Indole compound as well as preparation method and antiviral application thereof

Abstract

The invention relates to an indole compound as well as a preparation method and antiviral application thereof, the structure of the indole compound is as shown in formula I. Experiments prove that the indole compound has antiviral activity equivalent to or better than that of arbidol, and a new direction is provided for research and development of antiviral drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology. Specifically, the present invention relates to an indole compound, a preparation method thereof, and an antiviral application thereof. Background Art

[0002] Arbidol (also known as Arbidol) is an antiviral drug developed by the Soviet Union's Research Center for Pharmaceutical Chemistry. It was first marketed in Russia in 1993 and was approved for marketing in China in 2006 for the treatment of upper respiratory tract infections caused by influenza virus type A, B, etc. Arbidol mainly exerts a broad-spectrum antiviral effect by inhibiting virus entry into cells, regulating non-specific immunity, and inducing interferon synthesis. In recent years, relevant studies have confirmed that Arbidol has strong inhibitory activity against a variety of other viruses, including hepatitis B / C virus, coronavirus, herpes simplex virus, coxsackievirus, respiratory syncytial virus, hantavirus, Ebola virus, and Zika virus, etc.

[0003]

[0004] However, since this compound needs to be administered at a large dose to achieve a therapeutic effect and has a relatively high risk of adverse reactions, it has not been approved for marketing in other countries. Since the listing of Arbidol, the structural optimization aiming to improve the activity of Arbidol has never stopped, but no new Arbidol derivatives have entered the clinic. Further studies on the mechanism of action found that Arbidol targets hemagglutinin (HA) and exerts anti-influenza virus activity by increasing the stability of HA.

[0005] The present invention aims to design a series of new indole compounds based on the binding mode of Arbidol and HA, using Arbidol as a lead compound, in order to obtain antiviral candidate molecules with better activity. Summary of the Invention

[0006] The first object of the present invention is to provide a new class of indole compounds with ideal antiviral activity.

[0007] The second object of the present invention is to provide a composition containing the above indole compound.

[0008] The third object of the present invention is to provide a preparation method of the above indole compound.

[0009] The fourth object of the present invention is to provide the application of the above indole compound in the field of anti-tumor.

[0010] To achieve the above objects, the technical solutions adopted by the present invention are as follows:

[0011] As used in the description of the embodiments of the present invention and the appended claims, the singular forms "a", "an", "the", and "said" refer to both the singular and plural of the article, unless the context clearly indicates otherwise. For example, a compound includes one or more than one compound.

[0012] In a first aspect, the present invention provides an indole compound or a pharmaceutically acceptable salt thereof, and the structure of the indole compound is shown as Formula I:

[0013]

[0014] Wherein, R is selected from

[0015] Q is selected from O, NR1, CHR1;

[0016] m is selected from 1, 2 or 3; n is selected from 0, 1, 2 or 3;

[0017] R1 is selected from H, halogen, OH, C1-C5 alkyl, C1-C5 alkyl substituted with 1-3 halogens, C1-C4 alkoxycarbonyl, C1-C4 acyl;

[0018] As a preferred embodiment of the present invention, the halogen is F, Cl, Br, I;

[0019] The C1-C5 alkyl is selected from CH3, CH2CH3, CH(CH3)2, (CH2)2CH3, (CH2)3CH3, (CH2)4CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CH(CH3)(CH2)2CH3, CH2CH(CH2)2CH3, CH2C(CH2)3;

[0020] The C1-C4 alkoxycarbonyl is selected from CH3OC(O)-, CH3CH2OC(O)-, CH3(CH2)2OC(O)-, HC(CH3)2OC(O)-, C(CH3)3OC(O)-, CH3(CH2)3OC(O)-, CH(CH3)2CH2OC(O)-, CH3CH2CH(CH3)OC(O)-;

[0021] The C1-C4 acyl is selected from formyl, acetyl, propionyl, n-butyryl, isobutyryl.

[0022] As a preferred embodiment of the present invention, R1 is selected from H, OH, F, Cl, Br, CF3, CH3, C(CH3)3OC(O)-, acetyl.

[0023] As a preferred embodiment of the present invention, the indole compound includes the following structures:

[0024]

[0025] As a preferred embodiment of the present invention, the pharmaceutical salt is a salt formed by the indole compound shown in Formula I and an inorganic acid or an organic acid. The inorganic acids include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, etc.; organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, barmic acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, etc.

[0026] As a more preferred embodiment of the present invention, the pharmaceutical salt is the hydrochloride, phosphate, mesylate or sulfate of the compound shown in Formula I.

[0027] In a second aspect, the present invention provides a pharmaceutical composition which comprises an indole compound shown in Formula I or its pharmaceutical salt and any one of pharmaceutically acceptable carriers or excipients.

[0028] As used herein, the "pharmaceutical composition" contains a therapeutically effective amount of the indole compound shown in Formula I and its pharmaceutical salt, and one or more pharmaceutically acceptable carriers, and is prepared in the form of tablets, capsules, granules, powders, suspensions, emulsions, powders, solutions, gels, syrups, pills, tinctures, medicated wines, decoction extracts, lozenges, mixtures, suppositories, injections, inhalants or sprays, etc. The pharmaceutical composition preferably contains 0.1%-99.5% by weight of the poly-substituted benzheterocyclic compound of the present invention or its pharmaceutical salt as an active ingredient, and more preferably contains 0.5%-99.5% by weight of the active ingredient.

[0029] As used herein, "pharmaceutically acceptable carriers or excipients" include: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, thickening agents, antioxidants, preservatives, stabilizers, surfactants and buffering agents. Those skilled in the art will understand that certain pharmaceutically acceptable excipients can be used with more than one function and with alternative functions, depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. For example: When used orally, oral formulations can be prepared, such as tablets, capsules, granules, pills, etc., containing fillers (such as sugar derivatives like lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives like corn starch, potato starch, dextrin and carboxymethyl starch; cellulose derivatives like crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose; gum arabic; dextran; silicate derivatives like magnesium aluminum metasilicate; phosphate derivatives like calcium phosphate; carbonate derivatives like calcium carbonate; sulfate derivatives like calcium sulfate, etc.), binders (such as gelatin, polyvinylpyrrolidone and polyethylene glycol), disintegrants (such as cellulose derivatives like sodium carboxymethyl cellulose, polyvinylpyrrolidone), lubricants (such as talc, calcium stearate, magnesium stearate, cetyl alcohol, boric acid, sodium benzoate, leucine), stabilizers (methyl paraben, propyl paraben, etc.), flavoring agents (such as common sweetening agents, souring agents and fragrances, etc.). When used parenterally, injectables can be prepared, including sterile powders for injection and solvents for injection, and the carriers or excipients used include sterile water, Ringer's solution and isotonic sodium chloride solution. Appropriate additives such as antioxidants, buffering agents and bacteriostatic agents can also be added according to the nature of the drug. When used for rectal administration, the drug can be made into suppositories, etc. When used for pulmonary administration, the drug can be made into inhalants or sprays, etc. There are many resources available to those skilled in the art that describe pharmaceutically acceptable excipients and can be used to select suitable pharmaceutically acceptable excipients, such as books like "Remington: The Science and Practice of Pharmacy", "Chinese Pharmaceutical Yearbook", "Pharmaceutics", etc.

[0030] In a third aspect, the present invention provides a method for preparing the indole compound represented by the above formula I, which comprises the following steps:

[0031]

[0032] The high temperature is 60 - 85 °C.

[0033] Although the compounds of the present invention can be prepared by the methods as described above, the conditions of the methods, such as reactants, solvents, acids, bases, amounts of compounds used, reaction temperatures, reaction times, etc., are not limited to the following descriptions. Various combinations of synthetic methods described in this specification or known to those skilled in the art can also be optionally used to conveniently prepare the compounds of the present invention, and those skilled in the art of the present invention can easily make such combinations.

[0034] The fourth aspect of the present invention provides an application of the indole compound shown in the above formula I or its pharmaceutically acceptable salt in the preparation of antiviral drugs.

[0035] As some preferred embodiments of the present invention, the antiviral agents are selected from anti-influenza virus, anti-hepatitis B virus, anti-hepatitis C virus, anti-Ebola virus, and anti-coronavirus.

[0036] The beneficial effects produced by adopting the above technical solutions are as follows:

[0037] The compounds developed and studied in the present invention have been verified to have antiviral activities equivalent to or better than those of arbidol and are expected to become potential antiviral drugs. Description of the Drawings

[0038] Figure 1 It is the survival rate curve of mice in Biological Example 2 of this application, where Control is the negative control group, APB (200 mg / kg) is the ARB group, Compound 10 (200 mg / kg) is the Compound 10 group of Example 10 at 200 mg / kg, and Compound 10 (100 mg / kg) is the Compound 10 group of Example 10 at 100 mg / kg. Detailed Embodiments

[0039] The present invention will be described below in conjunction with specific embodiments. These embodiments are not intended to limit the scope of the present invention, but to provide guidance for those skilled in the art to prepare and use the compounds, compositions, and methods of the present invention. For those conditions not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. For reagents or instruments whose manufacturers are not specified, they are all conventional products that can be obtained through commercial purchase.

[0040] The chemical names of the compounds described in this application are usually generated from ChemDraw Ultra (ChambridgeSoft) and / or generally follow the principles of IUPAC nomenclature.

[0041] Example 1

[0042]

[0043] Pyridine (0.55 mL, 68.5 mmol) was added to a solution of compound A (500 mg, 2.28 mmol) in acetic anhydride (4.3 mL, 45.7 mmol), and the mixture was refluxed for 1 h. The reaction was monitored by TLC until completion, and then quenched by slowly adding saturated aqueous sodium bicarbonate solution (40 mL). The mixture was extracted with ethyl acetate (3×40 mL), washed with water (40 mL), dried over anhydrous sodium sulfate, and concentrated to obtain white solid compound B (571 mg, yield 96%).

[0044] Under ice-bath cooling, iodomethane (815 mg, 5.74 mmol) and sodium hydride (115 mg, 4.79 mmol) were added to a solution of compound B (500 mg, 1.91 mmol) in DMF (5.5 mL), and the mixture was stirred at the same temperature for 1.5 h. The reaction was monitored by TLC until completion, and then quenched by adding a small amount of water (5.0 mL). The mixture was extracted with ethyl acetate (3×40 mL), washed with water (40 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound C (500 mg, yield 95%).

[0045] Benzoyl peroxide (31 mg, 0.13 mmol) was added to a solution of compound C (500 mg, 1.16 mmol) in carbon tetrachloride (5 mL), and then dry bromine (276 μL, 5.38 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to reflux, and the reaction was monitored by TLC until completion. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 20 minutes until the orange color in the solution disappeared. An equal volume of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound D (625 mg, yield 80%).

[0046] 3-Hydroxybenzenethiol (146 mg, 1.16 mmol) was added to a solution of sodium hydroxide (46 mg, 1.15 mmol) in methanol (6 mL), and the mixture was stirred at room temperature for 2 h. Compound D (500 mg, 1.16 mmol) was added, and the reaction was carried out at room temperature under argon protection. The reaction was monitored by TLC until completion, and the pH was adjusted to 5 with glacial acetic acid to precipitate a solid. The solid was filtered, an equal volume of water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound E (476 mg, yield 86%).

[0047] Sodium hydroxide (33 mg, 0.825 mmol) was added to a solution of compound E (400 mg, 0.836 mmol) in methanol (5 mL), and the reaction was carried out at room temperature. The reaction was monitored by TLC until completion, and the pH was adjusted to 5 with glacial acetic acid to precipitate a solid. The solid was filtered, an equal volume of water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain compound F (291 mg, yield 80%).

[0048] To a solution of pyrrolidine (20 mg, 0.282 mmol) and paraformaldehyde (8 mg, 0.264 mmol) in 1,4-dioxane, stir at 70 - 80 °C for 0.5 h. Then add compound F (100 mg, 0.229 mmol), protect with argon, monitor the reaction by TLC until completion, remove 1,4-dioxane under vacuum, and separate and purify by preparative liquid chromatography. Thus, compound 1 (10 mg, yield 9%) was obtained. 1 H NMR (500 MHz, CDCl3) δ 7.41 (s, 1H), 7.07 (t, J = 7.9 Hz, 1H), 6.79 (d, J = 6.6 Hz, 2H), 6.70 (s, 1H), 4.60 (s, 2H), 4.22 (q, J = 7.0, 5.2 Hz, 4H), 3.46 (d, J = 4.7 Hz, 3H), 2.91 (s, 4H), 1.92 (q, J = 3.6 Hz, 4H), 1.32 (t, J = 7.1 Hz, 4H). 13 C NMR (151 MHz, CDCl3) δ 165.69, 157.58, 131.73, 129.82, 124.38, 122.44, 115.01, 113.30, 112.96, 109.73, 105.34, 60.52, 53.18, 45.64, 31.93, 30.10, 29.77, 29.70, 23.64, 14.28, 8.70; ESI-MS (m / z): 519 (M + H) + 。

[0049] Example 2

[0050]

[0051] The preparation method is the same as that of compound 1. Using piperidine instead of pyrrolidine, compound 2 can be obtained. 1 H NMR (500 MHz, DMSO) δ 7.69 (s, 1H), 7.10 (t, J = 8.1 Hz, 1H), 6.80–6.71 (m, 2H), 6.66 (d, J = 8.3 Hz, 1H), 4.59 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 4.05 (s, 2H), 3.65 (s, 3H), 1.56 (dd, J = 10.9, 5.6 Hz, 4H), 1.24 (s, 6H), 1.11 (t, J = 7.4 Hz, 3H). 1313C NMR (151 MHz, DMSO) δ 165.35, 158.17, 150.85, 142.12, 135.86, 131.76, 130.37, 124.03, 121.64, 117.75, 114.81, 113.36, 112.64, 107.75, 105.67, 60.38, 58.94, 53.34, 46.17, 40.55, 31.74, 30.61, 29.19, 29.08, 25.82, 23.87, 14.54, 14.41. ESI-MS (m / z): 533 (M+H) + 。

[0052] Example 3

[0053]

[0054] The preparation method is the same as that of Compound 1. Compound 3 can be obtained by using morpholine instead of pyrrolidine. 1 1H NMR (600 MHz, CDCl3) δ 7.42 (s, 1H), 7.11 (t, J = 8.3 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.76–6.72 (m, 2H), 4.38 (s, 2H), 4.24 (dd, J = 13.2, 6.0 Hz, 4H), 3.76 (s, 4H), 3.55 (s, 3H), 2.66 (s, 4H), 1.33 (t, J = 7.2 Hz, 3H). 13 13C NMR (151 MHz, CDCl3) δ 165.67, 156.35, 150.72, 141.82, 135.73, 132.10, 130.02, 124.34, 123.79, 118.44, 114.99, 112.91, 112.13, 108.22, 106.01, 66.64, 66.59, 60.56, 58.59, 53.42, 52.84, 52.61, 52.53, 45.85, 30.18, 30.02, 29.70, 14.34, 14.18, 8.57. ESI-MS (m / z): 535 (M+H) + 。

[0055] Example 4

[0056]

[0057] The preparation method is the same as that of Compound 1. Compound 4 can be obtained by using 4-methylpiperidine instead of pyrrolidine. 11H NMR (500 MHz, CDCl3) δ 7.41 (s, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.74 (dd, J = 8.2, 2.4 Hz, 1H), 6.62 (t, J = 2.1 Hz, 1H), 4.33 (s, 2H), 4.23 (q, J = 7.1 Hz, 2H), 4.14 (s, 2H), 3.48 (s, 3H), 3.09–3.02 (m, 2H), 1.68 (d, J = 13.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 4H), 1.27–1.24 (m, 3H). 13 13C NMR (151 MHz, CDCl3) δ 165.72, 156.90, 141.50, 131.57, 129.96, 124.36, 122.42, 116.86, 114.59, 112.85, 105.56, 60.54, 30.05, 29.70, 29.28, 14.28, 14.11, 8.64. ESI-MS (m / z): 545 (M+H) + .

[0058] Example 5

[0059]

[0060] The preparation method is the same as that of Compound 1. Compound 5 can be prepared by using 4-hydroxypiperidine instead of pyrrolidine. 1 1H NMR (500 MHz, DMSO) δ 7.43 (s, 1H), 6.84 (t, J = 8.0 Hz, 1H), 6.49 (d, J = 7.4 Hz, 2H), 6.41 (d, J = 7.2 Hz, 1H), 4.33 (s, 2H), 3.91 (q, J = 7.1 Hz, 2H), 3.82 (s, 2H), 3.39 (s, 3H), 2.49 (s, 2H), 2.05 (s, 2H), 1.51 (d, J = 12.9 Hz, 2H), 1.19 (s, 2H), 0.99 (t, J = 7.1 Hz, 3H). 13 13C NMR (151 MHz, DMSO) δ 164.76, 157.61, 150.23, 141.57, 135.28, 131.26, 129.75, 123.48, 121.13, 117.29, 114.29, 112.82, 112.27, 107.21, 105.18, 66.26, 59.78, 30.03, 28.61, 13.95; ESI-MS (m / z): 549 (M+H) + .

[0061] Example 6

[0062]

[0063] The preparation method is the same as that of Compound 1. Compound 6 can be prepared by using 4-fluoropiperidine instead of pyrrolidine. 1 H NMR(600MHz,CDCl3)δ7.43(s,1H),7.11(dd,J=8.6,7.6Hz,1H),6.86(d,J=7.7Hz,1H),6.75(d,J=6.8Hz,2H),4.40(s,2H),4.26(s,2H),4.22(q,J=7.1Hz,2H),3.56(s,3H),3.09(t,J=7.3Hz,1H),2.28(s,2H),2.08(s,2H),1.91(d,J=12.8Hz,2H),1.78–1.70(m,2H),1.32(t,J=7.1Hz,3H). 13 CNMR(151MHz,CDCl3)δ165.70,156.30,150.97,141.84,135.75,132.08,130.03,124.27,123.81,118.42,114.99,112.86,112.43,108.26,60.56,51.46,45.94,30.19,30.07,29.70,24.37,14.30,8.58;ESI-MS(m / z):551(M+H) + 。

[0064] Example 7

[0065]

[0066] The preparation method is the same as that of Compound 1. Compound 7 can be prepared by using 4-chloropiperidine instead of pyrrolidine. 1 H NMR(600MHz,CDCl3)δ7.43(s,1H),7.11(dd,J=8.6,7.6Hz,1H),6.86(d,J=7.7Hz,1H),6.75(d,J=6.8Hz,2H),4.40(s,2H),4.26(s,2H),4.22(q,J=7.1Hz,2H),3.56(s,3H),3.09(t,J=7.3Hz,1H),2.28(s,2H),2.08(s,2H),1.91(d,J=12.8Hz,2H),1.78–1.70(m,2H),1.32(t,J=7.1Hz,3H). 13CNMR(151MHz,CDCl3)δ165.70,156.30,150.97,141.84,135.75,132.08,130.03,124.27,123.81,118.42,114.99,112.86,112.43,108.26,60.56,51.46,45.94,30.19,30.07,29.70,24.37,14.30,8.58;ESI-MS(m / z):567(M+H) + 。

[0067] Example 8

[0068]

[0069] The preparation method is the same as that of Compound 1. Compound 8 can be prepared by using 4-trifluoromethylpiperidine instead of pyrrolidine. 1 H NMR(600MHz,CDCl3)δ7.43(s,1H),7.11(dd,J=8.6,7.6Hz,1H),6.86(d,J=7.7Hz,1H),6.75(d,J=6.8Hz,2H),4.40(s,2H),4.26(s,2H),4.22(q,J=7.1Hz,2H),3.56(s,3H),3.09(t,J=7.3Hz,1H),2.28(s,2H),2.08(s,2H),1.91(d,J=12.8Hz,2H),1.78–1.70(m,2H),1.32(t,J=7.1Hz,3H). 13 C NMR(151MHz,CDCl3)δ165.70,156.30,150.97,141.84,135.75,132.08,130.03,124.27,123.81,118.42,114.99,112.86,112.43,108.26,105.96,60.56,51.46,45.94,30.19,30.07,29.70,24.37,14.30,8.58;ESI-MS(m / z):601(M+H) + 。

[0070] Example 9

[0071]

[0072] The preparation method is the same as that of Compound 1. Compound 9 can be prepared by using N-Boc piperazine instead of pyrrolidine. 11H NMR (500 MHz, CDCl3) δ 7.43 (s, 1H), 7.12 (t, J = 8.3 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.78–6.69 (m, 2H), 4.44 (s, 2H), 4.21 (dd, J = 14.5, 7.4 Hz, 4H), 3.54 (d, J = 46.1 Hz, 7H), 1.46 (s, 9H), 1.32 (t, J = 7.1 Hz, 3H). 13 13C NMR (151 MHz, CDCl3) δ 165.60, 156.13, 154.50, 150.76, 141.75, 135.69, 132.12, 130.02, 124.30, 124.12, 118.69, 114.98, 112.84, 108.14, 106.09, 80.14, 60.52, 58.11, 51.98, 50.89, 30.20, 30.13, 29.33, 28.40, 27.22, 14.31, 14.11; ESI-MS (m / z): 634 (M + H) + .

[0073] Example 10

[0074]

[0075] The preparation method is the same as that of Compound 1. Compound 10 can be obtained by using N-methylpiperazine instead of pyrrolidine. 1 1H NMR (500 MHz, CDCl3) δ 7.41 (s, 1H), 7.08 (t, J = 8.0 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 6.76–6.69 (m, 2H), 4.38 (s, 2H), 4.26–4.15 (m, 4H), 3.56 (s, 3H), 2.79 (d, J = 128.1 Hz, 8H), 2.32 (s, 3H), 1.30 (s, 3H). 13 13C NMR (151 MHz, CDCl3) δ 165.59, 156.70, 150.88, 141.66, 135.53, 131.96, 129.93, 124.18, 123.63, 118.74, 115.10, 112.66, 112.43, 108.19, 106.08, 60.50, 58.30, 54.56, 51.82, 45.73, 45.60, 30.14, 29.94, 29.70, 14.33; ESI-MS (m / z): 548 (M + H) + .

[0076] Biological Example 1

[0077] Experimental cells: MDCK cells were seeded into 96-well plates at a density of 2×10 4 cells / well and cultured at 37°C and 5% CO2 for 24 h. When the cell density reached about 80%, the antiviral activity detection experiment of the drug was carried out.

[0078] Test drugs: The starting concentration of the compounds in each example, the control drug arbidol (ARB, control group 1), the control drug ribavirin (RBV, control group 2), and the control drug BMCL-11 (BMCL-11, control group 3) was 5 mM, and they were serially diluted 2-fold with DMSO for 8 concentrations.

[0079] Experimental viruses: Single-round infection viruses of 6 influenza subtypes (influenza A virus: group 1 (H1N1, H5N1), group 2 (H3N2, H7N7); Yamagata / Phuket (B-P), Victoria / Washington (B-W)) (HA gene was replaced with Gluc, and different subtypes of HA proteins were supplemented externally. The virus could only complete single-round infection and could not replicate) were diluted to 100 CCID50 / mL with DMEM medium containing 2% fetal bovine serum.

[0080] Detection method:

[0081] Discard the culture supernatant of the 96-well plate pre-filled with MDCK cells, inoculate 100 μL / well of the virus dilution solution of 100 CCID50 / mL into the 96-well plate, and then add the test drug at a ratio of 1:100. Culture at 37°C and 5% CO2 for 4 h, discard the culture supernatant, replace it with a new DMEM medium containing 2% fetal bovine serum, and supplement the drug at the same concentration at the same time. Continue to culture for 48 h. The virus infection level was judged by detecting the activity of secreted luciferase (Gluc) released in the culture supernatant, and the inhibition rate was calculated by comparing with the DMSO group. IC was calculated using GraphPad Prism 8 50 .

[0082] The results of the compounds against H1 virus in this application are shown in Table 1. The inhibitory activities of most compounds against IAV H1N1 are better than those of ARB (arbidol) and the compound BMCL-11 reported in the literature (Bioorg. Med. Chem. Lett., 2017, 27, 3744).

[0083] Table 1 Anti-IAV H1N1 activity

[0084]

[0085]

[0086] The antiviral activities of Compound 10 of the present application against different virus strains are shown in Table 2. The results indicate that the compounds in the present application possess antiviral activities equivalent to or superior to those of Arbidol, Ribavirin, and BMCL-11.

[0087] Table 2 Antiviral activities against different viruses

[0088]

[0089] In vivo antiviral activities of some compounds in Biological Example 2

[0090] In this experiment, BALB / c mice were selected and randomly divided into 4 groups, with 5 mice in each group.

[0091] Virus strain: Influenza A virus PR8 (H1N1).

[0092] Group: 1. Negative control group: 0.2 ml of normal saline.

[0093] 2. ARB group: 0.2 ml of normal saline containing ARB, and the dosage of ARB is 200 mg / kg.

[0094] 3. 200 mg / kg Compound 10 of Example 10 group: 0.2 ml of normal saline of Compound 10 of Example 10, and the dosage of Compound 10 is 200 mg / kg.

[0095] 4. 100 mg / kg Compound 10 of Example 10 group: 0.2 ml of normal saline of Compound 10 of Example 10, and the dosage of Compound 10 is 100 mg / kg.

[0096] Gavage administration was started 1 day before virus challenge, once a day for 7 consecutive days. On the day of virus challenge, the mice were slightly anesthetized and then instilled with PR8 virus solution through the trachea. The challenge dose was 10 LD50. From the day of virus challenge, the survival rate of the mice within 14 days was recorded. The results are as Figure 1 shown. The results indicate that the survival rate of the mice in the 200 mg / kg Compound 10 of Example 10 group is significantly superior to that of the ARB group; the 100 mg / kg Compound 10 of Example 10 group is also superior to the ARB group.

[0097] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features. However, such modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. An indole compound or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the indole compound is shown in Formula I: Among them, R is selected from Q is selected from O, NR1, CHR1; m is selected from 1, 2 or 3; n is selected from 0, 1, 2 or 3; R1 is selected from H, halogen, OH, C1-C5 alkyl, C1-C5 alkyl substituted with 1-3 halogens, C1-C4 alkoxycarbonyl, C1-C4 acyl.

2. An indole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The halogen is F, Cl, Br, I; The C1-C5 alkyl group is selected from CH3, CH2CH3, CH(CH3)2, (CH2)2CH3, (CH2)3CH3, (CH2)4CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CH(CH3)(CH2)2CH3, CH2CH(CH2)2CH3, CH2C(CH2)3; The C1-C4 alkoxycarbonyl group is selected from CH3OC(O)-, CH3CH2OC(O)-, CH3(CH2)2OC(O)-, CH(CH3)2OC(O)-, C(CH3)3OC(O)-, CH3(CH2)3OC(O)-, CH(CH3)2CH2OC(O)-, CH3CH2CH(CH3)OC(O)-; The C1-C4 acyl group is selected from formyl, acetyl, propionyl, n-butyryl, and isobutyryl.

3. An indole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R1 is selected from H, OH, F, Cl, Br, CF3, CH3, C(CH3)3OC(O)-, and acetyl.

4. An indole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The indole compounds include the following structure:

5. An indole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The pharmaceutically acceptable salt is the hydrochloride, phosphate, methanesulfonate or sulfate of the compound represented by formula I.

6. A pharmaceutical composition, characterized in that It comprises the indole compound represented by formula I in claim 1 or a pharmaceutically acceptable salt thereof and any pharmaceutically acceptable carrier or excipient.

7. A method for preparing an indole compound of formula I as claimed in any one of claims 1 to 5, characterized in that: It includes the following steps: The high temperature is 60-85°C.

8. Use of an indole compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5 in the preparation of an antiviral drug.

9. The use according to claim 8, characterized in that: The antiviral agent is selected from anti-influenza virus, anti-hepatitis B virus, anti-hepatitis C virus, anti-Ebola virus, and anti-coronavirus.

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