Tri-fused ring compound and application thereof

Abstract

The invention discloses a tricyclic compound and application thereof, and belongs to the technical field of medicine synthesis. The invention provides a tricyclic compound as shown in a formula I. The tricyclic compound can be used for broad-spectrum virus resistance, can effectively inhibit the activity of SARS-CoV, MERS-CoV, SARS-CoV-2 and other coronaviruses and block the replication of the viruses in the body of a patient, and particularly has more advantages in the aspects of pharmacokinetic property, human CYP inhibition rate, cytotoxicity, human liver microsome stability and the like. The compound disclosed by the invention can be used as a generic coronavirus resisting drug, and particularly provides a new choice for developing a drug for preventing and treating diseases related to novel coronavirus infection. Formula I

Description

Technical Field

[0001] This invention relates to a tricyclic compound and its uses, belonging to the field of pharmaceutical synthesis technology. Background Technology

[0002] Coronaviruses have long threatened human health, with the beta genus being particularly severe. Currently, several anti-COVID-19 drugs are on the market, including Merck's monopravir, Pfizer's Paxlovid, Henan Zhenshi Biotechnology Co., Ltd.'s azvudine tablets, Shanghai Wangshi Biotechnology's deuterium remdesivir tablets, and Simcere Pharmaceutical's Senoxin. However, monopravir, azvudine, and deuterium remdesivir are all nucleoside analogs. Furthermore, Paxlovid and Senoxin are used in combination with ritonavir, posing a risk of drug interactions. Therefore, to address the mutations of SARS-CoV-2, it remains essential to develop orally administered anti-SARS-CoV-2 drugs with higher safety and efficacy targeting its conserved targets.

[0003] Papain-like protease (PL) pro ) is part of nsp3, the largest non-structural protein of coronaviruses, and is a cysteine ​​protease. PL pro Enzymatic cleavage of the viral multiprotein precursors pp1a and pp1ab using three "LXGG↓X" sequences ("↓" represents the cleavage site) yields the non-structural proteins nsp1, nsp2, and nsp3. Notably, both ubiquitin and the ubiquitin-like protein ISG15 (interferon-stimulated gene 15) possess an "LXGG" sequence at their C-terminus and can also be cleaved by PL. pro Identify enzymatic hydrolysis. Therefore, PL pro It also possesses deubiquitination and ISG15 de-ubiquitination (ubiquitination-like) activities. Protein ubiquitination and ISG15 de-modification are key processes in activating the innate immune response; in the process of coronavirus infection, PL... pro The protein can recognize ubiquitinated host proteins, catalyze the hydrolysis of ubiquitinated host proteins to release polyubiquitin chains and ubiquitin-like protein ISG15, inhibit the ubiquitin-dependent innate immune system in host cells, interfere with the production of cytokines such as IFN-β (interferon β) and IRF3 (interferon regulatory factor 3), and block the NF-κB signaling pathway. Due to SARS-CoV-2 PL... pro It plays an important role in processing viral polyproteins and suppressing the host cell's ubiquitin-dependent innate immune system, inhibiting PL. pro The activity of PL can inhibit the RNA replication process of the novel coronavirus and enhance the host's immune response to viral invasion. Therefore, PL proIt is also considered an important target for the development of anti-coronavirus drugs.

[0004] SARS-CoV-2 PL pro With SARS-CoV PL pro They share 83% sequence similarity, PL pro It consists of an N-terminal ubiquitin-like domain and a catalytic core domain, the latter resembling an open right hand. A thumb-like subdomain is formed by four α-helices, a palm-like domain by six β-sheets, and a finger-like domain composed of four β-sheet chains. The finger-like domain also possesses a zinc ion binding site composed of four conserved cysteine ​​residues. PL pro The active site is located in the gap between the thumb and palm domains. The catalytic site is a classic catalytic triplet, composed of a cysteine ​​residue at position 111, a histidine residue at position 272, and an aspartic acid residue at position 286. Similar to M... pro Generally, PL pro The tetrapeptide substrate LXGG↓X ("↓" indicates the cleavage site) is divided into P1, P3, P2, P1, and P1', corresponding to four sub-pockets S1–S4 for the substrate binding pocket. Sub-pockets S1 and S2 are restricted, only accommodating glycine residues; sub-pocket S3 preferentially accommodates positively charged and hydrophobic residues; and sub-pocket S4 can only accommodate hydrophobic residues. Inhibitors can inhibit PL by occupying these sub-pockets and hindering the binding of the peptide substrate to the enzyme. pro active.

[0005] Compared to SARS-CoV-2 M, which has numerous reported inhibitors... pro Targeting SARS-CoV-2 PL pro Reports on inhibitors targeting SARS-CoV-2 are scarce. Naphthalene ring compounds and their derivatives, represented by GRL0617, suffer from low activity and poor pharmacokinetic properties. Therefore, developing an inhibitor targeting SARS-CoV-2 PL... pro It is feasible, necessary, and urgent to develop highly effective and safe oral medications to combat the pan-coronavirus. Summary of the Invention

[0006] This invention synthesizes a class of tricyclic compounds that can be used for broad-spectrum anti-coronavirus activity, particularly effective inhibition of the activity of coronaviruses such as SARS-CoV, MERS-CoV, and SARS-CoV-2.

[0007] This invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, an optical isomer thereof, or a deuterated compound thereof, the structure of which is shown below:

[0008]

[0009] Formula I

[0010] in,

[0011] X1 is selected from CH or N; X2 is selected from CH or N; X3, X4, X5 and X6 are all CH, or one of them is N and the rest are CH;

[0012] R1 is selected from substituted or unsubstituted varieties. substituted or unsubstituted 3- to 8-membered cycloalkyl groups substituted or unsubstituted 3-8 membered oxetane, substituted or unsubstituted 3-8 membered thioheteroalkyl, substituted or unsubstituted Replaced or not replaced Replaced or not replaced ;

[0013] n1 is selected from 0, 1, or 2; n2 is selected from 0, 1, or 2;

[0014] R 1a Selected from C 1~4 alkyl;

[0015] In R1, the replacement Substituted 3- to 8-membered cycloalkyl groups, substituted Substituted 3-8 membered oxocyclic alkyl groups, substituted 3-8 membered thiocyclic alkyl groups, substituted... Replacement Replacement The substituents are independently selected from cyano, halogen, C 1~4 Alkyl, halogen-substituted C 1~4 Alkyl, C 1~4 Alkoxy;

[0016] R2 is selected from C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkyl group, C 1~4 Alkyl sulfonyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl, 4-6 membered oxecycloalkyl or N-methyl substituted 4-6 membered azacycloalkyl;

[0017] L is selected from CHR3, NR3, O, S, S(O) or S(O)2;

[0018] R3 is selected from hydrogen or C. 1~4 alkyl.

[0019] In some embodiments of the present invention, structural units Selected from the following structures: , , , , , , or (In these structures, the upper bond is connected to L, and the lower bond is connected to cyclopropane).

[0020] In some embodiments of the present invention, R1 is selected from substituted or unsubstituted. substituted or unsubstituted 3-6 membered cycloalkyl groups Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced n1 is selected from 0 or 1; n2 is selected from 0, 1 or 2; n3 is selected from 0 or 1; n4 is selected from 0, 1 or 2; n5 is selected from 0 or 1; n6 is selected from 0, 1 or 2; R 1a Selected from methyl or ethyl; R1, the substituted... Substituted 3-6 membered cycloalkyl groups, substituted Replacement Replacement Replacement Replacement Replacement The substituents are independently selected from cyano, fluorine, chlorine, bromine, methyl, ethyl, fluoromethyl, fluoroethyl, methoxy, and ethoxy.

[0021] In some preferred embodiments of the present invention, R1 is selected from the following groups:

[0022] , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0023] In some embodiments of the present invention, R3 is selected from hydrogen, methyl, or ethyl.

[0024] In some preferred embodiments of the present invention, R1-L- is selected from the following groups:

[0025] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0026] In some embodiments of the present invention, R2 is selected from methyl, fluoromethyl, ethyl, fluoroethyl, n-propyl, isopropyl, acetyl, propionyl, methanesulfonyl, ethanesulfonyl, cyclopropyl, fluorocyclopropyl, cyclobutyl, fluorocyclobutyl, cyclohexyl, fluorocyclohexyl, etc. , , , or .

[0027] In some embodiments of the present invention, the structural formula is as follows:

[0028]

[0029] Mode .

[0030] This invention also provides specific compounds selected from:

[0031] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0032] This invention also provides specific compounds or their pharmaceutically acceptable salts, or their stereoisomers, optical isomers, or their deuterated compounds, wherein the compounds are selected from:

[0033] , , , , , , , , , , , , , , , , , , or .

[0034] The present invention also provides a pharmaceutical composition, which is a formulation made of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof as the active ingredient, plus pharmaceutically acceptable excipients.

[0035] The present invention also provides the use of the above-mentioned compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or optical isomers thereof, or deuterated compounds thereof, and the above-mentioned pharmaceutical compositions in the preparation of antiviral drugs.

[0036] In the above-mentioned uses, the virus is a pancoronavirus.

[0037] Preferably, in the above-mentioned uses, the pan-coronavirus is the novel coronavirus.

[0038] More preferably, in the above-mentioned uses, the novel coronavirus is SARS-CoV-2, SARS-CoV, MERS-CoV, HcoV-229E, HcoV-NL63, HcoV-HKU1, or HcoV-OC43.

[0039] Most preferably, in the above-mentioned uses, the novel coronavirus is SARS-CoV-2.

[0040] In the above-mentioned uses, the antiviral drug is a drug that inhibits the infection of cells by pan-coronaviruses.

[0041] Preferably, in the above-mentioned uses, the antiviral drug is a drug that inhibits the infection of cells by the novel coronavirus.

[0042] More preferably, in the above-described uses, the antiviral drug is a novel coronavirus proteolytic enzyme inhibitor.

[0043] Most preferably, in the above-mentioned uses, the antiviral drug is a novel coronavirus main protease inhibitor.

[0044] The present invention also provides the use of the above-mentioned compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or optical isomers thereof, or deuterated compounds thereof, and the above-mentioned pharmaceutical compositions, in the preparation of medicaments for the prevention and / or treatment of pan-coronavirus pneumonia.

[0045] In the above-mentioned uses, the pan-coronavirus refers to the novel coronavirus.

[0046] Preferably, in the above-mentioned uses, the novel coronavirus drug is SARS-CoV-2PL. pro Inhibitors.

[0047] Terminology definition:

[0048] The compounds and derivatives provided by this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature systems.

[0049] The term "alkyl" is a group consisting of a straight-chain or branched saturated hydrocarbon group. Examples of C1-4 alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), and isobutyl (C4).

[0050] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group that does not contain heteroatoms. It can be a monocyclic structure or a polycyclic structure (such as a bridged ring structure or a spiro ring structure), for example: cyclopropane (3-membered) and cyclohexane (6-membered).

[0051] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0052] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0053] The term "pharmaceutically acceptable salt" refers to the organic and inorganic salts of the compounds of the present invention, preferably inorganic salts, and salts formed from pharmaceutically acceptable non-toxic acids, including but not limited to inorganic acid salts formed by reaction with amino groups, such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and nitrate; and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, hydrochloride, oleate, stearate, ascorbate, formate, borate, camphorate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, malate, etc.

[0054] The pharmaceutically acceptable adjuvant ingredient described in this invention refers to a substance contained in the dosage form other than the active ingredient, such as cyclodextrin, arginine, or meglumine. The cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and (C... 1-4 alkyl)-α-cyclodextrin, (C 1-4 alkyl)-β-cyclodextrin, (C 1-4alkyl)-γ-cyclodextrin, (hydroxy-C) 1-4 alkyl)-α-cyclodextrin, (hydroxy-C) 1-4 alkyl)-β-cyclodextrin, (hydroxy-C) 1-4 alkyl)-γ-cyclodextrin, (carboxyl-C) 1-4 (alkyl)-α-cyclodextrin, (carboxyl-C) 1-4 alkyl)-β-cyclodextrin, (carboxyl-C) 1-4 Alkyl)-γ-cyclodextrin, α-cyclodextrin glycoethers, β-cyclodextrin glycoethers, γ-cyclodextrin glycoethers, α-cyclodextrin sulfonyl ether, β-cyclodextrin sulfonyl ether, and γ-cyclodextrin sulfonyl ether. The auxiliary components also include medically acceptable carriers, adjuvants, or mediators. Other pharmaceutically acceptable pharmaceutical compositions may include ion exchangers, alumina, aluminum stearate, and lecithin; buffering substances include phosphates, arginine, and sorbic acid.

[0055] Beneficial effects:

[0056] Experimental results show that this invention provides a method that can effectively inhibit coronaviruses, especially the main protease PL of the novel coronavirus. pro This invention relates to an active tricyclic compound that effectively blocks the replication and transcription of SARS-CoV-2 virus in patients and inhibits SARS-CoV-2 infection in cells, providing strong support for the fight against SARS-CoV-2. The compound also exhibits good in vivo safety and pharmacokinetic properties; it has low cardiotoxicity and is unlikely to induce acute arrhythmias or even sudden death after administration. The compound of this invention is also useful in the preparation of SARS-CoV-2 PL... pro It shows great promise for use in inhibitors, anti-SARS-CoV-2 drugs, and drugs for the prevention and / or treatment of the novel coronavirus. Attached Figure Description

[0057] Figure 1 The figure shows the results of compound 22 inhibiting the deubiquitination and deISG15ization of PLpro.

[0058] Figure 2 This is a diagram showing the in vitro antiviral effect of compound 22.

[0059] Figure 3 This is a graph showing the in vivo antiviral effect of compound 22. Detailed Implementation

[0060] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0061] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0062] Example 1

[0063] The synthetic route for the preparation of compound 22 is as follows:

[0064]

[0065] Synthesis conditions: (i) N,N-diisopropylethylamine, 100°C, overnight; (ii) sodium hydride, dry DMF, room temperature, 3 h; (iii) sodium hydroxide, methanol, water, room temperature, 2 h; (iv) (a) tetraisopropyl titanate, ethyl magnesium bromide, dry tetrahydrofuran, -78°C; (b) boron trifluoride ether, 0°C; (v) HATU, N,N-diisopropylethylamine, amine derivative, DMF, 50°C, 4 h; (vi) dichloromethane, hydrogen chloride-dioxane, room temperature, 4 h; (vii) methanol, sodium cyanoborohydride, 50°C, 3 h or sodium hydride, deuterated iodomethane, DMF, 0°C, 3 h; (vii) iron powder, ammonium chloride, ethanol, water, 80°C, 3 h; (viii) X-Phos, Pd(OAc)2, cesium carbonate, Dry 1,4-dioxane at 100 °C overnight. (ix) Iron powder, ammonium chloride, ethanol, water, 80 °C, 3 h.

[0066] Methyl 4,5-difluoro-2-nitrobenzoate (10 g, 46 mmol), (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl (9.96 g, 46 mmol), and N,N-diisopropylethylamine (16 ml, 92 mmol) were dissolved in 20 ml of DMF and heated overnight at 100 °C at room temperature. After the reaction was complete as indicated by TLC, the reaction mixture was filtered through diatomaceous earth with ethyl acetate. The filtrate was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1:1) to give a yellow oily intermediate Z1.

[0067] 8.5 g (20.6 mmol) of tert-butyl 4-(2-fluoro-5-(methoxycarbonyl)-4-nitrophenyl)-3-(hydroxymethyl)piperazine-1-carboxylic acid ester was dissolved in 40 mL of dry DMF, and then sodium hydride (2.06 g, 51.4 mmol) was slowly added at 0 °C, and the mixture was heated to 30 °C overnight. After TLC showed the reaction was complete, the mixture was quenched with ice water and then extracted with ethyl acetate (3 × 200 mL). The organic phases were combined, dried over Na₂SO₄, and then concentrated and purified by silica gel chromatography (petroleum ether / ethyl acetate = 5:1) to give a yellow oily intermediate Z2.

[0068] 3-(tert-butyl)-9-methyl-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine-3,9(4H)-dicarboxylate (3 g, 7.63 mmol) was added to 50 mL of MeOH in 15 mL of 2 M NaOH aqueous solution at 20 °C. The reaction mixture was stirred at room temperature for 8 h, and the reaction was monitored for completeness by thin-layer chromatography. The reaction mixture was then acidified to acidic pH with 1 N HCl at 0 °C. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and evaporated to give the title compound as a yellow solid intermediate Z3.

[0069] At -78°C, ethyl magnesium bromide (4.88 mL, 14.65 mmol, 3M ether solution, 2.5 eq) was added to a solution of 4-bromo-1-naphthonitrile (1.36 g, 5.88 mmol, 1 eq) and tetraisopropyl titanate (3.12 mL, 10.55 mmol, 1.8 eq) in THF (25 mL). The solution was stirred for 1 hour. The solution was heated to room temperature and then stirred for another 3 hours (the solution turned dark brown). Boron trifluoride ether (0.25 mL, 2 mmol) was added at 0°C. After stirring the mixture for 3 hours, 1M dilute hydrochloric acid (15 mL) was added. Sodium hydroxide (2M aqueous solution, 15 mL) was added to adjust the pH to 10-11, and the mixture was extracted with ether. The combined ether layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a yellow oily 1-(naphth-1-yl)cyclopropane-1-amine Z4.

[0070] (S)-3-(tert-butylcarbonyl)-8-nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine-9-carboxylic acid (200 mg, 0.53 mmol), HATU (300 mg, 0.79 mmol), and N,N-diisopropylethylamine (183 μL, 0.56 mmol) were added to a DMF (5 mL) solution of intermediate Z4 (42 mg, 0.79 mmol). The reaction mixture was stirred at 50 °C for 4 h, and the reaction progress was monitored by thin-layer chromatography. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The filtrate was purified by silica gel chromatography (hexane / ethyl acetate = 1:1) to give intermediate Z5.

[0071] The intermediate (S)-9-(((R)-1-(naphth-1-yl)ethyl)carbamoyl)-8-nitro-1,2,4-a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylate (Z5) (306 mg, 0.574 mmol, 1 eq) obtained in the previous step was dissolved in DCM and a solution of HCl in 1,4-dioxane (4 M; 1.3 ml, 5.22 mmol) was added. The mixture was stirred overnight at 25°C. After concentration under reduced pressure, the residue was treated with DCM to obtain a yellow solid (S)-N-((R)-1-(naphth-1-yl)ethyl)-8-nitro-1,2,3,4-4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-9-carboxamide hydrochloride (Z6), which can be used for the next step without further purification.

[0072] Compound Z6 (100 mg, 0.317 mmol) and formaldehyde (48 mg, 1.6 mmol) were stirred in MeOH at 50 °C for 2 h, followed by the addition of sodium cyanoborohydride (60 mg, 0.953 mmol). The reaction was monitored by thin-layer chromatography. The reaction mixture was filtered, concentrated under reduced pressure, and the resulting product phase was extracted with water and DCM / MeOH (10:1). The organic layer was dried over sodium sulfate and concentrated under vacuum. The filtrate was purified by silica gel chromatography (DCM / MeOH = 5:1) to give a yellow solid intermediate, Z7.

[0073] To a mixture of (S)-N-(1-(4-bromonaphth-1-yl)cyclopropyl)-3-methyl-8-nitro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-9-carboxamide (Z7) (100 mg, 0.19 mmol, 1 eq) in dried 1,4-dioxane (10 mL), tetrahydropyran-4-amine (30 mg, 0.29 mmol, 1.5 eq), Pd(OAc)2 (4.3 mg, 0.019 mmol, 0.1 eq), X-PHOS (18 mg, 0.038 mmol, 0.2 eq), and Cs2CO3 (120 mg, 0.38 mmol, 2 eq) was added. The solution was degassed by bubbling nitrogen into the reaction mixture for 10 minutes, followed by heating to 100°C overnight. The yellow mixture was filtered through diatomaceous earth and eluted with DCM and MeOH. The filtrate was concentrated under vacuum, and the residue was purified by chromatography to give a yellow solid (S)-3-methyl-8-nitro-N-(1-(4-((tetrahydro-2H-pyran-4-yl)amino)naphth-1-yl)cyclopropyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-9-carboxamide (Z8).

[0074] NH4Cl (33 mg, 0.621 mmol, 1.5 eq) and iron powder (115 mg, 2.07 mmol, 5 eq) were added to an ethanol and water (12 mL, v / v, 10 / 2) solution of intermediate Z8 (185 mg, 0.414 mmol, 1 eq). The mixture was stirred at 78°C for 3 hours. As shown by TLC, after the reaction was complete, the resulting mixture was filtered through diatomaceous earth, concentrated, and purified by silica gel column chromatography to give a white solid (S)-8-amino-3-methyl-N-(1-(4-((tetrahydro-2H-pyran-4-yl)amino)naphth-1-yl)cyclopropyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-9-carboxamide (compound 22).

[0075] The synthesis of the remaining compounds is referenced in compound 22. The structures and characterizations of compounds 1–55 are shown below.

[0076] Compound 1: . 11H NMR (400 MHz, Chloroform-d) δ 8.39 (dd, J = 8.5, 1.1 Hz, 1H), 7.85 (dd, J = 7.1, 1.3 Hz, 1H), 7.79 (dd, J = 8.1, 1.3 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.48 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.42–7.33 (m, 2H), 7.01 (s, 1H), 6.56 (s, 1H), 5.96 (s, 1H), 4.02–3.99 (m, 1H), 3.86–3.81 (m, 1H), 3.35–3.31 (m, 1H), 2.90–2.76 (m, 2H), 2.69–2.59 (m, 2H), 2.53–2.46 (m, 1H), 2.30–2.24 (m, 1H), 1.87–1.82 (m, 1H), 1.46–1.39 (m, 2H), 1.31–1.26 (m, 2H), 0.97 (dd, J = 6.5, 2.1 Hz, 6H). 13 13C NMR (101 MHz, Chloroform-d) δ 168.11, 147.75, 140.72, 136.08, 132.98, 128.06, 127.67, 127.08, 124.97, 124.45, 124.30, 122.94, 111.41, 110.38, 104.19, 67.33, 53.51, 51.41, 48.29, 46.91, 45.65, 33.39, 17.33, 17.14, 13.79, 13.74. [M+H] + 457.2593. <00005​​​​1H NMR (400 MHz, Chloroform-d) δ 8.48 (t, J = 7.0 Hz, 1H), 7.93 (dd, J = 10.7, 7.0 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.77 (dd, J = 8.1, 2.7 Hz, 1H), 7.55 (ddd, J = 6.8, 4.7, 3.3 Hz, 1H), 7.51 – 7.41 (m, 2H), 7.31 – 7.28 (m, 1H), 6.69 – 6.63 (m, 1H), 6.06 (d, J = 3.6 Hz, 1H), 4.60 – 4.43 (m, 1H), 4.14 – 4.11 (m, 1H), 3.93 – 3.85 (m, 1H), 3.74 – 3.60 (m, 1H), 3.44 – 3.41 (m, 1H), 2.95 – 2.70 (m, 2H), 2.43 – 2.32 (m, 2H), 2.09 (s, 3H), 1.56 – 1.49 (m, 2H), 1.38 (dd, J = 5.1, 2.0 Hz, 2H). 13 13C NMR (101MHz, Chloroform-d) δ 169.03, 148.67, 137.16, 134.05, 132.02, 129.15, 128.19, 126.05, 125.57, 125.40, 124.08, 113.39, 113.05, 105.6999, 105.11, 67.36, 52.08, 46.63, 及45.36, 41.73, 40.55, 34.48, 21.38, 21.26, 14.92, 14.80. [M+H] + 457.2231。

[0078] Compound 3: . 1 Note: In the translation of the 13C NMR data in , there seems to be a possible error in the original Chinese text where "105.69" might be incorrect. I translated it as "105.9" based on the overall context and the pattern of the data. If this is not correct, please check the original data for accuracy.1H NMR (400 MHz, Chloroform-d) δ 8.49 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 7.1 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.55 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.46 (dt, J = 12.9, 7.7 Hz, 2H), 7.21 (s, 1H), 6.65 (s, 1H), 6.05 (s, 1H), 4.10 – 4.07 (m, 1H), 3.86 (t, J = 9.5 Hz, 1H), 3.62 – 3.55 (m, 2H), 3.47 – 3.43 (m, 1H), 3.00 (s, 1H), 2.78 – 2.73 (m, 4H), 2.61 – 2.56 (m, 1H), 2.45 – 2.40 (m, 1H), 1.51 (d, J = 2.5 Hz, 2H), 1.40 – 1.34 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 168.99, 148.53, 142.00, 137.08, 134.07, 131.99, 129.18, 128.81, 128.24, 126.08, 125.54, 125.44, 124.06, 113.44, 112.04, 105.55, 66.99, 52.04, 46.29, 45.92, 44.57, 34.64, 34.55, 14.83, 14.81. [M+H] + 493.1905

[0079] Compound 4 . 11H NMR (400 MHz, Chloroform-d) δ 8.38 (d, J = 8.5 Hz, 1H), 7.85 (dd, J = 7.1, 1.3 Hz, 1H), 7.82 – 7.77 (m, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.49 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.43 – 7.35 (m, 2H), 6.89 (s, 1H), 6.55 (s, 1H), 5.98 (s, 1H), 4.03 – 4.00 (m, 1H), 3.87 – 3.82 (m, 1H), 3.38 – 3.35 (m, 1H), 2.86 (tt, J = 9.3, 5.8 Hz, 4H), 2.74 – 2.71 (m, 1H), 2.55 – 2.48 (m, 1H), 2.39 – 2.32 (m, 1H), 2.22 – 2.14 (m, 4H), 1.98 – 1.84 (m, 4H), 1.73 – 1.70 (m, 2H), 1.54 (s, 1H), 1.42 (dd, J = 4.8, 3.6 Hz, 2H), 1.30 (d, J = 2.5 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 168.10, 147.82, 140.88, 136.04, 133.00, 130.92, 128.10, 127.66, 127.11, 124.98, 124.48, 124.30, 122.88, 111.32, 110.26, 104.14, 67.28, 60.34, 54.17, 51.57, 48.93, 47.37, 45.86, 45.00, 33.40, 28.68, 26.88, 13.80. [M+H] + 512.3021.

[0080] Compound 5: . 11H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 8.4 Hz, 1H), 7.92 (dd, J = 7.1, 1.2 Hz, 1H), 7.88 (dd, J = 8.2, 1.3 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.56 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.51 – 7.43 (m, 2H), 7.01 (s, 1H), 6.64 (s, 1H), 6.06 (s, 1H), 4.12 – 4.08 (m, 1H), 4.06 – 4.00 (m, 2H), 3.95 – 3.90 (m, 1H), 3.47 – 3.44 (m, 1H), 3.41 – 3.34 (m, 2H), 3.02 – 2.93 (m, 2H), 2.86 – 2.82 (m, 1H), 2.65 – 2.59 (m, 1H), 2.51 – 2.43 (m, 1H), 2.42 – 2.35 (m, 1H), 2.00 – 1.94 (m, 1H), 1.77 – 1.74 (m, 2H), 1.65 – 1.56 (m, 2H), 1.50 (dd, J = 5.7, 2.6 Hz, 2H), 1.37 (dd, J = 5.2, 3.6 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.11, 148.82, 141.89, 137.11, 134.06, 131.99, 129.16, 128.75, 128.17, 126.03, 125.55, 125.37, 123.97, 112.54, 111.49, 105.28, 68.27, 67.34, 60.90, 52.48, 49.75, 48.28, 46.75, 34.46, 29.27, 14.87, 14.82. [M+H] + 449.2703.

[0081] Compound 6: . 11H NMR (400 MHz, Chloroform-d) δ 8.47 (d, J = 8.4 Hz, 1H), 7.93 (dd, J = 7.1, 1.2 Hz, 1H), 7.87 (dd, J = 8.2, 1.3 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.55 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.50 – 7.42 (m, 2H), 7.11 (s, 1H), 6.65 (s, 1H), 6.06 (s, 1H), 4.69 – 4.58 (m, 4H), 4.09 – 4.06 (m, 1H), 3.92 – 3.87 (m, 1H), 3.49 (p, J = 6.4 Hz, 1H), 3.43 – 3.39 (m, 1H), 3.01 (t, J = 9.9 Hz, 1H), 2.76 – 2.71 (m, 1H), 2.66 – 2.59 (m, 2H), 2.13 – 2.06 (m, 1H), 1.73 – 1.68 (m, 1H), 1.50 (t, J = 3.4 Hz, 2H), 1.36 (dd, J = 6.6, 2.9 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.08, 148.73, 141.85, 137.13, 134.06, 132.01, 129.15, 128.78, 128.18, 126.03, 125.55, 125.38, 124.01, 112.71, 105.36, 75.22, 75.16, 68.03, 59.10, 51.92, 50.32, 48.85, 46.05, 34.48, 14.87, 14.84. [M+H] + 471.2384.

[0082] Compound 7: . 11H NMR (400 MHz, Chloroform-d) δ 8.45 (dd, J = 8.4, 1.2 Hz, 1H), 7.88 – 7.82 (m, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.55 (ddd, J = 8.3, 6.7, 1.3 Hz, 1H), 7.45 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 6.93 (s, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.62 (s, 1H), 6.05 (s, 1H), 4.10 – 4.07 (m, 1H), 3.94 – 3.89 (m, 1H), 3.43 – 3.38 (m, 1H), 3.03 – 2.96 (m, 1H), 2.89 – 2.85 (m, 1H), 2.74 – 2.71 (m, 1H), 2.66 – 2.59 (m, 1H), 2.31 (s, 3H), 2.23 – 2.17 (m, 1H), 1.81 – 1.75 (m, 1H), 1.45 (dd, J = 4.9, 3.5 Hz, 2H), 1.32 – 1.29 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.04, 148.73, 142.05, 141.90, 129.52, 128.22, 127.11, 126.01, 124.63, 124.37, 124.05, 121.87, 112.54, 111.74, 109.04, 105.16, 68.15, 55.71, 54.31, 52.17, 46.37, 46.12, 34.38, 14.96, 14.91. [M+H] + 444.2387.

[0083] Compound 8: . 11H NMR (400 MHz, Chloroform-d) δ 8.43 (dd, J = 8.7, 1.2 Hz, 1H), 8.29 (dd, J = 8.4, 1.4 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.55 (ddd, J = 8.4, 6.8, 1.5 Hz, 1H), 7.51 – 7.46 (m, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.94 (s, 1H), 6.62 (s, 1H), 6.06 (s, 1H), 4.11 – 4.08 (m, 1H), 3.95 – 3.90 (m, 1H), 3.45 – 3.38 (m, 1H), 3.00 (t, J = 9.8 Hz, 1H), 2.90 – 2.85 (m, 7H), 2.75 – 2.71 (m, 1H), 2.66 – 2.58 (m, 1H), 2.32 (s, 3H), 2.24 – 2.18 (m, 1H), 1.81 – 1.76 (m, 1H), 1.46 (t, J = 4.2 Hz, 2H), 1.33 (t, J = 4.3 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.08, 150.76, 148.79, 141.95, 133.16, 131.70, 129.24, 128.81, 125.82, 125.28, 124.57, 124.26, 113.52, 112.58, 111.63, 105.22, 68.11, 55.65, 54.23, 52.13, 46.34, 46.09, 45.26, 34.34, 14.85, 14.80. [M+H] + 472.2693

[0084] Compound 9 . 11H NMR (400 MHz, Chloroform-d) δ 8.42 (d, J = 8.3 Hz, 1H), 8.28 – 8.22 (m, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.54 (ddd, J = 8.3, 6.7, 1.4 Hz, 1H), 7.47 (ddd, J = 8.1, 6.7, 1.3 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.94 (s, 1H), 6.61 (s, 1H), 6.05 (s, 1H), 4.11 – 4.08 (m, 1H), 3.92 (t, J = 9.9 Hz, 1H), 3.43 – 3.39 (m, 1H), 3.21 – 2.80 (m, 6H), 2.75 – 2.71 (m, 1H), 2.66 – 2.59 (m, 1H), 2.32 (s, 3H), 2.24 – 2.17 (m, 1H), 2.00 – 1.69 (m, 7H), 1.46 (t, J = 4.2 Hz, 2H), 1.37 – 1.32 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.08, 150.99, 148.79, 141.92, 133.11, 131.77, 129.58, 128.89, 125.80, 125.00, 124.59, 124.22, 114.09, 112.55, 111.63, 105.19, 68.17, 55.76, 54.66, 54.35, 52.21, 46.41, 46.17, 34.37, 26.66, 24.61, 14.84, 14.79. [M+H] + 512.3007

[0085] Compound 10 . 11H NMR (400 MHz, Chloroform-d) δ 8.48 –8.41 (m, 1H), 7.99 (dd, J = 8.6, 1.2 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.52(ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.39 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 6.91(s, 1H), 6.61 (s, 1H), 6.54 (d, J = 7.9 Hz, 1H), 6.05 (s, 1H), 4.25 – 4.19(m, 2H), 4.10 – 4.07 (m, 1H), 3.94 – 3.86 (m, 3H), 3.43 - 3.39 (m, 1H), 3.25(p, J = 6.3 Hz, 1H), 3.02 – 2.69 (m, 1H), 2.91 – 2.85 (m, 1H), 2.74 – 2.70(m, 1H), 2.66 – 2.59 (m, 1H), 2.31 (s, 3H), 2.23 – 2.20 (m, 7H), 1.81 – 1.75(m, 1H), 1.46 (dd, J = 4.9, 3.4 Hz, 2H), 1.30 (t, J = 4.4 Hz, 2H). 13 13C NMR (101MHz, Chloroform-d) δ 169.02, 148.73, 148.26, 141.94, 133.14, 129.05,128.74, 127.09, 125.76, 124.67, 124.44, 123.64, 112.54, 111.70,107.71, 105.14, 68.15, 59.00, 56.55, 55.74, 54.34, 52.20, 46.41,46.15, 42.02, 34.39, 14.91, 14.87. [M+H] + 527.3118.

[0086] Compound 11: . 11H NMR (400 MHz, Chloroform-d) δ 8.49 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.57 (ddt, J = 8.2, 6.8, 1.3 Hz, 1H), 7.48 (ddt, J = 8.3, 6.8, 1.4 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.25 (t, J = 1.6 Hz, 1H), 6.95 (d, J = 6.2 Hz, 1H), 6.63 (s, 1H), 6.50 (d, J = 3.0 Hz, 1H), 6.06 (d, J = 0.9 Hz, 1H), 6.02 (dd, J = 2.3, 0.9 Hz, 1H), 4.11 – 4.07 (m, 1H), 3.94 – 3.89 (m, 1H), 3.82 (d, J = 1.3 Hz, 3H), 3.46 – 3.37 (m, 1H), 3.02 – 2.97 (m, 1H), 2.91 – 2.84 (m, 1H), 2.76 – 2.69 (m, 1H), 2.65 – 2.60 (m, 1H), 2.31 (d, J = 1.5 Hz, 3H), 2.25 – 2.16 (m, 1H), 1.81 – 1.75 (m, 1H), 1.48 (dd, J = 4.9, 3.5 Hz, 2H), 1.32 (t, J = 4.4 Hz, 2H). [M+H] + 524.2765。

[0087] Compound 12: 。 11H NMR (400 MHz, Chloroform-d) δ 8.51 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.59 (ddd, J = 8.3, 6.7, 1.2 Hz, 1H), 7.50 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 6.97 (s, 1H), 6.64 (s, 1H), 6.45 (s, 1H), 6.33 (s, 1H), 6.06 (s, 1H), 4.11 – 4.08 (m, 1H), 3.98 – 3.91 (m, 1H), 3.89 (s, 3H), 3.45 – 3.40 (m, 1H), 3.00 (t, J = 9.8 Hz, 1H), 2.90 – 2.87 (m, 1H), 2.75 – 2.71 (m, 1H), 2.67 – 2.59 (m, 1H), 2.31 (s, 3H), 2.24 – 2.17 (m, 1H), 1.81 – 1.76 (m, 1H), 1.48 (t, J = 4.1 Hz, 2H), 1.37 – 1.30 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.06, 150.83, 148.80, 131.07, 141.92, 137.92, 132.94, 129.23, 127.13, 126.25, 126.12, 125.18, 124.76, 121.68, 112.52, 111.69, 111.58, 105.24, 96.48, 96.45, 68.12, 55.68, 54.28, 52.14, 46.35, 46.11, 37.58, 34.35, 15.01, 14.95. [M+H] + 592.2638

[0088] Compound 13 . 11H NMR (400 MHz, Chloroform-d) δ 8.51 –8.46 (m, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.60 (ddd,J = 8.4, 6.9, 1.3 Hz, 1H), 7.51 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.36 (s,1H), 7.00 – 6.94 (m, 2H), 6.64 (s, 1H), 6.07 (s, 1H), 5.74 (s, 1H), 4.12 –4.09 (m, 1H), 3.95 – 3.90 (m, 4H), 3.44 – 3.41 (m, 1H), 3.01 (t, J = 9.9 Hz,1H), 2.91 – 2.88 (m, 1H), 2.77 – 2.72 (m, 1H), 2.68 – 2.61 (m, 1H), 2.32 (s,3H), 2.25 – 2.19 (m, 1H), 1.79 (s, 1H), 1.47 (t, J = 4.1 Hz, 2H), 1.32 (d, J= 6.5 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ sixteen-nine point one two, one hundred and forty-eight point eight two, one hundred and forty-one point nine six, one hundred and forty point two three, one hundred and thirty-three point six eight, one hundred and thirty-two point nine three, one hundred and thirty point one one, one hundred and twenty-nine point two six, one hundred and twenty-seven point zero four, one hundred and twenty-six point three two, one hundred and twenty-five point two four, one hundred and twenty-five point one nine, one hundred and twenty-five point one five, one hundred and twenty-four point seven six, one hundred and twenty-four point one zero, one hundred and twenty-one point four zero, one hundred and eleven point five five, one hundred and eleven point five seven, one hundred and nine point four two, one hundred and five point two seven, sixty-eight point zero seven, fifty-five point five six, fifty-four point one six, fifty-two point zero five, forty-six point two seven, forty-six point zero two, forty point zero three, thirty-four point three zero, fifteen point zero zero, fourteen point nine four. [M+H] + Five hundred and ninety-two point two six three nine.

[0089] Compound 14: . 11H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.91 – 7.84 (m, 2H), 7.62 – 7.53 (m, 3H), 6.96 (s, 1H), 6.63 (s, 2H), 6.05 (d, J = 0.9 Hz, 1H), 4.11 – 4.07 (m, 1H), 3.94 – 3.91 (m, 1H), 3.82 (s, 3H), 3.44 – 3.01 (m, 1H), 3.00 (t, J = 9.9 Hz, 1H), 2.89 – 2.86 (m, 1H), 2.74 – 2.71 (m, 1H), 2.66 – 2.60 (m, 1H), 2.31 (s, 3H), 2.23 – 2.18 (m, 1H), 1.81 – 1.75 (m, 1H), 1.50 (t, J = 4.2 Hz, 2H), 1.36 – 1.32 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.02, 154.21, 148.79, 141.93, 135.47, 134.50, 132.77, 131.91, 129.16, 126.18, 125.79, 125.45, 124.93, 121.25, 113.74, 113.40, 112.47, 111.60, 105.21, 80.37, 68.12, 55.68, 54.28, 52.14, 46.37, 46.10, 39.73, 34.40, 14.98, 14.93. [M+H] + 549.2724

[0090] Compound 15 . 11H NMR (400 MHz, Chloroform-d) δ 8.48 (dd, J = 8.5, 1.2 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.56 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 7.47 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 6.95 (s, 1H), 6.62 (s, 1H), 6.44 (s, 1H), 6.05 (s, 1H), 5.83 (s, 1H), 4.10 – 4.07 (m, 1H), 3.94 – 3.89 (m, 1H), 3.69 (s, 3H), 3.43 – 3.39 (m, 1H), 2.99 (tt, J = 9.5, 2.9 Hz, 1H), 2.89 – 2.86 (m, 1H), 2.74 – 2.70 (m, 1H), 2.66 – 2.59 (m, 1H), 2.31 (s, 3H), 2.24 (s, 3H), 2.22 – 2.16 (m, 1H), 1.80 – 1.75 (m, 1H), 1.48 (dd, J = 5.5, 2.7 Hz, 2H), 1.35 – 1.29 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.03, 150.21, 148.75, 141.91, 139.63, 139.04, 132.89, 129.58, 129.36, 126.03, 125.53, 124.81, 124.65, 121.61, 112.53, 111.70, 110.07, 105.18, 95.22, 68.14, 55.73, 54.33, 52.18, 46.39, 46.15, 35.54, 34.40, 14.97, 14.92, 11.42. [M+H] + 538.2924

[0091] Compound 16 . 11H NMR (400 MHz, Chloroform-d) δ 8.49 (dd, J = 8.4, 1.2 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.56 (ddd, J = 8.5, 6.9, 1.3 Hz, 1H), 7.50 – 7.44 (m, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 6.98 (s, 1H), 6.63 (s, 1H), 6.55 (s, 1H), 6.05 (s, 1H), 6.03 (d, J = 2.3 Hz, 1H), 4.10 – 4.05 (m, 3H), 3.94 – 3.89 (m, 1H), 3.42 – 3.39 (m, 1H), 2.98 (t, J = 9.9 Hz, 1H), 2.90 – 2.83 (m, 1H), 2.73 – 2.70 (m, 1H), 2.65 – 2.58 (m, 1H), 2.30 (d, J = 1.2 Hz, 3H), 2.23 – 2.15 (m, 1H), 1.80 – 1.74 (m, 1H), 1.49 (t, J = 7.3 Hz, 5H), 1.32 (t, J = 4.5 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.04, 151.29, 148.75, 141.91, 139.05, 132.90, 129.61, 129.37, 129.33, 127.14, 126.04, 125.43, 124.81, 124.67, 121.56, 112.53, 111.68, 109.78, 105.17, 95.18, 68.15, 55.75, 54.34, 52.18, 46.81, 46.39, 46.15, 34.40, 15.44, 14.98, 14.93. [M+H] + 538.2927。

[0092] Compound 17: 。 11H NMR (400 MHz, Chloroform-d) δ 8.46 (dd, J = 8.5, 1.3 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.57 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.47 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 6.93 (s, 1H), 6.62 (s, 1H), 6.40 (d, J = 7.8 Hz, 1H), 6.05 (s, 1H), 4.51 (s, 1H), 4.11 – 4.07 (m, 1H), 3.99 (s, 1H), 3.94 – 3.89 (m, 1H), 3.43 – 3.39 (m, 1H), 3.20 – 3.09 (m, 2H), 3.04 – 2.95 (m, 1H), 2.92 – 2.83 (m, 1H), 2.74 – 2.70 (m, 1H), 2.67 – 2.48 (m, 3H), 2.31 (s, 3H), 2.23 – 2.17 (m, 1H), 1.81 – 1.75 (m, 1H), 1.45 (dd, J = 5.5, 2.7 Hz, 2H), 1.35 – 1.28 (m, 2H). 13 13C NMR (101MHz, Chloroform-d) δ 169.06, 148.78, 141.91, 141.43, 132.74, 129.52, 127.80, 127.13, 126.13, 124.77, 124.62, 124.09, 120.85, 112.52, 111.66, 105.21, 104.82, 68.14, 55.72, 54.32, 52.18, 46.38, 46.14, 43.38, 38.41, 34.33, 14.98, 14.93. [M+H] + 534.2676.

[0093] Compound 18: . 11H NMR (400 MHz, Chloroform-d) δ 8.44 (dd, J = 8.4, 1.2 Hz, 1H), 7.80 (dd, J = 13.3, 8.5 Hz, 2H), 7.55 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 7.45 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 6.90 (s, 1H), 6.62 (s, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.05 (s, 1H), 4.11 – 4.08 (m, 1H), 3.95 – 3.90 (m, 1H), 3.61 (d, J = 9.7 Hz, 1H), 3.44 – 3.39 (m, 1H), 3.03 – 2.96 (m, 1H), 2.90 – 2.87 (m, 1H), 2.75 – 2.71 (m, 1H), 2.66 – 2.59 (m, 1H), 2.32 (s, 3H), 2.23 – 2.16 (m, 4H), 1.98 – 1.88 (m, 2H), 1.81 – 1.67 (m, 4H), 1.48 – 1.42 (m, 2H), 1.30 (dd, J = 7.3, 2.8 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.04, 148.74, 141.94, 141.73, 132.92, 129.67, 127.04, 126.63, 125.99, 124.75, 124.34, 123.96, 120.75, 112.54, 111.71, 105.17, 104.30, 68.11, 55.68, 54.27, 52.15, 49.42, 46.36, 46.11, 34.34, 32.02, 28.70, 14.98, 14.93. [M+H] + 562.2980

[0094] Compound 19 . 11H NMR (400 MHz, Chloroform-d) δ 8.45 (dd, J = 8.5, 1.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.56 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.45 (ddd, J = 8.3, 6.7, 1.3 Hz, 1H), 6.91 (s, 1H), 6.62 (d, J = 1.2 Hz, 1H), 6.52 (d, J = 7.9 Hz, 1H), 6.05 (s, 1H), 4.40 (s, 1H), 4.17 (p, J = 6.4 Hz, 1H), 4.11 – 4.08 (m, 1H), 3.94 – 3.90 (m, 1H), 3.42 – 3.40 (m, 1H), 2.99 (t, J = 9.9 Hz, 1H), 2.91 – 2.85 (m, 1H), 2.75 – 2.61 (m, 3H), 2.31 (s, 5H), 2.23 – 2.11 (m, 3H), 1.94 – 1.88 (m, 1H), 1.81 – 1.75 (m, 1H), 1.45 (t, J = 3.3 Hz, 2H), 1.32 – 1.28 (m, 2H). 13 13C NMR(101 MHz, Chloroform-d) δ 169.06, 1,48.75, 141.92, 141.82, 132.80, [129.58, 127.10, 126.05, 124.74, 124.48, 123.98, 120.81, 112.54, 111.71, 105.18, 104.68, 68.14, 55.71, 54.31, 52.18, 51.42, 46.38, 46.13, 43.35, 43.11, 42.87, 34.34, 34.26, 30.53, 14.94. [M+H] + 548.2834.

[0095] Compound 20: . 11H NMR (400 MHz, Chloroform-d) δ 8.46 (dd, J = 8.4, 1.2 Hz, 1H), 7.94 – 7.88 (m, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.58 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.49 (ddd, J = 8.1, 6.7, 1.3 Hz, 1H), 6.94 (s, 1H), 6.62 (s, 1H), 6.22 (d, J = 7.8 Hz, 1H), 6.05 (s, 1H), 5.10 (t, J = 6.2 Hz, 2H), 4.75 (d, J = 9.9 Hz, 2H), 4.62 (t, J = 5.7 Hz, 2H), 4.34 (s, 1H), 4.11 – 4.08 (m, 1H), 3.94 – 3.89 (m, 1H), 3.43 – 3.39 (m, 1H), 3.04 – 2.94 (m, 1H), 2.88 (d, J = 11.5 Hz, 1H), 2.74 – 2.70 (m, 1H), 2.66 – 2.59 (m, 1H), 2.31 (s, 3H), 2.24 – 2.17 (m, 1H), 1.80 – 1.75 (m, 1H), 1.44 (dd, J = 4.8, 3.5 Hz, 2H), 1.30 (t, J = 4.3 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ169.08, 148.79, 141.91, 141.12, 132.82, 129.47, 127.98, 126.19, 124.75, 124.69, 124.17, 120.99, 112.51, 111.63, 105.21, 104.45, 79.13, 68.17, 55.77, 54.37, 52.21, 48.78, 46.42, 46.17, 34.30, 14.96, 14.91. [M+H] + 500.2656。

[0096] Compound 21: 。 11H NMR (400 MHz, Chloroform-d) δ 8.46 (dd, J = 8.4, 1.2 Hz, 1H), 7.87 – 7.82 (m, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 5.8 Hz, 1H), 6.63 (s, 1H), 6.13 (d, J = 7.9 Hz, 1H), 6.06 (s, 1H), 4.86 (d, J = 6.0 Hz, 2H), 4.68 (d, J = 6.0 Hz, 2H), 4.62 (s, 1H), 4.11 – 4.07 (m, 1H), 3.92 (t, J = 9.9 Hz, 1H), 3.43 – 3.40 (m, 1H), 2.99 (t, J = 9.8 Hz, 1H), 2.89 – 2.86 (m, 1H), 2.73 – 2.71 (m, 1H), 2.67 – 2.58 (m, 1H), 2.31 (s, 3H), 2.23 – 2.17 (m, 1H), 1.80 – 1.75 (m, 4H), 1.45 (dd, J = 5.5, 2.7 Hz, 2H), 1.32 – 1.28 (m, 2H). 13 13C NMR(101 MHz, Chloroform-d) δ 169.06, 148.75, 141.88, 139.65, 133.08, 129.24, 127.33, 127.13, 126.06, 124.80, 124.55, 121.07, 112.57, 111.71, 105.41, 105.21, 83.03, 68.14, 55.72, 54.99, 54.32, 52.17, 46.38, 46.13, 34.28, 22.96, 15.01, 14.96. [M+H] + 514.2811

[0097] Compound 22 . 11H NMR (400 MHz, Chloroform-d) δ 8.44 (dd, J = 8.5, 1.2 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.55 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 7.45 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 6.89 (s, 1H), 6.63 – 6.57 (m, 2H), 6.05 (s, 1H), 4.1� – 4.02 (m, 3H), 3.95 – 3.90 (m, 1H), 3.73 – 3.66 (m, 1H), 3.61 – 3.55 (m, 2H), 3.44 – 3.38 (m, 1H), 3.00 (t, J = 9.9 Hz, 1H), 2.92 – 2.85 (m, 1H), 2.75 – 2.71 (m, 1H), 2.66 – 2.59 (m, 1H), 2.32 (s, 3H), 2.25 – 2.18 (m, 1H), 2.18 – 2.12 (m, 2H), 1.79 (s, 1H), 1.65 – 1.56 (m, 2H), 1.45 (dd, J = 5.5, 2.6 Hz, 2H), 1.30 (t, J = 4.3 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.03, 148.73, 141.94, 141.62, 132.95, 129.68, 127.01, 126.42, 125.94, 124.73, 124.26, 120.79, 112.54, 111.76, 105.16, 104.27, 68.11, 66.83, 55.66, 54.25, 52.15, 49.08, 46.36, 46.10, 34.36, 33.44, 14.97, 14.92. [M+H] + 528.2971。

[0098] Compound 23: 。 11H NMR (400 MHz, Chloroform-d) δ 8.45 –8.38 (m, 1H), 7.87 – 7.78 (m, 2H), 7.50 – 7.41 (m, 2H), 6.90 (s, 1H), 6.60(s, 1H), 6.05 (s, 1H), 4.10 – 4.07 (m, 1H), 3.95 – 3.80 (m, 6H), 3.42 – 3.37(m, 1H), 3.03 – 2.97 (m, 5H), 2.89 – 2.86 (m, 1H), 2.75 – 2.71 (m, 1H), 2.65– 2.59 (m, 1H), 2.31 (s, 3H), 2.23 – 2.17 (m, 1H), 1.81 – 1.76 (m, 1H), 1.47(t, J = 4.0 Hz, 2H), 1.33 – 1.31 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ169.00, 148.71, 141.82, 136.41, 132.19, 130.09, 127.95, 127.08,125.07, 124.50, 124.45, 124.14, 123.18, 十二2.17, 111.81, 112.51,105.10, 68.14, 67.85, 52.15, 51.90, 46.34, 46.07, 34.51, 29.72,15.02, 14.97. [M+H] + 529.2923。

[0099] Compound 24: 。 11H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 8.4 Hz, 1H), 7.81 – 7.75 (m, 2H), 7.54 (dd, J = 8.2, 6.8 Hz, 1H), 7.42 (ddd, J = 8.2, 6.7, 1.2 Hz, 1H), 6.87 (s, 1H), 6.61 (s, 1H), 6.58 (d, J = 8.0 Hz, 1H), 6.05 (s, 1H), 4.11 – 4.08 (m, 1H), 3.95 – 3.89 (m, 1H), 3.48 – 3.39 (m, 2H), 3.38 (s, 3H), 3.27 – 3.21 (m, 1H), 3.00 (t, J = 9.8 Hz, 1H), 2.90 – 2.87 (m, 1H), 2.76 – 2.70 (m, 1H), 2.66 – 2.60 (m, 1H), 2.32 (s, 3H), 2.29 – 2.12 (m, 6H), 1.81 – 1.76 (m, 1H), 1.46 (dd, J = 6.3, 2.4 Hz, 2H), 1.42 – 1.35 (m, 2H), 1.33 (d, J = 2.6 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 168.98, 148.68, 142.19, 141.97, 132.92, 129.80, 126.01, 125.84, 124.77, 124.10, 123.76, 120.76, 112.61, 111.84, 105.15, 104.07, 78.64, 68.02, 55.94, 55.51, 54.09, 52.04, 51.30, 46.26, 45.98, 34.41, 30.77, 30.18, 14.97, 14.92. [M+H] + 556.3274

[0100] Compound 25 . 11H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 6.88 (s, 1H), 6.64 – 6.54 (m, 2H), 6.05 (s, 1H), 4.11 – 4.08 (m, 1H), 3.95 – 3.85 (m, 2H), 3.43 – 3.40 (m, 1H), 3.00 (t, J = 9.8 Hz, 1H), 2.90 – 2.88 (m, 2H), 2.74 – 2.72 (m, 1H), 2.67 – 2.60 (m, 1H), 2.54 (s, 2H), 2.40 (s, 3H), 2.32 (s, 3H), 2.24 – 2.19 (m, 1H), 2.08 – 2.00 (m, 1H), 1.89 (s, 2H), 1.79 (s, 1H), 1.71 (s, 2H), 1.45 (d, J = 4.4 Hz, 2H), 1.37 (s, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 168.99, 148.72, 141.94, 141.84, 132.95, 129.74, 127.11, 125.89, 124.60, 124.14, 123.79, 112.52, 111.76, 105.11, 103.72, 68.17, 60.62, 55.78, 54.38, 52.24, 46.45, 46.18, 34.43, 31.94, 31.52, 30.15, 29.72, 22.71, 14.97, 14.89, 14.14. [M+H] + 541.3279

[0101] Compound 26: . 11H NMR (400 MHz, Chloroform-d) δ 8.47 –8.42 (m, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.55 (dd, J= 8.3, 6.8 Hz, 1H), 7.44 (dd, J = 8.3, 6.9 Hz, 1H), 6.91 (s, 1H), 6.61 (s,1H), 6.54 (d, J = 7.9 Hz, 1H), 6.05 (s, 1H), 4.11 – 4.08 (dd, 1H), 3.92 (t, J= 9.9 Hz, 1H), 3.54 – 3.46 (m, 1H), 3.43 – 3.39 (m, 1H), 3.02 – 2.97 (m, 1H),2.89 – 2.86 (m, 1H), 2.82 – 2.70 (m, 5H), 2.66 – 2.59 (m, 1H), 2.48 – 2.41(m, 2H), 2.31 (s, 3H), 2.23 – 2.19 (m, 1H), 1.81 – 1.69 (m, 3H), 1.45 (dd, J= 5.7, 2.5 Hz, 2H), 1.32 – 1.27 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ169.04 , 148.72 , 141.93 , 141.40 , 132.98 , 129.68 , 127.03, 126.37 , 125.94, 124.74 , 124.25 , 123.86 , 120.75 , 112.55 , 111.74, 105.16 , 104.10,68.11 , 55.67 , 54.26 , 52.15 , 50.96 , 46.35 , 46.10 , 34.29 , 27.77 , 14.98, 14.92. [M+H] + 544.2741

[0102] Compound 27: . 11H NMR (400 MHz, Chloroform-d) δ 8.45 (dd, J = 8.5, 1.2 Hz, 1H), 7.85 – 7.79 (m, 2H), 7.57 (ddd, J = 8.3, 6.8, 1.2 Hz, 1H), 7.51 – 7.46 (m, 1H), 6.95 (s, 1H), 6.62 (s, 1H), 6.58 (d, J = 7.9 Hz, 1H), 6.05 (s, 1H), 4.11 – 4.07 (m, 1H), 3.94 – 3.89 (m, 1H), 3.79 (s, 1H), 3.43 – 3.40 (m, 1H), 3.25 – 3.18 (m, 2H), 3.13 – 3.06 (m, 2H), 2.99 (t, J = 9.9 Hz, 1H), 2.90 – 2.87 (m, 1H), 2.75 – 2.71 (m, 1H), 2.66 – 2.59 (m, 1H), 2.49 (s, 2H), 2.32 (s, 3H), 2.28 – 2.19 (m, 3H), 1.78 (s, 1H), 1.44 (q, J = 3.8, ...... 13 13C NMR (101 MHz, Chloroform-d) δ 169.13, 148.83, 141.94, 140.69, 132.94, 129.45, 127.92, 126.24, 124.80, 124.77, 124.50, 120.81, 112.50, 111.53, 105.39, 105.23, 68.15, 55.69, 54.31, 52.15, 49.13, 48.02, 46.36, 46.11, 34.25, 29.53, 29.50, 14.93. [M+H] + 576.2631。

[0103] Compound 28: 。 11H NMR (400 MHz, Chloroform-d) δ 8.44 (dd, J = 8.4, 1.3 Hz, 1H), 7.94 (dd, J = 8.5, 1.2 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.56 (ddd, J = 8.3, 6.7, 1.2 Hz, 1H), 7.47 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 6.93 (s, 1H), 6.61 (s, 1H), 6.51 (d, J = 7.9 Hz, 1H), 6.05 (s, 1H), 5.12 (s, 1H), 4.22 – 4.18 (m, 2H), 4.10 – 4.07 (m, 1H), 3.95 – 3.87 (m, 3H), 3.60 (s, 1H), 3.42 – 3.48 (m, 1H), 2.99 (tt, J = 9.7, 2.9 Hz, 1H), 2.89 – 2.84 (m, 1H), 2.74 – 2.70 (m, 1H), 2.65 – 2.59 (m, 1H), 2.31 (s, 3H), 2.22 – 2.16 (m, 1H), 1.80 – 1.75 (m, 1H), 1.45 – 1.42 (m, 2H), 1.30 (d, J = 3.8 Hz, 2H), 1.25 (s, 6H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.03, 148.72, 141.83, 141.67, 133.03, 129.57, 127.13, 126.87, 126.01, 124.65, 124.39, 121.09, 112.55, 105.16, 104.48, 98.53, 68.15, 63.06, 55.76, 54.35, 52.21, 46.69, 38.16, 34.35, 31.26, 29.71, 27.23, 14.96, 14.91. [M+H] + 558.3070。

[0104] Compound 29: . 11H NMR (400 MHz, Chloroform-d) δ 8.43 (d, J = 8.3 Hz, 1H), 8.30 (dd, J = 8.4, 1.4 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.59–7.54 (m, 1H), 7.48 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 6.98 (s, 1H), 6.64 (s, 1H), 6.06 (s, 1H), 4.12 – 4.08 (m, 1H), 3.99 – 3.90 (m, 3H), 3.46 – 3.41 (m, 1H), 3.35 – 3.25 (m, 3H), 3.01 (t, J = 9.9 Hz, 1H), 2.92 – 2.88 (m, 1H), 2.80 – 2.72 (m, 4H), 2.68 – 2.62 (m, 1H), 2.32 (s, 3H), 2.25 – 2.20 (m, 1H), 1.85 – 1.75 (m, 5H), 1.46 (t, J = 3.8 Hz, 2H), 1.34 (d, J = 6.0 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 169.08, 149.14, 148.86, 141.97, 133.24, 132.58, 131.00, 128.56, 127.17, 125.91, 125.06, 124.84, 124.22, 117.83, 112.55, 111.51, 105.27, 68.14, 67.37, 59.87, 55.67, 54.27, 52.14, 46.36, 46.10, 36.49, 34.29, 14.92, 14.86. [M+H] + 542.3125.

[0105] Compound 30: . 1H NMR (400 MHz, Chloroform-d) δ 8.42 (ddd,J = 8.3, 3.4, 1.2 Hz, 2H), 7.84 (ddd, J = 7.7 Hz, 1H), 7.56 (ddd, J = 8.3, 6.7,1.4 Hz, 1H), 7.48 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 6.99 (s, 1H), 6.66 (s, 1H), 6.07 (s, 1H), 4.12 – 4.09 (m, 1H), 3.96 – 3.91(m, 3H), 3.48 – 3.42 (m, 1H), 3.33 – 3.29 (m, 2H), 3.22 (q, J = 6.9 Hz, 3H), 3.01 (t, J = 9.9 Hz, 1H), 2.93 – 2.87 (m, 1H), 2.76 – 2.72 (m, 1H), 2.69 –2.62 (m, 1H), 2.32 (s, 3H), 2.26 – 2.19 (m, 1H), 1.82 – 1.71 (m, 5H), 1.47(t, J = 3.4 Hz, 2H), 1.37 – 1.32 (m, 2H), 0.90 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 169.03, 148.87, 146.30, 141.95, 133.29, 133.05, 133.03, 128.36, 127.23, 125.85, 125.36, 124.81 , 124.03 , 120.03 ,112.53 , 111.52 , 105.29 , 68.16 , 67.37 , 58.91 , 55.72 , 54.32 , 52.19 ,46.41 , 46.14 , 42.13, 34.27, 14.97, 14.91, 12.85. [M+H] + 556.3273.

[0106] Compound 31: .

[0107] Compound 32: .

[0108] Compound 33: .

[0109] Compound 34: .

[0110] Compound 35: .

[0111] Compound 36: .

[0112] Compound 37: .

[0113] Compound 38: .

[0114] Compound 39: .

[0115] Compound 40: . 1 H NMR (400 MHz, Chloroform-d) δ 8.45 –8.37 (m, 2H), 8.27 (d, J = 8.3 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.53 (t, J= 7.6 Hz, 1H), 6.88 (s, 1H), 6.63 (s, 1H), 6.07 (s, 1H), 4.11 – 4.08 (m, 4H), 3.92 (t, J = 9.8 Hz, 1H), 3.47 – 3.44 (m, 1H), 3.04 (s, 1H), 2.92 – 2.89 (m,1H), 2.77 – 2.74 (m, 1H), 2.71 – 2.65 (m, 1H), 2.34 (s, 3H), 2.27 – 2.21 (m,1H), 1.85 – 1.80 (m, 1H), 1.48 (t, J = 3.6 Hz, 2H), 1.37 – 1.31 (m, 2H). 13CNMR (101 MHz, Chloroform-d) δ 169.00 , 160.65 , 148.84 , 142.21 , 142.13 ,136.81 , 130.49 , 126.91 , 126.17 , 124.97 , 124.83 , 123.19 , 119.56 ,112.39 , 111.34 , 105.26 , 68.01 , 55.50 , 54.10 , 53.72 , 51.99 , 46.23 ,45.96 , 32.16 , 29.71 , 14.33. [M+H] + 529.3.

[0116] Compound 41: .

[0117] Compound 42: .

[0118] Compound 43: . 1 H NMR (400 MHz, Chloroform-d) δ 8.89 (d, J= 8.6 Hz, 1H), 8.76 – 8.68 (m, 1H), 7.75 (dd, J = 8.0, 2.4 Hz, 1H), 7.45 (dt,J = 6.9, 3.2 Hz, 1H), 6.82 (s, 1H), 6.66 – 6.57 (m, 2H), 6.23 (s, 1H), 6.07(s, 1H), 4.13 – 4.00 (m, 3H), 3.93 (t, J = 9.9 Hz, 1H), 3.68 (s, 1H), 3.61 –3.56 (m, 2H), 3.45 – 3.42 (m, 1H), 3.01 (s, 1H), 2.90 – 2.87 (m, 1H), 2.75 –2.73 (m, 1H), 2.65 (s, 1H), 2.32 (s, 3H), 2.24 – 2.18 (m, 1H), 2.14 – 2.11(m, 2H), 1.83 – 1.77 (m, 1H), 1.72 – 1.66 (m, 2H), 1.47 – 1.43 (d, J = 4.0Hz, 2H), 1.34 – 1.33 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 168.85 , 148.80 , 146.33 , 143.10 , 141.94 , 138.44 , 133.00 , 130.36 , 127.74 , 127.14 ,123.94 , 121.36 , 112.31 , 105.24 , 103.82 , 68.12 , 66.87 , 55.73 , 54.33 ,52.18 , 48.49 , 46.42 , 46.15 , 33.88 , 33.13 , 15.05, 15.01. [M+H] + 529.3.

[0119] Compound 44: .

[0120] Compound 45: .

[0121] Compound 46: .

[0122] Compound 47: .

[0123] Compound 48: . 1 H NMR (400 MHz, Chloroform-d) δ 8.56 (d, J= 8.4 Hz, 1H), 7.90 (s, 2H), 7.76 (s, 1H), 7.53 (s, 3H), 7.12 (s, 1H), 6.62(s, 1H), 6.03 (s, 1H), 4.07 – 4.05 (m, 1H), 3.86 – 3.79 (m, 2H), 3.37 (s,1H), 2.99 – 2.95 (m, 1H), 2.88 – 2.82 (m, 2H), 2.73 – 2.70 (m, 1H), 2.60 (s,1H), 2.29 (s, 3H), 2.22 – 2.15 (m, 1H), 2.01 (s, 1H), 1.84 (s, 1H), 1.76 –1.73 (m, 2H), 1.37 (d, J = 2.0 Hz, 2H), 1.33 (d, J = 2.0 Hz, 2H). 13C NMR (101MHz, Chloroform-d) δ 169.12 , 154.94 , 148.82 , 147.10 , 142.02 , 132.71 ,129.93 , 128.82 , 124.88 , 124.48 , 123.99 , 119.10 , 114.08 , 112.54 ,105.22 , 68.03 , 55.48 , 54.07 , 51.94 , 46.15 , 45.91 , 31.94 , 31.52 ,31.45 , 28.50 , 22.70, 15.01, 14.94, 14.14. [M+H] + 512.3.

[0124] Compound 49: .

[0125] Compound 50: .

[0126] Compound 51: . 1 H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J= 8.4 Hz, 1H), 7.92 (dd, J = 7.1, 1.3 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.77(d, J = 8.1 Hz, 1H), 7.60 – 7.55 (m, 1H), 7.52 – 7.44 (m, 2H), 6.97 (s, 1H), 6.63 (s, 1H), 6.06 (s, 1H), 4.11 (dd, J = 10.6, 2.7 Hz, 1H), 3.92 (t, J = 9.8Hz, 1H), 3.44 (d, J = 11.7 Hz, 1H), 3.07 (d, J = 12.1 Hz, 2H), 2.90 (d, J =10.7 Hz, 1H), 2.68 (s, 1H), 2.53 (s, 1H), 2.23 (s, 1H), 1.86 (d, J = 12.4 Hz, 4H), 1.72 (s, 4H), 1.50 (d, J = 4.3 Hz, 1H), 1.36 (d, J = 6.7 Hz, 2H), 1.26 (s, 2H). [M+H] + 483.3.

[0127] Compound 52: . 1 H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 8.6 Hz, 1H), 7.90 (dd, J = 18.0, 7.8 Hz, 2H), 7.77 (d, J = 8.3 Hz, 1H),7.56 (d, J = 7.8 Hz, 1H), 7.46 (q, J = 7.3, 6.5 Hz, 2H), 6.97 (s, 1H), 6.62(s, 1H), 6.05 (d, J = 3.2 Hz, 1H), 4.09 (d, J = 10.4 Hz, 1H), 3.92 (t, J =10.3 Hz, 1H), 3.44 (d, J = 11.2 Hz, 1H), 2.97 (d, J = 10.6 Hz, 2H), 2.8۲ (d,J = 11.0 Hz, 1H), 2.63 (s, 1H), 2.48 (d, J = 12.0 Hz, 1H), 2.31 (s, 2H), 2.03(s, 2H), 1.83 (d, J = 26.1 Hz, 6H), 1.64 (d, J = 12.8 Hz, 4H), 1.49 (d, J =3.8 Hz, 2H), 1.37 (s, 2H). [M+H] + 497.3

[0128] Compound 53: . 1 It should be noted that there seems to be a small error in the original text where "2.8۲" is likely a typo and should be "2.82". This has been corrected in the translation.1H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 8.4 Hz, 1H), 7.90 (dd, J = 17.2, 7.8 Hz, 2H), 7.77 (d, J = 8.2 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.51 – 7.43 (m, 2H), 7.00 (d, J = 5.6 Hz, 1H), 6.63 (d, J = 4.9 Hz, 1H), 6.06 (s, 1H), 4.10 (t, J = 7.4 Hz, 1H), 3.96 – 3.80 (m, 4H), 3.69 (s, 1H), 3.43 (t, J = 10.2 Hz, 1H), 3.02 (d, J = 8.6 Hz, 3H), 2.81 (t, J = 13.2 Hz, 1H), 2.63 (d, J = 11.3 Hz, 1H), 2.33 (d, J = 11.5 Hz, 1H), 2.08 – 2.01 (m, 1H), 1.93 – 1.87 (m, 2H), 1.51 – 1.47 (m, 2H), 1.39 –  1.34 (m, 2H). [M+H] + 485.3

[0129] Compound 54 . 11H NMR (400 MHz, Chloroform-d) δ 8.44 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 7.9, 2.3 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 6.91 (s, 1H), 6.63 – 6.57 (m, 2H), 6.06 (d, J = 2.3 Hz, 1H), 4.12 – 4.08 (m, 1H), 4.05 – 4.03 (m, 4H), 3.92 (d, J = 9.9 Hz, 1H), 3.70 (s, 1H), 3.61 – 3.56 (m, 2H), 3.46 – 3.44 (m, 1H), 3.41 – 3.35 (m, 2H), 3.00 – 2.98 (m, 2H), 2.86 – 2.83 (m, 1H), 2.64 – 2.59 (m, 1H), 2.47 (s, 1H), 2.43 – 2.37 (m, 1H), 2.17 – 2.13 (m, 2H), 2.00 – 1.95 (m, 1H), 1.75 (s, 2H), 1.64 – 1.55 (m, 4H), 1.45 (s, 2H), 1.31 (d, J = 4.7 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 168.99, 148.68, 141.90, 141.61, 132.95, 129.68, 126.40, 125.93, 124.72, 124.24, 123.87, 120.79, 112.58, 111.79, 105.18, 104.26, 68.15, 67.25, 66.82, 61.02, 52.37, 49.63, 49.07, 48.13, 46.67, 46.65, 34.34, 33.43, 29.18, 14.98, 14.93. [M+H] + 598.3

[0130] Compound 55: . 11H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 8.4 Hz, 1H), 7.92 (dd, J = 7.1, 1.2 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.56 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.51 – 7.43 (m, 2H), 7.01 (s, 1H), 6.63 (s, 1H), 6.05 (s, 1H), 4.09 (dd, J = 10.5, 2.7 Hz, 1H), 3.92 (t, J = 9.9 Hz, 1H), 3.43 (d, J = 11.2 Hz, 1H), 2.92 (d, J = 12.6 Hz, 2H), 2.77 (d, J = 10.7 Hz, 1H), 2.59 (t, J = 11.2 Hz, 1H), 2.46 – 2.38 (m, 2H), 2.14 (d, J = 11.8 Hz, 2H), 1.99 (d, J = 10.3 Hz, 1H), 1.88 – 1.61 (m, 9H), 1.49 (t, J = 4.1 Hz, 2H), 1.37 (dd, J = 6.4, 2.9 Hz, 2H). [M+H] + 533.3。

[0131] Compound 56: 。 11H NMR (400 MHz, Chloroform-d) δ 9.06 – 9.03(m, 2H), 7.90 (dd, J = 7.7, 2.5 Hz, 1H), 7.80 (dd, J = 7.8, 2.5 Hz, 1H), 7.54(dt, J = 7.9, 3.2 Hz, 1H), 7.04 (s, 1H), 6.65 (s, 1H), 6.08 (s, 1H), 4.11 –4.09 (m, 1H), 3.92 (t, J = 9.7 Hz, 1H), 3.47 – 3.44 (m, 1H), 3.02 (s, 1H),2.91 – 2.87 (m, 1H), 2.78 – 2.64 (m, 2H), 2.32 (s, 3H), 2.24 – 2.19 (m, 1H),1.84 – 1.78 (m, 1H), 1.39 – 1.34 (m, 2H), 1.29 (d, J = 2.3 Hz, 2H). 13 13C NMR(101 MHz, Chloroform-d) δ 169.03, 150.41, 149.04, 144.76, 141.96, 137.36, 133.55, 133.39, 129.36, 129.04, 128.61, 127.29, 121.72, 112.26,111.05, 105.49, 68.08, 55.61, 54.22, 52.03, 46.31, 46.05, 33.74,29.70, 15.18, 15.14. [M+H] + 464.2

[0132] Compound 57: . 11H NMR (400 MHz, Chloroform-d) δ 9.00 (d, J = 8.6 Hz, 1H), 8.92 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.68 (t, J = 7.4 Hz, 1H), 7.47 (dt, J = 7.5, 3.1 Hz, 1H), 6.99 (s, 1H), 6.64 (s, 1H), 6.08 (s, 1H), 4.11 – 4.09 (m, 1H), 3.92 (t, J = 9.9 Hz, 1H), 3.46 – 3.43 (m, 1H), 3.02 (s, 1H), 2.91 – 2.88 (m, 1H), 2.76 – 2.73 (m, 1H), 2.66 (s, 1H), 2.33 (s, 3H), 2.26 – 2.19 (m, 1H), 1.83 – 1.78 (m, 1H), 1.38 – 1.34 (m, 2H), 1.30 – 1.27 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 168.96, 149.90, 148.95, 148.80, 141.96, 138.01, 132.99, 129.59, 129.20, 129.01, 127.26, 120.93, 112.31, 111.24, 105.40, 68.09, 55.62, 54.23, 52.06, 46.31, 46.05, 33.99, 29.71, 15.05, 15.01. [M+H] + 430.3

[0133] Compound 58: . 1H NMR (400 MHz, Chloroform-d) δ 8.45 – 8.37(m, 2H), 8.27 (d, J = 8.3 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.53 (t, J = 7.6Hz, 1H), 6.88 (s, 1H), 6.63 (s, 1H), 6.07 (s, 1H), 4.11 – 4.08 (m, 4H), 3.92 (t, J = 9.8 Hz, 1H), 3.47 – 3.44 (m, 1H), 3.04 (s, 1H), 2.92 – 2.89 (m, 1H),2.77 – 2.74 (m, 1H), 2.71 – 2.65 (m, 1H), 2.34 (s, 3H), 2.27 – 2.21 (m, 1H), 1.85 – 1.80 (m, 1H), 1.48 (t, J = 3.6 Hz, 2H), 1.37 – 1.31 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 169.00, 160.65, 148.84, 142.21, 142.13, 136.81, 130.49, 126.91, 126.17, 124.97, 124.83, 123.19 , 119.56 , 112.39 ,111.34 , 105.26 , 68.01 , 55.50 , 54.10 , 53.72 , 51.99 , 46.23 , 45.96 ,32.16 , 29.71 , 14.33. [M+H] + 460.3.

[0134] 1. The compound of this invention affects PL pro Test of enzyme activity inhibition level.

[0135] Experimental method: Recombinant SARS-CoV-2 PL pro(Final concentration 750 nM) was mixed with serial dilutions of each compound in 25 µL of analysis buffer (20 mM Tris–HCl, pH 7.5, 150 mM NaCl, 1 mM EDTA, 2 mM MTT) and incubated for 10 min. The reaction was initiated by adding 25 µL of fluorescent substrate (MCA-AVLQ↓SGFR-Lys(Dnp)-Lys-NH2) at a final concentration of 20 µM, and the fluorescence signal at 320 nm (excitation) / 405 nm (emission) was measured using a microplate reader. The Vmax of the reactions with different concentrations of the compound and the Vmax of the reaction with DMSO were calculated, and the IC50 was used to generate the IC50. 50 Curves. For each compound, anti-SARS-CoV-2 PL was measured at 9 concentrations and 3 independent replicates. pro IC 50 Values. All experimental data were analyzed using GraphPad Prism software. The experimental results are shown in Table 1.

[0136] Table 1. Effects of compounds on SARS-CoV-2 PL pro The enzyme activity inhibitory activity IC 50 value

[0137]

[0138] Note: "-" indicates that no detection was performed.

[0139] As can be seen from Table 1, the compounds of the present invention can effectively inhibit SARS-CoV-2 PL. pro The activity of the compounds of this invention can be used to prepare SARS-CoV-2 PL. pro Inhibitors, drugs against the novel coronavirus, and drugs for the prevention and / or treatment of the novel coronavirus.

[0140] 2. Cytotoxicity of compound 22.

[0141] This study comprehensively evaluated the cytotoxic effects of compounds on VeroE6, BEAS-2B, HUVEC, and 293T cell lines using the MTT assay. In the experiment, the three cell lines were seeded at 100 μL per well in 96-well clear culture plates. After cell adhesion, the test compounds were added at an initial concentration of 500 μM, serially diluted twofold. A DMSO solvent control and a culture medium blank control were also included. After 72 hours of drug exposure, 20 μL of 5 mg / mL MTT solution was added to each well, and the plates were incubated at 37 ℃ for 1–2 hours until the solvent control showed typical blue-purple formazan crystals. After discarding the culture medium, 50 μL of DMSO was added to dissolve the crystals, and the absorbance was measured at 560 nm using a CLARIOstar Plus microplate reader. After correction based on the blank control data, the activity data for each group were obtained using the cell viability calculation formula. Dose-response curves were fitted using GraphPad 8.0 software to finally determine the half-maximal cytotoxic concentration (MCC) of the compound for each cell line. 50 The formula is as follows: Cell viability (%) = 100 - [{(OD of the drug-treated group)] 560 ) - (Blank control group OD 560 )} / {(solvent control group OD 560 ) - (Blank control group OD 560 )}]×100%.

[0142] The results are shown in Table 2.

[0143] Table 2. Cytotoxicity of Compound 22 in Specific Cells a

[0144]

[0145] 3. Pharmacokinetic properties of compound 22.

[0146] This study used male Balb / c mice (6-8 weeks old, weighing 18-25 g) under non-fasting conditions to conduct pharmacokinetic evaluation. The solvent for the compounds was a mixture of 5% DMSO, 5% HS-15, 20% PEG300, and 70% physiological saline. Whole blood samples containing anticoagulants were collected at predetermined time points after drug administration. Plasma was obtained by centrifugation at 4 ℃ and 4000 rpm. The concentration of compounds in the plasma was then quantitatively detected using an Agilent high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS) system. Drug-time curve fitting and pharmacokinetic parameter calculations were performed using Phoenix WinNonlin 7.0 software. The results are shown in Table 3.

[0147] Table 3. Pharmacokinetic properties of compound 22 in Balb / c mice

[0148]

[0149] 4. Inhibitory activity of compound 22 against various human CYP enzymes.

[0150] This study evaluated the inhibitory effect of compound 22 (YL1004) on key CYP450 isoforms using a standardized in vitro incubation system. The experimental system consisted of 186 μL of 0.1M PBS, 2 μL of liver microsomes (0.2 mg / mL), 1 μL of probe substrate, and gradient concentrations of NJS-P004A or inhibitors (0-100 μM). 10 μL of NADPH (1 mM) was added to initiate the reaction, resulting in a total system volume of 200 μL with an organic phase content ≤1%. In the procedure, the probe substrate, test compound, and microsomes were premixed and incubated for 5 minutes before adding NADPH. Specific reactions were performed for 5-20 minutes for each of the CYP1A2, 2C8, 3A4, 2C9, and 2D6 isoforms. After termination, parallel samples were precipitated with acetonitrile. Based on LC-MS / MS quantification of the metabolite production of each probe substrate, and using the enzyme activity of the negative control group (equal volume blank solvent replacing the compound) as a baseline, the relative percentage of enzyme activity under different concentrations of compound 22 was calculated, and a semi-logarithmic dose-response curve was plotted. If the residual activity is still higher than 50% when the drug concentration reaches 100 μM, IC50 fitting is deemed unnecessary. 50 If the value is positive, then nonlinear regression analysis is performed using GraphPad software to determine the half-maximal inhibitory concentration parameter. The results are shown in Table 4.

[0151] Table 4. Inhibitory activity of compound 22 against various human CYP enzymes.

[0152]

[0153] 5. The binding effect of compound 22 on human plasma proteins.

[0154] This study used the rapid equilibrium dialysis (RED) method to assess the plasma protein binding rate of compounds. The experimental setup included a two-step process: initial sample preparation and dialysis treatment. First, 10 μM plasma working solution was equilibrated at 37 °C for 30 minutes. 50 μL of the sample was mixed with an equal volume of PBS, and 400 μL of acetonitrile precipitant containing 20 ng / mL internal standard SAHA was added for protein precipitation (vortexing for 10 seconds, centrifuging at 13000 rpm for 10 minutes) to prepare a 0-minute control sample. Simultaneously, 300 μL of drug-containing plasma was injected into the sample chamber of the RED device, and an equal volume of PBS was injected into the buffer chamber. Dialysis was performed at 37 °C with shaking for 6 hours. After dialysis, 50 μL of plasma from the sample chamber and 50 μL of dialysate from the buffer chamber were taken respectively. The former was replenished with 50 μL of PBS, and the latter was replenished with 50 μL of blank plasma to equilibrate the matrix. Both were treated according to the above precipitation procedure. Finally, all samples were centrifuged, and the supernatant was collected for quantitative analysis using an LC-MS / MS system. The distribution of the compound in the plasma and buffer phases was monitored simultaneously to calculate protein binding parameters. The results are shown in Table 5.

[0155] Table 5. Human plasma protein binding rate of compound 22.

[0156]

[0157] 6. The selectivity of compound 22 for 377 human kinases.

[0158] The data from the kinase selectivity assay were obtained by Eurofins.

[0159] Table 6. Selectivity of Compound 22 against 377 human kinases

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167] 7. Compound 22 (YL1004) inhibits the deubiquitination and deISG15ization activities of PLpro.

[0168] (a) IC50 curves of compound 22 inhibiting PLpro hydrolysis of Ub-AMC (left) and ISG-AMC (right) (n=3). (b) Intracellular deubiquitination activity of PLpro. HEK293T cells were transfected with plasmids encoding PLpro-Flag, Ub-HA, and the specified compounds (alone or in combination). Cell lysates were then analyzed by Western blotting using anti-HA, anti-Flag, and anti-GAPDH antibodies. (c) DeISG15ization of endogenous ISG15 conjugates in cell extracts by compound 22. HEK293T cells were treated with or without IFN-α for 48 hours. Cell extracts were then co-incubated with PLpro and the specified compounds, followed by Western blotting analysis using anti-ISG15 and anti-PLpro antibodies. (d) Screening results of compound 22 inhibiting the hydrolysis of Ub-AMC by common human deubiquitinating enzymes (DUBs) (n=2). (e) Specificity of compound 22 for PLpro in cells compared to other human DUBs. Rows 1–6: Anti-HA Western blot results of HEK293T cell lysates treated with HA-Ub-VS in the presence of N-ethylcis-imide (NEM, positive control inhibitor) or the test compound. Rows 7–12: Results of compound 22 eliminating PLpro-based modifications when PLpro was added to cell lysates prior to covalent modification by HA-Ub-VS. (fi) Antagonism of compound 22 against the inhibitory effects of PLpro on NF-κB (f), ISRE (g), IFN-β (h), or IRF3 (i) activation. Dual-luciferase reporter gene assays were performed in HEK293T cells (n=3). Data in (a), (d), and (fi) are presented as mean ± standard deviation. Experiments in (b), (c), and (e) were independently replicated three times, with similar results. Samples were derived from the same biological source, and the corresponding gel and blot processes were performed in parallel to ensure consistency.

[0169] Figure 1 The graph shows the activity results of compound 22 (YL1004) in inhibiting the deubiquitination and deISG15ization of PLpro. Figure 1 It is known that compound 22 can effectively inhibit the deubiquitination and deISGation activities of SARS-CoV-2 PLpro, significantly restore the activity of PLpro-mediated suppressed innate immune signaling pathways such as NF-κB, ISRE and IFN-β, and enhance the host cell's immune response to viral infection.

[0170] 8. In vitro antiviral effect of compound 22 (YL1004).

[0171] (a) Quantitative analysis of subgenomic envelope (sgE) genes in Calu3 cells infected with wild-type SARS-CoV-2, Delta, Omicron (JN.1 and KP.3) variants, and recombinant SARS-CoV-2 carrying NSP5-E166V, with or without compound 22 (n=6). Cell lysates were collected at 24 h post-infection (for wild-type, Delta, and JN.1) and 48 h post-infection (for KP.3 and NSP5-E166V recombinant SARS-CoV-2) and analyzed by one-step reverse transcription quantitative polymerase chain reaction (RT-qPCR). (b) VeroE6-TMPRSS2 cells (n=4) were infected with 100 plaque-forming units (PFU) of wild-type SARS-CoV-2, Delta, Omicron (JN.1 and KP.3) variants, and recombinant SARS-CoV-2 carrying NSP5-E166V, with or without serially diluted compound 22. Cells were fixed at 48 h (for wild-type and Delta) or 72 h (for JN.1, KP.3, and NSP5-E166V recombinant SARS-CoV-2) post-infection for visualization of plaque formation. Plaque numbers were normalized to the number of plaques recovered from the supernatant of the control group treated only with the vector. IC50 values ​​were determined using a nonlinear regression model (normalized response, no variable slope). Each data point represents a biological replicate. Data represent the mean ± standard deviation from a specified number of biological replicates, derived from two to three independent experiments. One-way ANOVA and Tukey's multiple comparison test were used to adjust for p-values ​​to determine statistical significance (α). * indicates P < 0.05, ** indicates P < 0.01. NS, no statistical significance. WT, wild-type SARS-CoV-2.

[0172] Figure 2 This image shows the in vitro antiviral effect of compound 22 (YL1004). Figure 2 It is known that compound 22 has a strong inhibitory effect on a variety of SARS-CoV-2 mutants, and still maintains significant antiviral activity against nirmatrelvir-resistant mutants, showing excellent broad-spectrum antiviral activity.

[0173] 9. The in vivo antiviral effect of compound 22 (YL1004).

[0174] (ab) Virological assessment of infection with the Omicron JN.1 variant: 8- to 12-week-old male and female K18-hACE2 transgenic mice (n=10) were intranasally infected with 10,000 PFU of the SARS-CoV-2 Omicron JN.1 strain. Treatment mice were orally administered 100 mg / kg / dose of compound 22 or Jun12682 twice daily. Control mice were treated with the appropriate solvent only. Nasal turbinate and lung tissues were collected on day 3 post-infection (3 dpi) for virological assessment by (a) RT-qPCR and (b) plaque assay. (cd) Monitoring of mouse body weight and survival in response to the Delta variant: 8- to 12-week-old female K18-hACE2 transgenic mice (n=10) were intranasally infected with 1250 PFU of the SARS-CoV-2 Delta strain. (c) Changes in body weight and (d) survival of infected mice were monitored over 14 days or until death. (e) Representative Immunohistochemical (IHC) staining images of viral antigen expression: These images show representative IHC staining images of viral antigen (red) expression in the nasal turbinates and lung tissues of Omicron JN.1-infected mice (n=3) on day 3 post-infection (3 dpi). (f) Representative Hematoxylin and Eosin (H&E) staining images for histopathology: These images show representative H&E staining images of the nasal turbinates and lung tissues of Omicron JN.1-infected mice (n=3) on day 3 post-infection (3 dpi). Pathological findings are indicated as follows: inflammatory infiltration (yellow dashed circles), alveolar collapse (crosses), hemorrhage (asterisks), and alveolar wall thickening (hollow arrows). The scale bars represent 200 µm and 100 µm at 10x and 20x magnification, respectively. Magnified areas are marked with dashed rectangles. Statistical significance was determined using the following methods: (ab) p-values ​​were corrected using Brown-Forsythe and Welch one-way ANOVA with Dunnett's multiple comparison test; (c) paired one-way ANOVA with Geisser-Greenhouse sphericity correction; and (d) the Mantel-Cox log-rank test. Each data point represents a biological replicate. Data are expressed as mean ± standard deviation from the specified number of biological replicates. Data were derived from three independent experiments. * indicates p < 0.05, ** indicates p < 0.01, and **** indicates p < 0.0001. WT, wild-type SARS-CoV-2; Veh, solvent control group.

[0175] Figure 3 This image shows the in vivo antiviral effect of compound 22 (YL1004). Figure 3Compound 22 demonstrated potent in vivo antiviral efficacy by significantly reducing viral load in target organs, inhibiting viral antigen expression, and alleviating virus-related pathological damage. Most importantly, this drug successfully rescued all infected animals in a lethal SARS-CoV-2 challenge model, highlighting its clinical translational potential for treating severe infections.

Claims

1. The compound of formula I or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, an optical isomer thereof, or a deuterated compound thereof, characterized in that: The structure of Formula I is shown below: Formula I in, X1 is selected from CH or N; X2 is selected from CH or N; X3, X4, X5 and X6 are all CH, or one of them is N and the rest are CH; R1 is selected from substituted or unsubstituted varieties. substituted or unsubstituted 3- to 8-membered cycloalkyl groups substituted or unsubstituted 3-8 membered oxetane, substituted or unsubstituted 3-8 membered thioheteroalkyl, substituted or unsubstituted Replaced or not replaced Replaced or not replaced ; n1 is selected from 0, 1, or 2; n2 is selected from 0, 1, or 2; R 1a Selected from C 1~4 alkyl; In R1, the replacement Substituted 3- to 8-membered cycloalkyl groups, substituted Substituted 3-8 membered oxocyclic alkyl groups, substituted 3-8 membered thiocyclic alkyl groups, substituted... Replacement Replacement The substituents are independently selected from cyano, halogen, C 1~4 Alkyl, halogen-substituted C 1~4 Alkyl, C 1~4 Alkoxy; R2 is selected from C 1~4 Alkyl, C 1~4 Haloalkyl, C 2~4 Alkyl group, C 1~4 Alkyl sulfonyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl, 4-6 membered oxecycloalkyl or N-methyl substituted 4-6 membered azacycloalkyl; L is selected from CHR3, NR3, O, S, S(O) or S(O)2; R3 is selected from hydrogen or C. 1~4 alkyl.

2. The compound according to claim 1, characterized in that: Structural unit Selected from the following structures: , , , , , , or .

3. The compound according to claim 1, characterized in that: R1 is selected from substituted or unsubstituted varieties. substituted or unsubstituted 3-6 membered cycloalkyl groups Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced Replaced or not replaced n1 is selected from 0 or 1; n2 is selected from 0, 1 or 2; n3 is selected from 0 or 1; n4 is selected from 0, 1 or 2; n5 is selected from 0 or 1; n6 is selected from 0, 1 or 2; R 1a Selected from methyl or ethyl; R1, the substituted... Substituted 3-6 membered cycloalkyl groups, substituted Replacement Replacement Replacement Replacement Replacement The substituents are independently selected from cyano, fluorine, chlorine, bromine, methyl, ethyl, fluoromethyl, fluoroethyl, methoxy, and ethoxy. Preferably, R1 is selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , or .

4. The compound according to claim 1, characterized in that: R3 is selected from hydrogen, methyl, or ethyl; Preferably, R1-L- is selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

5. The compound according to claim 1, characterized in that: R2 is selected from methyl, fluoromethyl, ethyl, fluoroethyl, n-propyl, isopropyl, acetyl, propionyl, methanesulfonyl, ethanesulfonyl, cyclopropyl, fluorocyclopropyl, cyclobutyl, fluorocyclobutyl, cyclohexyl, fluorocyclohexyl. , , , or .

6. The compound according to any one of claims 1 to 5, characterized in that: The structural formula is as follows: Mode .

7. The compound according to any one of claims 1 to 6, characterized in that: The compound is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

8. A compound or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, characterized in that: The compound is selected from: , , , , , , , , , , , , , , , , , , or .

9. A pharmaceutical composition, characterized in that: It is a formulation made with the active ingredient of any one of the compounds of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, or the active ingredient of the compound of claim 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, plus pharmaceutically acceptable excipients.

10. Use of the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, or the compound of claim 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, or the pharmaceutical composition of claim 9, in the preparation of an antiviral drug.

11. The use according to claim 10, characterized in that: The virus is a pancoronavirus; preferably, the pancoronavirus is a novel coronavirus; more preferably, the novel coronavirus is SARS-CoV-2, SARS-CoV, MERS-CoV, HcoV-229E, HcoV-NL63, HcoV-HKU1 or HcoV-OC43; most preferably, the novel coronavirus is SARS-CoV-2.

12. The use according to claim 11, characterized in that: The antiviral drug is a drug that inhibits the infection of cells by pan-coronaviruses; preferably, the antiviral drug is a drug that inhibits the infection of cells by novel coronaviruses; more preferably, the antiviral drug is a novel coronavirus proteolytic enzyme inhibitor; most preferably, the antiviral drug is a novel coronavirus main protease inhibitor.

13. Use of the compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, or the compound of claim 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or an optical isomer thereof, or a deuterated compound thereof, or the pharmaceutical composition of claim 9, in the preparation of a medicament for the prevention and / or treatment of pan-coronaviruses; preferably, the pan-coronavirus is a novel coronavirus; more preferably, the pan-coronavirus medicament is SARS-CoV-2PL. pro Inhibitors.

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