WO2022143424A1 - 一种多环吡啶酮衍生物和药物组合物及其应用 - Google Patents

一种多环吡啶酮衍生物和药物组合物及其应用 Download PDF

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WO2022143424A1
WO2022143424A1 PCT/CN2021/140943 CN2021140943W WO2022143424A1 WO 2022143424 A1 WO2022143424 A1 WO 2022143424A1 CN 2021140943 W CN2021140943 W CN 2021140943W WO 2022143424 A1 WO2022143424 A1 WO 2022143424A1
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substituent
optionally substituted
hydroxy
alkyl
alkoxy
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French (fr)
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蒋宇扬
唐林
张存龙
吴伟彬
李安琪
陈大伟
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深圳市坤健创新药物研究院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the invention belongs to the field of medicine, and in particular, relates to a polycyclic pyridone derivative, a pharmaceutical composition containing the polycyclic pyridone derivative, and a combination of the polycyclic pyridone derivative and the pharmaceutical composition. application.
  • Influenza is mainly caused by influenza virus infection, which causes an average of three to five million hospitalizations and 290,000 to 650,000 deaths each year. Influenza A virus is often the cause of major influenza outbreaks.
  • highly invasive virus strains such as H1N1, H5N1 and H7N9
  • the existing anti-influenza drugs can no longer meet people's needs. Therefore, it is necessary to develop anti-influenza drugs with novel mechanisms of action.
  • the life cycle of influenza virus is a complex biological process, which can be divided into the following steps: (I) the virus binds to the host cell surface receptor; (II) the virus is endocytosed into the host cell, the viral membrane and endosome Membrane fusion; (III) release of viral ribonucleoproteins (vRNPs) into the cytoplasm, which are then transported into the nucleus; (IV) transcription and replication of viral RNA; (V) export of mRNA and vRNP from the nucleus, synthesis of related proteins ; (VI) Assembly of progeny viruses, which are released from cells in the form of budding.
  • the viral proteins and host cell proteins involved in the influenza virus infection cycle are important targets for the development of anti-influenza virus drugs. Many anti-influenza drugs have been developed against these targets.
  • Small molecule anti-influenza virus preparations are mainly divided into five categories: (I) M2 ion channel protein inhibitors (amantadine, rimantadine, etc.); (II) neuraminidase (NA) inhibitors (zanamivir, oseltamivir, peramivir, lanimivir, etc.); (III) hemagglutinin (HA) inhibitors (arbidol, nitazoxanide, etc.); (IV) RNA-dependent RNA polymerase ( RdRp) inhibitors (favipiravir, baloxavir, etc.); (V) nucleoprotein (NP) inhibitors (naproxen, etc.). So far, only a handful of anti-influenza drugs have been approved.
  • M2 ion channel protein inhibitors amantadine, rimantadine, etc.
  • NA neuraminidase
  • HA hemagglutinin
  • RdRp RNA-
  • NAIs neuroneuraminidase inhibitors
  • drug-resistant influenza virus mutants have emerged, which not only reduces the efficacy of clinical anti-influenza drugs, but also poses a further threat to public health security. Therefore, it is of great significance and broad application prospect to develop anti-influenza drugs with new mechanisms.
  • Baloxavir marboxil trade name Xofluza
  • Baloxavir marboxil trade name Xofluza
  • baloxavir prevents the release of progeny virions from infected host cells
  • baloxavir is a novel cap-dependent endonuclease (CEN) inhibitor
  • CEN cap-dependent endonuclease
  • cap Dependent endonucleases are present in the polymerase acidic protein (PA) subunit of influenza A and B viruses.
  • Viral mRNA transcription depends on a unique "cap-snatching" mechanism: PB2 binds to the 5'-cap transcript in the host, and the cap-dependent endonuclease in PA is approximately 12 nucleotides away from the 5'-cap The acid position was endo-cut, and the excised cap structure was used as a primer for viral mRNA transcription. Therefore, inhibition of this endonuclease can inhibit mRNA transcription, thereby inhibiting viral replication.
  • baloxavir compared with oseltamivir, baloxavir has the advantage of not requiring a course of treatment (5 days of continuous treatment with oseltamivir), and only needs to be administered once a day.
  • viral titer and safety are superior to oseltamivir and other advantages. This may break the pattern that neuraminidase inhibitors have dominated the influenza market in the past 20 years, and provide a new treatment mechanism for influenza, which has attracted widespread attention in the industry.
  • the object of the present invention is to provide a new class of compounds as influenza virus RNA polymerase inhibitors, more specifically, the present invention provides a class of new compounds as influenza virus cap-dependent endonuclease inhibitors, such compounds
  • the compositions and compositions thereof can be used for preventing, treating, treating or alleviating the symptoms of patients after influenza virus infection.
  • the compounds of the present invention can not only inhibit the replication of influenza virus well, but also have lower cytotoxicity, and the anti-influenza virus activity of one of the compounds is even better than that of similar compounds on the market. Therefore, the compounds provided by the present invention have better influenza virus activity compared with the existing similar compounds.
  • a first aspect of the present invention provides a polycyclic pyridone derivative, which is a compound represented by formula (I) or a stereoisomer, tautomer, Nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof;
  • P is hydrogen, benzyl, n-hexyl or a P R group forming a prodrug
  • a 1 is CR 1A R 1B , S or O;
  • a 2 is CR 2A R 2B , S or O;
  • a 3 is CR 3A R 3B , S or O;
  • a 4 is each independently CR 4A R 4B , S or O;
  • the number of heteroatoms in the ring-forming atoms of the ring composed of A 1 , A 2 , A 3 , n A 4 , the nitrogen atom adjacent to A 1 and the carbon atom adjacent to A 4 is 1 or 2;
  • R 1A and R 1B are each independently hydrogen, halogen, alkyl, haloalkyl, alkoxy or phenyl;
  • R 2A and R 2B are each independently hydrogen, halogen, alkyl, haloalkyl, alkoxy, or phenyl;
  • R3A and R3B are each independently hydrogen, halogen, alkyl, haloalkyl, alkoxy or phenyl;
  • R4A and R4B are each independently hydrogen, halogen, alkyl, haloalkyl, alkoxy or phenyl;
  • R3A and R3B optionally together with adjacent carbon atoms form a carbocyclic or heterocyclic ring
  • n 1 or 2;
  • R1 and R2 are each independently hydrogen , halogen, hydroxy, alkyl, alkoxy or haloalkyl;
  • P R is at least one of the groups selected from the following formulae a)-ac):
  • L is a straight-chain or branched-chain alkylene group, or a straight-chain or branched-chain alkenylene group
  • K is hydrogen or alkyl optionally substituted with substituent group A;
  • P R0 is alkyl optionally substituted by substituent A or alkenyl optionally substituted by substituent A;
  • R1 is carbocyclyl optionally substituted with substituent A, heterocyclyl optionally substituted with substituent A, alkylamino optionally substituted with substituent A, or alkyl optionally substituted with substituent A Sulfur group;
  • P R2 is alkyl optionally substituted with substituent A, carbocyclyl optionally substituted with substituent A, heterocyclyl optionally substituted with substituent A, carbocycloalkyl optionally substituted with substituent A , a heterocycloalkyl optionally substituted by a substituent A, or a trialkylsilyl;
  • P R3 are each independently hydrogen, alkyl
  • P R4 are each independently alkyl optionally substituted with substituent A, carbocyclyl optionally substituted with substituent A, heterocyclyl optionally substituted with substituent A, alkane optionally substituted with substituent A amino, carbocycloalkyl optionally substituted with substituent A, heterocycloalkyl optionally substituted with substituent A, or trialkylsilyl;
  • PR5 is independently OBn
  • P R6 is a carbocyclyl optionally substituted by substituent A, or a heterocyclyl optionally substituted by substituent A;
  • P R7 are each independently alkyl optionally substituted with substituent A;
  • P R8 is an alkoxy optionally substituted by substituent A
  • P R9 is alkoxy optionally substituted with substituent A, alkylamino optionally substituted with substituent A, carboepoxy optionally substituted with substituent A, heterocycle optionally substituted with substituent A oxy, carbocyclic amino optionally substituted with substituent A, or heterocyclic amino optionally substituted with substituent A;
  • P R8 and P R9 optionally together with adjacent phosphorus atoms form a heterocycle optionally substituted by substituent A;
  • P R10 is alkyl optionally substituted with substituent A, carbocyclyl optionally substituted with substituent A, heterocyclyl optionally substituted with substituent A, carbocycloalkyl optionally substituted with substituent A , or heterocycloalkyl optionally substituted by substituent A;
  • R11 is alkyl optionally substituted with substituent A, alkenyl optionally substituted with substituent A, carbocyclyl optionally substituted with substituent A, or heterocyclyl optionally substituted with substituent A;
  • Substituent A is at least one selected from the group consisting of oxo, alkyl, hydroxyalkyl, amino, alkylamino, carbocyclyl, heterocyclyl, carbocycloalkyl, alkylcarbonyl , halogen, hydroxyl, carboxyl, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyloxy, alkylaminocarbonyloxy , alkylaminoalkyl, alkoxy, cyano, nitro, azido, alkylsulfonyl, trialkylsilyl, and phosphoryl.
  • the polycyclic pyridone derivative is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or their prodrugs,
  • P is hydrogen, benzyl, n-hexyl or a P R group forming a prodrug
  • R1 and R2 are each independently hydrogen , halogen, hydroxy, alkyl, alkoxy or haloalkyl;
  • PR is at least one selected from the following groups:
  • L is a straight-chain or branched alkylene group
  • K is hydrogen or alkyl optionally substituted with substituent A;
  • P R0 is an alkyl group optionally substituted by substituent A;
  • P R1 is a carbocyclyl optionally substituted by a substituent A, a heterocyclyl optionally substituted by a substituent A;
  • P R2 is alkyl optionally substituted by substituent A, carbocyclyl optionally substituted by substituent A, heterocyclyl optionally substituted by substituent A, carbocycloalkyl optionally substituted by substituent A , a heterocycloalkyl optionally substituted by substituent A;
  • P R3 are each independently hydrogen, alkyl
  • P R4 is an alkyl group optionally substituted by substituent A, a carbocyclic group optionally substituted by substituent A, and a heterocyclic group optionally substituted by substituent A;
  • P R6 is a carbocyclyl optionally substituted by a substituent A, a heterocyclyl optionally substituted by a substituent A;
  • P R8 is an alkoxy optionally substituted by substituent A
  • P R9 is alkoxy optionally substituted by substituent A, alkylamino optionally substituted by substituent A, carboepoxy optionally substituted by substituent A, heterocycle optionally substituted by substituent A oxy, carbocyclic amino optionally substituted with substituent A, or heterocyclic amino optionally substituted with substituent A;
  • P R8 and P R9 optionally together with adjacent phosphorus atoms form a heterocycle optionally substituted by substituent A;
  • Substituent A is selected from at least one of the group consisting of: oxo, alkyl, alkylamino, carbocyclyl, heterocyclyl, , alkylcarbonyl, halogen, hydroxy, alkylcarbonylamino, Alkylcarbonyloxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylaminocarbonyloxy, alkoxy, nitro, azide, alkylsulfonyl, and trialkylsilyl.
  • R 1 and R 2 are each independently hydrogen, halogen, alkyl, and alkoxy; further preferably, R 1 and R 2 are each independently hydrogen, F , Cl, Br, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;
  • the C 1 -C 4 alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
  • the C 1 -C 4 alkoxy group is an alkoxy group corresponding to the above C 1 -C 4 alkyl group.
  • the compound shown in general formula II is selected from:
  • the present invention provides a method for preparing the above-mentioned compounds.
  • the compounds represented by the general formula II are obtained through a series of reactions using benzaldehydes with different substitutions as starting materials.
  • the specific synthetic route is shown in Figure 1.
  • a second aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned polycyclic pyridone derivative as an active ingredient and a pharmaceutically acceptable excipient.
  • the present invention can contain the derivatives of the compounds represented by the general formula I and their pharmaceutically acceptable salts and hydrates as active ingredients, mixed with pharmaceutically acceptable excipients to prepare a composition, and prepared into a clinically acceptable composition
  • pharmaceutically acceptable excipients refer to diluents, adjuvants or carriers that can be used in the pharmaceutical field.
  • dosage forms include injections, tablets, capsules, inhalants, suspensions and the like commonly used in clinical practice.
  • the compounds involved in the present invention or their pharmaceutically acceptable salts, hydrates and prodrugs can be used alone as the only anti-influenza drugs, or can be used in combination with existing anti-influenza drugs for prevention, treatment, treatment or Relief of symptoms in patients following influenza virus infection.
  • the third aspect of the present invention provides the above-mentioned polycyclic pyridone derivatives and/or pharmaceutical compositions in the preparation of treatment or prevention of diseases caused by viruses with cap-dependent endonucleases.
  • the viruses with cap-dependent endonucleases include, but are not limited to, influenza viruses.
  • the fourth aspect of the present invention provides the application of the above-mentioned polycyclic pyridone derivatives and/or pharmaceutical compositions in the preparation of influenza virus RNA polymerase inhibitors.
  • the fifth aspect of the present invention provides the use of the above-mentioned polycyclic pyridone derivatives and/or pharmaceutical compositions in the preparation of medicaments for preventing, treating, treating or alleviating symptoms of patients infected with influenza virus.
  • Fig. 1 is the synthetic route diagram of the polycyclic pyridone derivatives of the present invention.
  • Step 1 Add 20 mmol of compound 7a, 10 mL of tetrahydrofuran and 2 mL of absolute ethanol to a 100 mL reaction flask, slowly add 10 mmol of sodium borohydride under ice bath, and stir at room temperature for 1.5 hours.
  • the reaction solution was poured into ice water, most of the organic solvent was evaporated under reduced pressure, the product was then extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness under reduced pressure to obtain compound 8a, which was used directly for next reaction.
  • Step 2 1 mmol of compound 1, 1.2 mmol of compound 8a and 2.5 mmol of a 50 wt.% ethyl acetate solution of 1-propylphosphoric anhydride were added to a 100 mL reaction flask, and the mixture was stirred at 50°C overnight. After the completion of the reaction monitored by TLC, the reaction solution was poured into an appropriate amount of ice water, the product was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by thin chromatography (20cm x 20cm) to give compound 9a.
  • Step 3 0.5 mmol of compound 9a, 1.5 mmol of lithium chloride and 5 mL of DMA were added to a 50 mL reaction flask, and the reaction solution was stirred at 80° C. for 3 hours. Under stirring in an ice bath, 2 mL of acetone, 9 mL of dilute hydrochloric acid (0.5 M) and 4 mL of water were added to the reaction solution, and stirring was continued for 1 hour under an ice bath. The product was precipitated as a solid, which was filtered off with suction, and dried to obtain the target compound 10a as a pale pink solid. Yield 92.3%.
  • Step 1 Compound 2 (3.15 g, 21.0 mmol), NBS (4.09 g, 23.0 mmol) and 30 mL of chlorobenzene were sequentially added to a 100 mL reaction flask. The reaction solution was heated to 70°C, AIBN (0.13 g, 0.80 mmol) was slowly added, and stirring was continued at 70°C for 1 hour. After the reaction solution was cooled to room temperature, the solvent in the reaction solution was evaporated under reduced pressure to obtain the crude product of compound 3, which was directly used in the next reaction without purification.
  • Step 2 Compound 3 obtained in the previous step, triphenylphosphine (5.51 g, 21.0 mmol) and 25 mL of acetone were sequentially added to the 100 mL reaction flask, and the reaction solution was refluxed for 1 hour. After the reaction solution was cooled to room temperature, a white solid was obtained by suction filtration. The white solid obtained above, sodium methoxide (1.35 g, 25.0 mmol) and 30 mL of methanol were added to a 100 mL reaction flask. The reaction solution was stirred at room temperature for 0.5 hours, then heated to reflux, 11 mmol of 4b was added, and reflux was continued for 6 hours.
  • the reaction solution was cooled to room temperature, the reaction solution was poured into a large amount of ice water, the product was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain the crude product.
  • the crude product was fully mixed and stirred with 50 mL of petroleum ether, most impurities were precipitated as solids, the solids were filtered off, and the filtrate was evaporated to dryness under reduced pressure to obtain the preliminary purified compound 5b, which was directly used in the next reaction without further purification.
  • Step 3 The compound 5.0 mmol 5b obtained in the previous step, potassium hydroxide (0.56 g, 10.0 mmol), 20 mL methanol and 1 mL water were added to a 100 mL reaction flask, and the reaction solution was refluxed for 4 hours. After the reaction solution was cooled to room temperature, the reaction solution was poured into a large amount of ice water and kept stirring, and hydrochloric acid solution (4M) was added for acidification, and the crude product was precipitated as a solid. The solid was obtained by suction filtration. The dried solid was fully mixed and stirred with 50 mL of petroleum ether. Most of the impurities were dissolved in the petroleum ether.
  • Step 4 The compound 1.0 mmol 6b obtained in the previous step was added to a 100 mL reaction flask, dissolved in 20 mL of dichloromethane, thionyl chloride (0.13 g, 1.1 mmol) was slowly added under stirring at room temperature, and the reaction solution was refluxed for 1.5 hours. After the reaction solution was cooled to room temperature, 0.17 g of anhydrous aluminum chloride was slowly added, and the mixture was stirred at room temperature for 3 hours.
  • Step 5 Same as step 1 in Example 1 to obtain compound 8b.
  • 1 H NMR 400MHz, Chloroform-d
  • Step 6 Same as step 2 of Example 1 to obtain compound 9b. A pair of diastereomers in a 3:4 ratio.
  • 1 H NMR 400MHz, Chloroform-d
  • Step 7 The same as step 3 in Example 1, compound 10b was obtained in a yield of 91.5%. Diastereomers in a 3:7 ratio.
  • 1 H NMR 400MHz, Chloroform-d
  • ⁇ 7.69-7.30 m,5H
  • 7.21(t,J 7.6Hz,1H)
  • 7.11(t,J 8.9Hz,1H)
  • MDCK cells were seeded into a 96-well plate at a density of 2.5 ⁇ 10 4 /well.
  • the compound-containing virus maintenance solution (MEM medium supplemented with 2 ⁇ g/mL of TPCK, trypsin and 0.08% BSA) was added.
  • the highest detection concentration of the compound was 200nM, 3-fold dilution, and 8 concentrations: 100nM, 66.67nM, 22.22nM, 7.41nM, 2.47nM, 0.82nM, 0.27nM, 0.09nM.
  • a virus control group without drug addition and a cell control group without virus infection without drug addition were set. In the cytotoxicity experimental group, no virus was added, and the medium was used instead. There are two duplicate holes.
  • CPE cytopathic effect
  • Antiviral activity test and cytotoxicity test show that the compounds of the present invention have good antiviral activity, especially, some compounds have antiviral activity against influenza virus (A/FortMonmouth/1/1947) and influenza virus (A/WuhanHanFang/359/1995
  • the inhibitory activity of ) is comparable to that of baloxavir; at the same time, the compound of the present invention has very low cytotoxicity, and the TC 50 is far less than the cytotoxicity of baloxavir.
  • Table 1 TC 50 and IC 50 activity data of the compounds of the present invention against influenza virus (A/FortMonmouth/1/1947, A/WuhanHanFang/359/1995) in vitro
  • TC 50 the half toxic concentration of the drug
  • IC 50 the half inhibitory concentration of the drug to the virus.
  • Example A Pharmacokinetic experiment in large animal cynomolgus monkeys

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Abstract

提供了一种多环吡啶酮衍生物和药物组合物及其应用。该多环吡啶酮衍生物为式(I)所示化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药。与已有的同类化合物相比，所述化合物不仅能很好的抑制流感病毒的复制，还具有更低的细胞毒性。

Description

一种多环吡啶酮衍生物和药物组合物及其应用 技术领域
本发明属于药物领域，具体地，涉及一种多环吡啶酮衍生物，一种含有该多环吡啶酮衍生物的药物组合物，以及所述多环吡啶酮衍生物和所述药物组合物的应用。
背景技术
流行性感冒主要是由流感病毒感染引起，流感平均每年可以导致三百万到五百万的住院病例和29万到65万的死亡病例。引起流感大爆发的往往是甲型流感病毒。但是近年来，随着H1N1，H5N1和H7N9等高侵袭性病毒株的出现，以及越来越多的耐药病毒株的出现，现有的抗流感药物已经不能满足人们的需求。因此，开发出具有新型作用机制的抗流感药物十分必要。
流感病毒的生命周期是一个复杂的生物学过程，可分为以下几个步骤：(I)病毒与宿主细胞表面受体结合；(II)病毒被内吞到宿主细胞中，病毒膜和内体膜相融合；(III)病毒核糖核蛋白(vRNPs)释放到细胞质中，然后被转运到细胞核中；(IV)病毒RNA的转录和复制；(V)mRNA和vRNP从细胞核输出，相关蛋白的合成；(VI)子代病毒的组装，通过萌芽的形式从细胞中释放出来。流感病毒感染周期中涉及到的病毒蛋白和宿主细胞蛋白都是研发抗流感病毒药物的重要靶标。针对这些靶标已经开发了许多抗流感药物。
小分子抗流感病毒制剂主要分为五类：(I)M2离子通道蛋白抑制剂(金刚烷胺，金刚乙胺等)；(II)神经氨酸酶(NA)抑制剂(扎那米韦，奥司他韦，帕拉米韦，拉尼米韦等)；(III)血凝素(HA)抑制剂(阿比多尔，硝唑尼特等)；(IV)RNA依赖的RNA聚合酶(RdRp)抑制剂(法匹拉韦，巴洛沙韦等)；(V)核蛋白(NP)抑制剂(萘普生等)。到目前为止，只有少数几种抗流感病毒药物被批准上市。
目前，临床上使用的主要抗流感药物是神经氨酸酶抑制剂(NAI)。但近年来，耐药性流感病毒突变株不断出现，这不仅降低了临床上抗流感药的疗效，而且对公共卫生安全进一步构成了威胁。因此，开发具有新机制的抗流感药物具有重要的意义和广阔的应用前景。
巴洛沙韦(Baloxavir marboxil)，商品名Xofluza，于2018年10月获得FDA批准上 市，是近二十年来首个具有新作用机制的抗流感药物。它由日本盐野义公司开发，并于2018年2月在日本首次获得批准上市。与神经氨酸酶抑制剂不同，巴洛沙韦可防止子代病毒体从感染的宿主细胞中释放，巴洛沙韦是一种新型的帽依赖型核酸内切酶(CEN)抑制剂，帽依赖性核酸内切酶存在于甲型和乙型流感病毒的聚合酶酸性蛋白(PA)亚基中。病毒mRNA转录取决于独特的“抢帽(cap-snatching)”机制：PB2与宿主中5'-cap转录物结合，PA中的帽依赖核酸内切酶在距5'-cap约12个核苷酸的位置内切，将切下来的帽结构作为引物用于病毒mRNA转录。因此，抑制该核酸内切酶可以抑制mRNA转录，进而抑制病毒复制。此外，与奥司他韦相比，巴洛沙韦具有不需疗程化治疗(奥司他韦连续治疗5天)，仅需一天一次给药，疾病症状缓解时间与奥司他韦相比非劣效，病毒滴度和安全性方面优于奥司他韦等优势。这或将打破近20年来神经氨酸酶抑制剂主导流感市场的格局，为流感提供全新的治疗机制，得到业界广泛关注。
基于巴洛沙韦进行优化，以期得到活性更好的抗流感药物是本领域的进一步目标。
发明内容
本发明的目的是提供一类作为流感病毒RNA聚合酶抑制剂的新化合物，更具体地说，本发明提供一类作为流感病毒的帽依赖性核酸内切酶抑制剂的新化合物，此类化合物及其组合物可以用于预防、处理、治疗或减轻流感病毒感染后患者的症状。与已有的同类化合物相比，本发明的化合物不仅能很好的抑制流感病毒的复制，还具有更低的细胞毒性，其中一个化合物的抗流感病毒活性更是优于上市的同类化合物。因此，本发明提供的化合物相对于已有的同类化合物而言，具有更好的流感病毒活性。
为了实现上述目的，本发明的第一方面提供一种多环吡啶酮衍生物，其为式(I)所示化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药；
Figure PCTCN2021140943-appb-000001
其中，
P为氢、苄基、正己基或形成前药的P R基；
A 1为CR 1AR 1B、S或O；
A 2为CR 2AR 2B、S或O；
A 3为CR 3AR 3B、S或O；
A 4各自独立地为CR 4AR 4B、S或O；
并且，由A 1、A 2、A 3、n个A 4，与A 1邻接的氮原子以及与A 4邻接的碳原子所构成的环的成环原子中杂原子的个数为1个或2个；
R 1A和R 1B各自独立地为氢、卤素、烷基、卤代烷基、烷氧基或苯基；
R 2A和R 2B各自独立地为氢、卤素、烷基、卤代烷基、烷氧基或苯基；
R 3A和R 3B各自独立地为氢、卤素、烷基、卤代烷基、烷氧基或苯基；
R 4A和R 4B各自独立地为氢、卤素、烷基、卤代烷基、烷氧基或苯基；
R 3A和R 3B任选与邻接的碳原子共同形成碳环或杂环；
n为1或2；
R 1和R 2各自独立地为氢、卤素、羟基、烷基、烷氧基或卤代烷基；
P R为选自以下的式a)-ac)中的基团中的至少一种：
a)-C(＝O)-P R0；
b)-C(＝O)-P R1；
c)-C(＝O)-L-P R1；
d)-C(＝O)-L-O-P R1；
e)-C(＝O)-L-O-L-O-P R1；
f)-C(＝O)-L-O-C(＝O)-O-P R1；
g)-C(＝O)-O-P R2；
h)-C(＝O)-N(-K)(P R2)；
i)-C(＝O)-O-L-O-P R2；
j)-C(P R3) 2-O-P R4；
k)-C(P R3) 2-O-L-O-P R4；
l)-C(P R3) 2-O-C(＝O)-P R4；
m)-C(P R3) 2-O-C(＝O)-O-P R4；
n)-C(P R3) 2-O-C(＝O)-N(-K)-P R4；
o)-C(P R3) 2-O-C(＝O)-O-L-O-P R4；
p)-C(P R3) 2-O-C(＝O)-O-L-N(P R4) 2；
q)-C(P R3) 2-O-C(＝O)-N(-K)-L-O-P R4；
r)-C(P R3) 2-O-C(＝O)-N(-K)-L-N(P R4) 2；
s)-C(P R3) 2-O-C(＝O)-O-L-O-L-O-P R4；
t)-C(P R3) 2-O-C(＝O)-O-L-N(-K)-C(＝O)-P R4；
u)-C(P R3) 2-O-P(＝O)(-P R5) 2；
v)-C(P R3) 2(-P R6) 2；
w)-C(＝N +(P R7) 2)(-N(P R7) 2)；
x)-C(P R3) 2-C(P R3) 2-C(C＝O)-O-P R2；
y)-C(P R3) 2-N(-K)-C(C＝O)-O-P R2；
z)-P(＝O)(-P R8)(-P R9)；
aa)-S(＝O) 2-P R10；
ab)-P R11；
ac)-C(P R3) 2-C(P R3) 2-O-P R2；
式中，L为直链或支链状的亚烷基，或者直链或支链状的亚烯基；
K为氢或任选被取代基组A取代的烷基；
P R0为任选被取代基A取代的烷基或任选被取代基A取代的烯基；
P R1为任选被取代基A取代的碳环基、任选被取代基A取代的杂环基、任选被取代基A取代的烷基氨基，或任选被取代基A取代的烷基硫基；
P R2为任选被取代基A取代的烷基、任选被取代基A取代的碳环基、任选被取代基A取代的杂环基、任选被取代基A取代的碳环烷基、任选被取代基A取代的杂环烷基，或三烷基甲硅烷基；
P R3各自独立地为氢、烷基；
P R4各自独立地为任选被取代基A取代的烷基、任选被取代基A取代的碳环基、任选被取代基A取代的杂环基、任选被取代基A取代的烷基氨基、任选被取代基A取代的碳环烷基、任选被取代基A取代的杂环烷基，或三烷基甲硅烷基；
P R5各自独立地为OBn；
P R6为任选被取代基A取代的碳环基，或任选被取代基A取代的杂环基；
P R7各自独立地为任选被取代基A取代的烷基；
P R8为任选被取代基A取代的烷氧基；
P R9为任选被取代基A取代的烷氧基、任选被取代基A取代的烷基氨基、任选被取代基A取代的碳环氧基、任选被取代基A取代的杂环氧基、任选被取代基A取代的碳 环氨基，或任选被取代基A取代的杂环氨基；
并且，P R8及P R9任选与邻接的磷原子共同形成任选被取代基A取代的杂环；
P R10为任选被取代基A取代的烷基、任选被取代基A取代的碳环基、任选被取代基A取代的杂环基、任选被取代基A取代的碳环烷基，或任选被取代基A取代的杂环烷基；
P R11为任选被取代基A取代的烷基、任选被取代基A取代的烯基、任选被取代基A取代的碳环基，或任选被取代基A取代的杂环基；
取代基A选自由以下基团组成的组中的至少一种：氧代基、烷基、羟基烷基、氨基、烷基氨基、碳环基、杂环基、碳环烷基、烷基羰基、卤素、羟基、羧基、烷基羰基氨基、烷基羰基氨基烷基、烷基羰氧基、烷氧基羰基、烷氧基羰基烷基、烷氧基羰氧基、烷基氨基羰氧基、烷基氨基烷基、烷氧基、氰基、硝基、叠氮基、烷基磺酰基、三烷基甲硅烷基，及磷酰基。
具体地，所述多环吡啶酮衍生物为式(II)所示的化合物或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，
Figure PCTCN2021140943-appb-000002
其中，
P为氢、苄基、正己基或形成前药的P R基；
R 1和R 2各自独立地为氢、卤素、羟基、烷基、烷氧基或卤代烷基；
P R为选自以下基团中的至少一种：
a)-C(＝O)-P R0；
b)-C(＝O)-P R1；
g)-C(＝O)-O-P R2；
h)-C(＝O)-N(-K)(P R2)；
i)-C(＝O)-O-L-O-P R2；
l)-C(P R3) 2-O-C(＝O)-P R4；
m)-C(P R3) 2-O-C(＝O)-O-P R4；
o)-C(P R3) 2-O-C(＝O)-O-L-O-P R4；
v)-C(P R3) 2(-P R6) 2；
x)-C(P R3) 2-C(P R3) 2-C(C＝O)-O-P R2；
y)-C(P R3) 2-N(-K)-C(C＝O)-O-P R2；
z)-P(＝O)(-P R8)(-P R9)；
式中，L为直链或支链状的亚烷基；
K为氢或任选被取代基A取代的烷基；
P R0为任选被取代基A取代的烷基；
P R1为任选被取代基A取代的碳环基，任选被取代基A取代的杂环基；
P R2为任选被取代基A取代的烷基，任选被取代基A取代的碳环基，任选被取代基A取代的杂环基，任选被取代基A取代的碳环烷基，任选被取代基A取代的杂环烷基；
P R3各自独立地为氢、烷基；
P R4为任选被取代基A取代的烷基，任选被取代基A取代的碳环基，任选被取代基A取代的杂环基；
P R6为任选被取代基A取代的碳环基，任选被取代基A取代的杂环基；
P R8为任选被取代基A取代的烷氧基；
P R9为任选被取代基A取代的烷氧基，任选被取代基A取代的烷基氨基，任选被取代基A取代的碳环氧基，任选被取代基A取代的杂环氧基，任选被取代基A取代的碳环氨基，或任选被取代基A取代的杂环氨基；
并且，P R8及P R9任选与邻接的磷原子共同形成任选被取代基A取代的杂环；
取代基A选自由以下基团组成的组中的至少一种：氧代基、烷基、烷基氨基、碳环基、杂环基、、烷基羰基、卤素、羟基、烷基羰基氨基、烷基羰氧基、烷氧基羰基、烷氧基羰基烷基、烷基氨基羰氧基、烷氧基、硝基、叠氮基、烷基磺酰基、及三烷基甲硅烷基。
更具体地，式(II)所示的化合物中，R 1和R 2各自独立地为氢、卤素、烷基、烷氧基；进一步优选地，R 1和R 2各自独立地为氢、F、Cl、Br、C 1-C 4烷基、C 1-C 4烷氧基；
P R为
Figure PCTCN2021140943-appb-000003
所述C 1-C 4烷基包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基。所述C 1-C 4烷氧基为上述C 1-C 4烷基对应的烷氧基。
根据本发明，具体地，通式II所示化合物选自：
(R)-12-(5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(10a)；
(R)-7-羟基-12-((R/S)-2-溴-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10b)；
(R)-7-羟基-12-((R/S)-3-溴-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10c)；
(R)-7-羟基-12-((R/S)-1-氟-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10d)；
(R)-7-羟基-12-((R/S)-2-氟-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10e)；
(R)-7-羟基-12-((R/S)-3-氟-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10f)；
(R)-7-羟基-12-((R/S)-1-氯-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10g)；
(R)-7-羟基-12-((R/S)-2-氯-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10h)；
(R)-7-羟基-12-((R/S)-3-氯-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10i)；
(R)-7-羟基-12-((R/S)-3-甲基-5H-二苯并[a,d][7]-5-环戊烯基)-3,4,12,12a-四氢-1H-[[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10j)；
(R)-7-羟基-12-((R/S)-3-甲氧基-5H-二苯并[a,d][7]-5-环戊烯基)-3,4,12,12a-四氢-1H-[[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10k)；
(R)-((12-(5H-二苯并[a,d][7]环烯-5-基)-6,8-二氧基-3,4,6,8,12,12a-六氢-1H-[1,4]噁嗪[3,4-c]吡啶[2,1-f][1,2,4]三嗪-7-基)氧基)碳酸甲酯(11a)。
本发明提供上述化合物的制备方法，以不同取代的苯甲醛为起始原料，经过一些列反应得到通式II所示的化合物。具体合成路线如图1所示。
图1所示合成路线概括并描述了本发明通式II所示的化合物的制备，所有的原料都是通过这些流程中描述的方式，通过有机化学领域普通技术人员熟知的方法制备的，或者商购的。本发明的全部最终衍生物都是通过这些流程中描述的方法或者通过与其类似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。
本发明第二方面提供一种药物组合物，包含作为活性成分的上述多环吡啶酮衍生物以及药学上可接受的赋形剂。
本发明可以含有通式I所示化合物的衍生物及其药学上可接受的盐、水合物作为活性成分，与药学上可接受的赋形剂混合制备成组合物，并制备成临床上可接受的剂型，上述赋形剂是指可用于药学领域的稀释剂、辅助剂或载体。上述剂型包括临床上常用的注射剂、片剂、胶囊剂、吸入剂、混悬剂等。
本发明涉及的化合物或其药学上可接受的盐、水合物、前药可作为唯一的抗流感药物单独使用，或者可以与现已上市的抗流感药物联合使用，用于预防、处理、治疗或减轻流感病毒感染后患者的症状。
本发明第三方面提供上述多环吡啶酮衍生物和/或药物组合物在制备治疗或预防由具有帽依赖性核酸内切酶的病毒引起的疾病。所述具有帽依赖性核酸内切酶的病毒包括但不限于流感病毒。
本发明第四方面提供上述多环吡啶酮衍生物和/或药物组合物在制备流感病毒RNA聚合酶抑制剂中的应用。
本发明第五方面提供上述多环吡啶酮衍生物和/或药物组合物在制备用于预防、处理、治疗或减轻流感病毒感染后患者的症状的药物中的应用。
通过对两株流感病毒株(A/FortMonmouth/1/1947(H1N1)，A/WuhanHanFang/359/1995(H3N2))的活性抑制测试发现，本发明化合物或其药学上可接受的盐、水合物、前药对流感病毒具有显著的抑制活性，其中部分化合物活性和巴洛沙韦相当，甚至超过巴洛沙韦。
本发明的其它特征和优点将在随后具体实施方式部分予以详细说明。
附图说明
通过结合附图对本发明示例性实施方式进行更详细的描述，本发明的上述以及其它目的、特征和优势将变得更加明显。
图1为本发明多环吡啶酮衍生物的合成路线图。
具体实施方式
下面将更详细地描述本发明的优选实施方式。虽然以下描述了本发明的优选实施方式，然而应该理解，可以以各自形式实验本发明而不应被这里阐述的实施方式所限制。
在以下的实施例中，描绘了制备所述化合物的方法。应了解，以下方法及所属领域的普通技术人员已知的其他方法均可以适用于本发明所述的所有化合物的制备。实施例旨在阐述而不是限制本发明的范围。
Figure PCTCN2021140943-appb-000004
实施例1：(R)-12-(5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(10a)的合成
步骤1：100mL反应瓶中加入20mmol化合物7a、10mL四氢呋喃和2mL无水乙醇，冰浴下缓慢加入10mmol硼氢化钠，室温下搅拌1.5小时。将反应液倒入冰水中，减压蒸除大部分有机溶剂，然后用二氯甲烷萃取出产物，无水硫酸钠干燥有机相，减压蒸干有机相得到化合物8a，无需纯化，直接用于下一步反应。 1H NMR(400MHz, DMSO-d 6)δ7.68(dt,J＝7.8,1.1Hz,2H),7.39(td,J＝7.5,1.4Hz,2H),7.34(dd,J＝7.6,1.4Hz,2H),7.22(td,J＝7.4,1.4Hz,2H),7.13(s,2H),6.08(s,1H),4.99(d,J＝4.1Hz,1H).
步骤2：100mL反应瓶中加入1mmol化合物1、1.2mmol化合物8a和2.5mmol的50wt.％1-丙基磷酸酐乙酸乙酯溶液，50℃搅拌过夜。TLC监测反应结束后，将反应液倒入适量冰水中，用乙酸乙酯萃取产物，饱和食盐水洗涤有机相，无水硫酸钠干燥后减压蒸干。粗品用薄层析纯化(20cm×20cm)得到化合物9a。 1H NMR(400MHz,Chloroform-d)δ7.65–7.57(m,2H),7.48(dt,J＝4.9,2.9Hz,1H),7.46–7.40(m,2H),7.40–7.33(m,4H),7.31–7.25(m,2H),7.04(d,J＝6.3Hz,3H),6.56(dd,J＝7.7,1.3Hz,1H),6.25(d,J＝7.7Hz,1H),5.68–5.53(m,2H),5.41(d,J＝10.8Hz,1H),5.33(s,1H),4.58(dd,J＝13.6,2.5Hz,1H),3.90(dd,J＝9.9,3.0Hz,1H),3.61(dd,J＝11.8,3.3Hz,1H),3.51(dd,J＝10.8,3.1Hz,1H),3.18(td,J＝11.8,2.7Hz,1H),3.12–3.01(m,1H),2.76(ddd,J＝13.5,11.8,3.5Hz,1H)。
步骤3：50mL反应瓶中加入0.5mmol化合物9a、1.5mmol氯化锂和5mL DMA，反应液在80℃下搅拌3小时。冰浴搅拌下，向反应液中加入2mL丙酮、9mL稀盐酸(0.5M)和4mL水，继续冰浴下搅拌1小时。产物以固体形式析出，抽滤，干燥后得到淡粉色固体目标化合物10a。产率92.3％。 1H NMR(400MHz,Chloroform-d)δ7.55–7.39(m,5H),7.34(t,J＝7.5Hz,1H),7.19(t,J＝7.5Hz,1H),7.07(s,2H),6.91(d,J＝7.6Hz,1H),6.24(d,J＝7.7Hz,1H),5.58(d,J＝7.7Hz,1H),5.41(s,1H),4.57(dd,J＝13.5,2.6Hz,1H),4.03(dd,J＝10.0,3.1Hz,1H),3.70(dd,J＝12.0,3.4Hz,1H),3.61(dd,J＝11.0,3.1Hz,1H),3.40–3.23(m,2H),2.86(ddd,J＝15.1,11.8,3.5Hz,1H)； 13C NMR(101MHz,Chloroform-d)δ172.23,162.04,154.02,137.85,134.51,134.40,133.08,133.05,130.89,130.73,130.69,130.38,130.33,130.18,129.55,129.34,129.29,114.79,110.93,77.28,75.72,69.51,69.04,66.54,45.59；HRMS-ESI(m/z)Calcd.For C 25H 22N 3O 4[M+H] +:428.1610,Found:428.1602。
实施例2：(R)-7-羟基-12-((R/S)-2-溴-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10b)的合成
步骤1：100mL反应瓶中依次加入化合物2(3.15g,21.0mmol)、NBS(4.09g,23.0mmol)和30mL氯苯。反应液加热至70℃，缓缓加入AIBN(0.13g,0.80mmol)，在70℃下继续搅拌1小时。待反应液冷却至室温，减压蒸除反应液中的溶剂，得到化合物3的粗品，无需纯化，直接用于下一步反应。
步骤2：100mL反应瓶中依次加入上一步得到的化合物3、三苯基膦(5.51g，21.0 mmol)和25mL丙酮，反应液回流1小时。待反应液冷却至室温，抽滤得到白色固体。100mL反应瓶中加入上述得到的白色固体、甲醇钠(1.35g，25.0mmol)和30mL甲醇。反应液室温搅拌0.5小时后加热回流，继续加入11mmol 4b，继续回流6小时。待反应液冷却至室温，将反应液倒入大量冰水中，用二氯甲烷萃取出产物，无水硫酸钠干燥有机相，减压蒸干得到粗品。将粗品与50mL石油醚充分混合搅拌，大部分杂质以固体形式析出，滤除固体，减压蒸干滤液得到初步纯化的化合物5b，无需继续纯化，直接用于下一步反应。 1H NMR(400MHz,Chloroform-d)δ8.01(m,1H),7.34–7.32(m,2H),7.25–7.13(m,3H),7.11(d,J＝12.0Hz,1H),6.99–6.92(m,2H),6.57(d,J＝12.0Hz,1H),3.90(s,3H)。
步骤3：100mL反应瓶中加入上一步得到的化合物5.0mmol 5b、氢氧化钾(0.56g,10.0mmol)、20mL甲醇和1mL水，反应液回流4小时。待反应液冷却至室温，将反应液倒入大量冰水中并不停搅拌，加入盐酸溶液(4M)酸化，粗品以固体形式析出来。抽滤得到固体，干燥后的固体与50mL石油醚充分混合搅拌，杂质大部分溶于石油醚中，抽滤并用石油醚洗涤固体，得到初步纯化的化合物6b，无需继续纯化，直接用于下一步反应。 1H NMR(400MHz,Chloroform-d)δ8.13-8.11(m,1H),7.38–7.34(m,2H),7.24–7.18(m,3H),7.14(d,J＝12.0Hz,1H).7.01–6.94(m,2H),6.59(d,J＝12.0Hz,1H).
步骤4：100mL反应瓶中加入上一步得到的化合物1.0mmol 6b，用20mL二氯甲烷将其溶解，室温搅拌下缓慢加入氯化亚砜(0.13g,1.1mmol)，然后反应液回流1.5小时。待反应液冷却至室温，缓缓加入0.17g无水氯化铝，室温下搅拌3小时。将反应液倒入冰水中，用二氯甲烷萃取出产物，无水硫酸钠干燥有机相，减压蒸干有机相得到化合物7b的粗品，无需纯化，直接用于下一步反应。 1H NMR(400MHz,Chloroform-d)δ8.26–8.22(m,1H),8.11(d,J＝8.5Hz,1H),7.72(d,J＝2.0Hz,1H),7.71–7.64(m,2H),7.62–7.55(m,2H),7.12(d,J＝12.1Hz,1H),6.97(d,J＝12.1Hz,1H)。
步骤5：同实施例1步骤1，得到化合物8b。 1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.8Hz,1H),7.58(d,J＝8.3Hz,1H),7.56–7.49(m,2H),7.46(td,J＝7.5,1.5Hz,1H),7.38(dd,J＝7.7,1.4Hz,1H),7.32(dd,J＝7.4,1.3Hz,1H),7.17(d,J＝11.7Hz,1H),7.03(d,J＝11.7Hz,1H),5.37(s,1H)。
步骤6：同实施例1步骤2，得到化合物9b。一对非对映异构体，比例为3:4。 1H NMR(400MHz,Chloroform-d)δ7.68–7.63(m,4H),7.62–7.59(m,3H),7.55–7.52(m,3H),7.48–7.45(m,4H),7.38–7.35(m,4H),7.34–7.31(m,2H),7.16–7.02(m,4H),6.93(dd,J＝11.8,1.5Hz,2H),6.59–6.18(m,4H),5.77–5.55(m,4H),5.43(t,J＝11.4Hz,2H), 5.29(d,J＝13.2Hz,2H),4.59(ddd,J＝13.5,7.1,2.5Hz,2H),3.87(ddd,J＝25.7,9.9,3.0Hz,2H),3.63(td,J＝11.5,3.3Hz,2H),3.53(ddd,J＝10.0,6.5,3.0Hz,2H),3.26–3.13(m,2H),3.07(t,J＝10.4Hz,2H),2.76(dddd,J＝25.1,13.5,11.7,3.5Hz,2H)。
步骤7：同实施例1步骤3，得到化合物10b，产率91.5％。非对映异构体，比例为3:7。 1H NMR(400MHz,Chloroform-d)δ7.69–7.30(m,5H),7.21(t,J＝7.6Hz,1H),7.11(t,J＝8.9Hz,1H),7.05–6.72(m,2H),6.25(dd,J＝25.7,7.6Hz,1H),5.63(dd,J＝47.5,7.7Hz,1H),5.38(s,1H),4.57(dd,J＝13.2,8.6Hz,1H),4.01(ddd,J＝23.2,10.1,3.0Hz,1H),3.66(dtd,J＝36.2,9.3,6.7,3.2Hz,2H),3.32(dtd,J＝20.8,11.3,10.4,3.4Hz,2H),2.98–2.75(m,1H)； 13C NMR(101MHz,Chloroform-d)δ172.19,162.03,154.03,137.77,136.16,133.44,132.76,132.21,132.07,131.90,131.84,131.76,131.09,130.72,130.41,130.32,129.97,129.71,129.59,129.17,128.83,123.33,114.72,111.16,110.96,75.09,74.92,69.61,69.50,69.00,66.53,45.66；HRMS-ESI(m/z)Calcd.For C 25H 21BrN 3O 4[M+H] +:506.0715,Found:506.0708。
实施例3：(R)-7-羟基-12-((R/S)-3-溴-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10c)的合成
步骤：同实施例2步骤1-7，得到化合物10c，产率93.6％。非对映异构体，比例为1:1。 1H NMR(400MHz,DMSO-d 6)δ11.70(s,2H),7.99(d,J＝2.1Hz,1H),7.69(dd,J＝8.3,2.1Hz,1H),7.62(dq,J＝8.0,3.9Hz,2H),7.59–7.54(m,2H),7.54–7.47(m,4H),7.44(d,J＝8.3Hz,1H),7.38(td,J＝7.5,1.4Hz,1H),7.27–7.10(m,6H),6.35(dd,J＝15.6,7.7Hz,2H),5.85(d,J＝2.8Hz,2H),5.43(d,J＝7.7Hz,1H),5.34(d,J＝7.6Hz,1H),4.40(ddd,J＝16.2,13.4,2.5Hz,2H),3.85(dd,J＝8.4,4.6Hz,1H),3.76(dd,J＝9.5,3.5Hz,1H),3.59(ddd,J＝14.4,11.6,3.3Hz,2H),3.41(td,J＝10.0,9.0,3.6Hz,4H),3.29(dd,J＝11.3,2.7Hz,2H),2.84(ddd,J＝14.7,11.8,3.5Hz,1H),2.75(ddd,J＝15.2,11.1,3.4Hz,1H)； 13C NMR(101MHz,DMSO-d 6)δ171.39,161.71,153.44,138.58,135.93,135.03,133.86,133.67,133.62,133.48,133.39,132.73,132.29,132.14,131.84,131.57,131.42,131.26,131.18,130.95,130.50,129.86,129.71,129.62,129.40,122.67,122.26,116.00,115.93,110.36,110.33,72.63,72.52,69.94,69.69,68.22,65.94,45.72；HRMS-ESI(m/z)Calcd.For C 25H 21BrN 3O 4[M+H] +:506.0715,Found:506.0709。
实施例4：(R)-7-羟基-12-((R/S)-1-氟-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10d)的合成
步骤：同实施例2步骤1-7，得到化合物10d，产率92.1％。非对映异构体，比例为1:1。 1H NMR(400MHz,Chloroform-d)δ7.60–7.27(m,9H),7.18(ddt,J＝22.0,15.9,8.2Hz,6H),7.06(t,J＝9.1Hz,1H),6.90(d,J＝7.6Hz,1H),6.71(d,J＝7.6Hz,1H),6.33(d,J＝7.7Hz,1H),6.25(d,J＝7.7Hz,1H),5.66(d,J＝7.7Hz,1H),5.57(d,J＝7.7Hz,1H),5.44(s,2H),4.57(ddd,J＝13.4,6.0,2.5Hz,2H),4.04(ddd,J＝22.5,10.0,3.1Hz,2H),3.67(dtd,J＝35.1,11.5,3.3Hz,4H),3.32(dtd,J＝20.8,10.4,9.4,3.5Hz,4H),2.86(qd,J＝13.0,3.6Hz,2H)； 13C NMR(101MHz,Chloroform-d)δ172.20,162.00,154.07,154.03,137.78,137.72,134.31,134.20,133.00,132.93,131.91,131.62,131.04,130.71,130.56,130.41,130.34,129.88,129.64,129.57,126.17,125.77,121.91,121.46,121.38,116.33,116.19,116.10,114.75,114.69,111.09,110.97,75.10,75.04,69.69,69.54,69.01,68.98,66.53,45.61；HRMS-ESI(m/z)Calcd.For C 25H 21FN 3O 4[M+H] +:446.1516,Found:446.1507。
实施例5：(R)-7-羟基-12-((R/S)-2-氟-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10e)的合成
步骤：同实施例2步骤1-7，得到化合物10e，产率91.0％。非对映异构体，比例为1:1。 1H NMR(400MHz,Chloroform-d)δ7.58–7.47(m,3H),7.43(td,J＝8.7,8.0,4.9Hz,3H),7.37(td,J＝7.6,1.3Hz,1H),7.23(ddd,J＝9.2,6.4,1.8Hz,2H),7.19–7.08(m,4H),7.00(dd,J＝11.8,4.7Hz,2H),6.91(dd,J＝7.2,1.9Hz,3H),6.29(d,J＝7.7Hz,1H),6.23(d,J＝7.7Hz,1H),5.69(d,J＝7.7Hz,1H),5.59(d,J＝7.7Hz,1H),5.41(s,2H),4.59(ddd,J＝13.5,5.3,2.5Hz,2H),4.03(ddd,J＝11.1,10.0,3.1Hz,2H),3.72(ddd,J＝11.5,7.7,3.4Hz,2H),3.63(ddd,J＝10.8,7.5,3.1Hz,2H),3.32(dddd,J＝23.3,11.3,9.4,2.6Hz,4H),2.87(dtd,J＝15.4,12.1,3.5Hz,2H)； 13C NMR(101MHz,Chloroform-d)δ172.24,162.07,154.07,137.78,136.47,134.14,132.53,131.93,131.59,131.09,130.68,130.40,130.31,129.97,129.68,129.51,129.11,117.15,116.94,116.35,111.03,110.96,74.91,74.81,69.51,69.05,66.55,45.66,45.60；HRMS-ESI(m/z)Calcd.For C 25H 21FN 3O 4[M+H] +:446.1516,Found:446.1506。
实施例6：(R)-7-羟基-12-((R/S)-3-氟-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10f)的合成
步骤：同实施例2步骤1-7，得到化合物10f，产率93.3％。非对映异构体，比例为1:1。 1H NMR(400MHz,Chloroform-d)δ7.58–7.30(m,8H),7.19(q,J＝8.6,7.8Hz,3H),7.05(s,5H),6.90(d,J＝7.7Hz,1H),6.69(d,J＝8.6Hz,1H),6.28(dd,J＝29.0,7.7Hz,2H), 5.62(dd,J＝39.0,7.7Hz,2H),5.36(d,J＝4.6Hz,2H),4.59(t,J＝14.8Hz,2H),4.03(ddd,J＝23.6,9.9,3.1Hz,2H),3.83–3.53(m,4H),3.50–3.13(m,4H),3.03–2.76(m,2H)； 13C NMR(101MHz,Chloroform-d)δ172.21,162.06,161.99,154.05,137.79,134.43,134.25,132.86,132.78,132.41,132.29,132.03,130.89,130.76,130.31,130.19,129.87,129.69,129.58,129.46,129.21,117.45,116.94,116.71,111.04,110.95,75.03,69.70,69.49,69.03,68.93,66.55,45.69,45.65.；HRMS-ESI(m/z)Calcd.For C 25H 21FN 3O 4[M+H] +:446.1516,Found:446.1506。
实施例7：(R)-7-羟基-12-((R/S)-1-氯-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10g)的合成
步骤：同实施例2步骤1-7，得到化合物10g。 1H NMR(400MHz,Chloroform-d)δ7.56–7.33(m,12H),7.25–7.16(m,3H),7.10(t,J＝7.8Hz,1H),6.90(d,J＝7.6Hz,1H),6.83(d,J＝7.6Hz,1H),6.33(d,J＝7.6Hz,1H),6.26(d,J＝7.7Hz,1H),5.68(d,J＝7.7Hz,1H),5.59(d,J＝7.7Hz,1H),5.40(s,2H),4.57(ddd,J＝13.3,7.1,2.5Hz,2H),4.08(dd,J＝9.9,3.1Hz,1H),4.01(dd,J＝10.0,3.1Hz,1H),3.78–3.58(m,4H),3.41–3.23(m,4H),2.86(dddd,J＝15.3,13.4,11.8,3.5Hz,2H)； 13C NMR(101MHz,Chloroform-d)δ172.21,161.94,154.11,154.05,137.76,135.76,135.61,133.90,133.32,131.87,131.61,130.90,130.83,130.77,130.47,130.15,130.11,129.97,129.92,129.78,129.70,129.64,129.23,128.89,126.42,126.05,114.70,111.13,111.01,77.28,75.39,75.25,69.79,69.59,69.00,68.98,66.54,45.62,45.59；HRMS-ESI(m/z)Calcd.For C 25H 21ClN 3O 4[M+H] +:462.1221,Found:462.1211。
实施例8：(R)-7-羟基-12-((R/S)-2-氯-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10h)的合成
步骤：同实施例2步骤1-7，得到化合物10h，产率92.5％。非对映异构体，比例为1:1。 1H NMR(400MHz,Chloroform-d)δ7.57–7.30(m,11H),7.24–7.07(m,4H),6.98(dd,J＝11.8,5.5Hz,2H),6.87(dd,J＝16.6,7.9Hz,2H),6.29(d,J＝7.7Hz,1H),6.22(d,J＝7.7Hz,1H),5.68(d,J＝7.7Hz,1H),5.57(d,J＝7.6Hz,1H),5.39(s,2H),4.57(ddd,J＝13.7,7.1,2.4Hz,2H),4.01(ddd,J＝19.2,9.9,3.1Hz,2H),3.71(td,J＝11.3,3.4Hz,2H),3.61(ddd,J＝10.0,6.5,3.1Hz,2H),3.42–3.22(m,4H),2.95–2.76(m,2H)； 13C NMR(101MHz,Chloroform-d)δ172.19,162.02,154.02,137.79,135.89,135.25,134.19,132.89,132.07,131.90,131.73,131.69,131.09,130.70,130.48,130.41,130.33,129.94,129.78,129.71,129.58,129.27,129.14,128.91,114.75,111.14,110.96,77.28,75.00,74.86,69.59, 69.51,68.99,66.52,45.67,45.62；HRMS-ESI(m/z)Calcd.For C 25H 21ClN 3O 4[M+H] +:462.1221,Found:462.1208。
实施例9：(R)-7-羟基-12-((R/S)-3-氯-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10i)的合成
步骤：同实施例2步骤1-7，得到化合物10i，产率90.7％。非对映异构体，比例为1:1。 1H NMR(400MHz,Chloroform-d)δ7.56–7.29(m,11H),7.22(td,J＝7.5,1.4Hz,1H),7.13–6.99(m,4H),6.97(d,J＝2.1Hz,1H),6.94–6.88(m,1H),6.31(d,J＝7.7Hz,1H),6.24(d,J＝7.7Hz,1H),5.69(d,J＝7.7Hz,1H),5.58(d,J＝7.7Hz,1H),5.36(d,J＝2.8Hz,2H),4.60(ddd,J＝19.8,13.3,2.5Hz,2H),4.03(ddd,J＝23.8,9.9,3.1Hz,2H),3.73(ddd,J＝16.3,12.0,3.4Hz,2H),3.62(ddd,J＝10.9,9.3,3.1Hz,2H),3.42–3.23(m,4H),2.94(ddd,J＝13.4,11.7,3.5Hz,1H),2.84(ddd,J＝13.4,11.8,3.5Hz,1H)； 13C NMR(101MHz,Chloroform-d)δ172.22,162.05,154.10,137.81,137.75,135.55,134.40,132.99,132.90,132.64,132.49,132.12,131.27,131.09,130.97,130.80,130.34,130.29,130.01,129.86,129.65,129.59,129.53,129.45,129.36,129.23,114.67,114.64,110.95,77.25,75.08,74.92,69.68,69.48,69.04,68.95,66.56,66.51,45.68,45.63,29.71；HRMS-ESI(m/z)Calcd.For C 25H 21ClN 3O 4[M+H] +:462.1221,Found:462.1211。
实施例10：(R)-7-羟基-12-((R/S)-3-甲基-5H-二苯并[a,d][7]-5-环戊烯基)-3,4,12,12a-四氢-1H-[[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10j)的合成
步骤：同实施例2步骤1-7，得到化合物10j，产率85.3％。非对映异构体，比例为1:1。 1H NMR(400MHz,Chloroform-d)δ7.53–7.38(m,6H),7.35–7.27(m,3H),7.23(d,J＝1.8Hz,1H),7.16(ddd,J＝12.8,7.6,1.5Hz,2H),7.07–6.98(m,4H),6.88(d,J＝7.6Hz,1H),6.72(d,J＝1.7Hz,1H),6.25(dd,J＝7.6,4.9Hz,2H),5.67–5.46(m,2H),5.35(s,2H),4.58(ddd,J＝13.5,7.6,2.5Hz,2H),4.05(ddd,J＝16.5,9.9,3.1Hz,2H),3.70(dt,J＝11.9,4.2Hz,2H),3.65–3.54(m,2H),3.50–3.13(m,4H),2.86(ddt,J＝12.3,8.7,2.8Hz,2H),2.41(s,3H),2.20(s,3H)； 13C NMR(101MHz,Chloroform-d)δ172.20,162.01,153.97,140.05,139.67,138.03,137.90,134.58,132.94,132.87,131.92,131.30,130.89,130.82,130.80,130.67,130.63,130.34,130.26,130.21,130.16,130.10,130.06,129.78,129.44,129.33,129.27,129.25,129.07,114.87,114.83,110.91,110.76,75.80,69.48,69.04,66.52,45.57,21.13,20.96；HRMS-ESI(m/z)Calcd.For C 26H 24N 3O 4[M+H] +:442.1767,Found:442.1758。
实施例11：(R)-7-羟基-12-((R/S)-3-甲氧基-5H-二苯并[a,d][7]-5-环戊烯基)-3,4,12,12a-四氢-1H-[[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10k)的合成
步骤：同实施例2步骤1-7，得到化合物10k，产率94.9％。非对映异构体，比例为1:1。 1H NMR(400MHz,Chloroform-d)δ7.70–7.31(m,6H),7.08–6.84(m,3H),6.43(s,1H),6.31(d,J＝7.7Hz,1H),5.65(d,J＝7.7Hz,1H),5.34(s,1H),4.58(d,J＝12.9Hz,1H),4.03(dd,J＝9.8,3.0Hz,1H),3.85(d,J＝6.3Hz,1H),3.66(s,3H),3.32(dt,J＝21.7,11.1Hz,2H),2.86(t,J＝12.5Hz,1H)； 13C NMR(101MHz,Chloroform-d)δ172.15,160.93,153.97,138.04,132.37,131.76,130.74,130.37,129.91,129.31,128.91,128.46,115.61,115.34,110.92,75.85,69.44,69.03,66.54,55.61,45.58,29.71；HRMS-ESI(m/z)Calcd.For C 26H 24N 3O 5[M+H] +:458.1716,Found:458.1707。
实施例12：(R)-((12-(5H-二苯并[a,d][7]环烯-5-基)-6,8-二氧基-3,4,6,8,12,12a-六氢-1H-[1,4]噁嗪[3,4-c]吡啶[2,1-f][1,2,4]三嗪-7-基)氧基)碳酸甲酯(11a)的合成
步骤：在100mL反应瓶中将氯甲基碳酸甲酯(1.45g,9.30mmol)、碘化钾(1.03g，6.21mmol)、碳酸钾(1.72g，12.42mmol)、10a(3.00g，6.21mmol)溶解于30mL DMA中，加热至50℃搅拌反应过夜，TLC监测直至反应结束。冷却至室温，加入30mL水，继续搅拌1个小时，抽滤，滤饼用5mL甲醇打浆，然后过滤，滤饼于45℃下减压干燥得白色固体11a(3.04g，5.90mmol，收率95％)。 1H NMR(400MHz,Chloroform-d)δ7.54–7.41(m,5H),7.34(td,J＝7.6,1.2,Hz,1H),7.23(td,J＝7.6,1.2Hz,1H),7.11-7.04(m,3H),6.37(d,J＝7.6Hz,1H),5.88(q,J＝12.4,6.4Hz,2H),5.71(d,J＝7.6Hz,1H),5.48(s,1H),4.57(dd,J＝13.2,2.4Hz,1H),3.99(dd,J＝10.0,2.4Hz,1H),3.86(s,3H),3.67(dd,J＝11.6,3.2Hz,1H),3.59(dd,J＝10.8,3.2Hz,1H),3.33(td,J＝11.6,2.4Hz,1H),3.25(t,J＝10.4Hz,1H),2.86(td,J＝14.3,3.2Hz,1H)； 13C NMR(101MHz,Chloroform-d)δ173.98,155.21,155.09,149.57,139.73,134.57,134.39,133.06,133.00,132.95,131.15,130.82,130.71,130.51,130.27,130.10,129.59,129.27,129.25,128.23,114.18,90.58,75.76,69.00,68.88,66.51,54.88,45.94；HRMS-ESI(m/z)Calcd.For C 28H 25N 3O 7[M+H] +:515.1693,Found:516.1702。
Figure PCTCN2021140943-appb-000005
化合物的生物活性研究
在以下实施例中，检测了本发明化合物的抗病毒活性、细胞毒性及动物体内代谢情况。
抗病毒活性及细胞毒性测试
实施例A：细胞病变效应实验(CPE assay)
在体外细胞水平上检测化合物抑制病毒HlNl A/FortMonmouth/1/1947和H3N2 A/WuhanHanFang/95/359致细胞病变(CPE)的能力。
实验步骤：
(1)MDCK细胞以2.5×10 4/孔的密度种入96孔板。
(2)24h后，细胞用PBS洗一遍，用100半数组织细胞感染量(50％tissue culture infective doses，TCID 50)的病毒感染液(无血清的MEM培养基)感染MDCK细胞。流感病毒：A/FortMonmouth/1/1947(H1N1)，A/WuhanHanFang/359/1995(H3N2)。
(3)37℃感染2h后，未吸附的病毒被移除，加入含化合物的病毒维持液(MEM培养基补充2μg/mL的TPCK的胰酶和0.08％BSA)。化合物最高检测浓度为200nM，3倍稀释，8个浓度，依次为：100nM、66.67nM、22.22nM、7.41nM、2.47nM、0.82nM、0.27nM、0.09nM。同时设置不加药的病毒对照组和无病毒感染不加药的细胞对照组。细胞毒性实验组不加入病毒，用培养基代替。均设置两个复孔。
(4)37℃培养箱中继续孵育约2天左右，待病毒对照组细胞病变程度(cytopathic effect，CPE)为75％-100％时，读取化合物组CPE结果。
(5)通过Reed & Muench法计算药物的半数有效抑制浓度(50％inhibitory concentration，IC 50)，并根据TC 50/IC 50比值计算治疗指数(Selective Index，SI)。
抗病毒活性试验和细胞毒性试验表明，本发明化合物均具有很好的抗病毒活性，特别地，部分化合物对流感病毒(A/FortMonmouth/1/1947)和流感病毒(A/WuhanHanFang/359/1995)的抑制活性与巴洛沙韦相当；同时，本发明化合物具有 很低的细胞毒性，TC 50远远小于巴洛沙韦的细胞毒性。
表1 本发明化合物对流感病毒(A/FortMonmouth/1/1947，A/WuhanHanFang/359/1995)体外实验TC 50和IC 50活性数据
Figure PCTCN2021140943-appb-000006
注：TC 50：药物半数有毒浓度；IC 50：药物对病毒半数抑制浓度。
由表1可知，本发明化合物具有很好的抗流感病毒活性，同时具有很低的细胞毒性。
动物体内代谢试验
实施例A：大动物食蟹猴体内药代动力学实验
6只雄性普通级食蟹猴(Cynomolgus Monkey
Figure PCTCN2021140943-appb-000007
由上海市计划生育科学研究所实验动物经营部提供，动物许可证编号：SCXK桂2021-0004)，体重3kg～5kg，随机分成2组，每组3只。一组按着3.00mg/kg的剂量灌胃给化合物10a，另一组按着3.62mg/kg的剂量灌胃给化合物11a。于给药前、给药后0.25h、0.5h、1h、2h、4h、6h、8h和24h经静脉分别采血1mL，分离制备血浆(离心条件：2200g，10分钟，2-8℃)，采用液相色谱/串联质谱法测定血浆中代谢物10a的浓度，得到药物浓度-时间曲线。化合物10a和11a的体内药代动力学实验结果如表2所示。
由食蟹猴的体内代谢实验结果可以看出，与玛巴洛沙韦相比，本发明化合物及其前药均表现出非常优良的体内代谢性能，尤其是生物利用度和体内的暴露量都远远高于玛巴洛沙韦。本发明之前药11a其生物利用度和暴露量更优于活性药10a，展示了非常好的临床应用前景。
Figure PCTCN2021140943-appb-000008

Claims (10)

  1. 一种多环吡啶酮衍生物，其为式(I)所示化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药；
    Figure PCTCN2021140943-appb-100001
    其中，
    P为氢、苄基、正己基或形成前药的P R基；
    A 1为CR 1AR 1B、S或O；
    A 2为CR 2AR 2B、S或O；
    A 3为CR 3AR 3B、S或O；
    A 4各自独立地为CR 4AR 4B、S或O；
    并且，由A 1、A 2、A 3、n个A 4，与A 1邻接的氮原子以及与A 4邻接的碳原子所构成的环的成环原子中杂原子的个数为1个或2个；
    R 1A和R 1B各自独立地为氢、卤素、烷基、卤代烷基、烷氧基或苯基；
    R 2A和R 2B各自独立地为氢、卤素、烷基、卤代烷基、烷氧基或苯基；
    R 3A和R 3B各自独立地为氢、卤素、烷基、卤代烷基、烷氧基或苯基；
    R 4A和R 4B各自独立地为氢、卤素、烷基、卤代烷基、烷氧基或苯基；
    R 3A和R 3B任选与邻接的碳原子共同形成碳环或杂环；
    n为1或2；
    R 1和R 2各自独立地为氢、卤素、羟基、烷基、烷氧基或卤代烷基；
    P R为选自以下的式a)-ac)中的基团中的至少一种：
    a)-C(＝O)-P R0；
    b)-C(＝O)-P R1；
    c)-C(＝O)-L-P R1；
    d)-C(＝O)-L-O-P R1；
    e)-C(＝O)-L-O-L-O-P R1；
    f)-C(＝O)-L-O-C(＝O)-O-P R1；
    g)-C(＝O)-O-P R2；
    h)-C(＝O)-N(-K)(P R2)；
    i)-C(＝O)-O-L-O-P R2；
    j)-C(P R3) 2-O-P R4；
    k)-C(P R3) 2-O-L-O-P R4；
    l)-C(P R3) 2-O-C(＝O)-P R4；
    m)-C(P R3) 2-O-C(＝O)-O-P R4；
    n)-C(P R3) 2-O-C(＝O)-N(-K)-P R4；
    o)-C(P R3) 2-O-C(＝O)-O-L-O-P R4；
    p)-C(P R3) 2-O-C(＝O)-O-L-N(P R4) 2；
    q)-C(P R3) 2-O-C(＝O)-N(-K)-L-O-P R4；
    r)-C(P R3) 2-O-C(＝O)-N(-K)-L-N(P R4) 2；
    s)-C(P R3) 2-O-C(＝O)-O-L-O-L-O-P R4；
    t)-C(P R3) 2-O-C(＝O)-O-L-N(-K)-C(＝O)-P R4；
    u)-C(P R3) 2-O-P(＝O)(-P R5) 2；
    v)-C(P R3) 2(-P R6) 2；
    w)-C(＝N +(P R7) 2)(-N(P R7) 2)；
    x)-C(P R3) 2-C(P R3) 2-C(C＝O)-O-P R2；
    y)-C(P R3) 2-N(-K)-C(C＝O)-O-P R2；
    z)-P(＝O)(-P R8)(-P R9)；
    aa)-S(＝O) 2-P R10；
    ab)-P R11；
    ac)-C(P R3) 2-C(P R3) 2-O-P R2；
    式中，L为直链或支链状的亚烷基，或者直链或支链状的亚烯基；
    K为氢或任选被取代基A取代的烷基；
    P R0为任选被取代基A取代的烷基或任选被取代基A取代的烯基；
    P R1为任选被取代基A取代的碳环基、任选被取代基A取代的杂环基、任选被取代基A取代的烷基氨基，或任选被取代基A取代的烷基硫基；
    P R2为任选被取代基A取代的烷基、任选被取代基A取代的碳环基、任选被取代基A取代的杂环基、任选被取代基A取代的碳环烷基、任选被取代基A取代的杂环烷基， 或三烷基甲硅烷基；
    P R3各自独立地为氢、烷基；
    P R4各自独立地为任选被取代基A取代的烷基、任选被取代基A取代的碳环基、任选被取代基A取代的杂环基、任选被取代基A取代的烷基氨基、任选被取代基A取代的碳环烷基、任选被取代基A取代的杂环烷基，或三烷基甲硅烷基；
    P R5各自独立地为OBn；
    P R6为任选被取代基A取代的碳环基，或任选被取代基A取代的杂环基；
    P R7各自独立地为任选被取代基A取代的烷基；
    P R8为任选被取代基A取代的烷氧基；
    P R9为任选被取代基A取代的烷氧基、任选被取代基A取代的烷基氨基、任选被取代基A取代的碳环氧基、任选被取代基A取代的杂环氧基、任选被取代基A取代的碳环氨基，或任选被取代基A取代的杂环氨基；
    并且，P R8及P R9任选与邻接的磷原子共同形成任选被取代基A取代的杂环；
    P R10为任选被取代基A取代的烷基、任选被取代基A取代的碳环基、任选被取代基A取代的杂环基、任选被取代基A取代的碳环烷基，或任选被取代基A取代的杂环烷基；
    P R11为任选被取代基A取代的烷基、任选被取代基A取代的烯基、任选被取代基A取代的碳环基，或任选被取代基A取代的杂环基；
    取代基A选自由以下基团组成的组中的至少一种：氧代基、烷基、羟基烷基、氨基、烷基氨基、碳环基、杂环基、碳环烷基、烷基羰基、卤素、羟基、羧基、烷基羰基氨基、烷基羰基氨基烷基、烷基羰氧基、烷氧基羰基、烷氧基羰基烷基、烷氧基羰氧基、烷基氨基羰氧基、烷基氨基烷基、烷氧基、氰基、硝基、叠氮基、烷基磺酰基、三烷基甲硅烷基，及磷酰基。
  2. 根据权利要求1所述的多环吡啶酮衍生物，其中，所述多环吡啶酮衍生物为式(II)所示的化合物或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，
    Figure PCTCN2021140943-appb-100002
    其中，
    P为氢、苄基、正己基或形成前药的P R基；
    R 1和R 2各自独立地为氢、卤素、羟基、烷基、烷氧基或卤代烷基；
    P R为选自以下基团中的至少一种：
    a)-C(＝O)-P R0；
    b)-C(＝O)-P R1；
    g)-C(＝O)-O-P R2；
    h)-C(＝O)-N(-K)(P R2)；
    i)-C(＝O)-O-L-O-P R2；
    l)-C(P R3) 2-O-C(＝O)-P R4；
    m)-C(P R3) 2-O-C(＝O)-O-P R4；
    o)-C(P R3) 2-O-C(＝O)-O-L-O-P R4；
    v)-C(P R3) 2(-P R6) 2；
    x)-C(P R3) 2-C(P R3) 2-C(C＝O)-O-P R2；
    y)-C(P R3) 2-N(-K)-C(C＝O)-O-P R2；
    z)-P(＝O)(-P R8)(-P R9)；
    式中，L为直链或支链状的亚烷基；
    K为氢或任选被取代基A取代的烷基；
    P R0为任选被取代基A取代的烷基；
    P R1为任选被取代基A取代的碳环基，任选被取代基A取代的杂环基；
    P R2为任选被取代基A取代的烷基，任选被取代基A取代的碳环基，任选被取代基A取代的杂环基，任选被取代基A取代的碳环烷基，任选被取代基A取代的杂环烷基；
    P R3各自独立地为氢、烷基；
    P R4为任选被取代基A取代的烷基，任选被取代基A取代的碳环基，任选被取代基A取代的杂环基；
    P R6为任选被取代基A取代的碳环基，任选被取代基A取代的杂环基；
    P R8为任选被取代基A取代的烷氧基；
    P R9为任选被取代基A取代的烷氧基，任选被取代基A取代的烷基氨基，任选被取代基A取代的碳环氧基，任选被取代基A取代的杂环氧基，任选被取代基A取代的碳环氨基，或任选被取代基A取代的杂环氨基；
    并且，P R8及P R9任选与邻接的磷原子共同形成任选被取代基A取代的杂环；
    取代基A选自由以下基团组成的组中的至少一种：氧代基、烷基、烷基氨基、碳环基、杂环基、、烷基羰基、卤素、羟基、烷基羰基氨基、烷基羰氧基、烷氧基羰基、烷氧基羰基烷基、烷基氨基羰氧基、烷氧基、硝基、叠氮基、烷基磺酰基、及三烷基甲硅烷基。
  3. 根据权利要求2所述的多环吡啶酮衍生物，其中，
    R 1和R 2各自独立地为氢、卤素、烷基、烷氧基；
    P R为
    Figure PCTCN2021140943-appb-100003
  4. 根据权利要求3所述的多环吡啶酮衍生物，其中，
    R 1和R 2各自独立地为氢、F、Cl、Br、C 1-C 4烷基、C 1-C 4烷氧基。
  5. 根据权利要求1所述的多环吡啶酮衍生物，其中，通式II所示化合物选自：
    (R)-12-(5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(10a)；
    (R)-7-羟基-12-((R/S)-2-溴-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10b)；
    (R)-7-羟基-12-((R/S)-3-溴-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10c)；
    (R)-7-羟基-12-((R/S)-1-氟-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10d)；
    (R)-7-羟基-12-((R/S)-2-氟-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10e)；
    (R)-7-羟基-12-((R/S)-3-氟-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢 -1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10f)；
    (R)-7-羟基-12-((R/S)-1-氯-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10g)；
    (R)-7-羟基-12-((R/S)-2-氯-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10h)；
    (R)-7-羟基-12-((R/S)-3-氯-5H-二苯并[a,d][7]-5-环戊烯基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10i)；
    (R)-7-羟基-12-((R/S)-3-甲基-5H-二苯并[a,d][7]-5-环戊烯基)-3,4,12,12a-四氢-1H-[[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10j)；
    (R)-7-羟基-12-((R/S)-3-甲氧基-5H-二苯并[a,d][7]-5-环戊烯基)-3,4,12,12a-四氢-1H-[[1,4]噁嗪基[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(10k)；
    (R)-((12-(5H-二苯并[a,d][7]环烯-5-基)-6,8-二氧基-3,4,6,8,12,12a-六氢-1H-[1,4]噁嗪[3,4-c]吡啶[2,1-f][1,2,4]三嗪-7-基)氧基)碳酸甲酯(11a)。
  6. 一种药物组合物，其特征在于，该药物组合物包含作为活性成分的权利要求1-5中任意一项所述的多环吡啶酮衍生物以及药学上可接受的赋形剂。
  7. 根据权利要求6所述的药物组合物，其中，所述药物组合物还包括其他抗流感药物。
  8. 权利要求1-5中任意一项所述的多环吡啶酮衍生物和/或权利要求6-7中任意一项所述的药物组合物在制备流感病毒RNA聚合酶抑制剂中的应用。
  9. 权利要求1-5中任意一项所述的多环吡啶酮衍生物和/或权利要求6-7中任意一项所述的药物组合物在制备治疗或预防由具有帽依赖性核酸内切酶的病毒引起的疾病；所述具有帽依赖性核酸内切酶的病毒优选为流感病毒。
  10. 权利要求1-5中任意一项所述的多环吡啶酮衍生物和/或权利要求6-7中任意一项所述的药物组合物在制备用于预防、处理、治疗或减轻流感病毒感染后患者的症状的药物中的应用。
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