Novel Anti-viral compound and use thereof

Abstract

The present invention relates to the field of anti-infection drugs. Disclosed is a novel anti-viral compound. The structure of the novel anti-viral compound is shown in formula (I). The compound of formula (I) has an excellent anti-influenza virus effect, highly effective anti-viral activity against influenza A / B viruses, and anti-viral potential against influenza A / B virus variations.

Description

A novel antiviral compound and uses thereof TECHNICAL FIELD

[0001] The present application relates to the field of anti-infective drugs, in particular to a novel antiviral compound and uses thereof. BACKGROUND

[0002] According to the prevalence and scale, influenza can be divided into pandemic influenza, seasonal influenza and other highly pathogenic influenza (H5N1, H7N9, etc.). Since the 20th century, there have been six influenza pandemics in the world, and the "Spanish flu" in 1918 alone resulted in at least 50 million deaths. The harm of influenza virus to human health and the impact on the global economy are self-evident. During the COVID-19 pandemic, due to the impact of epidemic control measures, the number of influenza cases has continued to decline. But with the decline of the epidemic, in the 2022-2023 influenza season, the number of influenza cases in the country increased again, reaching 2.47 million cases, and some areas experienced "one drug in short supply". According to the "Global Strategy for Influenza, 2019-2030" released by the World Health Organization (WHO), influenza can spread rapidly around the world during an outbreak, affecting 10-20% of the total population. Even in non-outbreak years, seasonal influenza causes about 3-5 million severe cases and 290,000-650,000 deaths worldwide each year.

[0003] On the one hand, the incidence of influenza is high, and on the other hand, influenza viruses are prone to variation, and the extensive use of drugs targeting viral targets has further accelerated the emergence of drug-resistant variants, greatly affecting the therapeutic effect of drugs. Influenza virus M2 ion channel inhibitors amantadine and rimantadine have been basically eliminated from the market due to drug resistance. Oseltamivir, a neuraminidase inhibitor, has been used for more than 20 years, and literature reports that the sensitivity of the drug to a variety of influenza A virus strains has decreased significantly, and it must be used within 48 hours of infection to be effective.

[0004] Influenza virus is an RNA virus, and according to the antigenicity of viral nucleoprotein, influenza is divided into four types: A, B, C and D (or A, B, C and D), and the latter two types do not infect humans. Compared with influenza B virus, influenza A virus (including avian influenza) infection can cause higher morbidity and mortality. Therefore, the development of new drugs against influenza virus, especially new drugs against influenza A / B virus, is particularly important. SUMMARY

[0005] In order to solve the problem of drug resistance of existing influenza drugs and reduce the harm of influenza viruses to human health, the present application provides a new antiviral compound, the compound of the present application has excellent anti-influenza virus effect, has high antiviral activity on influenza A and B viruses, has antiviral potential to cope with influenza A and B virus variation, and also has antiviral activity on different subtypes of influenza A virus resistant to oseltamivir and marbovir.

[0006] In order to achieve the purpose of the present application, the present application provides a compound as shown in the following formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates thereof, and stereoisomers, tautomers, or isotopic forms thereof:

[0007] Among them:

[0008] X3 is =CR5- or -N(C 1-3 alkylene-Si(CH3)3)-, X4 is =CR4- or -N(C 1-3 alkylene-Si(CH3)3)-, and only one of X3 and X4 is -N(C 1-3 alkylene-Si(CH3)3)-;

[0009] The dotted line represents the presence or absence of a bond, when X3 is -N(C 1-3 alkylene-Si(CH3)3)-, the dotted line connected with X3 represents the absence of a bond, and the dotted line connected with X4 represents the presence of a bond; when X4 is -N(C 1-3 alkylene-Si(CH3)3)-, the dotted line connected with X4 represents the absence of a bond, and the dotted line connected with X3 represents the presence of a bond;

[0010] A is

[0011] R1, R2, R3, R4, R5, R6, R7, R8 and R9 are each independently H, D, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, -OH, -CN, -NH2;

[0012] R 10 is OR a , -NR a R b , C 1-3 alkyl-COOH, C 0-6 silyl, C 1-6 alkyl or C 3-6 cycloalkyl, the C 1- 3alkyl-COOH, C 0-6 silyl, C 1-6 alkyl, C3-6 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, CI, Br, CN, N02, NH2, OH, or cyclopropyl;

[0013] R a and R b each independently H, D, C 0-6 silyl, C 1-6 alkyl, or C 3-6 alkyl;

[0014] X1, X2are each independently selected from -CH- or nitrogen.

[0015] Further, in some embodiments of the present application, R6, R7, R8, and R9are H.

[0016] Further, in some embodiments of the present application, A is

[0017] Further, in some embodiments of the present application, R 10 is -OH, -C 1-3 alkyl, -NH2, or -O-C 1-3 alkyl.

[0018] Further, in some embodiments of the present application, R1is H, D, F, CI, Br, -OH, NH2, preferably F, CI, Br, -OH, NH2.

[0019] Further, in some embodiments of the present application, R2is H, D, F, CI, Br, NH2, preferably H, D, F, CI, Br.

[0020] Further, in some embodiments of the present application, R3is H, D, F, CI, Br, C 1-3 alkyl, C 1-3 haloalkyl, preferably H, methyl, halo-methyl.

[0021] Further, in some embodiments of the present application, R4and R5are each independently H, D, F, CI, Br, preferably H, D, F, CI, Br.

[0022] Further, in some embodiments of the present application, X1is -CH-, and X2is -CH-.

[0023] Further, in some embodiments of the present application, X1is nitrogen, and X2is -CH-.

[0024] Further, in some embodiments of the present application, X1is -CH- and X2is nitrogen.

[0025] Further, in some embodiments of the present application, X1is nitrogen and X2is nitrogen.

[0026] Further, in some embodiments of the present application, the present application provides a compound as shown below and pharmaceutically acceptable salts, esters, prodrugs, solvates thereof, and stereoisomers, tautomers, or isotopically enriched forms thereof:

[0027] The present application further relates to a pharmaceutical composition comprising a compound of the present application, as described above, a pharmaceutically acceptable salt, ester, prodrug, solvate thereof, a stereoisomer, tautomer, or isotopically enriched form thereof, and a pharmaceutically acceptable carrier or excipient.

[0028] In a preferred embodiment of the present application, the pharmaceutical composition is an oral administration formulation, a parenteral administration formulation (such as a subcutaneous administration formulation or an intravenous injection formulation), or an inhalation spray formulation.

[0029] The present application further provides the use of a compound of the present application, as described above, a pharmaceutically acceptable salt, ester, prodrug, solvate thereof, a stereoisomer, tautomer, or isotopically enriched form thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating or preventing a viral infection in a subject, wherein the viral infection is an influenza virus infection.

[0030] The present application further provides the use of a compound of the present application, as described above, a pharmaceutically acceptable salt, ester, prodrug, solvate thereof, a stereoisomer, tautomer, or isotopically enriched form thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating a respiratory disease in a subject, wherein the respiratory disease is an influenza virus infection.

[0031] In an embodiment of the present application, the influenza virus is influenza A and / or influenza B, preferably influenza A and influenza B, and more preferably influenza A. DETAILED DESCRIPTION

[0032] In order to make the objects, technical solutions and advantages of the present application clearer, the present application will be further described in detail below with reference to the accompanying drawings and examples. Additional aspects and advantages of the present application will be partially given in the following description, partially become obvious from the following description, or be understood by practice of the present application. It should be understood that the following description is only used to explain the present application, and is not used to limit the present application.

[0033] The indefinite articles "a" and "an," as used herein in the specification and in claims (if any), are defined as meaning one or at least one, unless specified otherwise or clear from context. Thus, phrases such as "a compound" and "an element" encompass the use of one or at least one such compound or element. As used herein in the specification and in claims (if any), the use of the singular is also meant to include the plural unless otherwise specified or clear from context. Conjunctive language such as the phrase "at least one of," unless specifically stated otherwise, is understood to allow for the presence of one or more of the enumerated items.

[0034] The terms "one embodiment," "some embodiments," "an example," "some examples," or "one example" as used herein describe specific embodiments or examples, but do not preclude the presence or addition of one or more other features or characteristics not mentioned in connection with the embodiment or example. The description herein of one or more embodiments or examples does not preclude the presence or addition of one or more other features or characteristics not mentioned in connection with the embodiment or example. The various embodiments described herein can be combined in different ways to provide various combinations of the features and characteristics described herein.

[0035] Unless otherwise indicated, the terms used in the specification and claims are defined as follows.

[0036] The term "alkyl" as used herein refers to a saturated, straight-chain or branched-chain hydrocarbon group. "C 1- "C4alkyl," "C 1- "C6alkyl," "C2-C4alkyl," or "C3-C6alkyl" refers to an alkyl group having from 1 to 4, 1 to 6, 2 to 4, and 3 to 6 carbon atoms, respectively. Examples of C1-C6alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyl.

[0037] The term "cycloalkyl" as used herein refers to a monocyclic or polycyclic saturated carbocyclic compound, or a bicyclic or tricyclic fused, bridged, or spiro system, and the carbon atoms can optionally be substituted with oxygen, or optionally with exocyclic olefinic double bonds.

[0038] The term "substituted" as used herein means that one, two or three or more hydrogen atoms are independently replaced with the substituents described below. Preferably, the substituted alkyl, cycloalkyl, silyl groups can be further substituted with one or more D, F, Cl, Br.

[0039] The compounds of the present application can be modified by the addition of appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and can include increasing the bio-penetration into a particular biological system (e.g., blood, lymphatic system, central nervous system), increasing oral availability, increasing solubility to allow administration by injection, altering the metabolism of the drug, and altering the rate of excretion, among others.

[0040] The term "pharmaceutically acceptable salt" means a salt of a compound of the present application, which is within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and commensurate with a reasonable benefit / risk ratio.

[0041] The term "pharmaceutically acceptable ester" means an ester of the present application that is hydrolyzed in the human body to form the parent compound or a salt thereof.

[0042] The term "prodrug" also known as drug precursor, drug precursor, prodrugs, etc. means a compound that is inactive or less active in vitro, but is converted into an active drug in vivo by enzymatic or non-enzymatic transformation to exert its pharmacological effect.

[0043] The term "subject" in the term "in vivo in a subject" includes humans and animals.

[0044] Antiviral activity

[0045] In certain embodiments, the present application provides a method for treating or preventing a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt, ester, prodrug, solvate thereof, and stereoisomers thereof. The virus is selected from the group consisting of influenza A virus, influenza B virus, influenza C virus, preferably from the group consisting of influenza A virus and influenza B virus. Preferably, the influenza A virus is selected from the group consisting of H1N1, H2N2, H3N2, H5N1, H7N1, H7N2, H7N3, H7N7, H7N9, H9N2 and H10N8 subtypes.

[0046] According to the method of treatment of the present application, a viral infection, disorder in a host, wherein the host is a human or another animal, is treated or prevented by administering to the patient a therapeutically effective amount of a compound of the present application, wherein the amount and frequency of administration are those necessary to achieve the desired result.

[0047] Synthetic methods

[0048] The compounds and methods of the present application will be better understood in connection with the following synthetic schemes that illustrate the methods of preparing the compounds of the present application, which are intended merely as an exemplification of the present application and not as a limitation thereof. Various changes and modifications that are obvious to one of skill in the art are intended to be within the spirit and scope of the application, including (without limitation) changes and modifications related to the chemical structures, substituents, derivatives, and / or methods of the present application.

[0049] The 1a, 2a, 1A, 2A, 1b, 2b, 1B, 2B, etc. in the steps of the operation of the embodiments of the present application are only for the convenience of referring to a certain compound in a specific synthetic process route, and the compounds referred to by 1a, 1A, 1b, 1B, etc. in different embodiments are not necessarily the same or different unless otherwise specified.

[0050] Example 1

[0051] The synthetic process route of the compound C1-229 is as shown below:

[0052] 1. Preparation of intermediate 2a

[0053] At room temperature, 1a (20 g, 106.38 mmol) and 1b (29.84 g, 127.66 mmol) were dissolved in N,N-dimethylformamide (200 mL), and N,N-diisopropylethylamine (41.25 g, 319.14 mmol) was slowly added. After the addition was completed, the temperature was raised to 100°C and reacted for 12 hours. LC-MS showed that the reaction had been completed. After cooling to room temperature, the reaction solution was poured into 5000 mL of water, and extracted with 600 mL*3 of ethyl acetate three times. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2a. LC-MS (ESI+): m / z = 349.3 [M+H] + .

[0054] 2. Preparation of intermediate 3a

[0055] At room temperature, 2a (40 g, 114.67 mmol) was dissolved in DCM (250 mL), and then HBr / AcOH (33%, 250 mL) was slowly added to the reaction system. After the addition was completed, the reaction was carried out at 25°C for 2 hours. LC-MS monitoring showed that the reaction had been completed. The reaction solution was concentrated under reduced pressure, and the residue was poured into 1000 mL of ice saturated potassium carbonate aqueous solution. The organic phase was extracted with 1000 mL*3 of ethyl acetate three times, washed with 1000 mL*2 of saturated potassium carbonate solution twice, and washed with 1000 mL*1 of saturated brine once. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3a. LC-MS (ESI+): m / z = 393.3 [M+H] +.

[0056] 3. Preparation of intermediate 4a

[0057] 3a (40 g, 10.17 mmol) was dissolved in methanol (100 mL) and THF (120 mL) at room temperature. Sodium hydroxide aqueous solution (8.14 g, 203.42 mmol dissolved in 150 ml water) was added slowly into the reaction system at room temperature. After the addition, the reaction system was warmed to 25 °C for 12 hours. LC-MS showed that the reaction had been completed. The reaction system was cooled to room temperature, and 1M dilute hydrochloric acid solution was slowly added to the reaction solution to adjust the pH value to 4. Ethyl acetate was extracted three times with 500 mL*3, and the combined organic phase was washed once with 500 mL*1 saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4a. LC-MS (ESI+): m / z = 365.2 [M+H] + .

[0058] 4. Preparation of intermediate 5a

[0059] 4a (38 g, 104.04 mmol) was dissolved in tetrahydrofuran (300 mL). N,N- diisopropyl-O-tert-butylisourea (83.37 g, 416.16 mmol) was added, and stirred at 70 °C for 30 minutes. LC-MS showed that the reaction had been completed. The reaction solution was cooled to room temperature, poured into ice water 1000 mL, and ethyl acetate 1000 mL was added, stirred, filtered, and the filtrate was separated into the upper organic phase, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (n-heptane: ethyl acetate = 5:1) to obtain 5a. LC-MS (ESI+): m / z = 421.3 [M+H] + .

[0060] 5. Preparation of intermediate 6a

[0061] 5a (38 g, 90.19 mmol) was dissolved in N,N-dimethylformamide (190 mL). Cesium carbonate (58.77 g, 180.38 mmol) was added, and stirred at 25 °C for 30 minutes, and then trimethylsilyl iodide (14.75 mL, 99.21 mmol) was slowly added to the reaction system. After the addition, the reaction system was stirred at 25 °C for 1 hour. LC-MS showed that the reaction had been completed. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (n-heptane: ethyl acetate = 10:1) to obtain 6a. LC-MS (ESI+): m / z = 509.0 [M+H] + .

[0062] 6. Preparation of intermediate 7a

[0063] Dissolve 6a (6.4 g, 12.61 mmol) in dichloromethane (30 mL). At 25 °C, trifluoroacetic acid (30 mL, 402.5 mmol) is slowly added to the reaction system. After addition, the reaction system is stirred at 25 °C for 2 hours. LC-MS shows that the reaction has been completed. The reaction solution is rotary evaporated, and the pH value is adjusted to 6 with saturated sodium bicarbonate solution. Ethyl acetate is extracted three times (50 mL*3), and the combined organic phase is washed with saturated brine once (100 mL*1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7a. LC-MS (ESI+): m / z = 453.3 [M+H] + .

[0064] 7. Synthesis of intermediate 8a

[0065] Add reactants 7a, IB, 1,4-dioxane, water, potassium phosphate, XPhos PG2 and XPhos to a reaction bottle, and protect it with nitrogen. The reaction solution is reacted at 95 °C, silica gel is added to the reaction solution, and column chromatography is used for purification to obtain the product 8a. LCMS (ESI+): m / z = 607.3 [M+1] + .

[0066] 9. Synthesis of compound C1-229

[0067] Add reactants 8a, DCM and TFA to a reaction bottle to obtain a solution; the reaction solution is reacted at room temperature, LCMS shows that the raw material has been completely reacted, and the reaction solution is concentrated. The crude product is purified by acetonitrile slurry to obtain the product C1-229. LCMS (ESI+): m / z = 507.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.65 (d, J = 9.6 Hz, 1H), 8.32 (s, 2H), 7.69 (s, 1H), 7.06 (s, 1H), 6.73 (s, 1H), 4.82 (s, 1H), 2.73 (d, J = 6.6 Hz, 1H), 2.03 (d, 2H), 1.91 - 1.70 (m, 3H), 1.68 - 1.39 (m, 5H), 0.07 (s, 9H).

[0068] Example 2

[0069] The synthesis process route of compound C1-230 is as shown below:

[0070] 1. Synthesis of intermediate 2A

[0071] To a reaction flask was added 1A (700 mg, 1.34 mmol) and THF (14 mL), the reaction was cooled to -30 °C with dry ice-acetone, then 1B (750 mg, 4.02 mmol) and isopropylmagnesium chloride (6.7 mL, 6.7 mmol, 1 M) were added, the reaction was continued at -20 to -10 °C for 2 h. To the reaction was added saturated aqueous sodium bicarbonate solution to quench the reaction, the aqueous phase was extracted with ethyl acetate (3*40 mL), the combined organic layers were washed with saturated NaCl solution (2*50 mL), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 2A, LCMS (ESI+): m / z = 521.4 [M+1] + .

[0072] 2. Synthesis of intermediate 3A

[0073] To a reaction flask was added 2A (400 mg, 0.77 mmol), 2B (380 mg, 0.77 mmol) and 2-methyltetrahydrofuran (8 mL), water (0.15 mL); then potassium phosphate (490 mg, 2.31 mmol), XPhos PG2 (60 mg, 0.077 mmol) and XPhos (37 mg, 0.077 mmol) were added, the reaction was protected with nitrogen, the reaction was carried out at 90 °C for 4 h. To the reaction was added silica gel for sample mixing, the crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 50:1-5:1) to give 3A. LC-MS (ESI+): m / z = 807.8 [M+H]+.

[0074] 3. Synthesis of intermediate 4A

[0075] To a reaction flask was added 3A (140 mg, 0.17 mmol) and DMSO (2 mL); 1 M aqueous lithium hydroxide solution (0.2 mL) was added, the reaction was carried out at room temperature for 3 days. LCMS showed that the starting material was completely reacted, the reaction was adjusted to neutral pH with 1 M aqueous hydrochloric acid solution, diluted with water (30 mL), the aqueous phase was extracted with ethyl acetate (3*40 mL), the combined organic layers were washed with saturated NaCl solution (2*50 mL), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 4A, LCMS (ESI+): m / z = 707.6 [M+1] + .

[0076] 3. Synthesis of intermediate 5A

[0077] To a reaction flask was added 4A (100 mg, 0.14 mmol) and DMF (3 mL) to give a yellow solution; to this was added cesium carbonate (114 mg, 0.35 mmol) and 4B (45 mg, 0.21 mmol) and the reaction was allowed to react at room temperature for 3.5 h. LCMS showed the reaction to be complete. The reaction was added dropwise to saturated ammonium chloride solution and the aqueous phase was extracted with ethyl acetate (3*25 mL), the organic layers were combined and washed with saturated NaCl solution (3*20 mL), the organic layers were combined and dried over anhydrous Na2S04, filtered and rotoevaporated; the crude product was purified by silica gel column chromatography (n-heptane: ethyl acetate = 50: 1 - 5: 1) to give 5A, LCMS (ESI+): m / z = 551.5 [M-Trt+1] + .

[0078] 4. Synthesis of final product 6A (Compound C1-230)

[0079] To a reaction flask was added 5A (95 mg, 0.12 mmol) and 33% hydrobromic acid in acetic acid (2 mL) to give a yellow solution; the reaction was allowed to react at 60 °C for 5 h. The reaction was concentrated and purified by silica gel plate (n-heptane: ethyl acetate = 1 :3) to give the product 6A, LCMS (ESI+): m / z = 523.5 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 9.01 (d, J = 2.4 Hz, 1H), 8.22 (dd, 1H), 7.20 (d, J = 6.9 Hz, 1H), 6.99 (d, J = 3.3 Hz, 1H), 6.60 (d, J = 3.3 Hz, 1H), 4.78 (d, J = 7.2 Hz, 1H), 3.82 (s, 2H), 2.71 (d, J = 6.9 Hz, 1H), 2.01 (s, 1H), 1.96 - 1.73 (m, 2H), 1.66 - 1.50 (m, 3H), 1.50 - 1.32 (m, 2H), 1.32 - 1.14 (m, 2H), 0.06 (s, 9H).

[0080] Example 3

[0081] The synthesis process route of compound C1-231 is shown below:

[0082] 1. Synthesis of intermediate 2A

[0083] Into a reaction vial, add reactant 1A, 1B and 1,4-dioxane, water; then add potassium phosphate, XPhos PdG2 and XPhos, protect with nitrogen, the reaction solution is reacted at 95 °C, LCMS shows that the raw material reaction is complete, the reaction solution is filtered through diatomite, the filtrate is concentrated, and the crude product is purified by silica gel large plate to obtain product 2A. LCMS (ESI+): m / z = 750.1 [M+1] + .

[0084] 2. Synthesis of final product 3A (compound C1-231)

[0085] Into a reaction vial, add reactant 2A, DCM and TFA to obtain a solution; the reaction solution is reacted at room temperature, LCMS shows that the raw material reaction is complete, the reaction solution is adjusted to pH 2 with 1M dilute hydrochloric acid aqueous solution, the aqueous phase is extracted with ethyl acetate, the combined organic layer is washed with saturated NaCl solution, the combined organic layer is dried over anhydrous Na2SO4, filtered and concentrated; the crude product is purified by silica gel large plate, and freeze-dried to obtain product 3A. LCMS (ESI+): m / z = 508.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.45 (s, 1H), 7.28 (s, 1H), 6.92 (s, 1H), 4.67 (s, 1H), 3.91 (s, 2H), 2.85 (s, 1H), 2.13 (d, J = 20.6 Hz, 2H), 1.78 (s, 2H), 1.52 (t, J = 27.6 Hz, 5H), 1.23 (d, J = 4.9 Hz, 1H), 0.08 (s, 9H).

[0086] Example 4

[0087] The synthesis process route of compound C1-232 is as follows:

[0088] 1. Preparation of intermediate 2a

[0089] Dissolve 1a and 1b in THF at room temperature. Then slowly add TEA. After addition, warm to 100 °C for reaction, LC-MS shows that the reaction has been completed. Cool to room temperature, pour the reaction solution into water, extract with ethyl acetate, dry the combined organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain solid 2a. The product does not need to be purified and can be directly used in the next reaction. LC-MS (ESI+): m / z = 349.4 [M+H] +

[0090] 2. Preparation of intermediate 3a

[0091] Dissolve 2a in DCM at room temperature, then slowly add HBr / AcOH solution to the reaction system. After addition, react at 25°C, LC-MS shows that the reaction is complete. Concentrate the reaction solution under reduced pressure, then pour the reaction solution into ice saturated potassium carbonate aqueous solution, extract with ethyl acetate, wash the combined organic phase with saturated potassium carbonate solution, saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain solid 3a. LC-MS (ESI+): m / z = 393.4 [M+H] +

[0092] 3. Preparation of intermediate 4a

[0093] Dissolve 3a in DCM at room temperature. Then slowly add Boc anhydride, TEA and DMAP in turn. After addition, react at 25°C, LC-MS shows that the reaction is complete. Pour the reaction solution into water, extract with ethyl acetate, wash the combined organic phase with 10% citric acid, saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain the crude product, and purify by column chromatography to obtain solid 4a. LC-MS (ESI+): m / z = 493.4 [M+H] +

[0094] 4. Preparation of intermediate 5a

[0095] Dissolve 5a and 5b in THF at room temperature, then add potassium carbonate, and after nitrogen replacement for three times, add Xphos-Pd-G2 and Xphos to the reaction system under nitrogen protection. Replace nitrogen again for three times. React at 85°C for 12 hours under nitrogen protection. LC-MS shows that the reaction is complete. Concentrate the reaction solution under reduced pressure, and purify the residue by column chromatography to obtain solid 5a. LC-MS (ESI+): m / z = 808.4 [M+H] +

[0096] 5. Preparation of intermediate 6a

[0097] Dissolve 5a in DMSO at room temperature. Add sodium hydroxide to the reaction system at room temperature. After addition, react at 25°C, LC-MS shows that the reaction is complete. Adjust the pH of the reaction solution to 6 with 1M dilute hydrochloric acid, extract with ethyl acetate for three times, wash the combined organic phase with saturated brine once, and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain solid 6a. LC-MS (ESI+): m / z = 680.7 [M+H] +

[0098] 6. Preparation of intermediate 7a

[0099] Intermediate 7a was prepared by dissolving 6a and 6b in DCM at room temperature, then adding DMAP and DIC at 0°C. After addition, the reaction was carried out at 25°C, and LC-MS showed that the reaction had been completed. The reaction solution was poured into water, extracted with ethyl acetate three times, and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column chromatography was used to separate the intermediate 7a. LC-MS (ESI+): m / z = 800.4 [M+H] +

[0100] 7. Preparation of intermediate 8a

[0101] Intermediate 8a was prepared by dissolving 7a and 7b in DMF at room temperature. Then cesium carbonate was added. After addition, the reaction was carried out at 25°C, and LC-MS showed that the reaction had been completed. The reaction solution was slowly poured into saturated ammonium chloride, extracted with ethyl acetate three times, and the organic phase was combined and washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain solid 8a. LC-MS (ESI+): m / z = 886.7 [M+H] +

[0102] 8. Preparation of compound C1-232

[0103] Compound C1-232 was prepared by dissolving 8a in DCM at room temperature. Then TFA was added under ice bath. After addition, the reaction was carried out at 25°C, and LC-MS showed that the reaction had been completed, and the crude product was concentrated under reduced pressure. Then solid C1-232 was obtained by preparative HPLC. LC-MS (ESI+): m / z = 524.5 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 10.8 (s, 1H), 9.7 (s, 1H), 8.5 (m, 1H), 7.7 (m, 1H), 7.2 (m, 1H), 6.95 (m, 1H), 6.8 (m, 1H), 3.6 (s, 2H), 2.8 (m, 1H), 2.3 (m, 1H), 1.68-1.54 (m, 4H), 1.32-1.15 (m, 6H), 0.18 (s, 3H), 0.12 (s, 3H), 0.05 (s, 3H).

[0104] Example 5

[0105] The synthesis process route of compound C1-233 is as follows:

[0106] 1. Synthesis of intermediate 2A

[0107] The starting material 1A, 1B, XPhos Pd G2, XPhos and potassium phosphate were dissolved in dioxane and water, and replaced with nitrogen three times. The reaction was carried out at 95°C under nitrogen protection, and LCMS showed that the starting material was completely converted. The reaction solution was diluted with dichloromethane, filtered with diatomite, and the filter cake was washed with dichloromethane. Directly concentrated and dried to obtain the crude product. The silica gel was dissolved in dichloromethane and the sample was mixed, and then purified by column chromatography to obtain solid 2A. LCMS (ESI+): m / z = 804.4 [M+H] + .

[0108] 2. Synthesis of final product 3A (compound C1-233)

[0109] 2A was dissolved in TFA and DCM, and the reaction solution was stirred at room temperature overnight. LCMS showed that the starting material was completely reacted. The solution was spin-dried, dissolved in prep-TLC with dichloromethane, and 1% FA in EA was used as the developing agent to obtain the product C1-233. LCMS (ESI+): m / z = 506.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 11.10 (s, 1H), 7.80 (s, 1H), 7.52 (s, 1H), 7.18 (d, J = 6.8 Hz, 2H), 6.95 (d, J = 3.3 Hz, 1H), 6.64 (s, 1H), 4.73 (s, 1H), 3.75 (s, 2H), 2.57 (s, 1H), 1.98 (s, 1H), 1.84 (d, J = 5.9 Hz, 1H), 1.71 (d, J = 12.2 Hz, 2H), 1.51 (d, J = 12.2 Hz, 3H), 1.30 (dd, J = 19.7, 13.5 Hz, 3H), 0.01 s, 9H).

[0110] Example 6

[0111] The synthesis process route of compound C1-234 is as follows:

[0112] 1. Preparation of intermediate 2a

[0113] 1a and 1b were dissolved in THF at room temperature, and TEA was slowly added. After addition, the temperature was raised to 100°C for reaction, and LC-MS showed that the reaction was completed. The reaction solution was poured into water, extracted with ethyl acetate three times, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain solid 2a. LC-MS (ESI+): m / z = 349.3 [M+H] + .

[0114] 2. Preparation of intermediate 3a

[0115] The 2a was dissolved in DCM at room temperature, then HBr / AcOH was added slowly into the reaction system. After addition, the reaction was carried out at 25 °C, LC-MS showed that the reaction had been completed. The reaction solution was concentrated under reduced pressure, the residue was poured into ice saturated potassium carbonate aqueous solution, extracted with ethyl acetate for three times, the organic phase was combined, washed with saturated potassium carbonate solution for two times, washed with saturated brine for one time, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain solid 3a. LC-MS (ESI+): m / z = 393.3 [M+H] + .

[0116] 3. Preparation of intermediate 4a

[0117] The 3a was dissolved in methanol and THF at room temperature. Lithium hydroxide aqueous solution was added slowly into the reaction system at room temperature. After addition, the reaction system was warmed to 50 °C for reaction, LC-MS showed that the reaction had been completed. The reaction system was cooled to room temperature, 1M dilute hydrochloric acid solution was slowly added into the reaction solution, and the pH value was adjusted to 6. Ethyl acetate was extracted for three times, the organic phase was combined, washed with saturated brine for one time, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain solid 4a. LC-MS (ESI+): m / z = 365.3 [M+H] + .

[0118] 4. Preparation of intermediate 5a

[0119] The 5a was dissolved in DCM at room temperature. Then TEA, DMAP and DIC were added under ice water bath. After addition, the reaction was carried out at 25 °C, LC-MS showed that the starting material had been completed, water was added into the reaction solution, dichloromethane was extracted for three times, the organic phase was combined, washed with saturated brine for one time, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain solid 5a. LC-MS (ESI+): m / z = 485.3 [M+H] + .

[0120] 5. Preparation of intermediate 6a

[0121] The 5a and 5b were dissolved in DMF at room temperature. Then cesium carbonate was added. After addition, the reaction was carried out at 40 °C, LC-MS showed that the reaction had been completed. The reaction solution was slowly added into saturated ammonium chloride aqueous solution, extracted with ethyl acetate for three times, the organic phase was combined, washed with saturated sodium chloride for one time, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by column chromatography to obtain solid 6a. LC-MS (ESI+): m / z = 615.6 [M+H] + .

[0122] 6. Preparation of intermediate 7a

[0123] At room temperature, 6a and 6b were dissolved in dioxane, potassium carbonate, Pd(dppf)Cl2 and Xphos were added under nitrogen protection. The reaction was heated to 85 °C, LC-MS showed the reaction was completed. The reaction was concentrated under reduced pressure to get solid crude, the crude was purified by column chromatography to get solid 7a. LC-MS (ESI+): m / z = 756.7 [M+H] + .

[0124] 7. Preparation of intermediate 8a

[0125] At room temperature, 7a was dissolved in THF. Then TBAF was added slowly. After the addition, the reaction system was heated to 80 °C, LC-MS showed that the raw material was consumed. The reaction was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate three times, the combined organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get solid 8a. LC-MS (ESI+): m / z = 506.6 [M+H] + .

[0126] 8. Preparation of intermediate 9a

[0127] At room temperature, 8a and 8b were dissolved in THF. DMAP and DIC were added under ice water bath. After the addition, the reaction was heated to room temperature 25 °C, LC-MS showed that the reaction was completed. The reaction was slowly poured into saturated aqueous ammonium chloride solution, then extracted with ethyl acetate three times, the combined organic phase was washed with saturated sodium chloride once, and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get solid 9a. LC-MS (ESI+): m / z = 626.7 [M+H] + .

[0128] 9. Preparation of intermediate 10a

[0129] At room temperature, 9a and 9b were dissolved in DMF. Then cesium carbonate was added. After the addition, the reaction was heated to 40 °C, LC-MS showed that the reaction was completed. The reaction was slowly poured into 30 mL of saturated aqueous ammonium chloride solution, then extracted with ethyl acetate three times, the combined organic phase was washed with saturated sodium chloride once, and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get solid 10a. LC-MS (ESI+): m / z = 712.7 [M+H] + .

[0130] 10. Preparation of compound C1-234

[0131] Dissolve 10a in DCM at room temperature. Then add TFA under ice-bath, after addition, warm up to 25°C and monitor the reaction by LC-MS. The reaction is complete. Concentrate the reaction solution under reduced pressure to dryness, then purify the product C1-234 by preparative HPLC. LC-MS (ESI+): m / z = 508.5 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 10.9 (s, 1H), 9.8 (s, 1H), 8.3 (m, 1H), 7.6 (m, 1H), 7.3 (m, 1H), 7.1 (m, 1H), 6.9 (m, 1H), 3.65 (s, 2H), 2.75 (m, 1H), 2.38 (m, 1H), 1.55-1.37 (m, 4H), 1.18-1.05 (m, 6H), 0.19 (s, 3H), 0.11 (s, 3H), 0.05 (s, 3H).

[0132] Example 7

[0133] The synthesis process route of compound C1-235 is shown below:

[0134] 1. Synthesis of intermediate 2A

[0135] Add reactant 1A, hexa-n-butyl distannane and anhydrous toluene into the reaction bottle, after complete dissolution, add tetra-triphenylphosphine palladium, vacuumize and replace with nitrogen, the reaction solution is reacted at 120°C, LCMS shows that the raw material is completely reacted, and the main peak is the target product peak. The reaction solution is concentrated, and the product 2A is obtained by silica gel column chromatography, LCMS (ESI+): m / z = 691.1 [M+1] + .

[0136] 2. Synthesis of intermediate 4A

[0137] Add reactant 3A, DHP and DCM into the reaction bottle, then slowly add p-toluenesulfonic acid, the reaction solution is reacted at 25°C, LCMS shows that the raw material is completely reacted, saturated sodium bicarbonate aqueous solution is added to the reaction solution to quench the reaction, the aqueous phase is extracted with dichloromethane, the combined organic layers are washed with saturated NaCl solution, the combined organic layers are dried with anhydrous Na2S04, filtered and rotary evaporated. The crude product is purified by silica gel column chromatography to obtain product 4A, LCMS (ESI+): m / z = 364.1 [M+1] + .

[0138] 3. Synthesis of intermediate 5A

[0139] Into a reaction flask, add reactant 4A, 2A and anhydrous toluene, after complete dissolution, add tetrakis triphenyl phosphine palladium, vacuum and replace with nitrogen, the reaction solution is reacted at 120°C, LCMS shows that the raw material is completely reacted, and the main peak is the target product peak. The reaction solution is concentrated, and silica gel column chromatography is carried out to obtain solid product 5A, LCMS (ESI+): m / z = 636.0 [M+1] + .

[0140] 4. Synthesis of final product 6A (compound C1-235)

[0141] Into a reaction flask, add reactant 5A, 6M hydrochloric acid solution to obtain a solution; the reaction solution is reacted at 60°C for 12 hours. The reaction solution is adjusted to pH = 6 with 1N NaOH solution, extracted with dichloromethane, and the organic phase is dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which is purified by preparative thin layer chromatography and freeze-dried to obtain product C1-235, LCMS (ESI+): m / z = 524.0 [M+1] + .

[0142] Example 8

[0143] The synthesis process route of compound C1-236 is as follows:

[0144] 1. Synthesis of intermediate 2A

[0145] Into a 25mL single-necked flask, add reactants 1A, 1B and anhydrous toluene, after complete dissolution, add tetrakis triphenyl phosphine palladium, vacuum and replace with nitrogen, the reaction solution is reacted at 120°C for 12 hours, LCMS shows that the raw material is completely reacted, and the main peak is the target product peak. The reaction solution is concentrated, and silica gel column chromatography is carried out to obtain solid product 2A, LCMS (ESI+): m / z = 637.7 [M+1] + .

[0146] 2. Synthesis of final product 3A (compound C1-236)

[0147] Into a reaction flask, add 2A and 6M hydrochloric acid aqueous solution to obtain a solution; the reaction solution is reacted at 95°C, and then diluted with water, the aqueous phase is extracted with ethyl acetate, the combined organic layers are washed with saturated NaCl solution, the combined organic layers are dried with anhydrous Na2SO4, filtered and rotary evaporated; the crude product is purified by silica gel column chromatography, and freeze-dried to obtain product C1-236, LCMS (ESI+): m / z = 525.5 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.68 (s, 1H), 7.68 - 7.50 (m, 1H), 7.36 (s, 1H), 7.13 (s, 1H), 6.67 (s, 1H), 4.75 (s, 1H), 3.85 (s, 2H), 2.97 (s, 1H), 2.72 (d, J = 7.3 Hz, 1H), 2.19 (s, 1H), 2.00 (s, 1H), 1.74 (s, 3H), 1.54 (s, 2H), 1.45 - 1.31 (m, 2H), 0.06 (s, 9H).

[0148] Example 9

[0149] The synthesis process route of compound C1-252 is shown below:

[0150] 1. Preparation of intermediate 2a

[0151] Dissolve 1a and 1b in DMF in a reaction bottle. Then add DIEA. Finally, react at 100°C, TLC shows that the raw material is consumed and a new point with increased polarity is generated. Slowly add the reaction solution to water, then extract with ethyl acetate three times, wash the combined organic phase with saturated brine once, and dry with anhydrous sodium sulfate. After filtration, concentrate under reduced pressure to obtain solid 2a. LC-MS (ESI+): m / z = 376.8 [M+H] +

[0152] 2. Preparation of intermediate 3a

[0153] Dissolve 2a in DCM in a reaction bottle. Then add HRr / AcOH. Finally, react at room temperature 25°C, TLC shows that the raw material is consumed and a new point with increased polarity is generated. After the reaction solution is concentrated under reduced pressure, solid 3a is obtained by column chromatography purification. LC-MS (ESI+): m / z = 393.4 [M+H] +

[0154] 3. Preparation of intermediate 4a

[0155] Dissolve 3a in DCM in a reaction bottle. Then add TEA and Boc20, and add DMAP at ice bath 0°C, then react at room temperature 25°C for 1, TLC shows that the raw material is consumed and a new point with decreased polarity is generated. Slowly pour the reaction solution into water, extract with dichloromethane three times, wash the combined organic phase with saturated brine once, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain solid 4a. LC-MS (ESI+): m / z = 493.4 [M+H] +

[0156] 4. Preparation of intermediate 5a

[0157] In a reaction flask, 4a and 4b were dissolved in THF, potassium carbonate, Pd(dppf)Cl2 were added under nitrogen protection, after three times of nitrogen replacement, the reaction was carried out at 85°C, LC-MS showed that the raw material was consumed, and the MS of the product was monitored. The reaction solution was slowly added to water, then extracted with dichloromethane three times, the organic phase was combined and washed with saturated brine once, then dried with anhydrous sodium sulfate. After filtration, the crude product was obtained by concentration under reduced pressure. Purification by column chromatography to obtain solid 5a. LC-MS (ESI+): m / z = 808.4 [M+H] +

[0158] 5. Preparation of intermediate 6a

[0159] In a reaction flask, 5a was dissolved in DMSO, and then an aqueous sodium hydroxide solution was prepared. The sodium hydroxide solution was slowly added to the system, and the reaction was carried out at room temperature 25°C, LC-MS showed that the raw material was consumed, and the MS of the product was monitored. Water was added to the reaction solution, then extracted with dichloromethane three times, the organic phase was combined and washed with saturated brine, dried with anhydrous sodium sulfate. After filtration, the product 6a was obtained by concentration under reduced pressure. LC-MS (ESI+): m / z = 680.7 [M+H] +

[0160] 6. Preparation of intermediate 7a

[0161] In a reaction flask, 6a and 6b were dissolved in DCM. Then DMAP and DIC were added. The reaction was carried out at room temperature 25°C, LC-MS showed that the raw material was consumed, and the MS of the product was monitored. Water was added to the reaction solution, then extracted with dichloromethane three times, the organic phase was combined and washed with saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the product 7a. LC-MS (ESI+): m / z = 800.4 [M+H] +

[0162] 7. Preparation of intermediate 8a

[0163] In a reaction flask, 7a and 7b were dissolved in DMF, and then cesium carbonate was added. The reaction was carried out at 45°C, LC-MS showed that the raw material was consumed, and the MS of the product was monitored. The reaction solution was slowly added to saturated aqueous ammonium chloride solution, then extracted with ethyl acetate three times, the organic phase was combined and dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain solid 8a. LC-MS (ESI+): m / z = 886.7 [M+H] +

[0164] 8. Preparation of compound C1-252

[0165] To the reaction flask was added 8a dissolved in DCM, then TFA was added. The reaction was carried out at room temperature 25 °C, LC-MS showed the reaction was completed. The crude product was concentrated under reduced pressure, then purified by preparative HPLC to obtain the product C1-252. LC-MS (ESI+): m / z = 524.5 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 9.97 - 9.82 (m, 1H), 9.22 - 8.92 (m, 1H), 7.65 - 7.39 (m, 1H), 7.12 - 6.93 (m, 5H), 6.96 - 6.88 (m, 1H), 6.55 - 6.48 (m, 1H), 5.19 - 4.96 (m, 2H), 4.32 - 3.78 (m, 2H), 3.98 (s, 3H), 2.93 - 2.85 (m, 1H), 2.56 - 2.42 (m, 1H), 1.16 - 1.08 (m, 1H), 0.85 - 0.82 (m, 1H), 0.25 (s, 3H), 0.15 (s, 3H), 0.06 (s, 3H).

[0166] Example 10

[0167] The synthesis process route of compound C1-313 (core1-313) is shown below:

[0168] 1. Preparation of intermediate 2a

[0169] To the reaction flask was added 1a, 1b dissolved in DMF, then added to the reaction system, and then added cesium carbonate. Then the reaction was carried out at 25 °C, LC-MS showed that the raw material was consumed, and the MS of the product was detected. The reaction solution was slowly added to saturated aqueous ammonium chloride solution for dilution, then extracted with ethyl acetate three times, the organic phase was combined, then washed with saturated brine, and dried with anhydrous sodium sulfate. After filtration, the solid 2a was obtained by concentrating under reduced pressure. LC-MS (ESI+): m / z = 349.4 [M+H] +

[0170] 2. Preparation of intermediate 3a

[0171] To the reaction flask was added 2a and 2b dissolved in THF. Then potassium carbonate, Xphos-Pd-G2 were added under nitrogen atmosphere, and the reaction was carried out at 85 °C under nitrogen atmosphere, LC-MS showed that the raw material was consumed, and the MS of the product was detected. The reaction was filtered and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain the solid 3a. LC-MS (ESI+): m / z = 794.5 [M+H] +

[0172] 3. Preparation of final product 4a (compound C1-313)

[0173] To the reaction flask was added 3a dissolved in DCM. Then TFA was added under ice bath condition. The reaction was carried out at room temperature 25 °C. LC-MS showed the starting material was consumed and the MS of the product was monitored. The reaction was concentrated under reduced pressure to dryness to get the crude product, which was further purified by preparative HPLC to get the product C1-313. LC-MS (ESI+): m / z = 552.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.5 (s, 1H), 7.85 (m, 1H), 7.21 (m, 1H), 6.89 (m, 1H), 6.50 (m, 1H), 4.42-3.77 (m, 2H), 3.32-3.17 (m, 2H), 2.93 (m, 1H), 2.28-2.22 (m, 2H), 1.63 - 1.32 (m, 9H), 1.22-1.15 (m, 2H), 0.21 (s, 3H), 0.10 (s, 3H), 0.03 (s, 3H).

[0174] Example 11

[0175] The synthesis route of compound C1-335 is shown below:

[0176] 1. Synthesis of intermediate 2A

[0177] The starting material 1A, 1B and potassium carbonate were dissolved in DMF, and stirred at 80 °C for 16 h. LCMS showed the starting material was converted completely. After dilution with water, the organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to get the crude product. The product was obtained by column chromatography on silica gel. LCMS (ESI+): m / z = 322.2 [M+H] + .

[0178] 2. Synthesis of intermediate 3A

[0179] The starting material 2A, 1B and potassium carbonate were dissolved in DMF, and stirred at 45 °C. LCMS showed 80% product was generated. The solvent was concentrated to dryness, and the product 3A was obtained by column chromatography. LCMS (ESI+): m / z = 462.1 [M+H] + .

[0180] 3. Synthesis of intermediate 4A

[0181] The starting material 3A was dissolved in hydrobromic acid acetic acid solution, and stirred at 60 °C for 3 h. LCMS showed the starting material was converted completely. The solvent was concentrated to dryness, and the product 4A was obtained by column chromatography on 300-400 mesh silica gel. LCMS (ESI+): m / z = 424.9 / 426.8 [M+1] + .

[0182] 4. Synthesis of intermediate 5A

[0183] The starting material 4A, 3B, XPhos Pd G2, XPhos and potassium phosphate were dissolved in dioxane and water, and replaced with nitrogen three times. Under nitrogen protection, the reaction solution was refluxed at 85°C for 16h. LCMS showed that the starting material was completely converted. The reaction solution was diluted with dichloromethane, filtered with celite, and the filter cake was washed with dichloromethane. The filtrate was directly concentrated to dryness to obtain the crude product. The product was dissolved in dichloromethane and purified by column chromatography to obtain product 5A. LCMS (ESI+): m / z = 740.1 [M+H] + .

[0184] 5. Synthesis of final product C1-335

[0185] 5A was dissolved in TFA and DCM, and the reaction solution was stirred at room temperature overnight. LCMS showed that the starting material was completely reacted. The solution was rotary evaporated to obtain the crude product, and prep-TLC DCM:MeOH = 10:1 to obtain the final product 6A (C1-335). LCMS (ESI+): m / z = 498.0 [M+1] + .

[0186] Example 12

[0187] The synthesis process route of compound C1-337 is shown below:

[0188] 1. Synthesis of intermediate 2A

[0189] 1A and 33% hydrobromic acid in acetic acid were added to a sealed tube to obtain a solution; the reaction solution was reacted at 60°C for 2h. The reaction solution was concentrated and purified by silica gel column chromatography to obtain product 2A. LCMS (ESI+): m / z = 427.0 [M+H] + .

[0190] 2. Synthesis of intermediate 3A

[0191] 2A, 2B and 1,4-dioxane, water were added to a reaction bottle; then potassium phosphate, XPhos PG2 and XPhos were added, and the reaction solution was reacted at 95°C for 12h. Silica gel was added to the reaction solution, and the product 3A was obtained by silica gel column chromatography. LC-MS (ESI+): m / z = 742.1 [M+H] + .

[0192] 3. Synthesis of final product 4A (C1-337)

[0193] To the reaction flask was added 3A and DCM to get a solution; then trifluoroacetic acid was added, and the reaction solution was reacted at 25 °C for 12 hours. The reaction solution was concentrated, and silica gel plate was purified to obtain the product 4A. LCMS (ESI+): m / z = 500.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 11.87 (s, 1H), 8.45 (d, J = 2.9 Hz, 1H), 8.32 (s, 1H), 6.96 (d, J = 3.6 Hz, 2H), 6.65 (d, J = 3.3 Hz, 1H), 5.05 (s, 1H), 3.79 (d, J = 4.6 Hz, 2H), 2.64 (dd, J = 15.1, 3.1 Hz, 1H), 2.44 (dd, J = 14.9, 10.7 Hz, 1H), 1.02 (s, 9H), 0.08 (s, 9H). Example 13

[0194] The synthesis process route of compound C1-355 is as follows:

[0195] 1. Preparation of intermediate 2a

[0196] In the reaction flask, 1a and 1b were dissolved in THF. Then TEA was slowly added, and the temperature was raised to 100 °C for reaction. LC-MS showed that the raw material was consumed, and the MS of the product was monitored. The reaction solution was slowly added to water for dilution, and then extracted with ethyl acetate. The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the product 2a was obtained by concentration under reduced pressure. LC-MS (ESI+): m / z = 347

[0197] 2. Preparation of intermediate 3a

[0198] In the reaction flask, 2a was dissolved in DCM, and HBr acetic acid solution was added, and the reaction was carried out at room temperature 25 °C. LC-MS showed that the raw material was consumed, and the MS of the product was monitored. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain the product 3a. LC-MS (ESI+): m / z = 390.8

[0199] 3. Preparation of intermediate 4a

[0200] In a reaction flask, 3a was dissolved in THF and methanol. Lithium hydroxide was dissolved in water. The aqueous solution of lithium hydroxide was slowly added to the reaction system, and the reaction was carried out at room temperature. LC-MS showed that the raw material was consumed, and the MS of the product was monitored. The reaction solution was diluted in water, and the pH of the solution was adjusted to neutral with dilute hydrochloric acid. Extraction was performed with ethyl acetate, washed with saturated brine, and dried with anhydrous sodium sulfate. After drying, the product 4a was obtained by concentration under reduced pressure. LC-MS (ESI+): m / z = 362.9

[0201] 4. Preparation of intermediate 5a

[0202] In a reaction flask, 4a was dissolved in THF, and 4b was added. The reaction was carried out at 70°C, and LC-MS showed that the raw material was consumed, and the MS of the product was monitored. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the product 5a. LC-MS (ESI+): m / z = 418.9

[0203] 5. Preparation of intermediate 6a

[0204] In a reaction flask, 5a and 5b were dissolved in DMF, and cesium carbonate was added. The reaction was carried out at 50°C, and LC-MS showed that the raw material was consumed, and the MS of the product was monitored. The reaction solution was slowly added to saturated aqueous ammonium chloride solution, extracted with ethyl acetate three times, and the organic phase was combined and washed with saturated brine, then dried with anhydrous sodium sulfate. After filtration, the product 6a was obtained by concentration under reduced pressure. LC-MS (ESI+): m / z = 505.1

[0205] 6. Preparation of intermediate 7a

[0206] In a reaction flask, 6a and 6b were dissolved in 1,4-Dioxane, and cesium carbonate and cata-Pd-G4 were added under a nitrogen atmosphere. The reaction was carried out at 70°C, and LC-MS showed that the raw material was consumed, and the MS of the product was monitored. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the product 7a. LC-MS (ESI+): m / z = 820.1

[0207] 7. Preparation of final product 8a (compound C1-355)

[0208] In a reaction flask, 7a was dissolved in DCM, and TFA was added under ice bath conditions. The reaction was carried out at room temperature 25°C, and LC-MS showed that the raw material was consumed, and the MS of the product was monitored. The reaction solution was concentrated under reduced pressure, and the final product 8a was obtained by TLC preparation purification. LC-MS (ESI+): m / z = 522. 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 12.36 (s, 1H), 8.47 (s, 1H), 8.31 (s, 1H), 6.95 (d, J = 3.3 Hz, 1H), 6.80 (d, J = 6.1 Hz, 1H), 6.54 (d, J = 3.4 Hz, 1H), 6.48 (d, J = 7.5 Hz, 1H), 6.23 (t, J = 7.2 Hz, 1H), 5.47 (s, 2H), 4.65 (d, J = 6.5 Hz, 1H), 3.79 (d, J = 2.9 Hz, 2H), 3.64 - 3.59 (m, 3H), 3.31 (s, 5H), 2.85 (d, J = 7.2 Hz, 1H), 1.95 - 1.47 (m, 9H), 1.34 - 1.07 (m, 4H), 0.98 (s, 22H), 0.04 (s, 8H).

[0209] Example 14

[0210] The synthesis route of compound C1-482 is shown below:

[0211] In a 10 mL vial, 1a (0.1 g, 0.19 mmol) and ammonium chloride (0.02 g, 0.38 mmol) were dissolved in THF (2 mL). Then TEA (0.038 g, 0.38 mmol) and HATU (0.11 g, 0.29 mmol) were added. The reaction was stirred at room temperature for 2 h. LC-MS showed the starting material was consumed and the MS of the product was detected. The reaction was diluted by slowly adding to 10 mL of water, then extracted with ethyl acetate three times, the organic phase was combined and washed with saturated brine three times, and dried over anhydrous sodium sulfate. After filtration, the crude product was concentrated under reduced pressure, and then purified by preparative TLC (PE:EA = 0:1) to give 2a (C1-482). LC-MS (ESI+): m / z = 523.1. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 2H), 7.28 (s, 2H), 6.85 (s, 2H), 4.1 (s, 2H), 3.6 (s, 2H), 2.89 - 2.61 (m, 2H), 2.10 - 1.92 (m, 3H), 1.83 - 1.65 (m, 2H), 1.62 - 1.38 (m, 5H), 0.03 (s, 9H).

[0212] Example 15

[0213] The synthesis route of compound C1-484 is shown below:

[0214] 1. Preparation of intermediate 2A

[0215] In a 40 mL vial, 1a (2 g, 6.73 mmol), TrtCl (2.25 g, 8.08 mmol) and cesium carbonate (3.28 g, 10.1 mmol) were dissolved in DMF (20 mL) at 25 °C for 3 h. LC-MS showed the starting material was consumed and the MS of product was detected. Water was added to precipitate, the filter cake was slurried with methanol to give 2A. LC-MS (ESI+): m / z = 540.1 [M+H] +

[0216] 2. Preparation of intermediate 3A

[0217] In a 10 mL vial, 2A (0.5 g, 0.93 mmol) and isopropoxy pinacol borate (0.225 g, 1.21 mmol) were dissolved in THF (5 mL). Then isopropyl magnesium chloride (0.63 mL 1.26 mmol, 2 mol / L) was added at -20 °C and reacted at -20 °C for 1 h. LC-MS showed the starting material was consumed and the MS of product was detected. The reaction was poured into saturated sodium bicarbonate solution, then extracted with ethyl acetate to give 3A. LC-MS (ESI+): m / z = 540.2 [M+H] +

[0218] 3. Preparation of intermediate 4A

[0219] In a 10 mL vial, 3A (0.13 g, 0.24 mmol) was dissolved in dioxane (5 mL). Then 1B (0.1 g, 0.2 mmol), potassium carbonate (0.33 g, 0.6 mmol), Catium Pd G4 (16 mg, 0.02 mmol) were added and reacted at 70 °C for 3 h. LC-MS showed the starting material was consumed and the MS of product was detected. The solvent was rotary evaporated, then purified by column chromatography (PE:EA = 10:1 to 5:1) to give 4A. LC-MS (ESI+): m / z = 841.5 [M+H] +

[0220] 4. Preparation of final product 5A (Compound C1-484)

[0221] In a 10 mL vial, 4A (0.06 g, 0.071 mmol) was dissolved in DCM (1 mL). Then TFA (1 mL) was added and reacted at room temperature 25 °C for 16 h. LC-MS showed the starting material was consumed and the MS of product was detected. The reaction was concentrated under reduced pressure to remove dichloromethane and trifluoroacetic acid, then purified by column chromatography (DCM:MeOH = 100:0 to 100:10) to give product 5A. LC-MS (ESI+): m / z = 542.2 [M+H] +

[0222] Example 16

[0223] The synthesis process route of compound C1-492 is as shown below:

[0224] 1. Synthesis of compound 2A

[0225] Dissolve 1A (2.00 g, 9.00 mmol) in DMAC (20 mL), add DIEA (2.45 g, 18.00 mmol) and 1B (3.15 g, 13.50 mmol) thereto, and react at 100°C overnight. Monitor the reaction completion of the raw material by LC-MS. Post-treatment: concentrate the reaction solution to obtain 2A. LC-MS (ESI+): m / z = 383.20 [M+H] + .

[0226] 2. Synthesis of compound 3A

[0227] Dissolve 2A (3.40 g, 8.88 mmol) in DCM (10 mL), add HBr / AcOH (30 mL) at room temperature, and stir overnight. Monitor the reaction completion of the raw material by LC-MS. Post-treatment: concentrate the reaction solution, add aqueous NaHCO3 solution, and adjust the pH to 7-8. Extract with EA (20 mL*3), combine the organic phases, and concentrate to obtain 3A. LC-MS (ESI+): m / z = 429.20 [M+H] + .

[0228] 3. Synthesis of compound 4A

[0229] Dissolve 3A (3.30 g, 7.72 mmol) in THF (20 mL), water (20 mL) and methanol (10 mL), add LiOH (2.59 g, 61.76 mmol) at room temperature, and stir overnight. Monitor the reaction completion of the raw material by LC-MS. Post-treatment: add dilute hydrochloric acid to adjust the pH to 3-4. Extract with EA (20 mL*3), combine the organic phases, and concentrate to obtain 4A. LC-MS (ESI+): m / z = 401.20 [M+H] + .

[0230] 4. Synthesis of compound 5A

[0231] Dissolve 4A (2.50 g, 6.26 mmol) in toluene (25 mL), add 2B (6.27 g, 31.30 mmol), and react at 70°C for 1 hour. Monitor the reaction completion of the raw material by LC-MS. Post-treatment: concentrate the reaction solution, pass through a silica gel column with Hex:EA = 10:1 to obtain 5A. LC-MS (ESI+): m / z = 457.20 [M+H] + .

[0232] 4. Synthesis of compound 6A

[0233] Dissolve 5A (1.00 g, 2.19 mmol) in DMF (10 mL), add Cs2CO3 (2.14 g, 6.57 mmol) and 3B (0.70 g, 3.29 mmol). React at room temperature for 1 hour. Monitor the reaction by LC-MS. The reaction is complete when the starting material is consumed. Work-up: Concentrate the reaction and purify the product by silica gel column with Hex:EA = 10:1-5:1 to get 6A. LC-MS (ESI+): m / z = 543.30 [M+H] + .

[0234] 5. Synthesis of compound 7A

[0235] Dissolve 6A (1.00 g, 1.85 mmol), 4B (0.97 g, 1.85 mmol), Pd(dppf)Cl2 (0.14 g, 0.19 mmol), K2CO3 (0.77 g, 5.55 mmol) in 1,4-Dioxane (10 mL) and water (0.2 mL). React at 100 °C for 2 hours under nitrogen atmosphere. Monitor the reaction by TLC (Hex:EA = 10:1, Rf = 0.3). The reaction is complete when the starting material is consumed. Work-up: Purify the product by silica gel column with Hex:EA = 15:1-10:1 to get 7A. LC-MS (ESI+): m / z = 858.60 [M+H] + .

[0236] 6. Synthesis of final product 8A (C1-492)

[0237] Dissolve 7A (1.00 g, 1.17 mmol) in DCM (7 mL) and add TFA (10 mL) at room temperature. React at room temperature for 2 hours. Monitor the reaction by TLC (DCM:MeOH = 20:1, Rf = 0.2). The reaction is complete when the starting material is consumed. Work-up: Concentrate the reaction and purify the product by silica gel column with DCM:MeOH = 20:1-10:1 to get 8A. LC-MS (ESI+): m / z = 558.40 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.39 (s, 1H), 7.31 (s, 1H), 6.38 (s, 1H), 3.93 - 3.77 (m, 2H), 2.69 (s, 1H), 2.09 (s, 1H), 2.00 (s, 1H), 1.89 (s, 1H), 1.75 (s, 2H), 1.51 (dd, 5H), 1.23 (s, 1H), 0.08 (s, 9H).

[0238] Example 17

[0239] The synthesis process route of compound C1-493 is as follows:

[0240] 1. Synthesis of compound 2A

[0241] The starting material 1A (2.5 g, 12.14 mmol) and 1B (3.59 g, 18.21 mmol) were dissolved in DMAC (10 mL), then DIEA (3.14 g, 24.28 mmol) was added, and the reaction was carried out at 100 °C for 16 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated, and water was added to precipitate the solid. The solid was filtered and dried to obtain 2A. LCMS (ESI + ): m / z = 365.10 [M+H] + .

[0242] 2. Synthesis of compound 3A

[0243] The starting material 2A (2 g, 9.71 mmol) was dissolved in a hydrobromic acid-acetic acid solution (20 mL), and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated, and water was added to precipitate the solid. The solid was filtered and washed with water three times to remove acetic acid. The filter cake was dried to obtain 3A. LCMS (ESI + ): m / z = 413.20 [M+H] + .

[0244] 3. Synthesis of compound 4A

[0245] The starting material 3A (2 g, 4.86 mmol) was dissolved in THF (5 mL) and methanol (5 mL), and lithium hydroxide monohydrate (2.04 g, 48.6 mmol) and water (5 mL) were added. The reaction was carried out for 3 hours. The organic phase was dried by rotary evaporation, and the water phase was adjusted to pH < 7. The water phase was extracted with ethyl acetate (3 * 100 mL), and the organic layer was dried with Na2SO4, filtered, and concentrated to obtain 4A. LCMS (ESI + ): m / z = 383.10 [M+H] + .

[0246] 4. Synthesis of compound 5A

[0247] 4A (1.6 g, 4.18 mmol) was dissolved in THF (20 mL), and the starting material 4B (5.02 g, 25.08 mmol) was added. The reaction was carried out at 70 °C under nitrogen protection for 0.5 hours. LCMS showed that the starting material was completely reacted. The crude product was obtained by concentration, and 5A was obtained by silica gel column chromatography (PE:EA = 100 / 1-5 / 1). LCMS (ESI + ): m / z = 439.20 [M+H] + .

[0248] 5. Synthesis of compound 6A

[0249] The starting material 5A (1.1 g, 2.50 mmol) was dissolved in DMF (8 mL), to which cesium carbonate (2.44 g, 7.5 mmol) was added, and (iodomethyl)trimethylsilane (0.64 g, 3 mmol) was added under ice bath, and reacted at room temperature for 3 hours, and LCMS was used to monitor the completion of the reaction. The reaction solution was poured into saturated aqueous ammonium chloride solution, and the aqueous phase was extracted with ethyl acetate (3*100 mL). The organic layer was combined and dried over Na2SO4, filtered and concentrated, and then purified by column chromatography (PE / EA = 100 / 1-5 / 1) to obtain 6A. LCMS (ESI + ): m / z = 527.30 [M+H] + .

[0250] 6. Synthesis of compound 7A

[0251] The starting material 6A (0.5 g, 0.95 mmol), 6B (0.59 g, 1.14 mmol), Cataxium-Pd-G4 (74 mg, 0.09 mmol) and cesium phosphate (0.93 g, 2.85 mmol) were dissolved in 1,4-dioxane (5 mL) and water (0.1 mL), and replaced with nitrogen three times. Under nitrogen protection, it was refluxed at 70°C for 3 hours. LCMS showed that the starting material was completely converted. The reaction solution was diluted with dichloromethane, filtered with celite, and the filter cake was washed with dichloromethane. Directly concentrated to obtain the crude product, and then purified by column chromatography (PE:EA = 100:1-5:1) to obtain 7A.

[0252] 7. Synthesis of final product C1-493

[0253] 7A (0.5 g, 0.59 mmol) was dissolved in DCM (3 mL), to which TFA (3 mL) was added. The reaction solution was stirred at room temperature for 2 hours, and LCMS showed that the starting material was completely reacted. The reaction solution was concentrated and purified by column chromatography (DCM:MeOH = 100:1-10:1) to obtain C1-493. LCMS (ESI + ): m / z = 542.40 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 12.16 (s, 1H), 8.48 (d, J = 3.02 Hz, 1H), 8.34 (s, 1H), 7.01 (d, J = 2.17 Hz, 1H), 6.62 (s, 1H), 4.77 (t, J = 6.96 Hz, 1H), 2.87 (d, J = 7.13 Hz, 1H), 2.11 (s, 1H), 1.99 - 1.90 (m, 2H), 1.81 - 1.72 (m, 2H), 1.62 - 1.49 (m, 3H), 1.46 - 1.31 (m, 3H), 1.23 (s, 1H), 0.07 (s, 9H).

[0254] Example 18

[0255] The synthesis process route of compound C1-271 is shown below:

[0256] 1. Synthesis of intermediate 2A

[0257] The starting material 1A (380 mg, 0.82 mmol), 1B (770.24 mg, 1.48 mmol), XPhos Pd G2 (32.26 mg, 0.084 mmol), XPhos (39.09 mg, 0.041 mmol) and potassium phosphate (552.18 mg, 2.46 mmol) were dissolved in 2-methyltetrahydrofuran (10 mL) and water (0.2 mL), and replaced with nitrogen three times. Under nitrogen protection, it was refluxed at 85°C for 3h. LCMS showed that the starting material was completely converted. The reaction solution was diluted with dichloromethane, filtered with diatomite, and the filter cake was washed with dichloromethane. It was directly concentrated to dryness to obtain the crude product. Silica gel was added to dissolve in dichloromethane, and column chromatography purification (PE / EA = 30 / 1 to 20 / 1) was performed to obtain 2A. LCMS (ESI+): m / z = 778.4 [M+H] + .

[0258] 2. Synthesis of intermediate 3A

[0259] 2A (270 mg, 0.59 mmol) was dissolved in TFA (6 mL) and DCM (6 mL), and the reaction solution was stirred at room temperature overnight. LCMS showed that the starting material was completely reacted. The solution was spin-dried, dissolved in dichloromethane and column-purified with PE:EA = 20:1-4:1 to obtain 3A. LCMS (ESI+): m / z = 535.3 [M+1] + .

[0260] 3. Synthesis of final product C1-271

[0261] Dissolve 3A (130 mg, 0.24 mmol) and lithium hydroxide monohydrate (30.21 mg, 0.72 mmol) in THF (2 mL) and water (2 mL), and stir the reaction mixture at room temperature overnight. LCMS shows that the starting material is completely reacted. Adjust the pH to 4, and extract with ethyl acetate. Dry the organic phase to obtain the product 4A (C1-271). LCMS (ESI+): m / z = 507.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.40 (d, J = 61.7 Hz, 2H), 7.39 - 7.23 (m, 1H), 7.15 (dq, J = 23.3, 9.3, 8.4 Hz, 2H), 6.94 - 6.48 (m, 1H), 4.68 (s, 1H), 2.67 (s, 1H), 1.94 (d, J = 29.6 Hz, 2H), 1.70 (q, J = 7.1 Hz, 4H), 1.63 - 1.27 (m, 7H), 1.19 (s, 2H), 0.93 (dd, J = 6.6, 2.3 Hz, 6H).

[0262] Example 19

[0263] The synthesis process route of compound C1-517 is shown as follows:

[0264] 1. Synthesis of compound 2A

[0265] Dissolve 1A (2.00 g, 9.90 mmol) in DMAC (20 mL), and add DIEA (2.51 g, 19.42 mmol) and 1B (2.93 g, 14.85 mmol) thereto, and react at 100°C overnight. LC-MS shows that the starting material is completely reacted. Treatment: concentrate the reaction mixture to obtain 2A. LC-MS (ESI+): m / z = 363.30 [M+H] + .

[0266] 2. Synthesis of compound 3A

[0267] Dissolve 2A (3.50 g, 11.02 mmol) in DCM (15 mL), and add HBr / AcOH (30 mL) at room temperature, and stir overnight. LC-MS shows that the starting material is completely reacted. Treatment: concentrate the reaction mixture, add aqueous NaHCO3 solution, and adjust the pH to 7-8. Extract with EA (20 mL*3), combine the organic phases, and concentrate to obtain 3A. LC-MS (ESI+): m / z = 409.20 [M+H] + .

[0268] 3. Synthesis of compound 4A

[0269] Dissolve 3A (3.90 g, 11.02 mmol) in THF (20 mL), water (20 mL) and methanol (10 mL), add LiOH (3.70 g, 88.16 mmol) at room temperature, stir overnight. Check the reaction by LC-MS. Work-up: adjust pH to 3-4 by adding dilute hydrochloric acid. Extract the organic phase by EA (20 mL*3), combine the organic phase, concentrate to get 4A. LC-MS (ESI+): m / z = 381.20 [M+H] + .

[0270] 4. Synthesis of compound 5A

[0271] Dissolve 4A (3.50 g, 10.55 mmol) in toluene (30 mL), add 2B (10.57 g, 52.75 mmol), react at 70 °C for 1 h. Check the reaction by LC-MS. Work-up: concentrate the reaction solution, pass through a silica gel column with Hex:EA = 10:1 to get 5A. LC-MS (ESI+): m / z = 437.30 [M+H] + .

[0272] 5. Synthesis of compound 6A

[0273] Dissolve 5A (1.00 g, 2.30 mmol) in DMF (10 mL), add Cs2CO3 (2.25 g, 6.90 mmol) and 3B (0.49 g, 2.3 mmol). React at room temperature for 1 h. Check the reaction by LC-MS. Work-up: concentrate the reaction solution, pass through a silica gel column with Hex:EA = 10:1-5:1 to get 6A. LC-MS (ESI+): m / z = 523.40 [M+H] + .

[0274] 6. Synthesis of compound 7A

[0275] Take 6A (1.00 g, 1.92 mmol), 4B (1.20 g, 2.30 mmol), Pd(dppf)Cl2 (0.14 g, 0.19 mmol), K2CO3 (0.80 g, 5.76 mmol) and dissolve in 1,4-Dioxane (10 mL) and water (0.2 mL). React at 100 °C for 2 h under nitrogen atmosphere. Check the reaction by TLC (DCM:MeOH = 20:1, Rf = 0.3). Work-up: pass through a silica gel column with Hex:EA = 15:1-10:1 to get 7A. Send LC-MS, LC-MS (ESI+): m / z = 836.60 [M+H] + .

[0276] 7. Synthesis of final product 8A (C1-517)

[0277] To 8A (1.00 g, 1.20 mmol) in DCM (7 mL) was added TFA (10 mL) at room temperature. The reaction was monitored by TLC (DCM:MeOH = 10:1, Rf = 0.3) and the starting material was consumed after 2 h at room temperature. Work-up: The reaction was concentrated and purified by silica gel column with DCM:MeOH = 20:1-10:1 to give 8A. LC-MS (ESI+): m / z = 538.50 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.48 (d, 1H), 7.00 (s, 1H), 4.69 (t, 1H), 3.87 - 3.74 (m, 2H), 2.98 (s, 1H), 2.47 - 2.41 (m, 3H), 2.06 (s, 2H), 1.94 (d, 1H), 1.76 (q, 2H), 1.48 (dd, 4H), 1.21 (s, 1H), 0.05 (s, 9H).

[0278] Example 20

[0279] The synthesis process route of compound C1-519 is shown as follows:

[0280] 1. Preparation of intermediate 2a

[0281] In a 50 mL bottle, 1a (2 g, 10.58 mmol) and 1b (2.86 g, 12.70 mmol) were dissolved in DMF (20 mL). Then DIEA (4.10 g, 31.74 mmol) was added. Finally, the reaction was carried out at 100 °C for 12 h. LC-MS showed that the starting material was consumed and the MS of the product was detected. The reaction was slowly added to 50 mL of water, and then extracted with ethyl acetate three times, 30 mL*3. The combined organic phase was washed with saturated brine twice, 50 mL*2, and then dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to give 2a. LC-MS (ESI+): m / z = 349.8 [M+H] +

[0282] 2. Preparation of intermediate 3a

[0283] In a 50 mL flask, add 2a (1 g, 2.86 mmol) dissolved in DCM (10 mL). Then add HBr in acetic acid (10 mL). And react at room temperature 25 °C for 2 h. LC-MS shows the starting material is consumed and the MS of the product is detected. Concentrate the reaction solution under reduced pressure to remove DCM and hydrobromic acid and acetic acid, and then purify by column chromatography (PE:EA = 10:1 to 1:1) to obtain 3a. LC-MS (ESI+): m / z = 394.2 [M+H] +

[0284] 3. Preparation of intermediate 4a

[0285] In a 50 mL flask, add 3a (1 g, 2.54 mmol) dissolved in DMSO (10 mL). And dissolve NaOH (0.3 g, 7.62 mmol) in water (3 mL). Then slowly add the aqueous sodium hydroxide solution to the reaction system, and react at room temperature 25 °C for 2 h. LC-MS shows that the starting material is consumed and the MS of the product is detected. Slowly pour the reaction solution into 30 mL of water for dilution, then extract with ethyl acetate three times 30 mL*3, combine the organic phase, then wash with saturated brine once 30 mL*1, and dry with anhydrous sodium sulfate. After filtration, concentrate under reduced pressure to obtain 4a. LC-MS (ESI+): m / z = 366.2 [M+H] +

[0286] 4. Preparation of intermediate 5a

[0287] In a 20 mL flask, add 4a (0.8 g, 2.18 mmol) dissolved in THF (10 mL). Then add 4b (2.62 g, 13.08 mmol). And react at 70 °C for 2 h. LC-MS shows that the starting material is consumed and the MS of the product is detected. Filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain the crude product, then purify by column chromatography (PE:EA = 10:1 to 2:1) to obtain 5a. LC-MS (ESI+): m / z = 493.4 [M+H] +

[0288] 5. Preparation of intermediate 6a

[0289] In a 10 mL vial, add 5a (0.4 g, 0.95 mmol) and 5b (0.31 g, 1.42 mmol) dissolved in DMF (10 mL). Then add cesium carbonate (0.93 g, 2.85 mmol) to the reaction system, and react at room temperature 25 °C for 2 h. LC-MS shows that the raw material is consumed, and the MS of the product is monitored. Slowly add the reaction solution to 60 mL of saturated aqueous ammonium chloride solution for dilution, then extract with ethyl acetate three times 30 mL*3, and then wash with saturated brine three times 50 mL*3, and then dry over anhydrous sodium sulfate. After filtration, concentrate under reduced pressure to obtain the crude product, and purify by column chromatography (PE:EA = 10:1 to 3:1) to obtain 6a. LC-MS (ESI+): m / z = 508.5 [M+H] +

[0290] 6. Preparation of intermediate 7a

[0291] In a 10 mL vial, add 6a (0.2 g, 0.39 mmol) and 6b (0.31 g, 0.58 mmol) dissolved in dioxane (10 mL) and water (0.3 mL). Then add potassium carbonate (0.16 g, 1.17 mmol) and Cataphos-Pd-G4 (0.31 g, 0.39 mmol). And react at 70 °C for 2 h. LC-MS shows that the raw material is consumed, and the MS of the product is detected. Filter the reaction solution and concentrate under reduced pressure to obtain the crude product, and then purify by column chromatography (PE:EA = 10:1 to 2:1) to obtain 7a. LC-MS (ESI+): m / z = 823.5 [M+H] +

[0292] 7. Preparation of final product 8a (compound C1-519)

[0293] In a 10 mL vial, add 7a (0.2 g, 0.24 mmol) dissolved in DCM (2 mL). Then add TFA (2 mL). And react at room temperature 25 °C for 2 h. LC-MS shows that the raw material is consumed, and the MS of the product is monitored. Concentrate the reaction solution under reduced pressure to remove dichloromethane and trifluoroacetic acid, and then purify by column chromatography (PE:EA = 10:1 to 1:1) to obtain 8a. LC-MS (ESI+): m / z = 525.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.55 (s, 1H), 8.04 (s, 1H), 7.89 (d, J = 6.4 Hz, 1H), 5.46 (d, J = 7.7 Hz, 2H), 4.76 (s, 1H), 3.89 (s, 2H), 3.61 (dp, J = 7.7, 6.5 Hz, 2H), 2.60 (d, J = 7.0 Hz, 1H), 2.13 (s, 1H), 2.05 - 1.85 (m, 2H), 1.70 (d, J = 12.3 Hz, 2H), 1.62 - 1.30 (m, 4H), 1.21 (d, J = 4.3 Hz, 1H), 0.97 (d, J = 6.5 Hz, 12H).

[0294] Example 21

[0295] The synthesis process route of compound C1-516 is shown as follows:

[0296] 1. Preparation of intermediate 2a

[0297] In a 50 mL bottle, 1a (2 g, 10.33 mmol) and 1b (2.82 g, 12.55 mmol) were dissolved in DMF (20 mL). Then DIEA (4.10 g, 31.74 mmol) was added. Finally, it was reacted at 100°C for 12 hrs. LC-MS showed that the raw material was consumed, and the MS of the product was detected. The reaction solution was slowly added to 50 mL of water, and then extracted with ethyl acetate three times of 30 mL*3. After the organic phase was combined, it was washed with saturated brine twice of 50 mL*2, and then dried with anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to obtain 2a. LC-MS (ESI+): m / z = 362.8 [M+H] +

[0298] 2. Preparation of intermediate 3a

[0299] In a 50 mL bottle, 2a (2.00 g, 5.51 mmol), 2b (2.25 g, 6.05 mmol) were dissolved in DMF (20 mL). Then DIEA (4.5 g, 11 mmol) was added. Finally, it was reacted at 100°C for 3h. LC-MS showed that the raw material was consumed, and the MS of the product was detected. The reaction solution was concentrated under reduced pressure to remove dichloromethane and hydrobromic acid acetic acid, and then purified by column chromatography (PE:EA = 10:1 to 1:1) to obtain 3a. LC-MS (ESI+): m / z = 407.3 [M+H] +

[0300] 3. Preparation of intermediate 4a

[0301] In a 100 mL flask, add 3a (1.00 g, 2.46 mmol) dissolved in DMSO (10 mL). And prepare sodium hydroxide (0.3 g, 7.38 mmol) aqueous solution (5 mL). Then slowly add the sodium hydroxide solution to the reaction system. And react at room temperature 25 ℃ for 2 h. LC-MS shows that the raw material is consumed. Slowly add the reaction solution to 30 mL of water for dilution, then adjust the pH to neutral with 1M dilute hydrochloric acid, and extract with ethyl acetate three times 30 mL*3, wash the combined organic phase with saturated brine three times 50 mL*3, and dry with anhydrous sodium sulfate. After filtration, concentrate under reduced pressure to obtain 4a. LC-MS (ESI+): m / z = 379.3 [M+H] +

[0302] 4. Preparation of intermediate 5a

[0303] In a 50 mL flask, add 4a (0.5 g, 1.32 mmol) dissolved in THF (5 mL). And add 3b (1.59 g, 7.92 mmol). Then react at 70 ℃ for 2 h. LC-MS shows that the raw material is consumed, and the MS of the product is monitored. Filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain the crude product. Purify by column chromatography (PE:EA = 10:1 to 2:1) to obtain 5a. LC-MS (ESI+): m / z = 493.4 [M+H] +

[0304] 5. Preparation of intermediate 6a

[0305] In a 50 mL flask, add 5a (0.5 g, 1.15 mmol) and 5b (0.37 g, 1.72 mmol) dissolved in DMF (5 mL). And add cesium carbonate (0.75 g, 2.3 mmol). Then react at 50 ℃ for 2 h. LC-MS shows that the raw material is consumed. Slowly add the reaction solution to 30 mL of saturated aqueous ammonium chloride solution, then extract with ethyl acetate three times 30 mL*3, wash the combined organic phase with saturated brine three times 30 mL*3, and dry with anhydrous sodium sulfate. After filtration, concentrate under reduced pressure to obtain 6a. LC-MS (ESI+): m / z = 808.4 [M+H] +

[0306] 6. Preparation of intermediate 7a

[0307] In a 10 mL vial, add 6a (0.2 g, 0.38 mmol) and 6b (0.3 g, 0.57 mmol) dissolved in dioxane (3 mL). Add potassium carbonate (0.25 g, 0.76 mmol) and Pd(dppf)Cl2(0.03 g, 0.038 mmol). React at 70 °C for 2 h. LC-MS shows the starting material is consumed. Filter the reaction and concentrate under reduced pressure to get the crude product. Purify by column chromatography (PE:EA = 10:1 to 1:1) to get 7a. LC-MS (ESI+): m / z = 521.5 [M+H] +

[0308] 7. Preparation of final product 8a (Compound C1-516)

[0309] In a 10 mL vial, add 7a (0.1 g, 0.12 mmol) dissolved in DCM (1 mL). Then add TFA (1.53 g, 13.42 mmol). React at room temperature 25 °C for 2 h. LC-MS shows the starting material is consumed and the MS of the product is detected. Concentrate under reduced pressure to remove DCM and trifluoroacetic acid from the reaction and purify by preparative TLC (PE:EA = 0:1) to get 8a. LC-MS (ESI+): m / z = 538.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (d, J = 3.0 Hz, 1H), 12.11 (s, 1H), 4.66 (s, 1H), 2.63 (d, J = 6.9 Hz, 1H), 2.31 (d, J = 1.0 Hz, 3H), 1.94 (s, 3H), 1.82 - 1.62 (m, 4H), 1.59 - 1.26 (m, 7H), 1.21 (s, 1H), 0.05 (s, 9H).

[0310] Example 22

[0311] The synthesis process route of compound C1-532 is shown below:

[0312] 1. Preparation of intermediate 2a

[0313] In a 10 mL vial, add 1a (1 g, 2.38 mmol) dissolved in tetrahydrofuran (10 mL) and CMBP (0.72 g, 2.83 mmol) under ice bath condition. React at 70 °C for 3 h. LC-MS shows the starting material is consumed. Dry the solvent and purify by column PE:EA = 5:1 to get 2a. LC-MS (ESI+): m / z = 521.2 [M+H] +

[0314] 2. Preparation of intermediate 3a

[0315] In a 10 mL vial, 2a (0.52 g, 1 mmol) was dissolved in Dioxane (5 mL). Then 1B (0.63 g, 1.2 mmol), Cesium carbonate (0.984 g, 3 mmol), Catium Pd G4 (80 mg, 0.05 mmol) were added. And reacted at 70 °C for 3 h. LC-MS showed the starting material was consumed. The solvent was spin dried, and purified by column chromatography (PE:EA = 10:1 to 5:1) to get solid 3a. LC-MS (ESI+): m / z = 836.4 [M+H] +

[0316] 3. Preparation of final product C1-532

[0317] In a 10 mL vial, 3a (0.4 g, 0.478 mmol) was dissolved in DCM (5 mL). Then TFA (5 mL) was added. And reacted at room temperature 25 °C for 16 h. LC-MS showed the starting material was consumed. The reaction was concentrated under reduced pressure to remove dichloromethane and trifluoroacetic acid, and then purified by column chromatography (DCM:MeOH = 100:0 to 100:10) to get product C1-532. LC-MS (ESI+): m / z = 538.2 [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 12.48 (s, 2H), 8.49 (d, J = 3.1 Hz, 1H), 8.35 (s, 1H), 7.86 (d, J = 3.6 Hz, 1H), 6.76 (s, 1H), 4.67 (s, 1H), 4.43 - 4.20 (m, 2H), 2.74 (s, 1H), 2.01 (d, J = 68.6 Hz, 3H), 1.85 - 1.68 (m, 2H), 1.63 - 1.49 (m, 3H), 1.49 - 1.34 (m, 2H), 1.22 - 1.16 (m, 3H), 0.03 (s, 9H).

[0318] Example 23

[0319] The synthesis process route of compound C1-573 is shown below:

[0320] 1. Preparation of intermediate 2A

[0321] In a 10 mL vial, add 1A (1.19 g, 2.28 mmol) dissolved in Dioxane (10 mL), water (0.2 mL). Then add 1B (1 g, 1.9 mmol), cesium carbonate (1.86 g, 0.6 mmol), Catium Pd G4 (80 mg, 0.1 mmol). Replace nitrogen three times, and react at 70 °C for 3 h. LC-MS shows the starting material is consumed, and the MS of the product is monitored. Spin dry the solvent, and purify by column chromatography (PE:EA = 10:1 to 5:1) to get 2A. LC-MS (ESI+): m / z = 858.5 [M+H] +

[0322] 2. Preparation of intermediate 3A

[0323] In a 10 mL vial, add 2A (0.3 g, 0.35 mmol) dissolved in Dioxane (3 mL). Then add tert-butyl carbamate (0.246 g, 2.1 mmol), cesium carbonate (0.342 g, 1.05 mmol), Pd2(dba)3 (27 mg, 0.035 mmol), XantPhos (35 mg, 0.07 mmol). Replace nitrogen three times, and react at 110 °C for 10 h. LC-MS shows the starting material is consumed, and the MS of the product is monitored. Spin dry the solvent, and purify by column chromatography (PE:EA = 10:1 to 5:1) to get 3A. LC-MS (ESI+): m / z = 940.2 [M+H] +

[0324] 3. Preparation of final product 4A (Compound C1-573)

[0325] In a 10 mL vial, add 3A (0.05 g, 0.053 mmol) dissolved in DCM (1 mL). Then add TFA (1 mL). And react at room temperature 25 °C for 16 h. LC-MS shows the starting material is consumed, and the MS of the product is monitored. Concentrate the reaction solution under reduced pressure to remove dichloromethane and trifluoroacetic acid, and purify by column chromatography (DCM:MeOH = 100:0 to 100:10) to get the product 4A. LC-MS (ESI+): m / z = 541.5 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ 12.45 (s, 2H), 8.15 (s, 1H), 7.15 (s, 2H), 4.82 (s, 1H), 3.79 (s, 2H), 1.99 (s, 2H), 1.75 (d, J = 23.3 Hz, 3H), 1.52 (d, J = 26.6 Hz, 3H), 1.39 (d, J = 25.5 Hz, 2H), 1.32 - 1.09 (m, 2H), 0.12 (d, J = 24.1 Hz, 9H).

[0326] Test of inhibitory effect of compound on virus:

[0327] 1. Detection principle

[0328] CCK8 is the full name of Cell Counting Kit-8 reagent, which can be used for simple and accurate cell proliferation and toxicity analysis. The basic principle is: the reagent contains water-soluble tetrazolium salt WST-8 (chemical name: 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonic acid phenyl)-2H-tetrazole monosodium salt), which is reduced to a highly water-soluble yellow formazan product under the action of electron carrier 1-methoxy-5-methyl phenylzolium sulfate dimethyl (1-methoxy PMS) by dehydrogenase in cells. The amount of generated formazan product is proportional to the number of living cells. Therefore, this property can be used to directly analyze cell proliferation and toxicity.

[0329] The cell activity is detected by CCK8 to determine the protective effect of the test compound on the cells and evaluate the inhibitory effect of the test compound on the virus.

[0330] 2. Preparation of samples

[0331] The weighing and preparation of the test sample, positive control (the positive control of the H1N1 virus is ondansetron, and the positive control of the H3N2 virus is ribavirin) are required to be weighed by a millionth level analytical balance, the data is printed and archived and uploaded to the ELN experimental record, the solvent is dissolved, the consistency of the solvent is ensured, and the pH value is maintained at 7-8. After the test sample and positive control are dissolved in the solvent, they are diluted to prepare solutions with appropriate concentrations. Eight concentration gradients are selected to determine the EC 50 .

[0332] 3. Experimental steps

[0333] Day 1: MDCK cells are trypsinized, centrifuged, resuspended in 10% serum medium, counted, and then diluted to a cell storage solution of 150,000 / ml. 100 μL / well is inoculated into a 96-well plate, and the plate is incubated in an incubator overnight.

[0334] Day 2: Infection and drug treatment

[0335] Cells were divided into three groups, namely blank solvent control group, virus control group (virus is H1N1-PR8, Influenza B Virus Victoria) and sample group.

[0336] The virus was diluted with 2% serum medium to a virus stock solution of 3000 pfu / ml, and stored at 4°C for standby. The sample to be tested was dissolved in DMSO to a stock solution of 10 mM, and then gradient diluted with 2% serum medium to obtain working solutions of different concentrations.

[0337] The blank solvent control group, the cell plate of Day 1 was aspirated to dry the medium supernatant, and 100 μL of DMSO and 2% serum medium containing the same content as the sample group were added.

[0338] The virus control group, the cell plate of Day 1 was aspirated to dry the medium supernatant, and 50 μL of virus stock solution was added, and 50 μL of DMSO and 2% serum medium containing the same content as the sample group were added.

[0339] The sample group to be tested, the cell plate of Day 1 was aspirated to dry the medium supernatant, and 50 μL of virus stock solution was added, and 50 μL of different concentrations of drug working solution was added.

[0340] Each group has three duplicate wells.

[0341] Incubate in an incubator, and observe the cytopathic state daily.

[0342] Day 5: Add 10 μL CCK-8 to each well of cells, and incubate in a cell incubator for 2 h before reading on a microplate reader.

[0343] 4. Data processing

[0344] Inhibition rate = (sample OD value-virus control group OD value) / (blank solvent control group OD value-virus control group OD value)

[0345] EC 50 Calculation: Graphpad Prism8 software.

[0346] The experimental results are shown in Table 1.

[0347] Among them, for the H1N1 virus, A is less than 0.1 μM, B is 0.1-0.2 μM, C is greater than or equal to 0.2 μM and less than 0.5 μM, D is greater than or equal to 0.5 μM; for the B virus, A is less than 0.5 μM, B is 0.5-2 μM, C is greater than or equal to 2 μM and less than 10 μM, D is greater than or equal to 10 μM and less than 100 μM, E is greater than or equal to 100 μM.

[0348] Table 1 enzyme activity test results

[0349] More specifically, for the Ebola virus, the EC50 of compounds C1-232, C1-493, C1-516, C1-532 50 Less than 0.15 μM, tested according to other test methods in the art (for example the method disclosed in patent CN108218873B), the results have no significant difference with the present application, the inhibitory effect of the preferred compounds of the present application on the virus is significantly better than the prior art.

[0350] Those skilled in the art will readily understand that the above description is only an embodiment of the present application and is not intended to limit the present application, any modification, equivalent replacement and improvement made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

Compounds of Formula (I) and pharmaceutically acceptable salts, esters, prodrugs, solvates, stereoisomers, tautomers, or isotopically enriched forms thereof: wherein: X3is =CR5- or -N(C 1-3 alkylene-Si(CH3)3)-, X4is =CR4- or -N(C 1-3 alkylene-Si(CH3)3)-, and only one of X3, X4is -N(C 1-3 alkylene-Si(CH3)3)-; dashed line represents the presence or absence of a bond, when X3is -N(C 1-3 alkylene-Si(CH3)3)-, the dashed line connected to X3represents the absence of a bond, and the dashed line connected to X4represents the presence of a bond; when X4is -N(C 1-3 alkylene-Si(CH3)3)-, the dashed line connected to X4represents the absence of a bond, and the dashed line connected to X3represents the presence of a bond; A is R1, R2, R3, R4, R5, R6, R7, R8, and R9are each independently H, D, a halogen atom, a C 1-6 alkyl group, -OH, -CN, -NH2; 1-6 alkyl group, -OH, -CN, -NH2; R 10 is OR a , -NR a R b , C 1-3 alkyl-COOH, C 0-6 silyl, C 1-6 alkyl or C 3-6 cycloalkyl, said C 1- 3alkyl-COOH, C 0-6 silyl, C 1-6 alkyl, C 3-6 cycloalkyl is optionally substituted with one or more substituents independently selected from D, F, Cl, Br, CN, NO2, NH2, OH or cyclopropyl; R a and R b each independently H, D, C 0-6 silyl, C 1-6 alkyl or C 3-6 cycloalkyl; X1, X2are each independently selected from -CH- or nitrogen. The compound of formula (I) according to claim 1 and pharmaceutically acceptable salts, esters, prodrugs, solvates thereof, and stereoisomers, tautomers, or isotopically enriched forms thereof, characterized in that, R6, R7, R8, and R9 are H; preferably, A is The compound of formula (I) according to claim 1 and pharmaceutically acceptable salts, esters, prodrugs, solvates thereof, and stereoisomers, tautomers, or isotopically enriched forms thereof, characterized in that, said R 10 is -OH, -C 1-3 alkyl, -NH2or -O-C 1-3 alkyl. The compound of formula (I) according to claim 1 and pharmaceutically acceptable salts, esters, prodrugs, solvates thereof, and stereoisomers, tautomers, or isotopically enriched forms thereof, characterized in that, said R1is H, D, F, Cl, Br, -OH, NH2, preferably F, Cl, Br, -OH, NH2. The compound of formula (I) according to claim 1 and pharmaceutically acceptable salts, esters, prodrugs, solvates thereof, and stereoisomers, tautomers, or isotopically enriched forms thereof, characterized in that, said R2is H, D, F, Cl, Br, preferably H, D, F, Cl, Br. The compound of formula (I) according to claim 1 and pharmaceutically acceptable salts, esters, prodrugs, solvates thereof, and stereoisomers, tautomers, or isotopically enriched forms thereof, characterized in that, R3is H, D, F, CI, Br, C 1-3 alkyl, C 1-3 haloalkyl, preferably H, methyl, halomethyl. The compound of formula (I) according to claim 1 and pharmaceutically acceptable salts, esters, prodrugs, solvates thereof, and stereoisomers, tautomers, or isotopically enriched forms thereof, characterized in that, said R4and R5are each independently H, D, F, Cl, Br, preferably H, D, F, Cl, Br. Compounds and pharmaceutically acceptable salts, esters, prodrugs, solvates, stereoisomers, tautomers, or isotopically enriched forms thereof, as shown below: A pharmaceutical composition, characterized in that, said pharmaceutical composition comprises a compound of any one of claims 1-8, a pharmaceutically acceptable salt, ester, prodrug, solvate thereof, a stereoisomer, tautomer, or an isotopic form thereof, and a pharmaceutically acceptable carrier or excipient; preferably, said pharmaceutical composition is an oral administration formulation, a parenteral administration formulation, or an inhalation spray formulation. use of a compound of any one of claims 1-8, a pharmaceutically acceptable salt, ester, prodrug, solvate thereof, a stereoisomer, tautomer, or an isotopic form thereof, or a pharmaceutical composition of claim 9 in the manufacture of a medicament for treating or preventing a viral infection in a subject, said viral infection being an influenza virus infection; preferably, said influenza virus is influenza A and / or influenza B, more preferably influenza A and influenza B.

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