WO2022268145A1 - 一种酰胺类化合物、其制备方法和制药用途 - Google Patents

一种酰胺类化合物、其制备方法和制药用途 Download PDF

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WO2022268145A1
WO2022268145A1 PCT/CN2022/100609 CN2022100609W WO2022268145A1 WO 2022268145 A1 WO2022268145 A1 WO 2022268145A1 CN 2022100609 W CN2022100609 W CN 2022100609W WO 2022268145 A1 WO2022268145 A1 WO 2022268145A1
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alkyl
virus
iiia
halogen
alkylcarbonyl
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PCT/CN2022/100609
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English (en)
French (fr)
Inventor
蒋翔锐
王延轶
张波
彭珂
付玉志
李锐
张哲瑞
张玉兰
蒋华良
沈敬山
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中国科学院上海药物研究所
中国科学院武汉病毒研究所
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Application filed by 中国科学院上海药物研究所, 中国科学院武汉病毒研究所 filed Critical 中国科学院上海药物研究所
Priority to CN202280045198.8A priority Critical patent/CN118076589A/zh
Publication of WO2022268145A1 publication Critical patent/WO2022268145A1/zh

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Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to an amide compound, its preparation method and pharmaceutical application.
  • Niclosamide was approved by the US Food and Drug Administration in 1960 for the treatment of intestinal tapeworm infection. Dead parasites. So far, niclosamide has been used safely for more than 50 years and has been included in the World Health Organization's list of essential medicines. In addition, niclosamide can also be used in the treatment of tapeworm infection in animals, and can also be used to kill snails and prevent schistosomiasis.
  • niclosamide has a wide range of biological activities and can regulate various signaling pathways and biological processes, such as Wnt/ ⁇ -catenin, mTORC1, STAT3, NF- ⁇ B, Notch, NS2B-NS protein interaction, etc. (Cancer Lett, 2014, 349, 8-14; Cell Res, 27, 1046-1064). Moreover, niclosamide exhibits antiviral pharmacological effects (Tuberculosis, 2019, 116, S28-S33; Nat.Med, 2016, 22, 1101-1107.)
  • Coronaviruses are a class of widely distributed single-stranded positive-sense RNA viruses that can infect a variety of higher animals and are also common human pathogens. Such as HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1 usually cause mild cold symptoms in humans (Academic Press, 2018, 100, 163-188). However, coronaviruses such as SARS-CoV, MERS-CoV, and SARS-CoV-2 can cause severe respiratory diseases and even death in humans. Currently, effective treatments for people infected with coronavirus have yet to be further developed. Wu et al.
  • niclosamide can inhibit the replication of SARS-CoV through the new application screening of old drugs on the market, and can completely inhibit the synthesis of viral antigens at 1.5 ⁇ M (Antimicrob.Agents Chemother, 2004, 48, 2693- 2696.).
  • Yang et al. found that niclosamide can inhibit the cytopathic effect (CPE) of SARS-CoV at 1 ⁇ M, and inhibit the replication of SARS-CoV in Vero E6 cells, and its EC50 value is less than 0.1 ⁇ M (J.Med.Chem, 2007, 50, 4087-4095).
  • Flavivirus is also a single-stranded positive-sense RNA virus, mainly including Zika virus, dengue virus, Japanese encephalitis virus, West Nile virus, Yellow fever virus, many of these viruses are human pathogens. It is known that niclosamide is a potential inhibitor of Zika virus infection by enzyme screening method, the IC50 of intracellular level is 0.37 ⁇ M, and niclosamide directly inhibits flavivirus NS2B-NS3 interaction, and niclosamide was also found Salamide is a broad-spectrum inhibitor of flaviviruses (Cell Res, 2017, 27, 1046-1064; Nat. Med, 2016, 22, 1101-1107).
  • Hepatitis C virus is also an envelope-positive single-stranded RNA virus of the Flaviviridae family. About 71 million people in the world suffer from chronic HCV infection. The EC50 of niclosamide to inhibit HCV virus replication is 0.16 ⁇ M. The mechanism of this inhibition of virus replication is similar to that of nitazoxanide and tizoxanide in regulating host cell processes (Antimicrob. Agents Chemother, 2008, 52, 4069-4071; Antiviral Res, 2011, 91, 233-240; ACS Med. Chem. Lett, 2011, 2, 849-854).
  • Ebola virus is a severe infectious disease virus that can cause Ebola hemorrhagic fever in humans and primates.
  • Niclosamide has strong Ebola virus inhibitory activity, with EC50 of 1.5 ⁇ M (ACS Infect. Dis, 2015, 1, 317-326).
  • Human rhinovirus is a member of the Picornaviridae family, a genus of the Rhinovirus genus, and is a major cause of the common cold and poses serious health risks to patients with asthma, chronic lung disease, and severe bronchiolitis in infants and young children.
  • Niclosamide is a pH-dependent inhibitor of HRV infection, with IC50 reaching micromolar levels; as a proton carrier, it inhibits the entry of HRV virus by blocking the acidification of endolysosomal compartments (Clin.Microbiol.Rev, 2013 , 26, 135-162; PLoS Pathog, 2012 8, e1002976).
  • Human adenoviruses are non-enveloped, double-stranded DNA viruses with seven subspecies. Adenoviruses are prevalent in the population, especially in infants and adolescents, mainly associated with respiratory, ocular- and gastrointestinal infections. At present, there is no really feasible drug for the treatment of such viral infections (FEMS Microbiol.Rev.2019,43,380-388; Antimicrob.Agents Chemother.2010,54,3871-3877; J.Med.Chem.2012, 55, 3170-3181). Studies have found that niclosamide can significantly inhibit the infection of human adenovirus, with an IC50 of 0.6 ⁇ M.
  • niclosamide has some obvious disadvantages, such as low oral bioavailability and insufficient antiviral activity. These factors limit the further development and application of niclosamide as an antiviral active compound. On the basis of the structure of niclosamide, it is of great significance to optimize the structure and find compounds with stronger antiviral activity and higher oral bioavailability, as well as broad-spectrum antiviral active compounds with anti-inflammatory effects.
  • an object of the present invention is to provide a class of amide compounds which have antiviral activity, especially anticoronavirus, bunyavirus and dengue virus activity.
  • One object of the present invention is to provide a process for the preparation of the above compounds.
  • Another object of the present invention is to provide the use of the above compounds in the preparation of medicines for treating or preventing viral infections.
  • an amide compound represented by the following general formula I its prodrug, pharmaceutically acceptable salt, complex or solvate:
  • Y is a benzene ring, a 5-6 membered heteroaromatic ring, a benzene ring with a 5-6 membered heteroaryl ring or a 5-6 membered heteroaryl ring with a 5-6 membered heteroaryl ring; preferably a benzene ring, a pyridine ring or a thiazole ring ;
  • Z is O or S
  • a 1 is C-OR 11 , C-SR 11 , C-NHR 11 , N or CR 12 ;
  • R 11 is hydrogen atom, C1 ⁇ C20 alkyl, C1 ⁇ C20 alkylcarbonyl, C1 ⁇ C20 alkylaminocarbonyl, C1 ⁇ C20 alkylcarbonyloxy C1 ⁇ C20 alkyl, C1 ⁇ C20 alkylphosphoryl, C1 ⁇ C20 alkylsulfonyl, C1 ⁇ C20 alkyl substituted 6-20 heterocyclic carbonyl containing 1-3 heteroatoms selected from O, N or S or
  • the above-mentioned C1-C20 alkyl group is optionally selected from hydroxyl, amino (-NH 2 ), C1-C20 alkylamino, cyano, carboxyl, halogen, One or more substitutions in C1-C10 alkylsulfonyl, C1-C10 alkyl phosphoryl, C1-C10 acyl;
  • R 11 is hydrogen atom, C1 ⁇ C10 alkyl, C1 ⁇ C10 alkylcarbonyl, C1 ⁇ C10 alkylaminocarbonyl, C1 ⁇ C10 alkylcarbonyloxy C1 ⁇ C10 alkyl, C1 ⁇ C10 alkyl substituted
  • the above-mentioned C1 ⁇ C10 alkyl groups are optionally selected from hydroxyl, amino, cyano, carboxyl, halogen, One or more substitutions in C1-C10 alkylsulfonyl, C1-C10 alkylphosphoryl, C1-C10 alkylcarbonyl;
  • R 11 is a hydrogen atom, C1 ⁇ C6 alkyl, halogenated C1 ⁇ C6 alkyl, amino C1 ⁇ C6 alkyl, hydroxyl, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkylcarbonyl, C1 ⁇ C6 alkane Aminocarbonyl, C1 ⁇ C6 alkylcarbonyloxy C1 ⁇ C6 alkyl, C1 ⁇ C6 alkylamino C1 ⁇ C6 alkylcarbonyl, amino C1 ⁇ C6 alkylcarbonyl, Substituted C1 ⁇ C6 alkylcarbonyl, C1 ⁇ C6 alkyl substituted 6-8 membered heterocyclic carbonyl containing 1-3 heteroatoms selected from O, N or S or
  • R 11 is hydrogen atom, C1 ⁇ C4 alkyl, C1 ⁇ C6 alkylcarbonyl, C1 ⁇ C5 alkylaminocarbonyl, C1 ⁇ C5 alkylcarbonyloxy C1 ⁇ C5 alkyl, Substituted C1 ⁇ C4 alkyl, substituted C1 ⁇ C4 alkylcarbonyl, or
  • R 7 is C1 ⁇ C10 alkyl, C1 ⁇ C10 alkylamino C1 ⁇ C10 alkyl or C3 ⁇ C10 cycloalkyl, preferably C1 ⁇ C6 alkyl, C1 ⁇ C6 alkylamino C1 ⁇ C6 alkyl or C3 ⁇ C7 cycloalkyl, more preferably C1 ⁇ C4 alkyl, C1 ⁇ C3 alkylamino C1 ⁇ C4 alkyl or C3 ⁇ C6 cycloalkyl;
  • R8 is hydrogen atom, halogen or C1 ⁇ C10 alkyl; preferably hydrogen atom, halogen or C1 ⁇ C2 alkyl, more preferably hydrogen atom or methyl;
  • R 12 is hydrogen atom, halogen, cyano, nitro or C1 ⁇ C20 alkyl, preferably hydrogen atom, halogen, cyano, nitro or C1 ⁇ C6 alkyl; more preferably hydrogen atom, halogen, cyano or C1 ⁇ C4 alkyl;
  • a 2 , A 3 , A 4 , A 5 are each independently N or CR 2 ; preferably, at most two of A 2 , A 3 , A 4 , A 5 are N;
  • R 2 are the same or different from each other, and are independently selected from hydrogen, hydroxyl, halogen, C1-C6 alkyloxy, C1-C6 alkyl, amino (-NH 2 ), nitro, cyano, carboxyl, aldehyde , C1 ⁇ C6 alkylcarbonyl, C1 ⁇ C6 alkylsulfonyl, C1 ⁇ C6 alkylsulfonylamino and C1 ⁇ C6 alkyloxycarbonyl, the above hydroxyl, amino, carboxyl, C1 ⁇ C6 alkyl are optionally One or more substitutions in hydroxyl, amino, cyano, carboxyl, halogen, C1-C10 alkylsulfonyl, C1-C10 alkylphosphoryl, C1-C10 alkylcarbonyl;
  • R are the same or different from each other, and are each independently selected from hydrogen , hydroxyl, halogen, C1-C4 alkyloxy, C1-C4 alkyl, amino, nitro, cyano and C1-C4 alkylcarbonyl , the above-mentioned C1-C4 alkyl group is optionally replaced by one or more of hydroxyl, amino, cyano, carboxyl, halogen, C1-C4 alkylsulfonyl, C1-C4 alkylphosphoryl, C1-C4 alkylcarbonyl kind of substitution;
  • R2 are the same or different from each other, and are independently selected from hydrogen , hydroxyl, halogen, C1-C2 alkoxy, C1-C2 alkyl, C1-C2 alkylcarbonyl, halogenated C1-C2 alkoxy Group, halogenated C1-C2 alkyl, halogenated C1-C2 alkylcarbonyl, amino and nitro;
  • R 3 is a hydrogen atom or a C1-C6 alkyl group, preferably, R 3 is a hydrogen atom or a C1-C4 alkyl group, more preferably, R 3 is a hydrogen atom;
  • R 4 to R 6 are each independently selected from hydrogen atom, hydroxyl, amino, halogen, nitro, cyano, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkyloxy and C1 ⁇ C6 alkylthio, the above C1 ⁇ C6 C6 alkyl is optionally substituted by one or more of hydroxyl, amino, cyano, carboxyl, halogen, C1-C6 alkylsulfonyl, C1-C6 alkylphosphoryl, C1-C6 alkylacyl;
  • R 4 to R 6 are each independently selected from a hydrogen atom, hydroxyl, amino, halogen, nitro, cyano, C1-C4 alkyl and C1-C4 alkyloxy, and the above-mentioned C1-C4 alkyl is optionally substituted by one or more of hydroxyl, amino, cyano, carboxyl, halogen;
  • R 4 to R 6 are each independently selected from a hydrogen atom, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, and halogenated C1-C4 alkoxy.
  • halogen refers to fluorine, chlorine, bromine, iodine
  • halogenated C1 ⁇ C4 alkyl refers to C1 ⁇ C4 alkyl substituted with one or more halogen atoms, preferably trifluoromethyl
  • halogen Substituted C1-C4 alkoxy refers to C1-C4 alkyloxy substituted with one or more halogen atoms, preferably trifluoromethoxy.
  • the amide compound represented by the general formula I is a compound represented by the following general formula II, IIIA or IIIB:
  • a 1 is C-OR 11 , C-SR 11 , C-NHR 11 or CR 12 ;
  • R 11 , R 12 , R 2 , R 4 to R 6 and Y are the same as in the general formula I.
  • the amide compound represented by the general formula I is a compound represented by the following general formula IV:
  • R 11 , R 2 , R 4 and R 5 are the same as in the general formula I.
  • each of the above-mentioned R 2 is independently selected from a hydrogen atom, a halogen (especially fluorine and chlorine), a hydroxyl group, a formyl group, an acetyl group, and a nitro group.
  • R 4 and R 5 are each independently selected from a hydrogen atom, halogen, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy, methylthio, trifluoromethyl Sulfur base.
  • above-mentioned R 11 is hydrogen.
  • the compound or salt is selected from the following structures:
  • the invention also provides a preparation method of the compound of the general formula.
  • compound I and/or IIIA can be reacted to obtain compound IIIB through hydrocarbylation, acylation, phosphorylation or sulfonylation.
  • the present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of one selected from the above compounds of the present invention, their prodrugs, pharmaceutically acceptable salts, complexes and solvates. or several, and optionally a pharmaceutically acceptable carrier.
  • the present invention provides the use of the compound, its prodrug, pharmaceutically acceptable salt, complex or solvate or the pharmaceutical composition in the preparation of antiviral drugs.
  • the virus is at least one selected from DNA viruses and RNA viruses.
  • the DNA virus is selected from hepatitis B virus, human papillomavirus, herpes virus, phage virus;
  • the RNA virus is selected from influenza virus, avian influenza virus, Zika virus, dengue virus, respiratory syndrome Cellular virus, SARS virus, MERS virus, novel coronavirus (SARS-CoV-2), bunya virus, HIV, Ebola virus, hepatitis C virus, Japanese encephalitis virus, rhinovirus, polio Viruses, Coxsackieviruses, Rotaviruses, Tobacco Mosaic Viruses, Phage Viruses, Marburg Viruses, Enteroviruses.
  • SARS-CoV-2 novel coronavirus
  • the RNA virus is at least one of coronavirus, bunya virus, and dengue virus.
  • the coronavirus is SARS-CoV-2.
  • the bunyavirus is Rift Valley fever virus.
  • the virus is dengue virus.
  • the present invention provides the use of the compound, its prodrug, pharmaceutically acceptable salt, complex or solvate or the pharmaceutical composition in the preparation of anti-inflammatory disease medicine.
  • the inflammatory disease is inflammatory skin disease, inflammatory bowel disease, inflammatory joint disease, and other autoimmune diseases.
  • the compound of the invention has the following beneficial effects: novel structure and significant antiviral activity.
  • TLC detects that the aniline reaction is complete before post-processing, adding a small amount of methanol to the reaction solution to quench phosphorus trichloride, then concentrating to remove most of the solvent, then extracting the liquid with ethyl acetate and water, and washing the organic solution with saturated sodium chloride solution. layer, dried over anhydrous sodium sulfate, filtered, mixed, and eluted with petroleum ether and ethyl acetate (50:1) to obtain the corresponding target compound IIIA-1 with a yield of 51.8%.
  • IIIA-3 was prepared according to the same method as in Example 1 except that 2-amino-5-trifluoromethylthiazole was used instead of 2-amino-4-trifluoromethylthiazole, and the yield was 55.5%.
  • IIIA-4 was prepared according to the same method as in Example 1, and the yield was 67.36%.
  • IIIA was prepared in the same manner as in Example 1 except that 2-hydroxybenzoic acid was used instead of 2-hydroxy-5-chloro-benzoic acid and 4-trifluoromethylaniline was used instead of 2-amino-4-trifluoromethylthiazole -5, yield: 7.11%.
  • IIIA-6 was prepared according to the same method as in Example 1, and the yield was: 54.38% .
  • ESI-MS m/z 330.0(MH) - .
  • 2-Amino-5-chlorobenzoic acid (1.368g) was dissolved in acetic acid (15mL), and acetic anhydride (1.34mL) was added, and the temperature was increased to 75°C. After 30 minutes, TLC detected that the reaction was complete.
  • Post-treatment Pour the reaction solution into ice water, stir, filter with suction, wash the filter cake with water, and dry to obtain 2-acetylamino-5-chlorobenzoic acid, which will be used in the next step.
  • Post-processing spin dry the organic solvent, add ethyl acetate and water to the concentrate, adjust the pH of the aqueous phase to be acidic with saturated ammonium chloride, separate the liquid, wash the organic phase with saturated saline, dry, filter, concentrate, and use the concentrate Petroleum ether (1.5 mL) and ethyl acetate (10 drops) were slurried and filtered to obtain 56 mg of compound IIIB-2, and the NMR was correct.
  • IIIB-4 was prepared according to the same method as in Example 35 except that compound IIIA-15 was used instead of IIIA-18, and the yield was 72%.
  • IIIB-5 was prepared according to the same method as in Example 35 except that compound IIIA-12 was used instead of IIIA-18, and the yield was 34%.
  • IIIB-6 was prepared according to the same method as in Example 35, and the yield was 74%.
  • IIIB-7 was prepared according to the same method as in Example 35, except that compound IIIA-15 was used instead of IIIA-18, isobutyric anhydride was used instead of acetic anhydride, and the reaction time was 1 hour. The yield was 76%.
  • IIIB-8 was prepared according to the same method as in Example 36, except that compound IIIA-12 was used instead of IIIA-18, isobutyric anhydride was used instead of acetic anhydride, and the reaction time was 1 hour. The yield was 65%.
  • IIIB-9-1 obtained in the previous step was dissolved in dichloromethane (1.5 mL), cooled on ice, added trifluoroacetic acid (0.3 mL), and stirred for 1 hour.
  • the solvent was spin-dried, extracted with ethyl acetate and water, washed with saturated sodium chloride solution, dried, concentrated, and eluted with petroleum ether and ethyl acetate (2:1) to obtain the free state of IIIB-9.
  • Methanol was added to the free compound, followed by 1.5 N methanolic hydrogen chloride solution, stirred for 15 minutes, concentrated, and then mixed with toluene and water (3 times) to obtain 70 mg of IIIB-9.
  • IIIB-10-1 obtained in the previous step was dissolved in dichloromethane (1.5 mL), cooled on ice, added trifluoroacetic acid (0.3 mL), and stirred for 1 hour.
  • the solvent was spin-dried, extracted with ethyl acetate and water, washed with saturated sodium chloride solution, dried, concentrated, and eluted with petroleum ether and ethyl acetate (2:1) to obtain the free form of IIIB-10.
  • Add methanol to the free compound add 1.5 N methanolic hydrogen chloride solution, stir for 15 minutes, concentrate, and add water with toluene (3 times) to obtain 70 mg of IIIB-10.
  • IIIB-11-1 obtained in the previous step was dissolved in dichloromethane (1.5 mL), cooled on ice, added trifluoroacetic acid (0.3 mL), and stirred for 1 hour.
  • the solvent was spin-dried, extracted with ethyl acetate and water, washed with saturated sodium chloride solution, dried, concentrated, and eluted with petroleum ether and ethyl acetate (2:1) to obtain the free form of IIIB-11.
  • Add methanol to the free compound add 1.5 N methanolic hydrogen chloride solution, stir for 15 minutes, concentrate, then add water with toluene (3 times) to obtain 70 mg of IIIB-11.
  • IIIB-12-1 obtained in the previous step was dissolved in dichloromethane (1.5 mL), cooled on ice, added trifluoroacetic acid (0.3 mL), and stirred for 1 hour.
  • the solvent was spin-dried, extracted with ethyl acetate and water, washed with saturated sodium chloride solution, dried, concentrated, and eluted with petroleum ether and ethyl acetate (2:1) to obtain the free form of IIIB-12.
  • Add methanol to the free compound add 1.5 N methanolic hydrogen chloride solution, stir for 15 minutes, concentrate, and add water with toluene (3 times) to obtain 30 mg of IIIB-12.
  • IIIB-13-1 obtained in the previous step was dissolved in dichloromethane (1.5 mL), cooled on ice, added trifluoroacetic acid (0.3 mL), and stirred for 1 hour.
  • the solvent was spin-dried, extracted with ethyl acetate and water, washed with saturated sodium chloride solution, dried, concentrated, and eluted with petroleum ether and ethyl acetate (2:1) to obtain the free state of IIIB-13.
  • Methanol was added to the free compound, followed by 1.5 N methanolic hydrogen chloride solution, stirred for 15 minutes, concentrated, and then mixed with toluene and water (3 times) to obtain 45 mg of IIIB-13.
  • Example 50 3-(((((4-Chloro-5-fluoro-2-(4-(trifluoromethoxy)phenylcarbamoyl)phenoxy)methoxy)carbonyloxy)-N -methylpropane-1-ammonium chloride)
  • Acetone (3mL), 3-(N-methyl-N-tert-butoxycarbonyl) propyl chloromethyl carbonate (422mg, 1.5mmol), sodium iodide (300mg, 2mmol), 60 °C and stirred for 3 hours. Filter and wash the filter cake with a small amount of acetone.
  • the anti-SRAS-CoV-2 activity of the compound is expressed by the inhibition rate (%) of the compound on the RNA copy number of the virus supernatant, see Table 1 and Table 2.
  • N/A No suppression; *: 1-25; **: 26-50; ***: 51-75; ****: 76-100
  • RVFV Anti-Rift Valley fever virus
  • SFTSV febrile thrombocytopenia syndrome virus
  • the cell nuclei were stained with DAPI dye (1:2000, at room temperature in the dark for 10 min), and the Operetta high-content drug screening system was used for detection.
  • DAPI dye 1:2000, at room temperature in the dark for 10 min
  • the Operetta high-content drug screening system was used for detection.
  • SFTSV infection group was fixed, incubate specific NP antibody (1:2000, 1h at room temperature or overnight at 4°C) and fluorescent secondary antibody (1:1000, 1h at room temperature in the dark) before using DAPI dye (1:2000, 10min at room temperature in the dark) ) to stain the nuclei, and finally, use the Operetta high-content drug screening system for detection.
  • the nuclei were detected by channel 405.
  • the less number of nuclei stained by DAPI indicated that the compound was cytotoxic at this concentration.
  • the virus signal was detected by channel 488.
  • the less number of detected cells indicated that the compound had an antiviral effect at this concentration.
  • the antiviral activity of the compound is represented by the inhibition rate (%) of the compound on virus replication, see Table 3 and Table 4.
  • N/A No suppression; *: 1-25; **: 26-50; ***: 51-75; ****: 76-100
  • N/A No suppression; *: 1-25; **: 26-50; ***: 51-75; ****: 76-100
  • the Vero cells were seeded into 6-well cell culture plates at a density of 600,000 cells per well, and cultured overnight in a 5% CO 2 , 37° C. incubator. Compounds (1-5 concentration points, single point) and virus (40-50 PFU/well) were added the next day.
  • the cells were cultured in an incubator at 5% CO2 and 37° C. for 2 hours, then the supernatant was aspirated, and the low-melting point agarose culture solution containing the corresponding concentration of the compound was added.
  • the cells were cultured in an incubator at 5% CO2 at 33°C or 37°C for 6-7 days until obvious virus plaques could be observed in the virus-infected control wells without compounds under the microscope. Cells were fixed with 4% paraformaldehyde and stained with crystal violet (see Table 5). Count the number of plaques in each well.
  • Cytotoxicity experiments were performed in parallel with antiviral experiments.
  • the Vero cells were seeded into 96-well cell culture plates at a density of 20,000 cells per well, and cultured overnight in a 5% CO 2 , 37° C. incubator. Compounds were added the next day (1-5 concentration points, single point). The cells were cultured in an incubator for 6-7 days under the conditions of 5% CO2, 33°C or 37°C. Then CCK-8 was used to detect cell viability in each well.
  • the antiviral activity and cytotoxicity of the compound are expressed by the compound's inhibition rate (%) and cell viability (%) on viral plaques respectively, and the inhibition rate is shown in Table 6. Calculated as follows:
  • Inhibition rate (%) 100-the number of plaques in test wells/the number of plaques in virus control wells ⁇ 100
  • EC 50 and CC 50 values were calculated by Prism software (version 5), and the inhibition curve fitting method was "log(inhibitor) vs. response--Variable slope”.
  • test compound 1 ⁇ M inhibition rate (%) Niclosamide *** IIIA ⁇ 4 **** IIIA ⁇ 6 **** IIIA-10 **** IIIA ⁇ 21 N/A
  • N/A No suppression; *: 1-25; **: 26-50; ***: 51-75; ****: 76-100
  • the cells were seeded into 48-well cell culture plates at a density of 50,000 cells per well, and cultured overnight in a 5% CO 2 , 37° C. incubator. The next day, first add the compound (1 concentration point, double wells), then add the cytokine interleukin-6 20 minutes later, keep it in a 5% CO 2 , 37°C incubator for 8 hours, collect the cells and measure the report after 8 hours Gene. See Table 7 for the inhibition rate results.
  • test compound 1 ⁇ M inhibition rate (%) Niclosamide *** IIIA ⁇ 4 ** IIIA ⁇ 3 ** IIIA ⁇ 2 * IIIA ⁇ 9 *** IIIA ⁇ 24 * IIIA-15 * IIIA ⁇ 26 * IIIA ⁇ 18 ***
  • N/A No suppression; *: 1-25; **: 26-50; ***: 51-75; ****: 76-100
  • test method is the same as the test for inhibiting interleukin-6 activity except that the cytokine interleukin-6 is changed to the cytokine interleukin-33. See Table 8 for the inhibition rate results.
  • N/A No suppression; *: 1-25; **: 26-50; ***: 51-75; ****: 76-100
  • test method is the same as the test for inhibiting interleukin 6 activity except that the cytokine interleukin 6 is changed to cytokine interleukin 1b. See Table 9 for the inhibition rate results.
  • Table 9 inhibits interleukin 1b secretion activity test result
  • IIIA ⁇ 18 *** **** IIIA-14 ** *** IIIA ⁇ 12 *** **** IIIA ⁇ 30 ** **** IIIA ⁇ 31 N/A N/A IIIA ⁇ 32 *** ****
  • N/A No suppression; *: 1-25; **: 26-50; ***: 51-75; ****: 76-100
  • test method is the same as the test for inhibiting interleukin 6 activity except that the cytokine interleukin 6 is changed to the cytokine interleukin TNF- ⁇ . See Table 10 for the inhibition rate results.
  • N/A No suppression; *: 1-25; **: 26-50; ***: 51-75; ****: 76-100
  • the compounds of the embodiments of the present application are superior to niclosamide in terms of anti-new coronavirus, Rift Valley fever virus and fever with thrombocytopenia syndrome virus activity, and can inhibit LPS
  • the induced secretion of interleukin-6 shows that some of the compounds in the examples of this application have broad-spectrum antiviral and anti-inflammatory activities, and can be developed into antiviral drugs or anti-inflammatory disease drugs.

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Abstract

本公开涉及一种通式I所表示的酰胺类化合物、其前药、药学上可接受的盐、络合物或溶剂合物。本公开的化合物结构新颖，具有显著的抗病毒活性和抗炎症性活性。

Description

一种酰胺类化合物、其制备方法和制药用途 技术领域
本发明属于药物化学领域，具体涉及一种酰胺类化合物、其制备方法和制药用途。
背景技术
氯硝柳胺于1960年被美国食品和药物管理局批准用于肠道绦虫感染的治疗，其作用机制是通过抑制虫体细胞内线粒体的氧化磷酸化过程，阻碍葡萄糖的吸收和摄取，进而杀死寄生虫。截止目前，氯硝柳胺已安全使用五十余年，并被列入世界卫生组织的基本药物清单。另外，氯硝柳胺也可以用于动物绦虫感染的治疗，也可用于杀灭钉螺，预防血吸虫病。
近年来的研究表明，氯硝柳胺具有广泛的生物活性，可以调节多种信号通路和生物过程，如Wnt/β-catenin、mTORC1、STAT3、NF-κB、Notch、NS2B-NS蛋白相互作用等(Cancer Lett,2014,349,8-14；Cell Res,27,1046-1064)。并且，氯硝柳胺表现出了抗病毒的药理作用(Tuberculosis,2019,116,S28-S33；Nat.Med,2016,22,1101-1107.)
冠状病毒是一类分布广泛的单股正链RNA病毒，能侵染多种高等动物，也是常见的人类病原体。如HCoV-229E，HCoV-OC43，HCoV-NL63，HCoV-HKU1通常会引起人的轻微感冒症状(Academic Press,2018,100,163-188)。但SARS-CoV，MERS-CoV，SARS-CoV-2等冠状病毒则会引起人体严重的呼吸疾病甚至死亡。目前针对冠状病毒感染者的有效治疗方法还有待进一步的开发。吴等通过对上市药物的老药新用筛选中发现，氯硝柳胺能抑制SARS-CoV的复制，在1.5μM时可以完全抑制病毒抗原的合成(Antimicrob.Agents Chemother,2004,48,2693-2696.)。杨等发现氯硝柳胺在1μM时可以抑制SARS-CoV的细胞病变效应(CPE)，并在Vero E6细胞中抑制SARS-CoV复制，其EC50值小于0.1μM(J.Med.Chem,2007,50,4087-4095)。
黄病毒也是一种单股正链RNA病毒，主要包括寨卡病毒(Zika virus)、登革热病毒(dengue virus)、日本乙型脑炎病毒(Japanese encephalitis virus)、西尼罗河病毒(West Nile virus)、黄热病病毒(yellow fever virus)，这些病毒很多都是人类病原体。通过酶筛选方法知道氯硝柳胺是一种潜在的寨卡病毒感染抑制剂，细胞内水平的IC50为0.37μM，并且氯硝柳胺直接抑制黄病毒NS2B-NS3相互作用，同时也发现氯硝柳胺是一种黄病毒广谱抑制剂(Cell Res,2017,27,1046-1064；Nat.Med,2016,22,1101-1107)。
丙型肝炎病毒(HCV)也是黄病毒科的一种包膜阳性单链RNA病毒。全世界约有7100万人患有慢性HCV感染，氯硝柳胺抑制HCV病毒复制的EC50为0.16μM，这种抑制病毒复制的作用机制跟硝唑尼特和替唑尼特调节宿主细胞进程相似(Antimicrob.Agents Chemother,2008,52,4069-4071；Antiviral Res,2011,91,233-240；ACS Med.Chem.Lett,2011,2,849-854)。
埃博拉病毒是一种能引起人类和灵长类动物产生埃博拉出血热的烈性传染病病毒。氯硝柳胺具有较强的埃博拉病毒抑制活性，EC50为1.5μM(ACS Infect.Dis,2015,1,317-326)。
人鼻病毒是小RNA病毒科，鼻病毒属的一种，是普通感冒的主要原因，对哮喘、慢性肺部疾病和婴幼儿重症细支气管炎患者有严重的健康风险。氯硝柳胺是一种pH依赖性HRV感染抑制剂，IC50达到微摩尔级别；其作为质子载体，通过阻断内溶酶体腔室的酸化来抑制HRV病毒的进入(Clin.Microbiol.Rev,2013,26,135-162；PLoS Pathog, 2012 8,e1002976)。
人腺病毒(Human adenoviruses)是一种无包膜，双链的DNA病毒，共有七个亚种。腺病毒在人群中流行，特别是婴幼儿和青少年，主要与呼吸道、眼部-和胃肠道感染相关。现目前，还未有真正可行的药物用于治疗此类病毒感染(FEMS Microbiol.Rev.2019,43,380-388；Antimicrob.Agents Chemother.2010,54,3871-3877；J.Med.Chem.2012,55,3170-3181)。研究发现，氯硝柳胺能够显著性的抑制人腺病毒的感染，IC50为0.6μM。
但是，氯硝柳胺具有一些明显的缺点，比如口服生物利用度低，抗病毒活性不够强等，这些因素限制了氯硝柳胺作为抗病毒活性化合物的进一步开发与应用。在氯硝柳胺的结构基础上，进行结构优化，发现具有更强抗病毒活性、口服生物利用度更高的化合物，同时具有抗炎作用的广谱抗病毒活性化合物具有非常重要的意义。
发明内容
发明目的
为了解决现有技术中的不足，本发明的一个目的是提供一类酰胺类化合物，其具有抗病毒活性，特别是抗冠状病毒、布尼亚病毒和登革热病毒活性。
本发明的一个目的是提供上述化合物的制备方法。
本发明的再一目的是提供上述化合物在制备用于治疗或预防病毒感染的药物中的用途。
技术方案
根据本发明的一个方面，其提供了一种下述通式I所表示的酰胺类化合物、其前药、药学上可接受的盐、络合物或溶剂合物：
Figure PCTCN2022100609-appb-000001
其中，
Y为苯环、5-6元杂芳环、苯环并5-6元杂芳环或5-6元杂芳环并5-6元杂芳环；优选为苯环、吡啶环或噻唑环；
Z为O或S；
A 1为C-OR 11、C-SR 11、C-NHR 11、N或CR 12；
R 11为氢原子、C1～C20烷基、C1～C20烷基羰基、C1～C20烷基氨基羰基、C1～C20烷基羰基氧基C1～C20烷基、
Figure PCTCN2022100609-appb-000002
C1～C20烷基磷酰基、C1～C20烷基磺酰基、C1～C20烷基取代的6-20元含有1-3个选自O、N或S的杂原子的杂环基羰基或
Figure PCTCN2022100609-appb-000003
上述C1～C20烷基任选地被选自羟基、氨基(-NH 2)、C1～C20烷基氨基、氰基、羧基、卤素、
Figure PCTCN2022100609-appb-000004
C1-C10烷基磺酰基、C1-C10烷基磷酰基、C1-C10酰基中的一种或多种取代；
优选地，R 11为氢原子、C1～C10烷基、C1～C10烷基羰基、C1～C10烷基氨基羰基、C1～C10烷基羰基氧基C1～C10烷基、C1～C10烷基取代的6-10元含有1-3个选自O、N或S的杂原子的杂环基羰基或
Figure PCTCN2022100609-appb-000005
上述C1～C10烷基任选地被选自羟基、氨基、氰基、羧基、卤素、
Figure PCTCN2022100609-appb-000006
C1-C10烷基磺酰基、C1-C10烷基磷酰基、C1-C10烷基羰基中的一种或多种取代；
更优选地，R 11为氢原子、C1～C6烷基、卤代C1～C6烷基、氨基C1～C6烷基、羟基、C1～C6烷基、C1～C6烷基羰基、C1～C6烷基氨基羰基、C1～C6烷基羰基氧基C1～C6烷基、C1～C6烷基氨基C1～C6烷基羰基、氨基C1～C6烷基羰基、
Figure PCTCN2022100609-appb-000007
取代的C1～C6烷基羰基、C1～C6烷基取代的6-8元含有1-3个选自O、N或S的杂原子的杂环基羰基或
Figure PCTCN2022100609-appb-000008
最优选地，R 11为氢原子、C1～C4烷基、C1～C6烷基羰基、C1～C5烷基氨基羰基、C1～C5烷基羰基氧基C1～C5烷基、
Figure PCTCN2022100609-appb-000009
取代的C1～C4烷基、取代的C1～C4烷基羰 基、
Figure PCTCN2022100609-appb-000010
或者
Figure PCTCN2022100609-appb-000011
R 7为C1～C10烷基、C1～C10烷基氨基C1～C10烷基或C3～C10环烷基，优选为C1～C6烷基、C1～C6烷基氨基C1～C6烷基或C3～C7环烷基，更优选为C1～C4烷基、C1～C3烷基氨基C1～C4烷基或C3～C6环烷基；
R 8为氢原子、卤素或C1～C10烷基；优选为氢原子、卤素或C1～C2烷基，更优选为氢原子或甲基；
R 12为氢原子、卤素、氰基、硝基或C1～C20烷基，优选为氢原子、卤素、氰基、硝基或C1～C6烷基；更优选为氢原子、卤素、氰基或C1～C4烷基；
A 2、A 3、A 4、A 5各自独立地为N或CR 2；优选地，A 2、A 3、A 4、A 5中至多两个为N；
R 2彼此相同或不同，且各自独立地选自氢、羟基、卤素、C1～C6烷基氧基、C1～C6烷基、氨基(-NH 2)、硝基、氰基、羧基、醛基、C1～C6烷基羰基、C1～C6烷基磺酰基、C1～C6烷基磺酰氨基和C1～C6烷基氧基羰基，上述羟基、氨基、羧基、C1～C6烷基任选地被羟基、氨基、氰基、羧基、卤素、C1-C10烷基磺酰基、C1-C10烷基磷酰基、C1-C10烷基羰基中的一种或多种取代；
优选地，R 2彼此相同或不同，且各自独立地选自氢、羟基、卤素、C1～C4烷基氧基、C1～C4烷基、氨基、硝基、氰基和C1～C4烷基羰基，上述C1～C4烷基任选地被羟基、氨基、氰基、羧基、卤素、C1-C4烷基磺酰基、C1-C4烷基磷酰基、C1-C4烷基羰基中的一种或多种取代；
更优选地，R 2彼此相同或不同，且各自独立地选自氢、羟基、卤素、C1～C2烷氧基、C1～C2烷基、C1-C2烷基羰基、卤代C1～C2烷氧基、卤代C1～C2烷基、卤代C1-C2烷基羰基、氨基和硝基；
R 3为氢原子或C1～C6烷基，优选地，R 3为氢原子或C1～C4烷基，更优选地，R 3为氢原子；
R 4至R 6各自独立地选自氢原子、羟基、氨基、卤素、硝基、氰基、C1～C6烷基、C1～C6烷基氧基和C1～C6烷基硫基，上述C1～C6烷基任选地被羟基、氨基、氰基、羧基、卤素、C1-C6烷基磺酰基、C1-C6烷基磷酰基、C1-C6烷基酰基中的一种或多种取代；
优选地，R 4至R 6各自独立地选自氢原子、羟基、氨基、卤素、硝基、氰基、C1～C4烷基和C1～C4烷基氧基，上述C1～C4烷基任选地被羟基、氨基、氰基、羧基、卤素中的一种或多种取代；
更优选地，R 4至R 6各自独立地选自氢原子、卤素、C1～C4烷基、卤代C1～C4烷基、C1～C4烷氧基、卤代C1～C4烷氧基。
在本发明中，卤素指的是氟、氯、溴、碘；卤代C1～C4烷基指的是用一个或多个卤素原子取代的C1～C4烷基，优选为三氟甲基；卤代C1～C4烷氧基指的是用一个或多个卤素原子取代的C1～C4烷基氧基，优选为三氟甲氧基。
在一些实施方式中，所述通式I所表示的酰胺类化合物为下面通式II、IIIA或IIIB所示的化合物：
Figure PCTCN2022100609-appb-000012
其中，
A 1为C-OR 11、C-SR 11、C-NHR 11或CR 12；
R 11、R 12、R 2、R 4至R 6和Y的定义与通式I中相同。
在一些实施方式中，所述通式I所表示的酰胺类化合物为下面通式IV所示的化合物：
Figure PCTCN2022100609-appb-000013
其中，
R 11、R 2、R 4和R 5的定义与通式I中相同。
在一些实施方式中，上述R 2各自独立地选自氢原子、卤素(特别是氟和氯)、羟基、甲酰基、乙酰基、硝基。
在一些实施方式中，上述R 4和R 5各自独立地选自氢原子、卤素、氰基、甲基、三氟甲基、甲氧基、三氟甲氧基、甲硫基、三氟甲硫基。
在一些实施方式中，上述R 11为氢。
在一些实施方式中，所述化合物或盐选自以下结构：
Figure PCTCN2022100609-appb-000014
Figure PCTCN2022100609-appb-000015
本发明还提供了通式化合物的制备方法。
其中，通式II、IIIA或IIIB可以通过如下方法一或方法二制备得到：
方法一：
Figure PCTCN2022100609-appb-000016
通过缩合反应制备通式化合物II及IIIA，以缩合剂或三氯化磷存在的条件下得到缩 合产物II及IIIA；
方法二：
Figure PCTCN2022100609-appb-000017
以缩合产物为原料，化合物I及或IIIA在通过烃基化、酰化、磷酰化或磺酰化反应得到化合物IIIB。
其中，各基团定义与前述定义相同。
另一方面，本发明还提供一种药物组合物，其包含治疗有效量的选自上述本发明的化合物、其前药、药学上可接受的盐、络合物和溶剂合物中的一种或几种，和任选的可药用载体。
另一方面，本发明提供所述化合物、其前药、药学上可接受的盐、络合物或溶剂合物或所述药物组合物在制备抗病毒药物中的用途。
在一些实施方式中，所述病毒为选自DNA病毒、RNA病毒中的至少一种。
在一些实施方式中，所述DNA病毒选自乙型肝炎病毒、人乳头瘤病毒、疱疹病毒、噬菌体病毒；所述RNA病毒选自流感病毒、禽流感病毒、寨卡病毒、登革热病毒、呼吸道合胞病毒、SARS病毒、MERS病毒、新型冠状病毒(SARS-CoV-2)、布尼亚病毒、艾滋病病毒、埃博拉病毒、丙型肝炎病毒、乙型脑炎病毒、鼻病毒、脊髓灰质炎病毒、柯萨奇病毒、轮状病毒、烟草花叶病毒、噬菌体病毒、马尔堡病毒、肠道病毒。
在一些实施方式中，所述RNA病毒为冠状病毒、布尼亚病毒、登革热病毒中的至少一种。
在一些实施方式中，所述冠状病毒为SARS-CoV-2。
在一些实施方式中，所述布尼亚病毒为裂谷热病毒。
在一些实施方式中，所述病毒为登革热病毒。
另一方面，本发明提供所述化合物、其前药、药学上可接受的盐、络合物或溶剂合物或所述药物组合物在制备抗炎症性疾病药物中的用途。
在一些实施方式中，所述炎症性疾病为炎症性皮肤病、炎症性肠病、炎症性关节病及其他自身免疫性疾病。
有益效果
本发明化合物具有以下有益效果：结构新颖、具有显著抗病毒活性。
具体实施方式
为了进一步理解本发明，下面结合实施例对本发明作进一步的说明，这些实施例描述只是为进一步详细说明本发明的特征，而不是对本发明范围或本发明权利要求范围的限制。在本领域内技术人员对发明所做的简单替换或改进等均应包含在本发明所保护的 技术方案之内。
其中通式化合物可以通过以下可以通过本领域技术人员所熟知的多种合成方法，一系列的合成步骤来制备。
实施例1：N-(4-三氟甲基噻唑)-5-氯水杨酰胺(IIIA-1)的合成
Figure PCTCN2022100609-appb-000018
依次向茄形瓶中加入称量好的2-羟基-5-氯-苯甲酸，加入分子筛干燥后的甲苯(10倍体积)，加入等当量的2-氨基-4-三氟甲基噻唑，然后加入三氯化磷(约1.1当量)，立即氮气置换，由室温升温至115℃，在此温度下搅拌8个小时，反应液逐渐澄清。TLC检测苯胺反应完全后再进行后处理，向反应液中加入少量甲醇淬灭三氯化磷，然后浓缩除去大部分溶剂，再以乙酸乙酯、水萃取分液，饱和氯化钠溶液洗涤有机层，无水硫酸钠干燥，过滤，拌样，以石油醚和乙酸乙酯(50:1)洗脱，获得相应的目标化合物IIIA-1，收率为：51.8％。 1H NMR(500MHz,DMSO-d 6)δ12.34(s,1H),11.73(s,1H),8.05(d,J＝1.1Hz,1H),7.90(d,J＝2.7Hz,1H),7.52(dd,J＝8.8,2.8Hz,1H),7.08(d,J＝8.8Hz,1H).ESI-MS m/z 307.9(M-H) -.
实施例2：N-(2-氯-4-三氟甲氧基苯基)-5-氯水杨酰胺(IIIA-2)的合成
Figure PCTCN2022100609-appb-000019
除了以2-氯-4-三氟甲氧基苯胺代替2-氨基-4-三氟甲基噻唑，以及反应时间为5小时以外，按照与实施例1相同的方法制备IIIA-2，收率为：65.9％。 1H NMR(600MHz,DMSO-d6)δ12.31(s,1H),10.96(s,1H),8.51(d,J＝9.1Hz,1H),7.98(d,J＝2.8Hz,1H),7.73(d,J＝2.8Hz,1H),7.52(dd,J＝8.7,2.8Hz,1H),7.47(dt,J＝9.1,1.8Hz,1H),7.08(d,J＝8.8Hz,1H).ESI-MS m/z 363.9(M-H) -.
实施例3：N-(4-三氟甲基噻唑)-5-氯水杨酰胺(IIIA-3)的合成
Figure PCTCN2022100609-appb-000020
除了以2-氨基-5-三氟甲基噻唑代替2-氨基-4-三氟甲基噻唑以外，按照与实施例1相同的方法制备IIIA-3，收率为：55.5％。 1H NMR(500MHz,DMSO-d 6)δ12.33(s,2H),8.22(s,1H),7.87(d,J＝2.7Hz,1H),7.52(dd,J＝8.8,2.8Hz,1H),7.06(d,J＝8.8Hz,1H).ESI-MS m/z 320.9(M-H) -.
实施例4：N-(4-三氟甲基苯基)-5-氯水杨酰胺(IIIA-4)的合成
Figure PCTCN2022100609-appb-000021
除了以4-三氟甲基苯胺代替2-氨基-4-三氟甲基噻唑，以及反应时间为7小时以外，按照与实施例1相同的方法制备IIIA-4，收率为：67.36％。 1H NMR(500MHz,DMSO-d 6)δ11.57(s,1H),10.64(s,1H),7.94(d,J＝8.5Hz,2H),7.88(d,J＝2.7Hz,1H),7.77–7.71(m,2H),7.48(dd,J＝8.8,2.7Hz,1H),7.03(d,J＝8.8Hz,1H).ESI-MS m/z 314.0(M-H) -.
实施例5：N-(4-三氟甲基苯基)水杨酰(IIIA-5)的合成
Figure PCTCN2022100609-appb-000022
除了以2-羟基苯甲酸代替2-羟基-5-氯-苯甲酸，以4-三氟甲基苯胺代替2-氨基-4-三氟甲基噻唑，按照与实施例1相同的方法制备IIIA-5，收率为：7.11％。 1H NMR(500MHz,DMSO-d 6)δ10.41(s,1H),9.48(s,1H),7.82(d,J＝8.4Hz,2H),7.66(d,J＝8.5Hz,2H),7.14(dd,J＝7.5,1.7Hz,1H),7.07(td,J＝7.7,1.8Hz,1H),6.80(dd,J＝8.1,1.2Hz,1H),6.75(td,J＝7.4,1.2Hz,1H),3.63(s,2H).ESI-MS m/z 280.0(M-H) -.
实施例6：N-(4-三氟甲氧基苯基)-5-氯水杨酰胺(IIIA-6)的合成
Figure PCTCN2022100609-appb-000023
除了以4-三氟甲氧基苯胺代替2-氨基-4-三氟甲基噻唑，以及反应时间为5小时以外，按照与实施例1相同的方法制备IIIA-6，收率为：54.38％。 1H NMR(500MHz,DMSO-d 6)δ11.69(s,1H),10.53(s,1H),7.91(d,J＝2.7Hz,1H),7.85–7.77(m,2H),7.47(dd,J＝8.8,2.7Hz,1H),7.41–7.36(m,2H),7.02(d,J＝8.8Hz,1H).ESI-MS m/z 330.0(M-H) -.
实施例7：N-(4-三氟甲氧基苯基)吡嗪酰胺(IIIA-7)的合成
Figure PCTCN2022100609-appb-000024
除了以吡嗪-2-羧酸代替2-羟基-5-氯-苯甲酸，以4-三氟甲氧基苯胺代替2-氨基-4-三氟甲基噻唑，以及反应时间为6小时以外，按照与实施例1相同的方法制备化合物IIIA-7，收率为：58.30％。 1H NMR(500MHz,DMSO-d 6)δ10.97(s,1H),9.31(d,J＝1.5Hz,1H),8.95(d,J＝2.5Hz,1H),8.83(dd,J＝2.5,1.5Hz,1H),8.06–7.99(m,2H),7.42–7.37(m, 2H).ESI-MS m/z 284.0(M+H) +.
实施例8：N-(4-三氟甲基苯基)吡嗪酰胺(IIIA-8)的合成
Figure PCTCN2022100609-appb-000025
除了以吡嗪-2-羧酸代替2-羟基-5-氯-苯甲酸，以4-三氟甲基苯胺代替2-氨基-4-三氟甲基噻唑，以及反应时间为6小时以外，按照与实施例1相同的方法制备化合物IIIA-8，收率为：56.17％。 1H NMR(500MHz,DMSO-d 6)δ11.10(s,1H),9.32(d,J＝1.5Hz,1H),8.96(d,J＝2.5Hz,1H),8.84(dd,J＝2.5,1.5Hz,1H),8.15(d,J＝8.5Hz,2H),7.75(d,J＝8.6Hz,2H).ESI-MS m/z 269.0(M+H) +.
实施例9：N-(3,5-双(三氟甲基)苯基)-5-氯水杨酰胺(IIIA-9)的合成
Figure PCTCN2022100609-appb-000026
除了以3,5-双(三氟甲基)苯胺代替2-氨基-4-三氟甲基噻唑，以及反应时间为7小时以外，按照与实施例1相同的方法制备化合物IIIA-9，收率为：44.38％。 1H NMR(500MHz,DMSO-d 6)δ11.38(s,1H),10.84(s,1H),8.84(m,2H),7.83-7.86(m,2H),7.47-7.51(m,1H),7.03-7.05(m,1H).ESI-MS m/z 382.0(M-H) -.
实施例10：N-(4-三氟甲基苯基)-3,5-二氯水杨酰胺(IIIA-10)的合成
Figure PCTCN2022100609-appb-000027
除了以2-羟基-3,5-二氯苯甲酸代替2-羟基-5-氯-苯甲酸，以4-三氟甲基苯胺代替2-氨基-4-三氟甲基噻唑，以及反应时间为6小时以外按照与实施例1相同的方法制备化合物IIIA-10，收率为：67.33％。 1H NMR(500MHz,DMSO-d 6)δ12.22(s,1H),10.88(d,J＝4.2Hz,1H),8.05(d,J＝2.5Hz,1H),7.93(d,J＝8.4Hz,2H),7.83(d,J＝2.5Hz,1H),7.77(d,J＝8.5Hz,2H).ESI-MS m/z 348.2.
实施例11：N-(4-三氟甲基苯基)-2-氰基-5-氯苯甲酰胺(IIIA-11)的合成
Figure PCTCN2022100609-appb-000028
除了以2-氰基-5-氯苯甲酸代替2-羟基-5-氯-苯甲酸，以4-三氟甲基苯胺代替2-氨基 -4-三氟甲基噻唑，以及反应时间为6小时以外，按照与实施例1相同的方法制备化合物IIIA-11，收率为：37.57％。 1H NMR(500MHz,DMSO-d 6)δ10.53(s,1H),8.34–8.28(m,1H),8.00–7.96(m,2H),7.90(d,J＝8.4Hz,2H),7.74(d,J＝8.2Hz,2H).ESI-MS m/z 323.1(M-H) -.
实施例12：N-(4-三氟甲氧基苯基)-4-氟-5-氯水杨酰胺(IIIA-12)的合成
Figure PCTCN2022100609-appb-000029
除了以2-羟基-4-氟-5-氯苯甲酸代替2-羟基-5-氯-苯甲酸，以4-三氟甲氧基苯胺代替2-氨基-4-三氟甲基噻唑，以及反应时间为10小时以外，按照与实施例1相同的方法制备化合物IIIA-12，收率为：51.72％. 1H NMR(500MHz,DMSO-d 6)δ12.20(s,1H),10.51(s,1H),8.12(d,J＝8.5Hz,1H),7.86–7.79(m,2H),7.43–7.38(m,2H),7.04(d,J＝10.8Hz,1H).ESI-MS m/z 348.2(M-H) -.
实施例13：N-(5-三氟甲基噻唑)-4-氟-5-氯水杨酰胺(IIIA-13)的合成
Figure PCTCN2022100609-appb-000030
除了以2-羟基-4-氟-5-氯苯甲酸代替2-羟基-5-氯-苯甲酸，以2-氨基-5-三氟甲基噻唑代替2-氨基-4-三氟甲基噻唑，以及反应时间为3小时以外，按照与实施例1相同的方法制备化合物IIIA-13，收率为：51.47％。 1H NMR(500MHz,DMSO-d 6)δ12.65(s,2H),8.25(s,1H),8.05(d,J＝8.7Hz,1H),7.03(d,J＝8.7Hz,1H).ESI-MS m/z 339.1(M-H) -.
实施例14：N-(4-三氟甲基苯基)-5-氟水杨酰胺(IIIA-14)的合成
Figure PCTCN2022100609-appb-000031
除了以2-羟基-5-氟苯甲酸代替2-羟基-5-氯-苯甲酸，以4-三氟甲基苯胺代替2-氨基-4-三氟甲基噻唑，以及反应时间为9小时以外，按照与实施例1相同的方法制备化合物IIIA-14，收率为：53.29％。 1H NMR(500MHz,DMSO-d 6)δ11.55(s,1H),10.56(s,1H),7.86(d,J＝8.3Hz,2H),7.80(d,J＝2.7Hz,1H),7.77–7.73(m,2H),7.48(dd,J＝8.3,2.7Hz,1H),7.03(d,J＝8.8Hz,1H).ESI-MS m/z 298.0(M-H) -.
实施例15：N-(4-三氟甲基苯基)-3,5-二氟水杨酰胺(IIIA-15)的合成
Figure PCTCN2022100609-appb-000032
除了以2-羟基-3,5-二氟苯甲酸代替2-羟基-5-氯-苯甲酸，以4-三氟甲基苯胺代替2-氨基-4-三氟甲基噻唑，以及反应时间为6小时以外，按照与实施例1相同的方法制备化合物IIIA-15，收率为：75.23％。 1H NMR(500MHz,DMSO-d 6)δ11.32(s,1H),10.72(s,1H),7.93(d,J＝8.5Hz,2H),7.76(d,J＝8.5Hz,2H),7.55(s,1H),7.53(d,J＝3.5Hz,1H).ESI-MS m/z 316.2(M-H) -.
实施例16：N-(4-三氟甲氧基苯基)-3,5-二氟水杨酰胺(IIIA-16)的合成
Figure PCTCN2022100609-appb-000033
除了以2-羟基-3,5-二氟苯甲酸代替2-羟基-5-氯-苯甲酸，以4-三氟甲氧基苯胺代替2-氨基-4-三氟甲基噻唑，以及反应时间为11小时以外(是否还有其他不同的反应条件)，按照与实施例1相同的方法制备化合物IIIA-16，收率为：50.05％。 1H NMR(500MHz,DMSO-d 6)δ11.48(s,1H),10.60(s,1H),7.84–7.79(m,2H),7.60–7.52(m,2H),7.40(m,2H).ESI-MS m/z 332.2(M-H) -.
实施例17：N-(3,5-二(三氟甲基)苯基)-4-氟-5-氯水杨酰胺(IIIA-17)的合成
Figure PCTCN2022100609-appb-000034
除了以2-羟基-4-氟-5-氯苯甲酸代替2-羟基-5-氯-苯甲酸，以3,5-双(三氟甲基)苯胺代替2-氨基-4-三氟甲基噻唑，以及反应时间为9小时以外，按照与实施例1相同的方法制备化合物IIIA-17，收率为：65％。 1H NMR(500MHz,DMSO-d6)δ11.90(s,1H),10.85(s,1H),8.44(d,J＝1.6Hz,2H),8.07(d,J＝8.6Hz,1H),7.87(s,1H),7.05(d,J＝10.8Hz,1H).ESI-MS m/z 400.2(M-H) -.
实施例18：N-(4-三氟甲基苯基)-4-氟-5-氯水杨酰胺(IIIA-18)的合成
Figure PCTCN2022100609-appb-000035
除了以2-羟基-4-氟-5-氯苯甲酸代替2-羟基-5-氯-苯甲酸，以4-三氟甲基苯胺代替2-氨基-4-三氟甲基噻唑，以及反应时间为7小时以外，按照与实施例1相同的方法制备化 合物IIIA-18，收率为：45.04％。 1H NMR(500MHz,DMSO-d 6)δ12.07(s,1H),10.63(s,1H),8.07(d,J＝8.6Hz,1H),7.93(d,J＝8.5Hz,2H),7.74(d,J＝8.5Hz,2H),7.02(d,J＝10.8Hz,1H).ESI-MS m/z 332.1(M-H) -.
实施例19：N-(4-三氟甲基苯基)-2-羟基-5-氯烟酰胺(IIIA-19)的合成
Figure PCTCN2022100609-appb-000036
除了以2-羟基-5-氯烟酸代替2-羟基-5-氯-苯甲酸，以4-三氟甲基苯胺代替2-氨基-4-三氟甲基噻唑，以及反应时间为12小时以外，按照与实施例1相同的方法制备化合物IIIA-19，收率为：69.72％。 1H NMR(500MHz,DMSO-d 6)δ13.25(s,1H),12.32(s,1H),8.36(d,J＝3.0Hz,1H),8.13(d,J＝3.1Hz,1H),7.90(d,J＝8.4Hz,2H),7.73(d,J＝8.5Hz,2H).ESI-MS m/z 315.0(M-H) -.
实施例20：N-(2-氯-4-三氟甲基苯基)-3,4,5-三羟基苯甲酰胺(IIIA-20)的合成
Figure PCTCN2022100609-appb-000037
向茄形瓶中加入3,4,5-三羟基苯甲酸(500mg)，甲醇(10mL)、硫酸(100uL)，搅拌回流12小时后，原料基本反应完全。旋干反应液，萃取，干燥后得到3,4,5-三羟基苯甲酸甲酯(510mg)，直接投下一步。
向上述产物中加入丙酮、酸钾(2.8g)，滴加溴苄(1.4mL)，66℃回流6小时，TLC检测原料反应完全。反应液直接过滤，旋干滤液，得到3,4,5-三苄氧基苯甲酸甲酯，直接投下一步。
向上述产物中加入甲醇/水(3:2)，加入氢氧化钠(480mg,5eq)，66℃回流过夜。后处理：旋蒸除去甲醇，乙酸乙酯萃取，调pH为5-6，分液、水洗、饱和食盐水洗涤、分液干燥、滤液旋干，正己烷打浆后得到淡黄色的3,4,5-三苄氧基苯甲酸(800mg)。
依次向茄形瓶中加入淡黄色固体(330mg)、干燥甲苯(8mL)、2-氯-4-三氟甲基苯胺(78uL)，室温下加入三氯化磷(56uL)，立即氮气保护。此时反应液为乳白色的悬浊液，升温至115℃回流过夜。向反应液中加入水，少量碳酸氢钠溶液，乙酸乙酯萃取，饱和食盐水洗涤，干燥，以石油醚和乙酸乙酯(100:1)洗脱，得到白色的N-(2-氯-4-三氟甲基苯基)-3,4,5-三苄氧基苯甲酰胺固体220mg。
取白色固体溶解于甲醇：四氢呋喃(1:1)，加入钯碳(20mg)，氢气置换，反应过夜， 次日TLC检测，原料反应完全，反应进行彻底。后处理：硅藻土助滤，滤液旋干，拌样，以二氯甲烷和甲醇(50:1)洗脱，得到目标化合物IIIA-20 60mg，收率45.80％。 1H NMR(500MHz,DMSO-d 6)δ9.71(s,1H),9.24(s,2H),8.91(s,1H),8.00–7.93(m,2H),7.74(dd,J＝8.6,2.1Hz,1H),6.99(s,2H).ESI-MS m/z 453.1(M-H) -.
实施例21：N-(4-三氟甲氧基苯基)-2,3,4-三羟基苯甲酰胺(IIIA-21)的合成
Figure PCTCN2022100609-appb-000038
依次向茄形瓶中加入2,3,4-三苄氧基苯甲酸(330mg)、干燥甲苯(8mL)、4-三氟甲氧基苯胺(100uL)，室温下加入三氯化磷(75uL)，立即氮气保护。此时反应液为乳白色的悬浊液，升温至115℃回流过夜，次日已澄清TLC检测，原料反应完全。向反应液中加入水，少量碳酸氢钠溶液，乙酸乙酯萃取，饱和食盐水洗涤，干燥，以石油醚和乙酸乙酯(100:1)洗脱，得到白色N-(4-三氟甲氧基苯基)-2,3,4-三苄氧基苯甲酰胺固体370mg。
取白色固体溶解于甲醇：四氢呋喃(1:1)，加入钯碳(100mg)，氢气置换，反应过夜，次日TLC检测，原料反应完全，反应进行彻底。后处理：硅藻土助滤，滤液旋干，拌样，以二氯甲烷和甲醇(50:1)洗脱，得到目标化合物IIIA-21 140mg，收率70％。 1H NMR(500MHz,DMSO-d 6)δ12.11(s,1H),10.27(s,1H),9.73(s,1H),8.57(s,1H),7.82–7.75(m,2H),7.43(d,J＝8.9Hz,1H),7.39–7.34(m,2H),6.42(d,J＝8.8Hz,1H).ESI-MS m/z 328.2(M-H) -.
实施例22：N-(4-三氟甲基苯基)-2,3,4-三羟基苯甲酰胺(IIIA-22)的合成
Figure PCTCN2022100609-appb-000039
依次向茄形瓶中加入2,3,4-三苄氧基苯甲酸(330mg)、干燥甲苯(8mL)、4-三氟甲基苯胺(94uL)，室温下加入三氯化磷(78uL)，立即氮气保护。此时反应液为乳白色的悬浊液，升温至115℃回流过夜，次日已澄清TLC检测，原料反应完全。向反应液中加入水，少量碳酸氢钠溶液，乙酸乙酯萃取，饱和食盐水洗涤，干燥，以石油醚和乙酸乙酯(100:1)洗脱，得到白色N-(4-三氟甲基苯基)-2,3,4-三苄氧基苯甲酰胺固体390mg。
取白色固体溶解于甲醇：四氢呋喃(1:1)，加入钯碳(100mg)，氢气置换，反应过夜，次日TLC检测，原料反应完全，反应进行彻底。后处理：硅藻土助滤，滤液旋干，拌样，以二氯甲烷和甲醇(50:1)洗脱，得到目标化合物IIIA-22 130mg，收率53％。 1H NMR(500MHz,DMSO-d 6)δ11.91(s,1H),10.40(s,1H),9.79(s,1H),8.62(s,1H),7.92(d,J＝8.5Hz,2H),7.72(d,J＝8.5Hz,2H),7.45(d,J＝8.8Hz,1H),6.43(d,J＝8.8Hz,1H).ESI-MS m/z 312.2(M-H) -.
实施例23：N-(4-三氟甲基苯基)-2-甲氧基-5-氯苯甲酰胺(IIIA-23)的合成
Figure PCTCN2022100609-appb-000040
依次向茄形瓶中加入5-氯-2-甲氧基苯甲酸(186mg)、干燥甲苯(5ml)、对三氟甲基苯胺(125uL)，室温下加入三氯化磷(105uL)，氮气保护。此时反应液为白色悬浊液，升温至115℃回流，回流过夜，TLC检测原料反应完全。向反应液中加入水，少量碳酸氢钠溶液，乙酸乙酯萃取，饱和食盐水洗涤，干燥，以石油醚和乙酸乙酯(100:1)洗脱，得到白色固体化合物IIIA-23，重150mg。 1H NMR(500MHz,DMSO-d6)δ10.54(s,1H),7.93(d,J＝8.4Hz,2H),7.71(d,J＝8.5Hz,2H),7.61(d,J＝2.7Hz,1H),7.56(dd,J＝8.9,2.8Hz,1H),7.22(d,J＝8.9Hz,1H),3.88(s,3H).ESI-MS m/z 328.0(M-H) -.
实施例24：N-(4-三氟甲基苯基)-5-氯-2-乙酰氨基苯甲酰胺(IIIA-24)的合成
Figure PCTCN2022100609-appb-000041
2-氨基-5-氯苯甲酸(1.368g)溶于醋酸(15mL)，加入醋酸酐(1.34mL)，室温至75℃，30分钟后TLC检测反应完全。后处理：将反应液倒入冰水中，搅拌，抽滤，滤饼水洗，干燥，得到2-乙酰氨基-5-氯苯甲酸，待投下一步。
向上述固体中加入干燥甲苯，对三氟甲基苯胺(878uL)，三氯化磷(800uL)，115℃回流过夜，次日未溶清，约反应90％。后处理：向反应液中加入水，少量碳酸氢钠溶液，旋蒸除去甲苯，乙酸乙酯萃取，饱和食盐水洗涤，干燥，以石油醚和乙酸乙酯(100:1)洗脱，得化合物IIIA-24，重1.9g。 1H NMR(500MHz,DMSO-d 6)δ8.06(d,J＝2.5Hz,1H),7.99(d,J＝8.2Hz,2H),7.91(d,J＝8.7,1H),7.77(d,J＝8.2Hz,2H),7.73(d,J＝8.7Hz,1H),2.14(s,3H).ESI-MS m/z 355.1(M-H) -.
实施例25：N-(4-三氟甲氧基苯基)-5-氯-2-乙酰氨基苯甲酰胺(IIIA-25)的合成
Figure PCTCN2022100609-appb-000042
依次向圆底烧瓶中加入实施例24中第一步所得白色固体(277mg)，干燥甲苯(5mL)，对三氟甲氧基苯胺(171.6uL)，三氯化磷(146uL)，氮气置换，由室温升至115℃，搅拌12小时，反应相始终是混浊状态，冷却后TLC检测，原料约反应90％。后处理：加入少量甲醇淬灭反应，旋蒸除去部分甲苯后，向体系中加入乙酸乙酯、水，分层，分液，饱和食盐水洗涤有机相，干燥，过滤，拌样，以石油醚和乙酸乙酯(100:1)洗脱，目标产 物点的洗脱剂为乙酸乙酯：甲醇＝30：1，得到目标化合物IIIA-25，304mg，核磁正确。 1H NMR(500MHz,DMSO-d 6)δ8.04(s,1H),7.90(d,J＝8.7Hz,1H),7.73(d,J＝8.6Hz,1H),7.65(d,J＝8.3Hz,2H),7.60(d,J＝8.3Hz,2H),2.15(s,3H).ESI-MS m/z 395.0(M+Na) +.
实施例26：N-(4-三氟甲基苯基)-5-氯-3-乙酰基水杨酰胺(IIIA-26)的合成
Figure PCTCN2022100609-appb-000043
依次向反应瓶中加入5-氯水杨酸(5g)，二氯甲烷(15mL)，DMF(10滴)，冰浴滴加草酰氯(3.5mL)，加毕转为室温反应，约3小时反应完全。将该溶液滴加到甲醇(25mL)中，加毕，搅拌10分钟后浓缩，乙酸乙酯、水萃取分液，饱和食盐水洗涤有机相，干燥，过滤，滤液浓缩，得5-氯-2-羟基苯甲酸甲酯(5.1 0g)，待投。
向上一步所获得的5-氯-2-羟基苯甲酸甲酯(5.1 0g)中加入醋酸酐(5mL)，硫酸(100uL)，室温搅拌30分钟。向反应体系中加入乙酸乙酯(15mL)，饱和碳酸氢钠溶液(分批慢加)，直到加入后不产生气泡为止。分液，饱和食盐水洗涤有机相，干燥，过滤，浓缩，得到5-氯-2-乙酰氧基苯甲酸甲酯，待投下一步。
将5-氯-2-乙酰氧基苯甲酸甲酯转移至双口瓶，加入三氯化铝(30g)，氯化钠(16g)，氮气保护，120℃条件下机械搅拌3小时，TLC检测原料基本反应完全。冰浴下向反应体系中加入1M氯化氢溶液(慢加)，待搅拌均匀后加入乙酸乙酯(30mL)，萃取分液，水层多次萃取。合并有机相，饱和食盐水洗涤，干燥，过滤，浓缩拌样，以石油醚和乙酸乙酯(10:1)洗脱，得到白色5-氯-3-乙酰基-2-羟基苯甲酸固体1.1g。
依次向反应瓶中加入5-氯-3-乙酰基2-羟基苯甲酸(990mg)，干燥甲苯(25mL)，对三氟甲基苯胺(554uL)，三氯化磷(446uL)，氮气保护，由室温升温至115℃，反应10小时。TLC显示，反应未完全。后处理：向反应体系加入少量甲醇，浓缩，拌样，以石油醚和乙酸乙酯(100:1)洗脱得到目标化合物IIIA-26，150mg。 1H NMR(500MHz,DMSO-d 6)δ13.01(s,1H),10.80(s,1H),8.13(d,J＝2.7Hz,1H),8.06(d,J＝2.8Hz,1H),7.95(d,J＝8.3Hz,2H),7.76(d,J＝8.4Hz,2H),2.74(s,3H).ESI-MS m/z 356.1(M-H) -.
实施例27：N-(4-三氟甲氧基苯基)-5-氯-3-乙酰基水杨酰胺(IIIA-27)的合成
Figure PCTCN2022100609-appb-000044
依次向反应瓶中加入实施例26中第三步所得固体(85mg)，干燥甲苯(2mL)，对三氟甲氧基苯胺(54uL)，三氯化磷(45uL)，氮气保护，由室温升温至115℃，反应13小时。TLC显示，反应未完全。后处理：向反应体系加入少量甲醇，浓缩，乙酸乙酯、水萃取，饱和食盐水洗涤，干燥，以石油醚和乙酸乙酯(100:1)洗脱得到目标化合物IIIA-27，18mg。 1H NMR(500MHz,DMSO-d 6)δ13.07(s,1H),10.72(s,1H),8.09–8.04(m,2H),7.85–7.79(m,2H),7.39(d,J＝8.6Hz,2H),2.71(s,3H).ESI-MS m/z 372.0(M-H) -.
实施例28：N-(4-三氟甲基苯基)-5-氯-3-硝基水杨酰胺(IIIA-28)的合成
Figure PCTCN2022100609-appb-000045
5-氯水杨酸(342mg)溶于浓硫酸，冰浴，加入浓硝酸(232mg)，冰浴反应4小时后TLC检测，原料反应完全。将反应液滴入冰水中，搅拌30分钟，过滤，滤饼用水洗涤，干燥，浓缩得到3-硝基-5-氯-2-羟基苯甲酸，待投下一步。
3-硝基-5-氯-2-羟基苯甲酸(310mg)，对三氟甲基苯胺(230mg)，干燥甲苯(20mL)，三氯化磷(149uL)，115℃回流。向反应液中加入水，少量碳酸氢钠溶液，旋蒸除去甲苯，乙酸乙酯萃取，饱和食盐水洗涤，干燥，以石油醚和乙酸乙酯(100:1)洗脱，得到目标化合物IIIA-28，150mg。 1H NMR(500MHz,DMSO-d 6)δ11.83(s,1H),8.17–8.15(m,1H),8.14–8.10(m,1H),7.91(d,J＝8.5Hz,2H),7.75(d,J＝8.4Hz,2H).ESI-MS m/z 359.0(M-H) -.
实施例29：N-(4-三氟甲巯基苯基)-4-氟-5-氯水杨酰胺(IIIA-29)的合成
Figure PCTCN2022100609-appb-000046
除了以2-羟基-4-氟-5-氯苯甲酸代替2-羟基-5-氯-苯甲酸，以4-三氟甲巯基苯胺代替2-氨基-4-三氟甲基噻唑，反应5小时以外，按照与实施例1相同的方法制备化合物IIIA-29，收率为：69.23％。 1H NMR(400MHz,DMSO-d6)δ12.08(s,1H),10.58(s,1H),8.06(d,J＝8.6Hz,1H),7.90–7.83(m,2H),7.76–7.69(m,2H),7.02(d,J＝10.8Hz,1H).ESI-MS m/z 363.0(M-H) -.
实施例30：N-(3-三氟甲基-4-氰基苯基)-4-氟-5-氯水杨酰胺(IIIA-30)的合成
Figure PCTCN2022100609-appb-000047
除了以2-羟基-4-氟-5-氯苯甲酸代替2-羟基-5-氯-苯甲酸，以3-三氟甲基-4-氰基苯胺代替2-氨基-4-三氟甲基噻唑以外，按照与实施例1相同的方法制备化合物IIIA-30，收率为：37.23％。 1H NMR(500MHz,DMSO-d6)δ11.83(s,1H),10.90(s,1H),8.40(s,1H),8.16(s,2H),7.99(d,J＝8.6Hz,1H),7.02(d,J＝10.8Hz,1H).ESI-MS m/z 358.0(M-H) -.
实施例31：N-(3-三氟甲基-4-氰基吡啶)-4-氟-5-氯水杨酰胺(IIIA-31)的合成
Figure PCTCN2022100609-appb-000048
除了以2-羟基-4-氟-5-氯苯甲酸代替2-羟基-5-氯-苯甲酸，以2-氰基-3-三氟甲基-5-氨基吡啶代替2-氨基-4-三氟甲基噻唑，反应时间为6小时以外，按照与实施例1相同的方法制备化合物IIIA-31，收率为：36.13％。 1H NMR(500MHz,DMSO-d6)δ11.90(s,1H),11.16(s,1H),9.24(d,J＝2.3Hz,1H),8.82(d,J＝2.3Hz,1H),7.99(d,J＝8.6Hz,1H),7.03(d,J＝10.8Hz,1H).ESI-MS m/z 359.0(M-H) -.
实施例32：N-(3-氯-4-三氟甲基)-5-氯水杨酰胺(IIIA-32)的合成
Figure PCTCN2022100609-appb-000049
除了以2-羟基-5-氯苯甲酸代替2-羟基-5-氯-苯甲酸，以3-氯-4-三氟甲基苯胺代替2-氨基-4-三氟甲基噻唑，反应时间为5小时以外，按照与实施例1相同的方法制备化合物IIIA-32，收率为：40.23％。 1H NMR(500MHz,DMSO-d6)δ11.92(s,1H),10.78(d,J＝6.0Hz,1H),8.14(d,J＝1.9Hz,1H),8.02(d,J＝8.6Hz,1H),7.89–7.81(m,2H),7.01(d,J＝10.8Hz,1H).ESI-MS m/z 348.01(M-H) -.
实施例33：(4-氯-5-氟-2-(((4-(三氟甲基)苯基)氨基甲酰基)苯氧基)甲基异丙基碳酸酯(IIIB-1)的合成
Figure PCTCN2022100609-appb-000050
依次向反应瓶中加入丙酮(1mL)，氯甲基异丙基碳酸酯(46mg)，碘化钠(45mg,)，60℃搅拌3小时。过滤，滤饼用少量丙酮洗涤。
依次向反应瓶中加入碳酸钾(40mg)，化合物IIIA-18(70mg)，丙酮(2mL)，DMF(10滴)助溶，搅拌下加入上述步骤所得的滤液，搅拌2小时TLC检测反应完全。浓缩反应液，向浓缩物中加入乙酸乙酯、水，水相用饱和氯化铵溶液调节pH，分液，饱和食盐水洗涤有机相，干燥，过滤，浓缩，浓缩物用石油醚(1.5mL)和乙酸乙酯(10滴)打浆，过滤得到化合物IIIB-1 60mg，核磁正确。 1H NMR(500MHz,DMSO-d 6)δ10.60(s,1H),7.90(d,J＝8.4Hz,2H),7.88(d,J＝8.4Hz,1H),7.74(d,J＝8.6Hz,2H),7.55(d,J＝8.6Hz,1H),5.88(s,2H),4.76(m,J＝6.3Hz,1H),1.20(d,J＝6.3Hz,6H).ESI-MS m/z 447.8(M-H) -.
实施例34:5-氯-4-氟-2-((5-甲基-2-氧代-1,3-二氧戊环-4-基)甲氧基)-N-(4-(三氟甲基) 苯基)苯甲酰胺(IIIB-2)的合成
Figure PCTCN2022100609-appb-000051
依次向反应瓶中加入丙酮(1mL)，4-氯甲基-5-甲基-1,3-二氧杂环戊烯-2-酮(44m)，碘化钠(45mg)，60℃搅拌3小时。过滤，滤饼用少量丙酮洗涤。
依次向反应瓶中加入碳酸钾(50mg)，化合物IIIA-18(70mg)，丙酮(2mL)，DMF(10滴)助溶，搅拌下加入步骤a所得的滤液，搅拌5小时TLC检测反应原料剩余。后处理：旋干有机溶剂，向浓缩物中加入乙酸乙酯、水，水相用饱和氯化铵调节pH为酸性，分液，饱和食盐水洗涤有机相，干燥，过滤，浓缩，浓缩物用石油醚(1.5mL)和乙酸乙酯(10滴)打浆，过滤得到化合物IIIB-2 56mg，核磁正确。 1H NMR(500MHz,DMSO-d 6)δ10.53(s,1H),7.89(d,J＝8.4Hz,2H),7.84(d,J＝8.5Hz,1H),7.72(d,J＝8.6Hz,2H),7.57(d,J＝11.4Hz,1H),5.18(s,2H),2.18(s,3H).ESI-MS m/z 444.1(M-H) -.
实施例35：N-(4-三氟甲基苯基)-2-乙酰氧基-4-氟-5-氯苯甲酰胺(IIIB-3)的合成
Figure PCTCN2022100609-appb-000052
依次向茄形瓶中加入称量好的水杨酰胺衍生物IIIA-18，加入乙酸酐(0.5mL)，浓硫酸(1滴)，室温搅拌45分钟，TLC检测原料几乎完全转化。向反应液中加入乙酸乙酯(4mL)，冰水(4mL)，萃取分液，乙酸乙酯层用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，拌样，以石油醚和乙酸乙酯(100:1)洗脱，获得相应的目标化合物IIIB-3，收率为：30％。 1H NMR(500MHz,DMSO-d6)δ10.79(s,1H),8.04(d,J＝8.1Hz,1H),7.89(d,J＝8.4Hz,2H),7.73(d,J＝8.5Hz,3H),7.57(d,J＝9.7Hz,1H),2.21(s,3H).
实施例36：N-(4-三氟甲基苯基)-2-乙酰氧基-3,5-二氟苯甲酰胺(IIIB-4)的合成
Figure PCTCN2022100609-appb-000053
除了以化合物IIIA-15代替IIIA-18以外，按照与实施例35相同的方法制备IIIB-4，收率为：72％。 1H NMR(500MHz,DMSO-d6)δ10.89(s,1H),7.91(d,J＝8.4Hz,2H),7.79–7.69(m,3H),7.57(ddd,J＝8.3,2.9,1.6Hz,1H),2.28(s,3H).
实施例37：N-(4-三氟甲氧基苯基)-2-乙酰氧基-4-氟-5-氯苯甲酰胺(IIIB-5)的合成
Figure PCTCN2022100609-appb-000054
除了以化合物IIIA-12代替IIIA-18以外，按照与实施例35相同的方法制备IIIB-5，收率为：34％。 1H NMR(500MHz,DMSO-d6)δ10.64(s,1H),8.01(d,J＝8.2Hz,1H),7.81–7.75(m,2H),7.56(d,J＝9.8Hz,1H),7.42–7.31(m,2H),2.21(s,3H).
实施例38：N-(4-三氟甲基苯基)-2-异丁酰氧基-4-氟-5-氯苯甲酰胺(IIIB-6)的合成
Figure PCTCN2022100609-appb-000055
除了以异丁酸酐代替乙酸酐，以及反应时间为1小时以外，按照与实施例35相同的方法制备IIIB-6，收率为：74％。 1H NMR(500MHz,DMSO-d6)δ10.82(s,1H),8.02(d,J＝8.1Hz,1H),7.90(d,J＝8.4Hz,2H),7.74(d,J＝8.6Hz,2H),7.60(d,J＝9.8Hz,1H),2.76(m,1H),1.15(d,J＝7.0Hz,5H).
实施例39：N-(4-三氟甲基苯基)-2-异丁酰氧基-3,5-二氟苯甲酰胺(IIIB-7)的合成
Figure PCTCN2022100609-appb-000056
除了以化合物IIIA-15代替IIIA-18，以异丁酸酐代替乙酸酐，以及反应时间为1小时以外，按照与实施例35相同的方法制备IIIB-7，收率为：76％。 1H NMR(500MHz,DMSO-d6)δ10.88(s,1H),7.89(d,J＝8.4Hz,2H),7.74(d,J＝8.8Hz,2H),7.72–7.69(m,1H),7.56–7.51(m,1H),2.82(m,1H),1.15(d,J＝7.0Hz,5H).
实施例40：N-(4-三氟甲氧基苯基)-2-异丁酰氧基-4-氟-5-氯苯甲酰胺(IIIB-8)的合成
Figure PCTCN2022100609-appb-000057
除了以化合物IIIA-12代替IIIA-18，以异丁酸酐代替乙酸酐，以及反应时间为1小时以外，按照与实施例36相同的方法制备IIIB-8，收率为：65％。 1H NMR(500MHz, DMSO-d6)δ10.64(s,1H),7.98(d,J＝8.2Hz,1H),7.80–7.75(m,2H),7.58(d,J＝9.8Hz,1H),7.37(d,J＝8.6Hz,2H),2.75(m,1H),1.14(d,J＝7.0Hz,5H).
实施例41：N-(4-三氟甲基苯基)-2-(L-丙氨酸)氧基-4-氟-5-氯苯甲酰胺盐酸盐(IIIB-9)的合成
Figure PCTCN2022100609-appb-000058
依次向茄形瓶中加入IIIA-18(150mg)，N-三苯基甲基-L-丙氨酸(150mg)，N,N-二甲基甲酰胺(3mL)，-10℃搅拌，加入环已基碳二酰亚胺(94mg)，维持此温度反应1小时，后转为室温反应6小时。期间析出白色固体，过滤，滤液以乙酸乙酯、水萃取，饱和氯化钠溶液洗涤乙酸乙酯层，干燥，，以石油醚和乙酸乙酯(50:1)洗脱柱层析，得到IIIB-9-1200mg，待投下一步。
将上一步所得的IIIB-9-1溶于二氯甲烷(1.5mL)，冰浴，加入三氟醋酸(0.3mL)，搅拌1小时。旋干溶剂，乙酸乙酯、水萃取，饱和氯化钠溶液洗涤，干燥，浓缩，，以石油醚和乙酸乙酯(2:1)洗脱得到IIIB-9的游离态。向此游离态的化合物中加入甲醇，再加1.5当量氯化氢甲醇溶液，搅拌15分钟后浓缩，再以甲苯带水(3次)得到IIIB-9 70mg。 1H NMR(500MHz,DMSO-d6)δ12.73(s,1H),10.54(s,1H),9.09(d,J＝6.6Hz,1H),8.26(d,J＝8.6Hz,1H),7.82(d,J＝8.5Hz,2H),7.69(d,J＝8.6Hz,2H),7.01(d,J＝10.8Hz,1H),4.65(p,J＝7.0Hz,1H),1.47(d,J＝7.1Hz,3H).ESI-MS m/z 403.04(M-H) -.
实施例42：N-(4-三氟甲基苯基)-2-(L-丙氨酸)氧基-3,5-二氟苯甲酰胺盐酸盐(IIIB-10)的合成
Figure PCTCN2022100609-appb-000059
依次向茄形瓶中加入IIIA-15(143mg)，N-三苯基甲基-L-丙氨酸(150mg)，N,N-二甲基甲酰胺(3mL)，-10℃搅拌，加入环已基碳二酰亚胺(94mg)，维持此温度反应1小时，后转为室温反应6小时。期间析出白色固体，过滤，滤液以乙酸乙酯、水萃取，饱和氯化钠溶液洗涤乙酸乙酯层，干燥，以石油醚和乙酸乙酯(50:1)洗脱，得到IIIB-10-1 195mg，待投下一步。
将上一步所得的IIIB-10-1溶于二氯甲烷(1.5mL)，冰浴，加入三氟醋酸(0.3mL)，搅拌1小时。旋干溶剂，乙酸乙酯、水萃取，饱和氯化钠溶液洗涤，干燥，浓缩，以石油醚和乙酸乙酯(2:1)洗脱得到IIIB-10的游离态。向此游离态的化合物中加入甲醇，再加1.5当量氯化氢甲醇溶液，搅拌15分钟后浓缩，再以甲苯带水(3次)得到IIIB-10 70mg。 1H NMR(500MHz,DMSO-d6)δ12.26(s,1H),10.55(s,1H),9.19(d,J＝6.6Hz,1H),7.83(d,J＝8.6Hz,2H),7.74(dt,J＝10.0,2.4Hz,1H),7.69(d,J＝8.6Hz,2H),7.55(ddd,J＝11.3,8.4,3.1Hz,1H),4.67(p,J＝7.0Hz,1H),1.48(d,J＝7.1Hz,3H).ESI-MS m/z 387.04(M-H) -.
实施例43：N-(4-三氟甲氧基苯基)-2-(L-丙氨酸)氧基-4-氟-5-氯苯甲酰胺盐酸盐(IIIB-11)的合成
Figure PCTCN2022100609-appb-000060
依次向茄形瓶中加入IIIA-12(136mg)，N-三苯基甲基-L-丙氨酸(132mg)，N,N-二甲基甲酰胺(3mL)，-10℃搅拌，加入环已基碳二酰亚胺(83mg)，维持此温度反应1小时，后转为室温反应6小时。期间析出白色固体，过滤，滤液以乙酸乙酯、水萃取，饱和氯化钠溶液洗涤乙酸乙酯层，干燥，以石油醚和乙酸乙酯(50:1)洗脱，得到IIIB-11-1 170mg，待投下一步。
将上一步所得的IIIB-11-1溶于二氯甲烷(1.5mL)，冰浴，加入三氟醋酸(0.3mL)，搅拌1小时。旋干溶剂，乙酸乙酯、水萃取，饱和氯化钠溶液洗涤，干燥，浓缩，以石油醚和乙酸乙酯(2:1)洗脱得到IIIB-11的游离态。向此游离态的化合物中加入甲醇，再加1.5当量氯化氢甲醇溶液，搅拌15分钟后浓缩，再以甲苯带水(3次)得到IIIB-11 70mg。
1H NMR(500MHz,DMSO-d6)δ12.73(s,1H),10.36(s,1H),9.08(d,J＝6.7Hz,1H),8.25(d,J＝8.6Hz,1H),7.74–7.70(m,2H),7.33(d,J＝8.7Hz,2H),7.00(d,J＝10.8Hz,1H),4.63(p,J＝7.0Hz,1H),1.45(d,J＝7.0Hz,3H).ESI-MS m/z 419.02(M-H) -.
实施例44：N-(4-三氟甲基苯基)-2-(L-丙氨酸)氧基-4-氟-5-氯苯甲酰胺盐酸盐(IIIB-12)的合成
Figure PCTCN2022100609-appb-000061
依次向茄形瓶中加入IIIA-18(166mg)，N-叔丁氧羰基-L-缬氨酸(108mg)，N,N-二甲基甲酰胺(3mL)，-10℃搅拌，加入环已基碳二酰亚胺(155mg)，维持此温度反应1小时，后转为室温反应6小时。期间析出白色固体，过滤，滤液以乙酸乙酯、水萃取，饱和氯化钠溶液洗涤乙酸乙酯层，干燥，以石油醚和乙酸乙酯(50:1)洗脱，得到IIIB-12-1 150mg，待投下一步。
将上一步所得的IIIB-12-1溶于二氯甲烷(1.5mL)，冰浴，加入三氟醋酸(0.3mL)，搅拌1小时。旋干溶剂，乙酸乙酯、水萃取，饱和氯化钠溶液洗涤，干燥，浓缩，以石 油醚和乙酸乙酯(2:1)洗脱得到IIIB-12的游离态。向此游离态的化合物中加入甲醇，再加1.5当量氯化氢甲醇溶液，搅拌15分钟后浓缩，再以甲苯带水(3次)得到IIIB-12 30mg。 1H NMR(500MHz,DMSO-d6)δ12.60(s,1H),10.65(s,1H),8.93(d,J＝8.1Hz,1H),8.23(d,J＝8.7Hz,1H),7.85(d,J＝8.5Hz,2H),7.78–7.68(m,2H),7.00(d,J＝10.7Hz,1H),4.57(t,J＝7.6Hz,1H),2.21(h,J＝6.8Hz,1H),0.99(dd,J＝6.7,1.5Hz,6H).ESI-MS m/z 431.05(M-H) -.
实施例45：N-(4-三氟甲氧基苯基)-2-(L-缬氨酸)氧基-4-氟-5-氯苯甲酰胺盐酸盐(IIIB-13)的合成
Figure PCTCN2022100609-appb-000062
依次向茄形瓶中加入IIIA-12(170mg)，N-叔丁氧羰基-L-缬氨酸(105mg)，N,N-二甲基甲酰胺(3mL)，-10℃搅拌，加入环已基碳二酰亚胺(83mg)，维持此温度反应1小时，后转为室温反应6小时。期间析出白色固体，过滤，滤液以乙酸乙酯、水萃取，饱和氯化钠溶液洗涤乙酸乙酯层，干燥，以石油醚和乙酸乙酯(50:1)洗脱，得到IIIB-13-1 90mg，待投下一步。
将上一步所得的IIIB-13-1溶于二氯甲烷(1.5mL)，冰浴，加入三氟醋酸(0.3mL)，搅拌1小时。旋干溶剂，乙酸乙酯、水萃取，饱和氯化钠溶液洗涤，干燥，浓缩，以石油醚和乙酸乙酯(2:1)洗脱得到IIIB-13的游离态。向此游离态的化合物中加入甲醇，再加1.5当量氯化氢甲醇溶液，搅拌15分钟后浓缩，再以甲苯带水(3次)得到IIIB-13 45mg。 1H NMR(500MHz,DMSO-d6)δ12.63–12.60(m,1H),10.48(s,1H),8.93(d,J＝8.2Hz,1H),8.23(d,J＝8.7Hz,1H),7.76–7.71(m,2H),7.35(d,J＝8.6Hz,2H),6.99(d,J＝10.7Hz,1H),4.54(t,J＝7.7Hz,1H),2.20(h,J＝6.6Hz,1H),0.98(dd,J＝6.8,1.6Hz,6H).ESI-MS m/z 447.08(M-H) -。
实施例46：(4-氯-5-氟-2-(((4-(三氟甲氧基)苯基)氨基甲酰基)苯氧基)甲基异丙基碳酸酯(IIIB-14)的合成
Figure PCTCN2022100609-appb-000063
依次向反应瓶中加入丙酮(1mL)，氯甲基异丙基碳酸酯(61mg)，碘化钠(62mg)，60℃搅拌3小时。过滤，滤饼用少量丙酮洗涤。
依次向反应瓶中加入碳酸钾(66mg)，化合物IIIA-12(70mg)，丙酮(2mL)，DMF(10滴)助溶，搅拌下加入上述步骤所得的滤液，搅拌2小时TLC检测反应完全。浓缩反应 液，向浓缩物中加入乙酸乙酯、水，水相用饱和氯化铵溶液调节pH，分液，饱和食盐水洗涤有机相，干燥，过滤，浓缩，浓缩物用石油醚(1.5mL)和乙酸乙酯(10滴)打浆，过滤得到化合物IIIB-14 70mg，核磁正确。 1H NMR(500MHz,DMSO-d6)δ10.41(s,1H),7.85(d,J＝8.4Hz,1H),7.83–7.77(m,2H),7.53(d,J＝11.0Hz,1H),7.38(d,J＝8.7Hz,2H),5.88(s,2H),4.76(hept,J＝6.2Hz,1H),1.20(d,J＝6.2Hz,6H).
实施例47：N-(4-三氟甲氧基苯基)-2-(缬氨酸酯基亚甲氧基)-4-氟-5-氯苯甲酰胺盐酸盐(IIIB-15)的合成
Figure PCTCN2022100609-appb-000064
依次向反应瓶中加入丙酮(3mL)，(S)-2-((叔丁氧基羰基)氨基)-3-甲基丁酸氯甲酯(397mg)，碘化钠(220mg)，60℃搅拌3小时。过滤，滤饼用少量丙酮洗涤。
依次向反应瓶中加入碳酸钾(66mg)，化合物IIIA-12(349mg)，丙酮(10mL)，搅拌下加入上述步骤所得的滤液，搅拌12小时。浓缩反应液，向浓缩物中加入乙酸乙酯、水，水相用饱和氯化铵溶液调节pH，饱和食盐水洗涤有机相，干燥，过滤，浓缩，拌样，以石油醚和乙酸乙酯(2:1)洗脱得到化合物IIIB-15-1 300mg。
将IIIB-15-1溶于二氯甲烷(6mL)，冰浴下加入三氟乙酸(0.75mL)，加毕，室温搅拌3小时。浓缩，二氯甲烷、水萃取，水层调pH至碱性，饱和氯化钠溶液洗涤，过滤，浓缩。向浓缩物中加入甲醇，再加1.5当量氯化氢甲醇溶液，搅拌15分钟后浓缩，再以甲苯带水(3次)得到IIIB-15 180mg。核磁正确。 1H NMR(500MHz,)δ10.49(d,J＝3.6Hz,1H),8.49(s,2H),7.88–7.79(m,3H),7.56(d,J＝11.0Hz,1H),7.37(d,J＝8.6Hz,2H),6.06(d,J＝6.9Hz,1H),6.01(d,J＝6.8Hz,1H),4.01(s,1H),2.13(dq,J＝11.4,6.9Hz,1H),0.89(t,J＝7.2Hz,6H).ESI-MS m/z 479.1(M+H) -。
实施例48：N-(4-三氟甲氧基苯基)-2-(4-甲基哌嗪酰氧基)-4-氟-5-氯苯甲酰胺盐酸盐(IIIB-16)的合成
Figure PCTCN2022100609-appb-000065
依次向反应瓶中加入化合物IIIA-12(175mg)，4-二甲氨基吡啶(18mg)，4-甲基哌嗪-1-甲酰氯盐酸盐(199mg)，吡啶，回流3小时。浓缩后用乙酸乙酯、水萃取，水层用饱和氯化铵洗涤，无水硫酸钠干燥，拌样，以石油醚和乙酸乙酯(1:1)洗脱，得到目标化合物IIIB-16 40mg。 1H NMR(500MHz,DMSO-d6)δ10.59(s,1H),7.91(d,J＝8.2Hz,1H),7.80–7.74(m,2H),7.56(d,J＝10.0Hz,1H),7.38(d,J＝8.6Hz,2H),3.50(s,2H),3.31(s,2H),2.14(s,4H),2.05(s,3H).ESI-MS m/z 476.1(M+H) -。
实施例49：(4,6-二氟-2-(((4-(三氟甲氧基)苯基)氨基甲酰基)苯氧基)甲基异丙基碳酸酯(IIIB-17)的合成
Figure PCTCN2022100609-appb-000066
依次向反应瓶中加入丙酮(1mL)，氯甲基异丙基碳酸酯(61mg)，碘化钠(62mg)，60℃搅拌3小时。过滤，滤饼用少量丙酮洗涤。
依次向反应瓶中加入碳酸钾(66mg)，化合物IIIA-15(85mg)，丙酮(2mL)，DMF(10滴)助溶，搅拌下加入上述步骤所得的滤液，搅拌2小时TLC检测反应完全。浓缩反应液，向浓缩物中加入乙酸乙酯、水，水相用饱和氯化铵溶液调节pH，分液，饱和食盐水洗涤有机相，干燥，过滤，浓缩，浓缩物用石油醚(1.5mL)和乙酸乙酯(10滴)打浆，过滤得到化合物IIIB-17 110mg。 1H NMR(500MHz,DMSO-d6)δ10.74(s,1H),7.90(d,J＝8.4Hz,2H),7.74(d,J＝8.5Hz,2H),7.64(ddd,J＝11.3,8.5,3.1Hz,1H),7.40(dt,J＝8.2,2.3Hz,1H),5.62(s,2H),4.61(hept,J＝6.3Hz,1H),1.12(d,J＝6.2Hz,6H).
实施例50：3-((((4-氯-5-氟-2-(4-(三氟甲氧基)苯基氨基甲酰基)苯氧基)甲氧基)羰基氧基)-N-甲基丙烷-1-氯化铵)
Figure PCTCN2022100609-appb-000067
依次向反应瓶中加入丙酮(3mL)，3-(N-甲基-N-叔丁氧羰基)丙基氯甲基碳酸酯(422mg,1.5mmol)，碘化钠(300mg,2mmol)，60℃搅拌3小时。过滤，滤饼用少量丙酮洗涤。
依次向反应瓶中加入碳酸钾(276mg)，化合物IIIA-12(349mg)，丙酮(10mL)，DMF(10滴)，搅拌下加入上述步骤所得的滤液，搅拌12小时。浓缩反应液，向浓缩物中加入乙酸乙酯、水，水相用饱和氯化铵溶液调节pH，饱和食盐水洗涤有机相，干燥，过滤，浓缩，拌样，以石油醚和乙酸乙酯(2:1)洗脱得到化合物IIIB-18-1 300mg。
依次向反应瓶中加入IIIB-18-1(300mg)，加入2M HCl(由4M HCl甲醇溶液经THF稀释得到)溶液，室温搅拌16小时，TLC检测原料反应完全。浓缩后，薄层色谱分离得油状化合物IIIB-18 200mg。 1H NMR(600MHz,DMSO-d6)δ10.56(s,1H),8.63(d,J＝9.2Hz,1H),8.54(s,2H),8.46(d,J＝2.7Hz,1H),8.31(dd,J＝9.2,2.7Hz,1H),7.97(d,J＝2.7Hz,1H),7.74(dd,J＝8.9,2.8Hz,1H),7.47(d,J＝8.9Hz,1H),6.05(s,2H),4.19(t,J＝6.3Hz,2H),2.95(t,J＝6.8Hz,2H),2.57–2.54(m,3H),1.99–1.95(m,2H).ESI-MS m/z 495.2(M+H) -。
药理实验：
抗新冠病毒(SRAS-CoV-2)活性测试实验
将实验细胞以8万每孔的细胞密度接种到24孔细胞培养板中、于5％CO 2、37℃培养箱中培养过夜。第二天加入化合物(1μM或1 0μM、双复孔)和SRAS-CoV-2(按照MOI＝0.01感染)。在5％CO 2、37℃条件下于培养箱中培养1天后收集上清，检测上清病毒RNA拷贝数。如含化合物孔的上清病毒RNA拷贝数明显低于未加化合物组则表明化合物对所测SRAS-CoV-2有抑制作用。
化合物的抗SRAS-CoV-2活性由化合物对病毒上清RNA拷贝数的抑制率(％)表示，见表1和表2。计算公式如下：抑制率(％)＝1-化合物组病毒RNA拷贝数/不含化合物组病毒RNA拷贝数×100％
表1. 10μM时对新冠病毒RNA拷贝数的抑制率
测试化合物 10μM抑制率(％)
IIIA-1 N/A
IIIA-2 ＊
IIIA-3 ＊＊＊＊
IIIA-4 ＊＊＊＊
IIIA-5 N/A
IIIA-6 ＊＊＊＊
IIIA-7 ＊＊
IIIA-8 N/A
IIIA-20 ＊＊＊＊
IIIA-21 ＊
IIIA-22 ＊＊＊
IIIA-29 ＊＊＊
表2. 1μM时对新冠病毒RNA拷贝数的抑制率
测试化合物 1μM抑制率(％)
氯硝柳胺 ＊
IIIA-4 ＊＊＊＊
IIIA-6 ＊＊＊
IIIA-9 ＊＊＊＊
IIIA-10 N/A
IIIA-11 N/A
IIIA-12 ＊＊＊＊
IIIA-13 ＊＊
IIIA-14 ＊＊＊＊
IIIA-15 ＊＊
IIIA-16 N/A
IIIA-17 ＊＊＊
IIIA-18 ＊＊＊＊
IIIA-19 ＊＊
IIIA-23 N/A
IIIA-24 ＊＊
IIIA-25 N/A
IIIA-26 ＊＊
IIIA-27 N/A
IIIA-28 ＊＊
IIIA-30 ＊＊＊＊
IIIA-31 ＊
IIIA-32 ＊
IIIA-33 ＊＊＊＊
IIIB-1 ＊＊
IIIB-2 ＊＊＊
IIIB-3 ＊＊＊
IIIB-4 N/A
IIIB-5 ＊＊
IIIB-6 ＊＊＊
IIIB-7 ＊
IIIB-8 ＊
IIIB-9 ＊
IIIB-10 ＊
IIIB-11 ＊
IIIB-12 ＊
IIIB-13 ＊
IIIB-14 ＊
说明：N/A：无抑制；＊：1-25；＊＊：26-50；＊＊＊：51-75；＊＊＊＊：76-100
抗裂谷热病毒(RVFV)和发热伴血小板减少综合征病毒(SFTSV)活性测试
将Vero细胞以1x10 4/孔接种到96孔细胞培养板中，于5％CO 2、37℃培养箱中培养过夜。第二天加入不同浓度的化合物(见表1)，每个浓度梯度2个复孔。以同等体积的DMSO作为阴性对照，10μM的Benidipine作为阳性对照。化合物预处理1h后加入RVFV-eGFP、SFTSV感染(MOI＝0.5)，于5％CO 2、37℃培养箱中继续培养24h。病毒感染24h后用4％多聚甲醛固定细胞。RVFV-eGFP感染组固定后用DAPI染料(1:2000，室温避光10min)对细胞核进行染色即可用Operetta高内涵药物筛选系统进行检测。SFTSV感染组固定后孵育特异性NP抗体(1：2000，室温1h或4℃过夜)及荧光二抗(1:1000，室温避光1h)后再使用DAPI染料(1:2000，室温避光10min)对细胞核进行染色，最后，使用Operetta高内涵药物筛选系统进行检测。细胞核用405通道检测，与DMSO组相比，DAPI染到细胞核数越少说明该化合物在该浓度下有细胞毒性。病毒信号用488通道检测，与DMSO组相比，检测到细胞数量越少说明该化合物在该浓度下有抗病毒效果。
化合物的抗病毒活性由化合物对病毒复制的抑制率(％)表示，见表3和表4。计算公式如下：抑制率(％)＝(DMSO组平均读值-药物孔平均读值)/DMSO组平均读值×100。
表3不同浓度化合物对RVFV抑制率
测试化合物 1μM抑制率(％) 0.1μM抑制率(％) 0.01μM抑制率(％)
IIIA-4 ＊＊＊＊ ＊ ＊
IIIA-9 ＊＊＊＊ ＊ ＊
IIIA-14 ＊＊＊＊ ＊ ＊
IIIA-18 ＊＊＊＊ ＊ ＊
氯硝柳胺 ＊＊＊ ＊ ＊
说明：N/A：无抑制；＊：1-25；＊＊：26-50；＊＊＊：51-75；＊＊＊＊：76-100
表4不同浓度化合物对SFTSV抑制率
测试化合物 1μM抑制率(％) 0.1μM抑制率(％) 0.01μM抑制率(％)
IIIA-4 ＊＊＊ ＊ ＊
IIIA-9 ＊＊＊＊ ＊ ＊
IIIA-14 ＊＊＊ ＊ ＊
IIIA-18 ＊＊＊＊ ＊ ＊
IIIA-25 N/A N/A N/A
IIIA-27 ＊＊ N/A N/A
IIIA-12 ＊＊ N/A N/A
IIIA-13 ＊ N/A N/A
IIIA-16 ＊＊ N/A N/A
IIIA-17 ＊＊＊＊ ＊ ＊
IIIA-30 ＊＊＊＊ ＊ ＊
IIIA-31 ＊ N/A N/A
IIIA-32 ＊＊ N/A N/A
IIIA-33 ＊＊＊ ＊ N/A
IIIB-1 ＊ N/A N/A
IIIB-3 ＊＊＊＊ ＊ ＊
IIIB-6 ＊＊＊＊ ＊ ＊
IIIB-7 ＊ N/A N/A
IIIB-4 ＊ N/A N/A
IIIB-8 ＊＊＊ ＊ N/A
IIIB-9 ＊ N/A N/A
IIIB-5 ＊＊＊ ＊ N/A
IIIB-10 ＊ N/A N/A
IIIB-11 ＊ N/A N/A
IIIB-12 ＊ N/A N/A
IIIB-13 ＊ N/A N/A
IIIB-14 ＊ N/A N/A
氯硝柳胺 ＊＊＊ ＊ ＊
说明：N/A：无抑制；＊：1-25；＊＊：26-50；＊＊＊：51-75；＊＊＊＊：76-100
抗登革热病毒活性测试实验
将Vero细胞以每孔600,000个细胞的密度接种到6孔细胞培养板中、于5％CO 2、37℃培养箱中培养过夜。第二天加入化合物(1-5个浓度点、单点)和病毒(40-50PFU/孔)。细胞在5％CO2、37℃条件下于培养箱中培养2个小时，随后吸去上清，加入含对应浓度化合物的低融点琼脂糖培养液。细胞在5％CO2、33℃或37℃条件下于培养箱中培养6-7天，直至显微镜下无化合物的病毒感染对照孔内可观察到明显的病毒空斑。使用4％多聚甲醛固定细胞，使用结晶紫染色(参见表5)。计算每孔内空斑数量。
细胞毒性实验与抗病毒实验平行进行。将Vero细胞以每孔20,000个细胞的密度接种到96孔细胞培养板中、于5％CO 2、37℃培养箱中培养过夜。第二天加入化合物(1-5个浓度点、单点)。细胞在5％CO2、33℃或37℃条件下于培养箱中培养6-7天。然后用CCK-8检测每孔细胞活力。
化合物的抗病毒活性和细胞毒性分别由化合物对病毒空斑的抑制率(％)和细胞活率(％)表示，抑制率参见表6。计算公式如下：
抑制率(％)＝100-测试孔空斑数/病毒对照孔空斑数×100
细胞活率(％)＝(测试孔读值-培养基对照平均值)/(细胞对照平均值-培养基对照平均值)×100
EC 50和CC 50值通过Prism软件(version 5)计算，抑制曲线拟合方法为“log(inhibitor)vs.response--Variable slope”。
表5抗登革热病毒活性测试处理方法
Figure PCTCN2022100609-appb-000068
表6抗登革热病毒活性测试结果
测试化合物 1μM抑制率(％)
氯硝柳胺 ＊＊＊
IIIA‐4 ＊＊＊＊
IIIA‐6 ＊＊＊＊
IIIA‐10 ＊＊＊＊
IIIA‐21 N/A
说明：N/A：无抑制；＊：1-25；＊＊：26-50；＊＊＊：51-75；＊＊＊＊：76-100
抑制白介素6分泌活性测试实验
将细胞以每孔50000个细胞的密度接种到48孔细胞培养板中，于5％CO 2、37℃培养箱中培养过夜。第二天先加入化合物(1个浓度点，双复孔)，于20分钟后加入细胞因子白介素6，在5％CO 2、37℃培养箱中保持8小时，8小时后收细胞并测报告基因。 抑制率结果参见表7。
表7抑制白介素6分泌活性测试结果
测试化合物 1μM抑制率(％)
氯硝柳胺 ＊＊＊
IIIA‐4 ＊＊
IIIA‐3 ＊＊
IIIA‐2 ＊
IIIA‐9 ＊＊＊
IIIA‐24 ＊
IIIA‐15 ＊
IIIA‐26 ＊
IIIA‐18 ＊＊＊
说明：N/A：无抑制；＊：1-25；＊＊：26-50；＊＊＊：51-75；＊＊＊＊：76-100
抑制白介素33分泌活性测试实验
测试方法除将细胞因子白介素6改为细胞因子白介素33外，其余与抑制白介素6活性测试相同。抑制率结果参见表8。
表8抑制白介素33分泌活性测试结果
测试化合物 1μM抑制率(％) 5μM抑制率(％)
氯硝柳胺 ＊＊ ＊＊＊
IIIA‐4 ＊＊ ＊＊
IIIA‐9 N/A N/A
IIIA‐15 ＊＊ ＊＊＊
IIIA‐18 ＊＊＊＊ ＊＊＊＊
IIIA‐14 ＊ ＊＊
IIIA‐12 ＊＊＊＊ ＊＊＊＊
IIIA‐30 ＊＊＊＊ ＊＊＊
IIIA‐31 N/A ＊
IIIA‐32 ＊＊＊ ＊＊＊＊
说明：N/A：无抑制；＊：1-25；＊＊：26-50；＊＊＊：51-75；＊＊＊＊：76-100
抑制白介素1b分泌活性测试实验
测试方法除将细胞因子白介素6改为细胞因子白介素1b外，其余与抑制白介素6活性测试相同。抑制率结果参见表9。
表9抑制白介素1b分泌活性测试结果
测试化合物 1μM抑制率(％) 5μM抑制率(％)
氯硝柳胺 ＊＊ ＊＊＊
IIIA‐4 ＊＊ ＊＊＊＊
IIIA‐9 ＊ ＊
IIIA‐15 ＊＊ ＊＊＊
IIIA‐18 ＊＊＊ ＊＊＊＊
IIIA‐14 ＊＊ ＊＊＊
IIIA‐12 ＊＊＊ ＊＊＊＊
IIIA‐30 ＊＊ ＊＊＊＊
IIIA‐31 N/A N/A
IIIA‐32 ＊＊＊ ＊＊＊＊
说明：N/A：无抑制；＊：1-25；＊＊：26-50；＊＊＊：51-75；＊＊＊＊：76-100
抑制TNF-α活性测试实验
测试方法除将细胞因子白介素6改为细胞因子白介素TNF-α外，其余与抑制白介素6活性测试相同。抑制率结果参见表10。
表10抑制TNF-α活性测试结果
测试化合物 1μM抑制率(％) 5μM抑制率(％)
氯硝柳胺 ＊ ＊＊
IIIA‐4 ＊ ＊＊＊＊
IIIA‐9 N/A N/A
IIIA‐15 ＊＊ ＊＊
IIIA‐18 ＊＊＊ ＊＊＊＊
IIIA‐14 ＊＊ ＊＊＊
IIIA‐12 ＊＊＊＊ ＊＊＊＊
IIIA‐30 ＊＊＊ ＊＊＊＊
IIIA‐31 N/A N/A
IIIA‐32 ＊＊ ＊＊
说明：N/A：无抑制；＊：1-25；＊＊：26-50；＊＊＊：51-75；＊＊＊＊：76-100
从以上表1-10中的数据可以看出，本申请实施例的化合物在抗新型冠状病毒、裂谷热病毒和发热伴血小板减少综合征病毒活性方面优于氯硝柳胺，并且能抑制LPS诱导的白介素-6分泌，说明本申请实施例的部分化合物具有广谱抗病毒活性和抗炎活性，可被开发成抗病毒药物或抗炎性疾病药物的潜力。

Claims (10)

  1. 一种下述通式I所表示的酰胺类化合物、其前药、药学上可接受的盐、络合物或溶剂合物：
    Figure PCTCN2022100609-appb-100001
    其中，
    Y为苯环、5-6元杂芳环、苯环并5-6元杂芳环或5-6元杂芳环并5-6元杂芳环；
    Z为O或S；
    A 1为C-OR 11、C-SR 11、C-NHR 11、N或CR 12；
    R 11为氢原子、C1～C20烷基、C1～C20烷基羰基、C1～C20烷基氨基羰基、C1～C20烷基羰基氧基C1～C20烷基、
    Figure PCTCN2022100609-appb-100002
    C1～C20烷基磷酰基、C1～C20烷基磺酰基、C1～C20烷基取代的6-20元含有1-3个选自O、N或S的杂原子的杂环基羰基或
    Figure PCTCN2022100609-appb-100003
    上述C1～C20烷基任选地被选自羟基、-NH 2、C1～C20烷基氨基、氰基、羧基、卤素、
    Figure PCTCN2022100609-appb-100004
    C1-C10烷基磺酰基、C1-C10烷基磷酰基、C1-C10酰基中的一种或多种取代；
    R 7为C1～C10烷基、C1～C10烷基氨基C1～C10烷基或C3～C10环烷基；
    R 8为氢原子、卤素或C1～C10烷基；
    R 12为氢原子、卤素、氰基、硝基或C1～C20烷基；
    A 2、A 3、A 4、A 5各自独立地为N或CR 2；
    R 2彼此相同或不同，且各自独立地选自氢、羟基、卤素、C1～C6烷基氧基、C1～C6烷基、氨基(-NH 2)、硝基、氰基、羧基、醛基、C1～C6烷基羰基、C1～C6烷基磺酰基、C1～C6烷基磺酰氨基和C1～C6烷基氧基羰基，上述羟基、氨基、羧基、C1～C6烷基任选地被羟基、氨基、氰基、羧基、卤素、C1-C10烷基磺酰基、C1-C10烷基磷酰基、C1-C10烷基羰基中的一种或多种取代；
    R 3为氢原子或C1～C6烷基；
    R 4至R 6各自独立地选自氢原子、羟基、氨基、卤素、硝基、氰基、C1～C6烷基、C1～C6烷基氧基和C1～C6烷基硫基，上述C1～C6烷基任选地被羟基、氨基、氰基、羧基、卤素、C1-C6烷基磺酰基、C1-C6烷基磷酰基、C1-C6烷基酰基中的一种或多种取 代。
  2. 根据权利要求1所述的酰胺类化合物、其前药、药学上可接受的盐、络合物或溶剂合物，其中，
    Y为苯环、吡啶环或噻唑环；
    R 11为氢原子、C1～C10烷基、C1～C10烷基羰基、C1～C10烷基羰基、C1～C10烷基氨基羰基氧基C1～C10烷基、C1～C10烷基取代的6-10元含有1-3个选自O、N或S的杂原子的杂环基羰基或
    Figure PCTCN2022100609-appb-100005
    上述C1～C10烷基任选地被选自羟基、氨基、氰基、羧基、卤素、
    Figure PCTCN2022100609-appb-100006
    C1-C10烷基磺酰基、C1-C10烷基磷酰基、C1-C10烷基羰基中的一种或多种取代；
    R 7为C1～C6烷基、C1～C6烷基氨基C1～C6烷基或C3～C7环烷基；
    R 8为氢原子、卤素或C1～C2烷基；
    R 12为氢原子、卤素、氰基、硝基或C1～C6烷基；
    R 2彼此相同或不同，且各自独立地选自氢、羟基、卤素、C1～C4烷基氧基、C1～C4烷基、氨基、硝基、氰基和C1～C4烷基羰基，上述C1～C4烷基任选地被羟基、氨基、氰基、羧基、卤素、C1-C4烷基磺酰基、C1-C4烷基磷酰基、C1-C4烷基羰基中的一种或多种取代；
    R 3为氢原子或C1～C4烷基；
    R 4至R 6各自独立地选自氢原子、羟基、氨基、卤素、硝基、氰基、C1～C4烷基和C1～C4烷基氧基，上述C1～C4烷基任选地被羟基、氨基、氰基、羧基、卤素中的一种或多种取代。
  3. 根据权利要求2所述的酰胺类化合物、其前药、药学上可接受的盐、络合物或溶剂合物，其中，
    R 11为氢原子、C1～C6烷基、卤代C1～C6烷基、氨基C1～C6烷基、羟基、C1～C6烷基、C1～C6烷基羰基、C1～C6烷基氨基羰基、C1～C6烷基羰基氧基C1～C6烷基、C1～C6烷基氨基C1～C6烷基羰基、氨基C1～C6烷基羰基、
    Figure PCTCN2022100609-appb-100007
    取代的C1～C6烷基羰基、C1～C6烷基取代的6-8元含有1-3个选自O、N或S的杂原子的杂环基羰基或
    Figure PCTCN2022100609-appb-100008
    R 7为C1～C4烷基、C1～C3烷基氨基C1～C4烷基或C3～C6环烷基；
    R 8为氢原子或甲基；
    R 12为氢原子、卤素、氰基或C1～C4烷基；
    A 2、A 3、A 4、A 5中至多两个为N；
    R 2彼此相同或不同，且各自独立地选自氢、羟基、卤素、C1～C2烷氧基、C1～C2烷基、C1～C2烷基羰基、卤代C1～C2烷氧基、卤代C1～C2烷基、卤代C1～C2烷基羰基、 氨基和硝基；
    R 3为氢原子；
    R 4至R 6各自独立地选自氢原子、卤素、C1～C4烷基、卤代C1～C4烷基、C1～C4烷氧基、卤代C1～C4烷氧基。
  4. 根据权利要求3所述的酰胺类化合物、其前药、药学上可接受的盐、络合物或溶剂合物，其中，
    R 11为氢原子、C1～C4烷基、C1～C6烷基羰基、C1～C5烷基氨基羰基、C1～C5烷基羰基氧基C1～C5烷基、
    Figure PCTCN2022100609-appb-100009
    取代的C1～C4烷基、取代的C1～C4烷基羰基、
    Figure PCTCN2022100609-appb-100010
    或者
    Figure PCTCN2022100609-appb-100011
  5. 根据权利要求1所述的酰胺类化合物、其前药、药学上可接受的盐、络合物或溶剂合物，其中，所述通式I所表示的酰胺类化合物为下面通式II、IIIA或IIIB所示的化合物：
    Figure PCTCN2022100609-appb-100012
    其中，A 1为C-OR 11、C-SR 11、C-NHR 11或CR 12；
    R 11、R 12、R 2、R 4至R 6和Y的定义与权利要求1中的定义相同。
  6. 根据权利要求1所述的酰胺类化合物、其前药、药学上可接受的盐、络合物或溶剂合物，其中，所述通式I所表示的酰胺类化合物为下面通式IV所示的化合物：
    Figure PCTCN2022100609-appb-100013
    其中，R 11、R 2、R 4和R 5的定义与权利要求1中的定义相同。
  7. 根据权利要求1所述的酰胺类化合物、其前药、药学上可接受的盐、络合物或溶剂合物，其中，所述化合物或盐选自以下结构：
    Figure PCTCN2022100609-appb-100014
    Figure PCTCN2022100609-appb-100015
  8. 一种药物组合物，其包含治疗有效量的选自权利要求1至7中任一项所述的化合物、其前药、药学上可接受的盐、络合物和溶剂合物中的一种或几种，和任选的可药用载体。
  9. 根据权利要求1至7中任一项所述的化合物、其前药、药学上可接受的盐、络合 物和溶剂合物或权利要求8所述的药物组合物在制备抗病毒药物或治疗抗炎症性疾病的药物中的用途。
  10. 根据权利要求9所述的用途，其中，所述病毒为选自DNA病毒、RNA病毒中的至少一种；
    特别地，所述DNA病毒选自乙型肝炎病毒、人乳头瘤病毒、疱疹病毒、噬菌体病毒；所述RNA病毒选自流感病毒、禽流感病毒、寨卡病毒、登革热病毒、呼吸道合胞病毒、SARS病毒、MERS病毒、新型冠状病毒(SARS-CoV-2)、布尼亚病毒、艾滋病病毒、埃博拉病毒、丙型肝炎病毒、乙型脑炎病毒、鼻病毒、脊髓灰质炎病毒、柯萨奇病毒、轮状病毒、烟草花叶病毒、噬菌体病毒、马尔堡病毒、肠道病毒，
    特别地，所述RNA病毒为冠状病毒、布尼亚病毒、登革热病毒中的至少一种；
    特别地，所述冠状病毒为SARS-CoV-2；所述布尼亚病毒为裂谷热病毒；
    更特别地，所述病毒为登革热病毒；
    所述炎症性疾病为炎症性皮肤病、炎症性肠病、炎症性关节病及其他自身免疫性疾病。
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DATABASE REGISTRY 6 July 2015 (2015-07-06), ANONYMOUS : "-3-Pyridinecarboxamide, 5-chloro-1,2-dihydro-2-oxo-N-[4- (trifluoromethyl)phenyl]-(CA INDEX NAME)", XP093017209, retrieved from STN Database accession no. 1795177-57-9 *
DATABASE REGISTRY ANONYMOUS : "-2-Pyrazinecarboxamide, N-[4-(trifluoromethoxy)phenyl]- (CA INDEX NAME) ", XP093017213, retrieved from STN *
DOLEŽAL MARTIN, ZITKO JAN, KEŠETOVIČOVÁ DIANA, KUNEŠ JIŘÍ, SVOBODOVÁ MICHAELA: "Substituted N-Phenylpyrazine-2-carboxamides: Synthesis and Antimycobacterial Evaluation", MOLECULES, vol. 14, no. 10, 1 January 2009 (2009-01-01), pages 4180 - 4189, XP093017204, DOI: 10.3390/molecules14104180 *
JÁN KOZIC, EVA NOVOTNÁ, MARIE VOLKOVÁ, JIŘINA STOLAŘÍKOVÁ, FRANTIŠEK TREJTNAR, JARMILA VINŠOVÁ: "Synthesis and in vitro antimycobacterial activity of 2-methoxybenzanilides and their thioxo analogues", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER MASSON SAS, vol. 56, 1 October 2012 (2012-10-01), pages 387 - 395, XP055068727, ISSN: 02235234, DOI: 10.1016/j.ejmech.2012.07.044 *
JUANG YU-PU; CHOU YU-TING; LIN RU-XIAN; MA HSIU-HUA; CHAO TAI-LING; JAN JIA-TSRONG; CHANG SUI-YUAN; LIANG PI-HUI: "Design, synthesis and biological evaluations of niclosamide analogues against SARS-CoV-2", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 235, 19 March 2022 (2022-03-19), AMSTERDAM, NL , XP087022544, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2022.114295 *
SHAMIM, K. ET AL.: "Application of Niclosamide and Analogs as Small Molecule Inhibitors of Zika Virus and SARS-Cov-2 Infection", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 40, 6 March 2021 (2021-03-06), XP086557976, DOI: 10.1016/j.bmcl.2021.127906 *
STACHULSKI, A. V. ET AL.: "Thiazolides as Novel Antiviral Agents. 2. Inhibition of Hepatitis C Virus Replication", JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, no. 24, 7 November 2011 (2011-11-07), pages 8670 - 8680, XP055977140, DOI: 10.1021/jm201264t *
XU JIMIN, BERASTEGUI-CABRERA JUDITH, CARRETERO-LEDESMA MARTA, CHEN HAIYING, XUE YU, WOLD ERIC A., PACHÓN JERÓNIMO, ZHOU JIA, SÁNCH: "Discovery of a Small Molecule Inhibitor of Human Adenovirus Capable of Preventing Escape from the Endosome", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 22, no. 4, pages 1617, XP093017201, DOI: 10.3390/ijms22041617 *

Cited By (1)

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