An acyl thiourea aatacs compound and its application in anti-coronavirus

Abstract

The application discloses an acyl thiourea AATacs compound and application thereof in anti-coronavirus, and relates to the technical field of coronavirus treatment drugs. Aiming at different types of coronaviruses, the acyl thiourea AATacs compound provided by the application can not only inhibit the coronavirus, but also can exert degradation activity; the acyl thiourea AATacs compound can be developed as a new anti-coronavirus drug, and has a wide application prospect.

Description

Technical Field

[0001] This invention relates to the field of coronavirus therapeutic drugs, and in particular to an anti-coronavirus acylthiourea compound (AATacs). Background Technology

[0002] Coronaviruses belong to the genus Coronavirus in the order Coronavirales. Based on phylogenetic relationships and genomic structural characteristics, they can be divided into four subgenera: α, β, γ, and δ. These viruses are positive-sense single-stranded RNA viruses (+ssRNA viruses) with an envelope structure derived from host cells. The envelope contains a trimeric spike protein (S protein), a membrane protein (M protein), and an envelope protein (E protein), and its +ssRNA genome is encapsulated by a nucleocapsid protein (N protein) to form a nucleocapsid structure.

[0003] Of the four subgenera mentioned above, alpha and beta coronaviruses primarily infect mammals (including humans), while gamma and delta coronaviruses primarily infect birds. However, recent studies have shown that some bat coronaviruses (such as NeoCoV) only require a single nucleotide mutation to acquire the ability to infect humans. Therefore, both coronaviruses currently confirmed to infect humans and those currently infecting other animals but posing a potential risk of cross-species transmission must be included in the prevention and control efforts to address potential future coronavirus outbreaks.

[0004] Currently, the coronavirus treatments approved by the U.S. Food and Drug Administration (FDA) are mainly divided into two categories: the first category is RNA-dependent RNA polymerase (RdRp) inhibitors, including Remdesivir and Molnupiravir; the second category is 3C-like protease (3CLpro) inhibitors, including Nirmatrelvir and Ensitrelvir. The aforementioned drugs provided important support for the treatment of coronavirus infection in the early stages of the COVID-19 pandemic, but all have significant limitations: (1) Remdesivir requires intravenous infusion, which makes it inconvenient to use in clinical practice; (2) Monupiravir has been shown to have potential genotoxicity and reproductive toxicity, which limits its clinical application (not recommended for pregnant women, breastfeeding women and minors); (3) Naphatvir needs to be used in combination with Ritonavir to achieve the ideal therapeutic effect; and as a cytochrome P450 enzyme inhibitor, Ritonavir can cause drug interactions between this combination therapy and a variety of commonly used clinical drugs (such as some lipid-lowering drugs, sedative-hypnotic drugs, etc.), further limiting its applicable population. (4) Although Ernstavir was first approved for marketing in Japan during the COVID-19 pandemic and was approved by the FDA in 2025, the latest research data shows that the drug may cause adverse reactions such as metabolic abnormalities and liver damage in patients.

[0005] In summary, existing coronavirus treatments suffer from limitations in administration methods, safety risks, and drug interactions, which prevent them from meeting the diverse needs of clinical treatment. Therefore, the development of treatments for the novel coronavirus is of urgent clinical necessity and practical significance.

[0006] Traditional small-molecule antiviral drugs typically exert their antiviral activity through an "occupancy-driven" mechanism; that is, the drug binds to the active site of the viral target protein to form a complex, thereby inhibiting the protein's function. However, this mechanism requires the drug to maintain a high concentration in vivo to continuously occupy the target protein's active site. This not only increases the difficulty of drug development but also raises the risk of viral resistance due to target protein mutations.

[0007] Therefore, developing a novel anti-coronavirus drug that neither occupies the target protein active site for a long time and maintains a high concentration in vivo, nor reduces drug resistance caused by viral target protein mutations, is an important research direction in this field. Summary of the Invention

[0008] To address the high risk of drug resistance associated with traditional "occupancy-driven" drugs, this application utilizes three amino acids (tryptophan and lysine) capable of triggering N-terminal degradation pathways to modify the structure of acylthiourea small molecule compounds into PROTACs (also known as AATacs). This allows them to exert antiviral activity by targeting and degrading key viral target proteins, and also to degrade coronaviruses. This approach has broad application prospects and can be developed as a novel antiviral drug against coronaviruses.

[0009] To address the shortcomings of the prior art, this invention provides an acylthiourea compound (AATacs) and its application in the fight against coronaviruses, specifically achieved through the following techniques.

[0010] In a first aspect, the present invention provides an acylthiourea-type AATacs compound, the general chemical structure of which is shown in Formula I;

[0011] Formula I;

[0012] Where n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

[0013] Further, the acylthiourea AATacs compounds specifically include: N-{[(4-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}phenyl)amino]thiolidemethyl}-4-(2-methylpropion-2-yl)benzamide, N-[({4-[(4-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}-1-oxylidenebutyl)amino]phenyl}amino)thiolidemethyl]-4-(2-methylpropion-2-yl)benzamide, N-[({4-[(6-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}-1-oxylidenehexyl)amino]phenyl}amino]phenyl [4-(2-methylprop-2-yl)benzamide, N-[({4-[(7-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}-1-oxylideneheptyl)amino]phenyl}amino]thionylmethyl]-4-(2-methylprop-2-yl)benzamide, N-[({4-[(8-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}-1-oxylideneoctyl)amino]phenyl}amino]thionylmethyl]-4-(2-methylprop-2-yl)benzamide, N-[({4-[(10-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino]amino] [1-Oxylidenedecyl)amino]phenyl]amino)thiolidenemethyl]-4-(2-methylprop-2-yl)benzamide, N-[({4-[(11-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}-1-oxylideneundyl)amino]phenyl]amino]thiolidenemethyl]-4-(2-methylprop-2-yl)benzamide, N-[({4-[(12-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}-1-oxylidenedodecyl)amino]phenyl]amino)thiolidenemethyl]-4-(2-methylprop-2-yl)benzamide, N-[({4-[(7-{[(2S)-2 [6-Diamino-1-oxylidenehexyl]amino}-1-oxylideneheptyl)amino]phenyl}amino)thiolidenemethyl]-4-(2-methylpropyl-2-yl)benzamide, N-[({4-[(8-{[(2S)-2,6-diamino-1-oxylidenehexyl]amino}-1-oxylideneoctyl)amino]phenyl}amino)thiolidenemethyl]-4-(2-methylpropyl-2-yl)benzamide, N-[({4-[(9-{[(2S)-2,6-diamino-1-oxylidenehexyl]amino}-1-oxylidenenonyl)amino]phenyl}amino)thiolidenemethyl]-4-(2-methylpropyl-2-yl)benzamide, N-[({4-[(10-{[(2S)-2,[6-Diamino-1-oxylidenehexyl]amino}-1-oxylidenedecyl)amino]phenyl}amino)thionylmethyl]-4-(2-methylpropyl-2-yl)benzamide, N-[({4-[(11-{[(2S)-2,6-diamino-1-oxylidenehexyl]amino}-1-oxylideneundecyl)amino]phenyl}amino)thionylmethyl]-4-(2-methylpropyl-2-yl)benzamide, N-[({4-[(12-{[(2S)-2,6-diamino-1-oxylidenehexyl]amino}-1-oxylidenedodecyl)amino]phenyl}amino)thionylmethyl]-4-(2-methylpropyl-2-yl)benzamide. ,

[0014] In a second aspect, the present invention provides a pharmacologically or physiologically acceptable salt of an acylthiourea compound (AATacs).

[0015] A third aspect of the present invention provides a method for preparing the above-mentioned acylthiourea AATacs compounds, comprising the following steps:

[0016] Compound M-1 and compound M-2 were condensed to obtain compound int-1;

[0017] The Boc protecting group of compound int-1 was removed, and then it was condensed with Boc-protected tryptophan or Boc-protected lysine to obtain compounds int-2 and int-3, respectively.

[0018] The Boc protecting group of compound int-2 or compound int-3 is removed to obtain the acylthiourea AATacs compound;

[0019] The chemical structural formula of compound M-1 is shown in Formula II; the chemical structural formula of compound M-2 is shown in Formula III.

[0020] Formula II;

[0021] Formula III;

[0022] Where n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11.

[0023] Furthermore, the preparation method of compound M-1 includes the following steps:

[0024] 4-tert-butylbenzoyl chloride was subjected to a nucleophilic substitution reaction with ammonium thiocyanate to obtain 4-tert-butylbenzoyl isothiocyanate;

[0025] The 4-tert-butylbenzoyl isothiocyanate was subjected to a nucleophilic addition reaction with 4-(tert-butoxycarbonylamino)aniline to obtain N-(4-tert-butylbenzoyl)-N'-(4-(tert-butoxycarbonylamino)phenyl)thiourea with a Boc protecting group.

[0026] The Boc protecting group of N-(4-tert-butylbenzoyl)-N'-(4-(tert-butyloxycarbonylamino)phenyl)thiourea with the Boc protecting group was removed to obtain the compound M-1.

[0027] In a fourth aspect, the present invention provides the use of an acylthiourea compound (AATacs) in the preparation of an anticoronavirus medicament.

[0028] In a fifth aspect, the invention provides the use of a pharmacologically or physiologically acceptable salt of an acylthiourea compound (AATacs) in the preparation of a medicament for treating coronaviruses.

[0029] In a sixth aspect, the present invention provides an anticoronavirus medicament comprising at least one of acylthiourea AATacs compounds, or comprising at least one of said acylthiourea AATacs compounds in a pharmacologically or physiologically acceptable salt.

[0030] Furthermore, the raw materials of the anti-coronavirus drug also include pharmaceutically acceptable carriers or excipients.

[0031] Furthermore, the coronaviruses include, but are not limited to, SARS-CoV-2, HCoV-229E, or HCoV-OC43.

[0032] Compared with the prior art, the advantages of the present invention are: the present invention provides a class of acylthiourea AATacs compounds that inhibit coronaviruses while also exhibiting degradation activity; it can be developed as a new anti-coronavirus drug and has broad application prospects. Attached Figure Description

[0033] Figure 1 A schematic diagram of the preparation route of the acylthiourea AATacs compounds provided by the present invention.

[0034] Figure 2 A schematic diagram of the preparation route for compound M-1, used to prepare acylthiourea AATacs compounds.

[0035] Figure 3 The results show the anti-OC43 activity of the target compound N 1-14. Detailed Implementation

[0036] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0037] In some embodiments of the present invention, an acylthiourea-type AATacs compound is provided, the general chemical structure of which is shown in Formula I;

[0038] Formula I;

[0039] Where n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

[0040] The R group is or .

[0041] For example, the specific structural formula is: Where n is 0, 3, 5, 6, 7, 9, 10 or 11.

[0042] For example, the specific structural formula is: Where m is 6, 7, 8, 9, 10 or 11.

[0043] Optionally, the specific chemical structures of acylthiourea AATacs compounds are shown in Table 1 below.

[0044] Table 1. Acylthiourea AATacs Compounds

[0045]

[0046]

[0047] In other embodiments of the present invention, methods for preparing acylthiourea AATacs compounds are also provided, such as... Figure 1 As shown, it includes the following steps:

[0048] Compound M-1 and compound M-2 were condensed to obtain compound int-1;

[0049] The compound int-1 was deprotected by the Boc protecting group and then condensed with Boc-protected tryptophan (Boc2-Trp) or Boc-protected lysine (Boc2-Lys) to obtain compounds int-2 and int-3, respectively.

[0050] The Boc protecting group of compound int-2 or compound int-3 is removed to obtain the acylthiourea AATacs compound.

[0051] In other embodiments of the present invention, a method for preparing compound M-1 is also provided, such as... Figure 2 As shown, it includes the following steps:

[0052] 4-tert-butylbenzoyl chloride was subjected to a nucleophilic substitution reaction with ammonium thiocyanate to obtain 4-tert-butylbenzoyl isothiocyanate;

[0053] The 4-tert-butylbenzoyl isothiocyanate was subjected to a nucleophilic addition reaction with 4-(tert-butoxycarbonylamino)aniline to obtain N-(4-tert-butylbenzoyl)-N'-(4-(tert-butoxycarbonylamino)phenyl)thiourea with a Boc protecting group.

[0054] The Boc protecting group of N-(4-tert-butylbenzoyl)-N'-(4-(tert-butyloxycarbonylamino)phenyl)thiourea with the Boc protecting group was removed to obtain the compound M-1.

[0055] Example 1: Preparation of AATacs compounds of acylthiourea class

[0056] 1. Preparation of compound M-1

[0057] (1) Dissolve 4-tert-butylbenzoyl chloride (1.96 g, 10 mmol) in 50 mL of acetonitrile, add ammonium thiocyanate (1.17 g, 15 mmol) under ice bath, and react for 1 h;

[0058] The filter residue was removed by filtration, and an acetonitrile solution of 4-tert-butylbenzoyl isothiocyanate was obtained. No further treatment was required for the next reaction.

[0059] (2) Add 4-(tert-butoxycarbonylamino)aniline (2.08 g, 10 mmol) to the solution obtained in the previous step and react at room temperature for 4 h;

[0060] The filtrate was removed by filtration and dried to obtain N-(4-tert-butylbenzoyl)-N'-(4-(tert-butyloxycarbonylamino)phenyl)thiourea.

[0061] (3) Dissolve N-(4-tert-butylbenzoyl)-N'-(4-(tert-butyloxycarbonylamino)phenyl)thiourea in dichloromethane, add 1 / 2 volume of trifluoroacetic acid in dichloromethane under ice bath, and stir at room temperature for 1 h to remove the Boc protecting group.

[0062] The solvent and excess trifluoroacetic acid were evaporated to obtain the compound M-1.

[0063] 2. Preparation of AATacs compounds of acylthiourea class

[0064] This step uses compound N-6 from Table 1 as an example; the synthesis methods for the other compounds are the same.

[0065] (1) Compound M-1 (327 mg, 1 mmol), 10-((tert-butoxycarbonyl)amino)decanoic acid (344 mg, 1.2 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (494 mg, 1.3 mmol), and N,N-diisopropylethylamine (318 mg, 3 mmol) were placed in a round-bottom flask, and 20 mL of dichloromethane was added as the reaction solvent. The mixture was stirred at room temperature for 4 h.

[0066] Dichloromethane / water extraction, washing with saturated brine, drying with anhydrous sodium sulfate, and separation by silica gel column chromatography yielded the intermediate compound int-1.

[0067] (2) Compound int-1 (611 mg, 1 mmol) was placed in a round-bottom flask, and dichloromethane was added until dissolved. Half a volume of trifluoroacetic acid was added under ice bath conditions, and the mixture was stirred at room temperature for 1 h to remove the Boc protecting group.

[0068] After evaporating the solvent and excess trifluoroacetic acid, Boc-protected tryptophan (304 mg, 1 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (494 mg, 1.3 mmol), and N,N-diisopropylethylamine (318 mg, 3 mmol) were added. 20 mL of dichloromethane was added as the reaction solvent, and the reaction was stirred at room temperature for 4 h.

[0069] Dichloromethane / water extraction, washing with saturated brine, drying with anhydrous sodium sulfate, and silica gel column chromatography were used to obtain the intermediate compound int-2.

[0070] (3) Compound int-2 (801 mg, 1 mmol) was placed in a round-bottom flask, and 20 mL of dichloromethane was added until dissolved. Half a volume of trifluoroacetic acid was added under ice bath conditions. The reaction was stirred at room temperature for 1 h to remove the Boc protecting group. The solvent and excess trifluoroacetic acid were evaporated to obtain the target compound N-6.

[0071] Experimental Example: Bioactivity Testing of Acylthiourea Compounds

[0072] 1. Cytotoxicity assay of acylthiourea compounds

[0073] The CCK8 assay is a method for detecting cell proliferation and cytotoxicity based on WST-8. The principle is that WST-8 is reduced to soluble formazan dye by intracellular dehydrogenase. The amount of dye produced is directly proportional to the number of live cells. The absorbance value is measured at a wavelength of 450 nm using an enzyme-linked immunosorbent assay (ELISA) reader, which can indirectly reflect the number of cells.

[0074] During the experiment, VeroE6 cells were stored at a density of 2 × 10⁶ cells per well. 4 The density was transferred to 96-well plates and incubated at 37°C for 24 hours. The culture medium was then aspirated, and cell culture medium containing various concentration gradients of compounds was added to each well. After 24 hours, 10 μL of CCK8 solution was added to each well, and the cell plates were incubated in a CO2 incubator at 37°C for 1 hour. The OD value at 450 nm was measured using a microplate reader.

[0075] The inhibition rate (%) of the compound = [1 - (EN) / (PN)] × 100; where "E" represents the OD value of the treated group, "P" represents the OD value of the untreated group, and "N" represents the OD value of the blank group. The half-maximal inhibitory concentration (CMC) of the compound... 50 (This can be used as an indicator of the compound's cytotoxicity.)

[0076] 2. In vitro anticoronavirus activity of acylthiourea compounds

[0077] The anti-SAR-COV-2 activity of the compound was evaluated by immunofluorescence staining, and the compound's activity against other coronaviruses, such as HCoV-OC43 (derived from ATCC VR-1558) and HCoV-229E (derived from ATCC VR-740), was evaluated by RT-qPCR and cytopathic effects.

[0078] In the anti-SAR-CoV-2 virus activity assay, 96-well plates filled with Vero E6 cells were infected with virus at an MOI of 0.01, and the drug was added simultaneously. After 24 hours, the cells were fixed with 4% paraformaldehyde, treated with immunofluorescence, and analyzed. In the anti-HCoV-OC43 virus activity assay, 24-well plates filled with RD cells were inoculated with OC43 at an MOI of 0.01. After 60 minutes, the virus-containing medium was removed, and medium containing a specific concentration of the test drug was added. After culturing at 33 °C and 5% CO2 for 24 hours, RNA was extracted using an RNA extraction kit and analyzed using Prism Graphad software.

[0079] The detection of anti-HCoV-229E used Huh-7 cells, which were plated in 96-well plates one day in advance. After confluence, the cells were exposed to the virus for 1 hour, followed by treatment with the compound. The condition of the drug-treated group was observed when the NC group showed complete lesions, and the EC50 was determined based on the lesions. 50This refers to the concentration required for a specific drug to effectively inhibit the viral load to 50% of that in the control well.

[0080] 3. Results and Analysis

[0081] Using remdesivir as a control, this invention examined the cytotoxicity and anti-multiple coronavirus activities of 14 synthesized compounds and calculated the selectivity index (SI) of the compounds. The results are shown in Tables 2 and 3. Figure 3 .

[0082] Table 2 Results of the anti-SARS-CoV-2 activity and cytotoxicity of the target compound N1-14 of this invention.

[0083]

[0084] The experimental results in Table 2 above indicate that the synthesized acylthiourea compounds possess anti-novel coronavirus activity. For example, compound N-1 (EC... 50 =22.46 μM, SI=4.33), N-3 (EC 50 =45.13 μM, SI=1.97), N-6 (EC 50 =0.07425 μM, SI=761.48), N-7 (EC 50 =1.261 μM, SI=129.26), N-11 (EC 50 =7.153 μM, SI=7.22), N-12 (EC 50 =28.6 μM, SI=5.50), N-13 (EC 50 =26.61 μM, SI=3.20), N-14 (EC 50 =46.65 μM, SI=2.26), especially compounds N-6 and N-7, both showed low molar levels of anti-novel coronavirus activity and high selectivity.

[0085] Table 3. Anti-HCoV-229E activity of the target compound N1-14 of this invention.

[0086] The above experimental results show that various synthesized acylthiourea compounds possess anti-coronavirus 229E activity, and compound N-6 (EC) 50 =0.3 μM), N-12 (EC 50 =1.25 μM), N-13 (EC 50 The concentration of 1.25 μM (=1.25 μM) showed low molar levels of activity against the novel coronavirus.

[0087] like Figure 3As shown, the experimental results indicate that the synthesized acylthiourea compounds have anti-coronavirus OC43 activity. All compounds in this series can inhibit 90% of viral copies at a concentration of 1 μM, demonstrating low molar levels of anti-novel coronavirus activity.

[0088] The above detailed embodiments describe the implementation of the present invention; however, the present invention is not limited to the specific details described in the above embodiments. Within the scope of the claims and technical concept of the present invention, various simple modifications and changes can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. An acylthiourea-type AATacs compound, characterized in that, Its general chemical structure is shown in Formula I; Formula I; Where n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11; The R group is or .

2. The acylthiourea AATacs compound according to claim 1, characterized in that, The acylthiourea AATacs compounds specifically include: N-{[(4-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}phenyl)amino]thiolidemethyl}-4-(2-methylpropion-2-yl)benzamide, N-{4-[(4-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}-1-oxylidenebutyl)amino]phenyl}amino)thiolidemethyl]-4-(2-methylpropion-2-yl)benzamide, N-{4-[(6-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}-1-oxylidenehexyl)amino]phenyl}amino)thiolidene [Methyl]-4-(2-methylprop-2-yl)benzamide, N-[({4-[(7-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}-1-oxylideneheptyl)amino]phenyl}amino)thiolidenemethyl]-4-(2-methylprop-2-yl)benzamide, N-[({4-[(8-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}-1-oxylideneoctyl)amino]phenyl}amino)thiolidenemethyl]-4-(2-methylprop-2-yl)benzamide, N-[({4-[(10-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}-1 [-Oxylidenedecyl)amino]phenyl}amino)thionylmethyl]-4-(2-methylpropyl-2-yl)benzamide, N-[({4-[(11-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}-1-oxylideneundecyl)amino]phenyl}amino)thionylmethyl]-4-(2-methylpropyl-2-yl)benzamide, N-[({4-[(12-{[(2R)-3-(1H-indol-3-yl)-2-aminopropionyl]amino}-1-oxylidenedodecyl)amino]phenyl}amino)thionylmethyl]-4-(2-methylpropyl-2-yl)benzamide, N-[({4-[(7-{[(2S)-2,6 -diamino-1-oxylidenehexyl]amino}-1-oxylideneheptyl)amino]phenyl}amino)thiolidenemethyl]-4-(2-methylpropyl-2-yl)benzamide, N-[({4-[(8-{[(2S)-2,6-diamino-1-oxylidenehexyl]amino}-1-oxylideneoctyl)amino]phenyl}amino)thiolidenemethyl]-4-(2-methylpropyl-2-yl)benzamide, N-[({4-[(9-{[(2S)-2,6-diamino-1-oxylidenehexyl]amino}-1-oxylidenenonyl)amino]phenyl}amino)thiolidenemethyl]-4-(2-methylpropyl-2-yl)benzamide, N-[({4-[(10-{[(2S)-2,[6-Diamino-1-oxylidenehexyl]amino}-1-oxylidenedecyl)amino]phenyl}amino)thiolidenemethyl]-4-(2-methylpropyl-2-yl)benzamide, N-[({4-[(11-{[(2S)-2,6-diamino-1-oxylidenehexyl]amino}-1-oxylideneundecyl)amino]phenyl}amino)thiolidenemethyl]-4-(2-methylpropyl-2-yl)benzamide, N-[({4-[(12-{[(2S)-2,6-diamino-1-oxylidenehexyl]amino}-1-oxylidenedodecyl)amino]phenyl}amino)thiolidenemethyl]-4-(2-methylpropyl-2-yl)benzamide. , 3. A pharmacologically or physiologically acceptable salt of the acylthiourea AATacs compound of claim 1 or 2.

4. The method for preparing the acylthiourea AATacs compound according to claim 1 or 2, characterized in that, Includes the following steps: Compound M-1 and compound M-2 were combined via a condensation reaction to obtain compound int-1; The Boc protecting group of compound int-1 was removed, and then it was condensed with Boc-protected tryptophan or Boc-protected lysine to obtain compounds int-2 and int-3, respectively. The Boc protecting group of compound int-2 or compound int-3 is removed to obtain the acylthiourea AATacs compound; The chemical structural formula of compound M-1 is shown in Formula II; the chemical structural formula of compound M-2 is shown in Formula III. Formula II; Formula III; Where n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11.

5. The method for preparing acylthiourea AATacs compounds according to claim 4, characterized in that, The preparation method of compound M-1 includes the following steps: 4-tert-butylbenzoyl chloride was subjected to a nucleophilic substitution reaction with ammonium thiocyanate to obtain 4-tert-butylbenzoyl isothiocyanate; The 4-tert-butylbenzoyl isothiocyanate was subjected to a nucleophilic addition reaction with 4-(tert-butoxycarbonylamino)aniline to obtain N-(4-tert-butylbenzoyl)-N'-(4-(tert-butoxycarbonylamino)phenyl)thiourea with a Boc protecting group. The Boc protecting group of N-(4-tert-butylbenzoyl)-N'-(4-(tert-butyloxycarbonylamino)phenyl)thiourea with the Boc protecting group was removed to obtain the compound M-1.

6. Use of an acylthiourea AATacs compound as described in claim 1 or 2 in the preparation of an anticoronavirus medicament.

7. The use of a pharmacologically or physiologically acceptable salt of the acylthiourea AATacs compound of claim 3 in the preparation of an anticoronavirus medicament.

8. A drug for treating coronaviruses, characterized in that, It includes at least one of the acylthiourea AATacs compounds of claim 1 or 2, or includes at least one of the acylthiourea AATacs compounds in a pharmacologically or physiologically acceptable salt.

9. The anticoronavirus drug according to claim 8, characterized in that, It also includes pharmaceutically acceptable carriers or excipients.

10. The anticoronavirus medicament according to claim 8, characterized in that, The coronaviruses mentioned include, but are not limited to, SARS-CoV-2, HCoV-229E, or HCoV-OC43.

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