), 3-methylbromobutane (1.36g), the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was washed with ethyl acetate (25mL×2) extraction, the organic phases were combined, saturated brine (50mL) was added, rapidly stirred for 10min, and the phases were separated; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:3) to obtain Light yellow gum N-(3-chloropyridin-4-yl)-2-(1-isopentyloxy-1H-indol-3-yl)acetamide (480 mg). ¹ H NMR (400MHz, acetone-d6): δ 8.66 (1H, brs, NH), 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"); ¹³ C NMR (400MHz, acetone-d6): δ 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-cyclopentanoxy-1H-indol-3-yl)acetamide

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), bromocyclopentane (1.4g), and the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, rapidly stirred for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2) Extracted, combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a light brown solid N- (2-Chlorophenyl)-2-(1-cyclopentanoxy-1H-indol-3-yl)acetamide (429 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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) -d ₆ ): δ170.0(C-9), 136.1(C-1'), 134.5(C-7a), 129.9(C-5'), 128.4(C-3'), 125.5(C-3a) ,4),125.2(C-2),124.5(C-2'),123.5(C-6),122.7(C-6'),120.7(C-5),119.9(C-4),109.5( C-7), 105.3(C-3), 90.9(C-1"), 34.6(C-8), 31.9(C-2", 5"), 24.1(C-3", 4");( +)-HR-ESIMS m/z _369.1363 [M ₊ H] ⁺ ( _calcd for C21H22ClN2O2, _369.1364 ).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), bromocyclopentane (1.4g), the reaction was stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), rapidly stirred for 10min, and the phases were separated; the aqueous phase was washed with ethyl acetate (25mL) ×2) extraction, combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:3) to obtain light yellow Gum N-(3-chloropyridin-4-yl)-2-(1-cyclopentyloxy-1H-indol-3-yl)acetamide (405 mg). ¹ H NMR (400MHz, acetone-d6): δ 8.64 (1H, brs, NH), 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"); ¹³ C NMR (400MHz, acetone-d6): δ171.0(C-9), 149.9(C-2'), 149.8(C-6'), 142.5(C-4'), 134.5( C-7a), 125.3(C-2), 124.4(C-3'), 123.6(C-6), 120.8(C-5'), 119.8(C-4), 115.0(C-3a), 109.5 (C-7), 104.7(C-3), 90.9(C-1”), 34.7(C-8), 31.9(C-2”, 5”), 24.1(C-3”, 4”); (+)-HR-ESIMS m/z 369.1249 [ _M +H] ⁺ ( _calcd for _C20H21ClN3O2 , _369.1244 ).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), 2-methylbutane (1.4g), and the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, rapidly stirred for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate ( 25mL×2) extraction, combine the organic phases, add saturated brine (50mL), stir rapidly for 10min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:3) to obtain a pale N-(3-chloropyridin-4-yl)-2-(1-methylbutoxy-1H-indol-3-yl)acetamide (610 mg) as a yellow solid. ¹ H NMR (500MHz, acetone-d6): δ 8.65 (1H, brs, NH), 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 ”); ¹³ C NMR (500MHz, acetone-d6): δ170.9(C-9), 149.9(C-2'), 149.8(C-6'), 142.5(C-4'), 133.7(C -7a), 124.5(C-2), 123.6(C-6), 120.8(C-3a), 119.9(C-5), 115.0(C-4), 109.3(C-7), 107.7(C- 3), 84.1(C-1”), 34.8(C-8), 34.7(C-2”), 26.6(C-3”), 16.6(C-5”), 11.5(C-4”); (+)-HR-ESIMS m/z 371.14 [ _M +H] ⁺ ( _calcd for _C20H22ClN3O2 , _371.1401 ).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), 3,3-dimethylbutane (1.5g), the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, rapidly stirred for 10min, and the phases were separated; the aqueous phase was treated with acetic acid Extracted with ethyl ester (25 mL×2), combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:3) , to give N-(3-chloropyridin-4-yl)-2-[1-(3,3-dimethylbutoxy)-1H-indol-3-yl]acetamide (480mg) as a pale yellow solid . ¹ H NMR (400MHz, acetone-d6): δ 8.67 (1H, brs, NH), 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"); ¹³ C NMR (400MHz, acetone-d6): δ 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/z 385.1554 [M+H] ⁺ (calcd for C ₂₁ H ₂₄ ClN ₃ O ₂ , 385.1557) .

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), 2-ethylbutane (1.5g), and the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, rapidly stirred for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate ( 25mL×2) extraction, combine the organic phases, add saturated brine (50mL), stir rapidly for 10min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:3) to obtain a pale N-(3-chloropyridin-4-yl)-2-(1-ethylbutoxy-1H-indol-3-yl)acetamide (615 mg) as a yellow solid. ¹ H NMR(500MHz,acetone-d6):δ8.66(1H,brs,NH),8.36(3H,m,H-2',5',6'),7.65(2H,m,H-2, 4), 7.46 (1H, d, J=8.0Hz, H-7), 7.25 (1H, t, J=7.5Hz, H-6), 7.10 (1H, t, J=7.5Hz, H-5) ,4.22(2H,m,H-1”),4.00(2H,s,H-8),1.71(1H,m,H-2”),1.57(4H,m,H-3”,5”) ,0.98(6H,m,H-4",6"); ^13C NMR(500MHz,acetone-d6):δ170.9(C-9),149.9(C-2'),149.8(C-6' ), 142.5(C-4'), 133.7(C-7a), 124.53(C-2), 124.47(C-6), 123.6(C-5), 120.8(C-4), 119.9(C-3a ), 115.0(C-4), 109.2(C-7), 105.0(C-3), 81.6(C-1”), 41.1(C-2”), 34.7(C-8), 23.9(C- 3", 5"), 11.4 (C-4", 6"); (+)-HR-ESIMS m/z 385.1562 [ _M +H] ⁺ ( _calcd for _C21H24ClN3O2 , _385.1557 ).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), propylene iodide (1.5g), stirred for 2h at room temperature; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25mL×2), combined To the organic phase, saturated brine (50 mL) was added, rapidly stirred for 10 min, and the phases were separated; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a light brown solid N-(2- Chlorophenyl)-2-(1-allyloxy-1H-indol-3-yl)acetamide (395 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.42 (1H, brs, NH-1), 8.29 (1H, d, J=8.0 Hz, 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); ¹³ C NMR (400MHz, acetone-d ₆ ): δ169.9 (C- 9), 136.1(C-1'), 134.1(C-7a), 133.1(C-2"), 129.9(C-5'), 128.3(C-3'), 125.5(C-3a,4) ,124.9(C-2),124.6(C-2'),123.5(C-6),122.8(C-6'),121.5(C-3"),120.8(C-5),119.9(C- 4), 109.5(C-7), 105.5(C-3), 79.8(C-1”), 34.6(C-8); (+)-HR-ESIMS m/z 341.1051[M+H] ⁺ ( calcd for C ₁₉ H ₁₈ ClN ₂ O ₂ , 341.1051).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-fluoro-4-aminopyridine (0.9g) was added , DMAP (0.15g), stirred for 3h at room temperature; added water (10mL), stirred rapidly for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; Crude N-(3-fluoropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was a reddish brown oil.

In the second step, N-(3-fluoropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-fluoropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-fluoropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phases were extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain crude N-(3-fluoropyridin-4-yl) )-2-(1-hydroxy-1H-indol-3-yl)acetamide.

The fourth step, N-(3-fluoropyridin-4-yl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), bromopropene (1.1g), stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), rapidly stirred for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2) Extracted, combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted 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). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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); ¹³ C NMR (400MHz, acetone-d ₆ ): δ 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 C ₁₈ H ₁₇ FN ₃ O ₂ , 325.1227).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), 1-bromo-3-butene (1.3g), the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, rapidly stirred for 10min, and the phases were separated; the aqueous phase was treated with ethyl acetate Ester (25mL×2) was extracted, the organic phases were combined, saturated brine (50mL) was added, rapidly stirred for 10min, and the phases were separated; the organic phase was separated by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (1:3), 2-[1-(Enbutoxy)-1-hydro-indol-3-yl]-N-(3-chloropyridin-4-yl)acetamide (520 mg) was obtained as a pale yellow solid. ¹ H NMR (400MHz, acetone-d6): δ 8.67 (1H, brs, NH), 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"); ¹³ C NMR (400MHz, acetone-d6): δ170.9 (C-9), 149.9 (C-2' ), 149.8(C-6'), 142.5(C-4'), 135.0(C-3"), 133.9(C-7a), 124.7(C-2), 124.5(C-4"), 123.6( C-6), 120.9(C-3a), 119.9(C-5), 117.8(C-4), 115.0(C-5'), 109.4(C-7), 105.1(C-3), 78.2( C-1”), 34.7(C-8), 34.3(C-2”); (+)-HR-ESIMS m/z355.1096[M+H] ⁺ (calcd for C ₁₉ H ₁₉ ClN ₃ O ₂ , 355.1088).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), 1-bromo-4-pentene (1.4g), the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, rapidly stirred for 10min, and the phases were separated; the aqueous phase was treated with ethyl acetate Ester (25mL×2) was extracted, the organic phases were combined, saturated brine (50mL) was added, rapidly stirred for 10min, and the phases were separated; the organic phase was separated by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (1:3), N-(3-chloropyridin-4-yl)-2-[1-(2-pentyl-4-en-1-yloxy)-1H-indol-3-yl] was obtained as a pale yellow gum Acetamide (540 mg). ¹ H NMR (400MHz, acetone-d6): δ 8.66 (1H, brs, NH), 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"); ¹³ C NMR (400MHz, acetone-d6): δ170.9 (C-9), 149.9(C-2'), 149.8(C-6'), 142.5(C-4'), 138.6(C-4"), 133.8(C-7a), 124.6(C-2 ), 124.5(C-5"), 123.6(C-6), 120.8(C-3a), 119.9(C-5), 115.7(C-4), 115.0(C-5'), 109.3(C- 7), 105.0(C-3), 78.6(C-1”), 34.7(C-8), 30.6(C-3”), 28.2(C-2”); (+)-HR-ESIMS m/ z 369.1259 [ _M +H] ⁺ ( _calcd for _C20H20ClN3O2 , _369.1244 ).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), 1-bromo-5-hexene (1.6g), the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was treated with ethyl acetate Ester (25mL×2) was extracted, the organic phases were combined, saturated brine (50mL) was added, rapidly stirred for 10min, and the phases were separated; the organic phase was separated by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (1:3), N-(3-chloropyridin-4-yl)-2-[1-(2-hexyl-5-en-1-yloxy)-1H-indol-3-yl]ethyl was obtained as a pale yellow gum amide (580 mg). ¹ H NMR (400MHz, acetone-d6): δ8.69 (1H, brs, NH), 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"); ¹³ C NMR (400MHz, acetone-d6): δ170.9(C-9), 149.9(C-2'), 149.8(C-6'), 142.5(C-4'), 139.2(C-2), 133.7 (C-7a), 124.6(C-6"), 124.4(C-3a), 123.5(C-6), 120.8(C-5), 120.1(C-3'), 119.9(C-4), 115.2(C-5"), 115.0(C-5'), 109.3(C-7), 104.9(C-3), 79.1(C-1"), 34.6(C-8), 34.1(C-4 ”), 28.4(C-2”), 25.8(C-3”); (+)-HR-ESIMS m/z 383.1406[M+H] ⁺ (calcd for C ₂₁ H ₂₃ ClN ₃ O ₂ , 383.1401 ).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), 1-bromo-3-butyne (1.2g), and the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, rapidly stirred for 10min, and the phases were separated; the aqueous phase was treated with ethyl acetate Ester (25mL×2) was extracted, the organic phases were combined, saturated brine (50mL) was added, rapidly stirred for 10min, and the phases were separated; the organic phase was separated by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (1:3), 2-[1-(Butyl-3-yn-1-yloxy)-1-hydro-indol-3-yl]-N-(3-chloropyridin-4-yl) was obtained as a pale yellow gum Acetamide (490 mg). ¹ H NMR (400MHz, acetone-d6): δ 8.69 (1H, brs, NH), 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"); ¹³ C NMR (400MHz, acetone-d6): δ 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/z 353.0935 [M+H] ⁺ (calcd for C ₁₉ H ₁₇ ClN ₃ O ₂ , 353.0931).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), 1-bromo-2-butyne (1.2g), the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was treated with ethyl acetate Ester (25mL×2) was extracted, the organic phases were combined, saturated brine (50mL) was added, rapidly stirred for 10min, and the phases were separated; the organic phase was separated by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (1:3), 2-[1-(Butyl-2-yn-1-yloxy)-1-hydro-indol-3-yl]-N-(3-chloropyridin-4-yl) was obtained as a pale yellow gum Acetamide (416 mg). ¹ H NMR (400MHz, acetone-d6): δ 8.69 (1H, brs, NH), 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=7.6 Hz, H-5), 4.90 (2H, s, H-1"), 4.00 (2H, s, H-8), 1.79 (3H, s, H-4"); ¹³ C NMR (400 MHz) , acetone-d6): δ170.9(C-9), 150.0(C-2'), 149.8(C-6'), 142.6(C-4'), 134.3(C-7a), 125.2(C- 2), 124.5(C-3'), 123.6(C-6), 121.0(C-5'), 120.3(C-5), 119.8(C-4), 115.0(C-3a), 109.8(C -7), 105.2(C-3), 86.9(C-2"), 74.2(C-3"), 68.9(C-1"), 34.6(C-8), 3.4(C-4"); (+)-HR-ESIMS m/z 353.0942 [ _M +H] ⁺ ( _calcd for _C19H16ClN3O2 , _353.0931 ).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), 3-chlorobromopropane (1.4g), and the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2) Extracted, combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a brown gum N -(2-Chlorophenyl)-2-[1-(3-chloropropoxy)-1H-indol-3-yl]acetamide (450 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (400MHz, acetone-d ₆ ): δ169.9(C-9), 136.0(C-1'), 133.8(C-7a), 129.8(C-5'), 128.3(C-3'), 125.5(C-3a,4), 124.6(C-2'), 124.5(C-2), 123.6(C-6), 122.9(C-6'), 120.8(C -5), 120.0(C-4), 109.2(C-7), 105.9(C-3), 75.8(C-1”), 42.0(C-3”), 34.5(C-8), 31.9( C-2"); (+)-HR-ESIMS m/z 377.0824 [M+H] ⁺ (calcd for C ₁₉ H ₁₉ Cl ₂ N ₂ O ₂ , 377.0818).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), 3-chloro-1-bromopropane (1.3g), the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, rapidly stirred for 10min, and the phases were separated; the aqueous phase was treated with ethyl acetate Ester (25mL×2) was extracted, the organic phases were combined, saturated brine (50mL) was added, rapidly stirred for 10min, and the phases were separated; the organic phase was separated by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (1:3), 2-[1-(3-Chloropropoxy)-1-hydro-indol-3-yl]-N-(3-chloropyridin-4-yl)acetamide (452 mg) was obtained as a pale yellow gum. ¹ H NMR (400MHz, acetone-d6): δ 8.69 (1H, brs, NH), 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"); ¹³ C NMR (400MHz, acetone-d6): δ 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 C ₁₈ H ₁₈ Cl ₂ N ₃ O ₂ , 377.0698).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), 4-chloro-1-bromobutane (1.4g), the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was treated with acetic acid Extracted with ethyl ester (25 mL×2), combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:3) , to give 2-[1-(4-chlorobutoxy)-1-hydro-indol-3-yl]-N-(3-chloropyridin-4-yl)acetamide (465 mg) as a pale yellow gum . ¹ H NMR (400MHz, acetone-d6): δ 8.70 (1H, brs, NH), 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"); ¹³ C NMR (400MHz, acetone-d6): δ 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-ESIMS m/z 391.0858[M+H] ⁺ (calcd for C ₁₉ H ₁₉ Cl ₂ N ₃ O ₂ , 391.0854).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), chloroacetonitrile (0.68g), stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), stirred rapidly for 10min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25mL×2), combined To the organic phase, saturated brine (50 mL) was added, rapidly stirred for 10 min, and the phases were separated; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a light brown solid N-(2- Chlorophenyl)-2-(1-cyanomethoxy-1H-indol-3-yl)acetamide (315 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.56 (1H, brs, NH-1), 8.24 (1H, d, J=8.4 Hz, 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=7.6 Hz, H-5), 5.33 (2H, s, H-10), 3.96 (2H, s, H-2); ¹³ CNMR (400MHz) , acetone-d ₆ ): δ169.6(C-9), 136.0(C-1'), 135.0(C-7a), 129.9(C-5'), 128.3(C-3'), 125.7(C -4'), 125.2(C-3a), 125.1(C-2), 124.2(C-6, 2'), 123.3(C-11), 121.7(C-6'), 120.2(C-5) , 116.4(C-4), 109.8(C-7), 108.1(C-3), 63.5(C-10), 34.3(C-8); (+)-HR-ESIMS m/z 340.0844[M+ H] ⁺ ( _calcd for _C18H15ClN3O2 , _{340.0847 )} .

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), bromoacetonitrile (0.9g), and the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, rapidly stirred for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2) Extract, combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; (3-Chloropyridin-4-yl)-2-[1-(cyanomethoxy)-1H-indol-3-yl]acetamide (670 mg). ¹ H NMR (400MHz, acetone-d6): δ 8.80 (1H, brs, NH), 8.44 (1H, s, H-2'), 8.35 (2H, m, H-5', 6'), 7.72 (1H,s,H-2),7.69(1H,d,J=8.0Hz,H-4),7.57(1H,d,J=8,4Hz,H-7),7.30(1H,t,J =7.6Hz,H-6),7.16(1H,t,J=7.6Hz,H-5),5.35(2H,s,H-1"),4.05(2H,s,H-8); ^13C NMR (400MHz, acetone-d6): δ170.6(C-9), 150.0(C-2'), 149.7(C-6'), 142.5(C-4'), 134.9(C-7a), 125.2 (C-2), 125.1(C-2"), 124.2(C-6), 121.8(C-5), 120.2(C-4), 116.4(C-3'), 115.3(C-5') , 109.9(C-7), 107.4(C-3), 63.6(C-1”), 34.4(C-8); (+)-HR-ESIMS m/z 340.0731[M+H] ⁺ (calcd for _{C17H14ClN4O2 , 340.0727 )} .

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (8 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), 3-hydroxybromopropane (1.25g), stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), rapidly stirred for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2) Extracted, combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a light brown gum N-(2-Chlorophenyl)-2-[1-(3-hydroxypropoxy)-1H-indol-3-yl]acetamide (340 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (400MHz, acetone-d ₆ ): δ170.0(C-9), 136.0(C-1'), 133.9(C-7a), 129.9(C-5'), 128.3(C- 3'), 125.5(C-3a, 4'), 124.6(C-2), 123.5(C-6'), 122.9(C-6, 2'), 120.7(C-5), 119.9(C- 4), 109.3(C-7), 105.5(C-3), 76.4(C-1"), 58.7(C-3"), 34.5(C-8), 32.3(C-2"); (+ )-HR-ESIMS m/z 359.1165 [ _M +H] ⁺ ( _calcd for _C19H20ClN2O3 , _359.1157 ).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), 3-bromopropanol (1.0g), and the reaction was stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL) and water (50mL), stirred rapidly for 10min, and the phases were separated; the aqueous phase was washed with ethyl acetate (25mL) ×2) extraction, combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:3) to obtain light yellow Gum N-(3-chloropyridin-4-yl)-2-[1-(3-hydroxypropoxy)-1H-indol-3-yl]acetamide (150 mg). ¹ H NMR (400MHz, acetone-d6): δ 8.70 (1H, brs, NH), 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"); ¹³ C NMR (400 MHz, acetone-d6): δ 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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-fluoro-4-aminopyridine (0.9g) was added , DMAP (0.15g), stirred for 3h at room temperature; added water (10mL), stirred rapidly for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; Crude N-(3-fluoropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was a reddish brown oil.

In the second step, N-(3-fluoropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-fluoropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-fluoropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phases were extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain crude N-(3-fluoropyridin-4-yl) )-2-(1-hydroxy-1H-indol-3-yl)acetamide.

The fourth step, N-(3-fluoropyridin-4-yl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), bromopropanol (1.2g), stirred for 2h at room temperature; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2 ) extraction, combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted 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 (120 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ171.1(C-9), 147.42(C-2'), 147.37(C-6'), 138.0(C-3'), 137.8(C-3'), 133.8(C-4'), 124.7 (C-7a), 124.3(C-2), 123.2(C-6), 120.5(C-4), 120.0(C-5), 115.6(C-5'), 109.3(C-7), 105.4 (C-3), 76.3(C-1”), 58.7(C-3”), 34.4(C-8), 32.3(C-2”); (+)-HR-ESIMS m/z 343.133 [M +H] ⁺ (calcd for C ₁₈ H ₁₉ FN ₃ O ₃ , 343.1332).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), bromomethylcyclopropane (1.2g), stirred for 2h at room temperature; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was washed with ethyl acetate (25mL) ×2) extraction, combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain light yellow Gum N-(3-chloropyridin-4-yl)-2-[1-(cyclopropylmethoxy)-1H-indol-3-yl]acetamide (105 mg). ¹ H NMR (300MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR (600MHz, acetone-d ₆ ): δ171.3(C-9), 149.9(C-5', 6'), 142.5(C-4'), 137.8(C-7a), 128.62(C-2'), 128.57(C- 3'), 122.7(C-2), 120.1(C-6), 119.5(C-5), 114.73(C-4), 114.66(C-3a), 110.8(C-7), 107.6(C- 3), 50.9(C-1”), 35.0(C-8), 12.2(C-2”), 4.2(C-3”, 4”); (+)-HR-ESIMS m/z 356.1156[M ₊ H] ⁺ ( _calcd for _C19H19ClN3O2 , _356.116 ).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-fluoro-4-aminopyridine (0.9g) was added , DMAP (0.15g), stirred for 3h at room temperature; added water (10mL), stirred rapidly for 10min, and separated the phases; added saturated brine (10mL) to the organic phase, stirred for 10min, and separated the phases; Crude N-(3-fluoropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was a reddish brown oil.

In the second step, N-(3-fluoropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-fluoropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-fluoropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phases were extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain crude N-(3-fluoropyridin-4-yl) )-2-(1-hydroxy-1H-indol-3-yl)acetamide.

The fourth step, N-(3-fluoropyridin-4-yl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), bromopropanol (1.2g), stirred for 2h at room temperature; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was mixed with ethyl acetate (25mL×2 ) extraction, combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted 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 (650 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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"); ¹³ C NMR ( 400MHz, acetone-d ₆ ): δ171.1(C-9), 147.44(C-2'), 147.39(C-6'), 138.0(C-3'), 137.8(C-3'), 133.9 (C-4'), 124.64(C-7a), 124.58(C-2), 123.2(C-6), 120.4(C-5), 119.9(C-4), 115.6(C-5'), 109.4(C-7), 105.4(C-3), 83.5(C-1”), 34.4(C-8), 10.2(C-2”), 3.6(C-3”, 4”); (+ )-HR-ESIMS m/z 339.1384 [M+H] ⁺ (calcd for C ₁₉ H ₁₉ FN ₃ O ₂ , 339.1383).

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

In the first step, indoleacetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; 3-chloro-4-aminopyridine (0.85g) was added , DMAP (0.15g), stirred and reacted at room temperature for 3h; deionized water (20mL) was added and rapidly stirred for 10min, and the phases were separated; saturated brine (10mL) was added to the organic phase and stirred for 10min, and the phases were separated; Crude N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was obtained as a light reddish brown oil.

In the second step, N-(3-chloropyridin-4-yl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), and triethylsilane (1.74 g) was added , 60 ℃ reflux reaction for 3h; the reaction solution was recovered solvent, added ethyl acetate (30mL), saturated aqueous sodium bicarbonate solution (30mL), rapidly stirred for 15min, phase separation; aqueous phase was extracted with ethyl acetate (30mL), phase separation; The organic phases were combined, saturated brine (30 mL) was added, stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(3-chloropyridin-4-yl)-2-(indole). olin-3-yl)acetamide.

In the third step, N-(3-chloropyridin-4-yl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and tungstic acid dihydrate was added. Sodium (0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; water The phase was extracted with dichloromethane (100 mL×2), and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain N-(3-chloropyridin-4-yl) - Crude 2-(1-hydroxy-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 (5 mL), stirred at room temperature, and anhydrous potassium carbonate was added (1.66g), 1-bromo-4-butyronitrile (1.2g), the reaction was stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), rapidly stirred for 10min, and the phases were separated; the aqueous phase was treated with ethyl acetate Ester (25mL×2) was extracted, the organic phases were combined, saturated brine (50mL) was added, rapidly stirred for 10min, and the phases were separated; the organic phase was separated by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (1:3), N-(3-chloropyridin-4-yl)-2-[1-(3-cyanopropoxy)-1H-indol-3-yl]acetamide (170 mg) was obtained as a pale yellow gum. ¹ H NMR (400MHz, acetone-d6): δ 8.70 (1H, brs, NH), 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"); ¹³ C NMR (400MHz, acetone-d6): δ170.8 (C-9), 149.9 (C-2'), 149.8 (C-6'), 142.5 (C-4'), 133.8(C-7a), 124.6(C-2), 123.7(C-6), 121.0(C-3a), 120.3(C-3'), 120.04(C-4") , 119.96(C-5), 115.1(C-4), 109.3(C-7), 105.4(C-3), 77.2(C-1”), 34.6(C-8), 25.1(C-3” ), 14.2 (C-2"); (+)-HR-ESIMS m/z 368.1044 [M+H] ⁺ (calcd for C ₁₉ H ₁₈ ClN ₄ O ₂ , 368.104).

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

The first step was to weigh indoleacetic acid (1.05g), add dichloromethane (20mL) to suspend and stir, add EDCI (1.27g) at room temperature, stir and dissolve; add methyl anthranilate (1g), DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude light reddish-brown oil Methyl-2-[2-(1H-indol-3-yl)acetamide]benzoate.

In the second step, methyl-2-[2-(1H-indol-3-yl)acetamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL) and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product methyl-2-[2-(indolin-3-yl)acetamide] Parabens.

In the third step, methyl-2-[2-(indolin-3-yl)acetamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain methyl-2-[2-(1-hydroxy-1H]. -Indol-3-yl)acetamide]benzoate crude.

In the fourth step, methyl-2-[2-(1-hydroxy-1H-indol-3-yl)acetamide]benzoate was added to dry dichloromethane (20 mL), stirred at 0-5 °C, and ethyl acetate was added. Acyl chloride (0.94g), triethylamine (1.2g), stirred at 0～5°C for 1 h; separated by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (1:4) to obtain yellow solid methyl-2 -[2-(1-Acetoxy-1H-indol-3-yl)acetamide]benzoate (410 mg). ¹ H NMR (400 MHz, acetone-d ₆ ): δ 10.97 (1H, brs, NH-1), 8.71 (1H, d, J=8.8 Hz, 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'); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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'); - ESIMS m/z 367.1287 [M+H] ⁺ (calcd for C ₂₀ H ₁₉ N ₂ O ₅ , 367.1288).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry dichloromethane (20 mL), stirred at 0-5 °C, and acetyl chloride was added. (0.94g), triethylamine (1.2g), the reaction was stirred at 0-5°C for 1 h; separated by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (1:4), to obtain a pale yellow solid 3-{2 -[(2-Chlorophenyl)amino]-2-acetoxy}-1H-indol-1-ylacetamide (480 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.52 (1H, brs, NH-1), 8.28 (1H, d, J=8.0 Hz, 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); ¹³ C NMR (400MHz, acetone-d ₆ ): δ169.7(C-9), 169.4(C-10), 136.1(C-1'), 135.3(C-7a), 129.9(C-5'), 128.3(C-3'), 125.8(C-4'), 125.6(C-2), 125.1(C-3a), 124.0(C-6), 123.0(C-2 '), 121.3(C-6'), 120.3(C-4), 109.4(C-7), 107.4(C-3), 34.4(C-8), 18.0(C-11); (+)- HR-ESIMS m/z 343.0845 [ _M +H] ⁺ ( _calcd for _C18H16ClN2O3 , _343.0849 ).

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

The first step was to weigh indoleacetic acid (1.05g), add dichloromethane (20mL) to suspend and stir, add EDCI (1.27g) at room temperature, stir and dissolve; add methyl anthranilate (1g), DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude light reddish-brown oil Methyl-2-[2-(1H-indol-3-yl)acetamide]benzoate.

In the second step, methyl-2-[2-(1H-indol-3-yl)acetamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL) and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product methyl-2-[2-(indolin-3-yl)acetamide] Parabens.

In the third step, methyl-2-[2-(indolin-3-yl)acetamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain methyl-2-[2-(1-hydroxy-1H]. -Indol-3-yl)acetamide]benzoate crude.

In the fourth step, methyl-2-[2-(1-hydroxy-1H-indol-3-yl)acetamide]benzoate was added to dry dichloromethane (20 mL), stirred at 0-5 °C, and benzene was added. Formyl chloride (1.36g), triethylamine (1.2g), stirred at 0～5°C for 1h; separated by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (1:5) to obtain orange-yellow crystal methyl methyl -2-[2-(1-Benzoyloxy-1H-indol-3-yl)acetamide]benzoate (568 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 11.04 (1H, brs, NH-1), 8.73 (1H, d, J=8.8 Hz, 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'); ¹³ C NMR (400MHz, acetone-d ₆ ): δ169.6 ( C-9), 168.1(C-7'), 164.6(C-10), 141.6(C-2'), 135.4(C-7a), 134.9(C-4'), 134.4(C-4") ,131.0(C-6'),130.3(C-3",5"),129.4(C-2",6"),126.8(C-1"),125.9(C-2),125.0(C- 3a), 123.5(C-6), 122.6(C-5'), 120.9(C-5), 120.2(C-3'), 119.6(C-4), 115.7(C-1'), 109.0( C-7),107.3(C-3),52.0(C-8'),35.0(C-8); (+)-HR-ESIMS m/z 429.1452[M+H] ⁺ (calcd for C ₂₅ H _20N2O5 , _{429.1445 )} .

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry dichloromethane (20 mL), stirred at 0-5 °C, and benzyl was added. Acyl chloride (1.36g), triethylamine (1.2g), stirred at 0～5°C for 1h; separated by silica gel column chromatography, eluted with ethyl acetate-petroleum ether (1:4) to obtain yellow crystals 3-{2 -[(2-Chlorophenyl)amino]-2-oxoethyl}-1H-indol-1-ylbenzoate (530 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.60 (1H, brs, NH-1), 8.29 (1H, d, J=8.0 Hz, 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=7.6 Hz, H-6), 7.07 (1H, t, J=7.6 Hz, H-5), 4.01 (2H, s, H-8); ¹³ CNMR (400 MHz, acetone-d ₆ ): δ 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/z 405.1010 [ _M +H] ⁺ ( _calcd for _C23H18ClN2O3 , _405.1006 ).

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

The first step was to weigh indoleacetic acid (1.05g), add dichloromethane (20mL) to suspend and stir, add EDCI (1.27g) at room temperature, stir and dissolve; add methyl anthranilate (1g), DMAP ( 0.15g), stirring at room temperature for 3h; adding 2N hydrochloric acid, rapidly stirring for 10min, and separating phases; adding saturated brine (10mL) to the organic phase, stirring for 10min, and separating phases; removing the solvent under reduced pressure in the organic phase at 40°C to obtain a crude light reddish-brown oil Methyl-2-[2-(1H-indol-3-yl)acetamide]benzoate.

In the second step, methyl-2-[2-(1H-indol-3-yl)acetamide]benzoate was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, 60 The reaction solution was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (30 mL) were added, and the phases were rapidly stirred for 15 min; the aqueous phase was extracted with ethyl acetate (30 mL) and the phases were separated; The phases were added with saturated brine (30 mL) and stirred for 10 min, and the phases were separated; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product methyl-2-[2-(indolin-3-yl)acetamide] Parabens.

In the third step, methyl-2-[2-(indolin-3-yl)acetamide]benzoate was dissolved in (50 mL) methanol, cooled to 15-20 °C and stirred, and sodium tungstate dihydrate ( 0.3g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Dichloromethane (100 mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200 mL), and the phases were separated; the solvent was removed from the organic phase under reduced pressure to obtain methyl-2-[2-(1-hydroxy-1H]. -Indol-3-yl)acetamide]benzoate crude.

The fourth step, methyl-2-[2-(1-hydroxy-1H-indol-3-yl)acetamide]benzoate was added to dry DMF (5mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g g), benzyl bromide (1.5g), stirred for 2h at room temperature; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25mL×2) , combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain yellow solid methyl-2 -[2-(1-Benzyloxy-1H-indol-3-yl)acetamide]benzoate (521 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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'); ¹³ C NMR (400MHz, acetone-d ₆ ): δ 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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (5 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), benzyl bromide (1.5g), and the reaction was stirred at room temperature for 2h; ethyl acetate (50mL) and water (50mL) were added to the reaction solution, stirred rapidly for 10min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25mL×2), The organic phases were combined, saturated brine (50 mL) was added, rapidly stirred for 10 min, and the phases were separated; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain light pink solid N-(2 -Chlorophenyl)-2-(1-benzyloxy-1H-indol-3-yl)acetamide (537 mg). ¹ H NMR (300MHz, acetone-d ₆ ): δ 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); ¹³ C NMR (300MHz, acetone-d ₆ ): δ169.9(C-9), 136.0(C-1'), 135.8(C-1"), 134.0(C-7a), 130.5(C -2",6"),129.81(C-6'),129.78(C-4"),129.7(C-3'),129.3(C-3",5"),128.3(C-5') ,125.5(C-4'),124.8(C-2),124.5(C-3a),123.4(C-6),122.9(C-2'),120.7(C-5),119.9(C-4 ), 109.4(C-7), 105.5(C-3), 80.9(C-10), 34.5(C-8); (+)-HR-ESIMS m/z391.1215[M+H] ⁺ (calcd for C ₂₃ H ₂₀ ClN ₂ O ₂ , 391.1208).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (8 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), p-methoxybenzyl bromide (1.8 g), stirred at room temperature for 2 h; added ethyl acetate (50 mL) and water (50 mL) to the reaction solution, stirred rapidly for 10 min, and separated the phases; the aqueous phase was washed with ethyl acetate (25 mL× 2) Extraction, combine the organic phases, add saturated brine (50 mL), stir rapidly for 10 min, and separate the phases; the organic phase is separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a light red solid N-(2-Chlorophenyl)-2-{1-[(4-methoxybenzyl)oxy]-1H-indol-3-yl}acetamide (728 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.39 (1H, brs, NH-1), 8.28 (1H, d, J=8.0 Hz, 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=8.4 Hz, H-3”, 5”), 5.22 (2H, s, H-10), 3.88 (2H, s, H-8), 3.76 (3H, s, OMe-7”); ¹³ C NMR (400MHz) , acetone-d ₆ ): δ169.9(C-9), 161.3(C-4"), 136.1(C-1'), 134.0(C-7a), 132.3(C-3", 5"), 129.9(C-5'), 128.3(C-3'), 127.9(C-1"), 125.5(C-3a), 125.0(C-4'), 124.6(C-6,2'), 123.4 (C-2), 122.9(C-6'), 120.7(C-5), 119.9(C-4), 114.7(C-2", 6"), 109.5(C-7), 105.4(C- 3), 80.6(C-10), 55.5(C-7”), 34.5(C-8); (+)-HR-ESIMS m/z421.1312[M+H] ⁺ (calcd for C ₂₄ H ₂₂ ClN ₂ O ₃ , 421.1313).

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

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (8 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), p-methylbenzyl bromide (1.67g), stirred and reacted at room temperature for 2h; added ethyl acetate (50mL) and water (50mL) to the reaction solution, stirred rapidly for 10min, and separated the phases; the aqueous phase was mixed with ethyl acetate (25mL×2 ) extraction, combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a khaki solid N -(2-Chlorophenyl)-2-{1-[(4-methylbenzyl)oxy]-1H-indol-3-yl}acetamide (605 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 8.38 (1H, brs, NH-1), 8.28 (1H, d, J=8.0 Hz, 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"); ¹³ C NMR (400MHz, acetone-d ₆ ): δ 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-phenethoxy-1H-indol-3-yl)acetamide

In the first step, indole acetic acid (1.05g) was weighed, added to dichloromethane (20mL) for suspension and stirring, EDCI (1.27g) was added at room temperature, stirred and dissolved; o-chloroaniline (0.84g), DMAP (0.15g) were added. ), stirred for 3 h at room temperature; added 2N hydrochloric acid, rapidly stirred for 10 min, and separated the phases; added saturated brine (10 mL) to the organic phase, stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 40 °C to obtain a light reddish brown oily crude product N- (2-Chlorophenyl)-2-(1H-indol-3-yl)acetamide.

In the second step, N-(2-chlorophenyl)-2-(1H-indol-3-yl)acetamide was dissolved in trifluoroacetic acid (10 mL), triethylsilane (1.74 g) was added, and the temperature was 60°C. The reaction was refluxed for 3 h; the solvent was recovered from the reaction solution, ethyl acetate (30 mL) was added, saturated aqueous sodium bicarbonate (30 mL) was added, and the phases were rapidly stirred for 15 min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (30 mL), and the phases were separated; the organic phases were combined , added saturated brine (30 mL), stirred for 10 min, and separated the phases; the organic phase was removed under reduced pressure at 50 °C to obtain a dark brown oily crude product N-(2-chlorophenyl)-2-(indolin-3-yl) Acetamide.

In the third step, N-(2-chlorophenyl)-2-(indolin-3-yl)acetamide was dissolved in (50 mL) methanol, cooled to 15-20 °C, stirred, and sodium tungstate dihydrate (0.3 g), 30% hydrogen peroxide (10mL) was added dropwise within 5min, the dropwise addition was completed, and the reaction was carried out at 15-20°C for 1h; dichloromethane (200mL) and water (200mL) were added, rapidly stirred for 10min, and the phases were separated; Chloromethane (100mL×2) was extracted, and the organic phases were combined; the organic phase was washed with saturated brine (200mL), and the phases were separated; the organic phase was removed the solvent under reduced pressure to obtain N-(2-chlorophenyl)-2-(1- Crude hydroxy-1H-indol-3-yl)acetamide.

In the fourth step, N-(2-chlorophenyl)-2-(1-hydroxy-1H-indol-3-yl)acetamide was added to dry DMF (8 mL), stirred at room temperature, and anhydrous potassium carbonate (1.66 g) was added. ), bromoethylbenzene (1.65g), and the reaction was stirred at room temperature for 2h; the reaction solution was added with ethyl acetate (50mL), water (50mL), rapidly stirred for 10min, and the phases were separated; the aqueous phase was extracted with ethyl acetate (25mL×2) , combined the organic phases, added saturated brine (50 mL), stirred rapidly for 10 min, and separated the phases; the organic phase was separated by silica gel column chromatography and eluted with ethyl acetate-petroleum ether (1:5) to obtain a purple gum N- (2-Chlorophenyl)-2-(1-phenethoxy-1H-indol-3-yl)acetamide (566 mg). ¹ H NMR (400MHz, acetone-d ₆ ): δ 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=6.8 Hz, H-11); ¹³ C NMR (400 MHz, acetone-d ₆ ): δ 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

This model uses the VSV G/HIV recombinant virus model technology to express the vesicular stomatitis virus glycoprotein (VSV-G) and the HIV-1 core gene (pNL4-3. It can be wild strain or containing 293T cells were co-transfected with plasmids of drug-resistant strains at the mutation site, and the VSV-G and HIV-1 cores expressed by the cells could be assembled into recombinant viruses. The recombinant virus is characterized by knocking out the env, vpr and nef genes in the HIV genome, so the recombinant virus particles can only infect cells once and replicate in cells, without the ability to repackage and reproduce, and can be used in conventional laboratories The operation is carried out; the luciferase gene is introduced and expressed at the nef gene, and the replication level of HIV can be reflected by measuring the expression of the reporter gene. 253-258.].

(2) Experimental method

One day before infection, 293T cells were seeded into 24-well plates at a cell number of 5×10 ⁴ /well. Compounds or positive drugs (nevirapine or efavirenz) in this example were dissolved in DMSO. Test compound/positive drug (final concentration of DMSO is 0.1%) was added 15 minutes before infection, DMSO was used as solvent control, and nevirapine and efavirenz were used as positive control. Then add 0.5mL of recombinant virus solution (diluted virus stock solution to 0.1–0.5ng p24/mL according to p24 concentration). 48h after infection, the medium was removed, 50 μL of cell lysate (Promega) was added to each well for lysis, 20 μL of cell lysate was added to 30 μL of luciferase substrate, mixed well, and the luciferase in cells was measured by FB12 fluorescence detector. The relative activity of , its activity intensity reflects the HIV replication level, with DMSO as the control, the results are shown in Table 1 and Table 2.

(3) Experimental results

1), the evaluation results of wild HIV replication activity

The present invention has studied the anti-HIV-1 activity of the example compounds 1-105, and found that 57 compounds have strong inhibitory activity against wild HIV-1 (the half inhibitory concentration is 10nM～20μM, Table 1), among which Examples 69, 81, and 97 The activities of 105 and 105 are comparable to that of the clinical first-line non-nucleoside reverse transcriptase inhibitor nevirapine.

Table 1. Evaluation results of in vitro inhibition of wild HIV-1 replication activity by some compounds

2), the results of the evaluation of the replication activity of drug-resistant HIV-1

HIV-1 is an RNA virus, and its reverse transcriptase lacks a corrective function, resulting in low fidelity of virus replication. Under drug selective pressure, mutant drug-resistant strains survive, while wild-type is inhibited, resulting in drug resistance. A large number of strains proliferate and drug resistance appears, which is a difficult point in AIDS treatment. The anti-AIDS non-nucleoside reverse transcriptase inhibitors nevirapine (NVP), delavirdine (DLV) and efavirenz (EFV) have been clinically used for more than ten years, and drug-resistant strains already exist in patients. ETR and RPV were approved for marketing in 2009 and 2011, respectively. Clinical studies have shown that, after 48 weeks of taking the drugs, resistant viruses to the two drugs appear in the body. Therefore, continuous research and development of drugs against drug-resistant HIV-1 strains is still an important topic in the field of antiviral drug research and development. The present invention determined the drug resistance of 17 target compounds to two non-nucleoside reverse transcriptase inhibitors with the highest clinical occurrence probability. Inhibitory activity of mutant strains HIV-1 _RT-K103N (occurrence probability 11%) and HIV-1 _RT-Y181C (occurrence probability 3%) [Cao Yingli, Li Shaoxiong, Chen Hong, Guo Ying. Non-nucleoside reverse transcriptase inhibitors Establishment of a pharmacological evaluation system for drug-resistant HIV-1, Chinese Journal of Pharmacy, 2009, 44: 355-361.], the results showed that 14 compounds had better inhibitory activity and drug resistance multiples than nevirapine ( Table 2).

Table 2. Evaluation results of in vitro inhibition of drug-resistant HIV-1 replication activity of some compounds

Experimental example 2. Anti-influenza virus activity

(1) Preparation of influenza virus:

To test the anti-influenza effect of the compounds, we prepared human influenza A/Puerto Rico/8/1934(H1N1), A/Hubei Hongshan/50/2005(H1N1), A/Jingfang 262/ 95(H1N1), Type A/Jingfang/359/95(H3N2), Type A/Jifang/15/90(H3N2) and Type B/Jiangxi Xinjian/BV/39/2008, the preparation methods are as follows: The virus stock solution was inoculated into the allantoic cavity and amniotic cavity of 9-day-old chicken embryos. After culturing the chicken embryos at 35°C for 2-3 days, the virus in the allantoic fluid and amniotic fluid was harvested, centrifuged, and then packaged and stored at -70°C. Select the sensitive cell line MDCK cells (canine kidney cells) suitable for the growth of influenza virus as virus-infected cells, DMEM+0.2%BSA+2μg/ml TPCK as virus maintenance solution, and inoculate the virus solution into MDCK cells as a 10-fold gradient dilution. Three duplicate wells were set for each gradient, and after culturing at 37°C for 3 days, cytopathic changes were observed, and the half-infectious dose of virus (TCID ₅₀ ) was calculated according to the Reed-Muench method.

(2) Compounds inhibit the cytopathic effects of influenza virus-infected host cells

One day before infection, MDCK cells were seeded in a 96-well plate at a density of 3×10 ⁴ cells per well, and the cell culture medium was DMEM+10% FBS (GIBCO), and the cell culture conditions were 37° C., 5% CO ₂ . On the day of infection, the cell culture medium was discarded after the MDCK cells grew to 90-100% full, and the cells were washed twice with PBS solution (pH 7.4) and once with serum-free DMEM medium (exclude serum for influenza virus infection of the host. cell interference). Influenza A/Puerto Rico/8/1934(H1N1), A/Hubei Hongshan/50/2005(H1N1), A/Jingfang 262/95(H1N1), A/Jifang /15/90(H3N2) and B/Jiangxi Xinjian/BV/39/2008 virus solutions were diluted to 100TCID ₅₀ , 316TCID ₅₀ , 100TCID ₅₀ , 100TCID ₅₀ and 43TCID ₅₀ , respectively, added to the cell wells, and no virus was added at the same time. The normal cell control group and the virus control group with only virus and no compound added, the virus solution was discarded after incubation at 37°C for 2 hours, washed twice with PBS solution (pH 7.4), and once with serum-free DMEM medium . Compounds were diluted with virus maintenance solution, 100 μl per well, 4 replicate wells were set up in each group, cytopathic changes (CPE) were observed after 3 days of incubation at 37°C, 5% CO ₂ , and the half-inhibition of compounds against virus infection was calculated according to the Reed-Muench method. concentration (IC ₅₀ ).

(3) Experimental results

The present invention has studied the anti-influenza virus activity of the example compounds 1-105, and found that 65 compounds have strong inhibitory activity against A/Puerto Rico/8/1934 (H1N1) infection (the half inhibitory concentration is 1.7 μM～77 μM, Table 3), Among them, the activity of Example Compounds 35 and 47 is better than that of the clinical first-line drug ribavirin. The inventors also measured these two compounds against influenza A virus A/Hubei Hongshan/50/2005 (H1N1), type A/Jingfang 262/95 (H1N1), type A/Jingfang/359/95 ( H3N2), type A/Jifang/15/90 (H3N2) and type B/Jiangxi Xinjian/BV/39/2008 infection activity, the results show that their activity is better than the clinical first-line drug Tamiflu (Table 4) . This result shows that such compounds not only have a good inhibitory effect on influenza A virus, but also have better blocking effect on influenza B virus replication than existing drugs, that is, such compounds have broad-spectrum anti-influenza effects.

Table 3 Results of the evaluation of the compound's infectious activity against influenza virus A/Puerto Rico/8/1934 (H1N1)

Table 4 Compounds against influenza virus type A/Hubei Hongshan/50/2005(H1N1), type A/Jingfang 262/95(H1N1), type A/jingfang/359/95(H3N2), type A / Ji Fang / 15/90 (H3N2) and B type B / Jiangxi Xinjian / BV/39/2008 Infectious activity evaluation results

ND: Not detect.

Claims (8)

1. The compound shown in (IA2) and a pharmaceutically acceptable salt thereof,

Wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy; X is selected from substituted or unsubstituted C ₁ alkyl, C ₅ cycloalkyl; wherein the substituents are: OH, C _1-6 alkyl, halogen, cyano, C _1-6 unsaturated alkyl, C ₃ cycloalkyl; Y is selected from hydrogen, halogen, C ₁ alkyl; R ₂ is mono-substituted, selected from halogen, C ₁ alkoxyacyl; wherein the mono-substituted is selected from the vicinal mono-substituted of amide group. 2. The compound according to claim 1 and a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (IA2a)

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy; Y is selected from hydrogen, halogen, C ₁ alkyl; R ₂ is mono-substituted, selected from halogen, C ₁ alkoxyacyl; wherein the mono-substituted is selected from the vicinal mono-substituted of amide group. 3. The compound according to claim 1 and a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (IA2b)

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy; Y is selected from hydrogen, halogen, C ₁ alkyl; R ₂ is mono-substituted, selected from halogen, C ₁ alkoxyacyl; wherein the mono-substituted is selected from the vicinal mono-substituted of amide group. 4. The compound according to claim 1 and a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (IA2c)

Wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy; Y is selected from hydrogen, halogen, C ₁ alkyl; R ₂ is mono-substituted, selected from halogen, C ₁ alkoxyacyl; wherein the mono-substituted is selected from the vicinal mono-substituted of amide group. 5. The compound according to claim 1 and a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (IA2d)

wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy; Y is selected from hydrogen, halogen, C ₁ alkyl; R ₂ is mono-substituted, selected from halogen, C ₁ alkoxyacyl; wherein the mono-substituted is selected from the vicinal mono-substituted of amide group. 6. The compound according to claim 1 and a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (IA2e)

Wherein, R is monosubstituted or polysubstituted, selected from hydrogen, halogen, C _1-6 alkyl or C _1-6 alkoxy; Y is selected from hydrogen, halogen, C ₁ alkyl; R ₂ is mono-substituted, selected from halogen, C ₁ alkoxyacyl; wherein the mono-substituted is selected from the vicinal mono-substituted of amide group. 7. The following compounds and pharmaceutically acceptable salts thereof:

8. A pharmaceutical composition, characterized by comprising a therapeutically effective amount of the compound of any one of claims 1-7 and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.