WO2023168844A1 - 氘代内酰胺类化合物及其制备方法、组合物和用途 - Google Patents

氘代内酰胺类化合物及其制备方法、组合物和用途 Download PDF

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WO2023168844A1
WO2023168844A1 PCT/CN2022/097751 CN2022097751W WO2023168844A1 WO 2023168844 A1 WO2023168844 A1 WO 2023168844A1 CN 2022097751 W CN2022097751 W CN 2022097751W WO 2023168844 A1 WO2023168844 A1 WO 2023168844A1
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compound
deuterated
compounds
pharmaceutically acceptable
sars
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French (fr)
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黄才古
孙辉
庄鸿达
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广州谷森制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • the invention belongs to the field of medicinal chemistry, specifically relates to a class of deuterated lactam compounds and their preparation methods, compositions and uses, and relates to the treatment or prevention of viral infections, which are novel coronavirus SARS-CoV-2, SARS Coronavirus and MERS coronavirus infection.
  • the SARS virus belongs to the order Nestoviridae, the family Coronaviridae, and the genus Coronavirus, and is a subgroup B coronavirus of the genus ⁇ .
  • Virus particles are mostly round, with an envelope, and have coronally arranged fibers on the periphery. They are distributed in the cytoplasm and are round in shape. The diameter of the virus is between 80 and 120nm.
  • SARS is an infectious disease that has an acute onset, spreads quickly, and has a high mortality rate. Most of the infected patients have direct or indirect contact with patients, or live in endemic areas.
  • MERS virus is a type of beta coronavirus, subgroup C, and its full name is Middle East Respiratory Syndrome Coronavirus (MERS-CoV). After infection, it causes Middle East Respiratory Syndrome (MERS). ). MERS-CoV was first discovered in Saudi Arabia in September 2012. In the early days, it was named "SARS-like virus” because its clinical symptoms were similar to SARS. It also became the sixth known human coronavirus and the first to be isolated in the past 10 years. 3 types.
  • the new coronavirus SARS-CoV-2 is a new strain of coronavirus that has never been found in humans before. It was first discovered and reported in 2019. It is still prevalent in many countries around the world, and has not been widely recognized in many countries and regions. Good control.
  • coronavirus Common signs of people infected with coronavirus include respiratory symptoms, fever, cough, shortness of breath and difficulty breathing. In more severe cases, infection can lead to pneumonia, severe acute respiratory syndrome, kidney failure, and even death, and there is currently no specific treatment for the illness caused by the new coronavirus.
  • the field still needs to develop more new 3CL protease inhibitor compounds, which have good inhibitory activity or pharmacokinetic properties, and at the same time can achieve drug production amplification and controllable quality, and the technical solution disclosed in the present invention just solves the problem solved the above problems.
  • the present invention relates to a new class of deuterated lactam compounds and their preparation methods, compositions and uses.
  • the present invention relates to a deuterated lactam compound represented by Formula 1-13, or a pharmaceutically acceptable salt, isomer, prodrug or co-crystal thereof:
  • R 1 to R 2 are each independently hydrogen or deuterium, and at least one of R 1 to R2 is deuterium.
  • R 1 to R2 are all deuterium.
  • “Pharmaceutically acceptable salts” refer to salts that are suitable for contact with human and lower animal tissues within the scope of reasonable medical judgment and do not have excessive toxicity, irritation, or allergic reactions. Pharmaceutically acceptable salts are those in this field. well known. For example, SM Berge et al., J. Pharmaceutical Sciences, 66:2-19 (1977), describe pharmaceutically acceptable salts in detail. Salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base functionality with a suitable organic acid.
  • the compounds described herein contain one or more asymmetric centers, thus giving rise to enantiomeric, diastereomeric and other stereoisomeric forms, which may be defined based on absolute stereochemistry as (R)- or ( S)- or (D)- or (L)-.
  • the present invention includes all these possible isomers, as well as their racemic and optically pure forms.
  • the invention discloses a preparation method of the above formula 1-13, which is selected from one of the following lines 1 to 4:
  • the condensing agent, reducing agent, and oxidizing agent can be any compound and/or solvent commonly used in this field.
  • the condensing agent can be HATU, DCC, T3P, HBUT, DPPA, HOBt and other compounds;
  • the reducing agent can be borohydride salt (such as sodium salt, potassium salt, lithium salt, etc.), triethylsilane, hydrogen, etc. ;
  • the oxidizing agent can be Dess-Martin reagent, oxygen, potassium permanganate, ozone, sulfuric acid, etc.
  • the invention discloses a pharmaceutical composition, which is characterized in that it contains a pharmaceutically acceptable carrier and the above compound, or a pharmaceutically acceptable salt, isomer, prodrug or co-crystal thereof.
  • the pharmaceutical composition is characterized in that it contains additional therapeutic drugs, and the additional therapeutic drugs are antiviral drugs.
  • the invention discloses the above-mentioned compound formulas 1-13 or its pharmaceutically acceptable salts, or the use of the pharmaceutical composition, which is characterized in that it is used to prepare a 3CL protease inhibitor pharmaceutical composition.
  • the invention discloses the use of the above pharmaceutical composition, which is characterized in that the pharmaceutical composition is used to prepare drugs for treating and preventing viral infections.
  • the viral infection is human coronavirus, novel coronavirus SARS-CoV-2, SARS coronavirus and MERS coronavirus.
  • the compound preferably has one of the structures shown in Table 1 below.
  • the present invention contemplates pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a compound disclosed herein.
  • pharmaceutical compositions are in the form of tablets, capsules, pills, or aqueous buffers, such as saline or phosphate buffers.
  • the disclosed pharmaceutical compositions may comprise a compound disclosed herein and a propellant.
  • the propellant is an aerosolized propellant, such as compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkane (HFA), 1,1,1,2-tetrafluoroethane , l,1,l,2,3,3,3-heptafluoropropane or combinations thereof.
  • the present invention contemplates pressurized or non-pressurized containers containing a compound or pharmaceutical composition described herein.
  • the container is a hand pump nebulizer, inhaler, metered dose inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic nebulizer.
  • the compound or pharmaceutical composition is administered orally, intravenously, or through the lungs, ie, pulmonary.
  • the present invention relates to the use of a compound described herein in the preparation of a medicament for the treatment or prevention of viral infections, such as novel coronavirus SARS-CoV-2, SARS coronavirus and MERS coronavirus. Viral infection.
  • the present invention relates to methods of preparing compounds disclosed herein by mixing starting materials and reagents disclosed herein under conditions that form the compounds disclosed herein.
  • the invention designs and discloses novel deuterated lactam compounds, which have good antiviral activity and pharmacokinetic properties and can be used to treat coronavirus infections.
  • the compounds of the present invention have a longer half-life, better exposure in the body, and have the advantages of high efficacy and safety.
  • HATU 2-(7-azabenzotriazole)-N,N,N’,N’-tetramethylurea hexafluorophosphate
  • PE petroleum ether
  • the preparation method of compound M-2 is the same as M-1 (using reaction raw material M-D-2).
  • the preparation method of compound M-3 is the same as M-1 (using reaction raw material M-D-3).
  • the preparation method of compound M-4 is the same as M-1 (using reaction raw material M-D-4).
  • the preparation method of compound M-5 is the same as M-1 (using reaction raw material M-D-5).
  • the preparation method of compound M-6 is the same as M-1 (using reaction raw material M-D-6).
  • the preparation method of compound M-7 is the same as M-1 (using reaction raw material M-D-7).
  • the preparation method of compound N-2 is the same as N-1 (using reaction raw material M-D-9).
  • the preparation method of compound P-2 is the same as P-1 (using reaction raw material M-D-9).
  • the preparation method of compound P-3 is the same as P-1 (using reaction raw material R 2 CN: phenyl isocyanate).
  • This example is a detection of targeting SARS-CoV-2 virus M Pro protease activity inhibition
  • 3-chymotrypsin-like Protease the main protease (M Pro , also known as 3CL Pro )
  • M Pro the main protease
  • ORF1 located in nsp5
  • ORF1 located in nsp5
  • the replicase polypeptide needs to be further cut into multiple proteins (such as RdRp, helicase, etc.), and further assembled into the replication and transcription machinery required for the virus to initiate the replication of its own genetic material.
  • M Pro has at least 11 cleavage sites on the replicase polypeptide. Only when these sites on the replicase polypeptide are cleaved normally will it assemble into a replication and transcription machine to initiate viral replication. Given that M Pro protease is crucial in the virus replication process and there is no similar protein in the human body, the main protease M Pro has become a potential key drug target against the new coronavirus.
  • the fluorescence resonance energy transfer method was used to evaluate the inhibitory activity of deuterated triazines against SARS-CoV-2-M Pro protease.
  • the volume of the enzymatic reaction system is 120 ⁇ L, the final concentration of protease is 30 nM, and the final concentration of the substrate is 20 ⁇ M.
  • the buffer of the reaction system includes 50mM Tris and pH 7.3 1mM EDTA.
  • the excitation light and emission light are 340nm and 405nm respectively.
  • the test time is 10 minutes, and the fluorescence value is read every 30 seconds.
  • the final result is based on the readings of the first 2 minutes to fit the reaction rate, and compared with the control group (DMSO) to calculate the inhibition rate.
  • Use Graghpad prism7 to plot and calculate the IC 50 value of the anti-SARS-CoV-2 virus compound at the corresponding time point. The specific values are shown in Table 2.
  • the deuterated compound of the present invention has good antiviral activity, and its IC50 values against SARS-CoV-2-M Pro protease are all less than ⁇ 0.1 ⁇ M.
  • This example is a pharmacokinetic study of compounds (M-1, P-1, compound 1 and compound 2) in rats.
  • Plasma samples were processed using a protein precipitation method using acetonitrile:methanol containing 500:50, containing propranolol (50ng/ml) as an internal standard, and then based on a standard curve prepared in blank plasma ( 0.1-2500ng/ml) for quantification. Quantification of analytes in plasma samples using LC-MS/MS. Briefly, a Waters ACQUITY UHPLC system coupled to a Sciex 6500 triple quadrupole mass spectrometer was used. Chromatographic separation was completed using a Waters Acquity UPLC BEH C18 column (1.7m, 2.1 50mm). Optimize the mobile phase to achieve good separation between analytes.
  • solvent A consists of 0.025% formic acid and 1 mM ammonium acetate in water/acetonitrile (95:5v/v)
  • solvent B includes 0.025% formic acid and 1mM ammonium acetate in water/acetonitrile (5:95v/v).
  • the gradient generally starts at 3-30% B until about 1.2 minutes, then increases to 50-65% B until 1.6 minutes, then decreases to 10-30% B until about 1.7-1.9 minutes.
  • Analyst 1.7 software was used for peak integration and standard curve regression.
  • Pharmacokinetic analysis Pharmacokinetic parameters were calculated using noncompartmental analysis (Watson v.7.5, Thermo Scientific).
  • compound 1 is a non-deuterated compound corresponding to compound M-1, and its structural formula is: (Synthesized by referring to the method disclosed in WO2022/020242A1).
  • Compound 2 is a non-deuterated compound corresponding to compound P-1, and its structural formula is: (Synthesized by referring to the method disclosed in WO2022/020242A1).
  • Pharmaceutical carriers used in oral tablets include regulators, fillers, binders, disintegrants, additives, glidants, lubricants, film coating materials, plasticizers, colorants, etc.
  • starch Fillers disintegrants 90 calcium hydrogen phosphate filler twenty three pregelatinized starch filler 45 citric acid regulator 3 sodium bisulfite additive 0.8 10% starch slurry Adhesive Appropriate amount Magnesium stearate Lubricant 1.7 White Opadry Coating premix about 4 water, ethanol Solvent Appropriate amount
  • compound M-1 is ground and sieved respectively, and then mixed evenly with the filler, disintegrant, and regulators and additives that have been ground and sieved, and 10% starch slurry is added to make a soft material in a mixer.
  • the soft material is made into wet pellets on a swing machine, dried in an oven, mixed evenly with lubricant, and pressed into tablet cores.
  • the tablet core is wrapped with Opadry to make a film-coated tablet.
  • Pharmaceutical carriers used in capsules include fillers, binders, disintegrants, additives, lubricants, etc.
  • Components effect Content (mg/tablet)
  • Compound M-1 active ingredients 150 Lactose monohydrate filler 76 pregelatinized starch Fillers, adhesives 41 sodium carboxymethyl starch disintegrant 13.1 Magnesium stearate Lubricant 1.7
  • compound M-1 and each auxiliary material are ground and sieved separately, mixed evenly with fillers, binders and disintegrants in a certain proportion, added to a dry granulator and pressed into strips, and then passed through a crusher Crushed into particles.
  • the granules are mixed evenly with an appropriate amount of lubricant and disintegrant and then filled into capsules.

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Abstract

公开了新型氘代内酰胺类化合物，其具有很好的抗病毒活性和药代动力学性质，可用于治疗冠状病毒的感染。还公开了上述氘代化合物的制备方法、组合物及应用。此外，相较于对应的非氘代化合物，化合物实现了更优的药动学性质和治疗效果。

Description

氘代内酰胺类化合物及其制备方法、组合物和用途 技术领域
本发明属于药物化学领域，具体涉及一类氘代内酰胺类化合物及其制备方法、组合物和用途，并涉及病毒感染的治疗或预防，所述病毒感染为新冠病毒SARS-CoV-2、SARS冠状病毒和MERS冠状病毒感染。
背景技术
人体内的冠状病毒最早于1960年代在英国被分离出来，病毒因其表面皇冠状的突起物而得名。它可能与人、猪、猫、狗、鼠和鸡的呼吸系统感染相关。
SARS病毒属于套式病毒目、冠状病毒科、冠状病毒属，为β属B亚群冠状病毒。病毒粒子多呈圆形，有囊膜，外周有冠状排列的纤突,分布于细胞浆中，呈圆形，病毒直径在80～120nm之间。SARS是一种起病急、传播快、病死率高的传染病，被传染的病人多数都与患者直接或间接接触，或生活在流行区内。
MERS病毒是一种β属C亚群冠状病毒，全名为中东呼吸综合征冠状病毒(Middle East Respiratory Syndrome Coronavirus，简称MERS-CoV)，感染后引发中东呼吸综合征(Middle East Respiratory Syndrome，简称MERS)。MERS-CoV最早于2012年9月在沙特被发现，早期因与SARS临床症状相似得名“类SARS病毒”，也成为第6种已知的人类冠状病毒，也是过去10年内被分离出来的第3种。
新型冠状病毒SARS-CoV-2是以前从未在人体中发现的冠状病毒新毒株，2019年首次被发现并报道，至今仍然在全球多个国家流行肆虐，并在很多国家区域并未得到很好的控制。
人感染冠状病毒后常见体征有呼吸道症状、发热、咳嗽、气促和呼吸困难等。在较严重病例中，感染可导致肺炎、严重急性呼吸综合征、肾衰竭，甚至死亡，而且目前对于新型冠状病毒所致疾病没有特异治疗方法。
Sho Konno等人报告发现了拟肽类3CL蛋白酶抑制剂具有抗SARS-CoV病毒活性，Bioorg.Med.Chem.2013,21,412-424；同年在Eur.J.Med.Chem.2013,68,372-384报道了系列二肽型同靶点化合物作为3CL蛋白酶抑制剂对SARS-CoV的抑制效果。
鉴于以上，本领域仍需要开发更多新型3CL蛋白酶抑制剂类化合物，具有较好的抑制活性或药动学性质，同时可实现药物生产放大、质量可控，而本发明公开的技术方案恰好解决了上述问题。
发明内容
本发明涉及一类新型氘代内酰胺类化合物及其制备方法、组合物和用途。
在某些实施方案中，本发明涉及一种式1-13所示的氘代内酰胺类化合物，或其药学上可接受的盐、异构体、前药或共晶物：
Figure PCTCN2022097751-appb-000001
其中：
R 1～R 2各自独立地为氢或氘，且R 1～R2中至少一个是氘。
优选地，R 1～R2均为氘。
“药学上可接受的盐”是指在合理的医学判断范围内，适用于与人类和低等动物组织接触，没有过度毒性、刺激性、过敏反应的盐.药学上可接受的盐是本领 域众所周知的。例如，SM Berge等人在J.Pharmaceutical Sciences,66:2-19(1977)中详细描述了药学上可接受的盐。盐可以在本发明化合物的最终分离和纯化过程中原位制备，或者通过使游离碱官能团与合适的有机酸反应单独制备。
本文所述的化合物含有一个或多个不对称中心，因此产生对映异构体、非对映异构体和其他立体异构体形式，其可以根据绝对立体化学定义为(R)-或(S)-或(D)-或(L)-。本发明包括所有这些可能的异构体，以及它们的外消旋和光学纯形式。
本发明公开了上述式1-13的制备方法，其选自以下线路1-线路4中的一种：
Figure PCTCN2022097751-appb-000002
上述路线1-4中的化合物的基团定义与相应化合物保持一致。
其中，缩合剂、还原剂、氧化剂可以为一切本领域通用的化合物和或溶剂。优选地，缩合剂可以HATU、DCC、T3P、HBUT、DPPA、HOBt等化合物；优选地，还原剂可以为硼氢化盐(如钠盐、钾盐、锂盐等)、三乙基硅烷、氢气等；优选地，氧化剂可以为Dess-Martin试剂、氧气、高锰酸钾、臭氧、硫酸等。
本发明公开了药物组合物，其特征在于，它含有药学上可接受载体和上述化合物，或其药学上可接受的盐、异构体、前药或共晶物。该药物组合物，其特征在于，它包含另外的治疗药物，所述的另外的治疗药物为抗病毒药物。
本发明公开的上述化合物式1-13或其药学上可接受的盐，或所述的药物组合物的用途，其特征在于，用于制备3CL蛋白酶抑制剂类药物组合物。
本发明公开了上述药物组合物的用途，其特征在于，所述的药物组合物用于制备治疗和预防病毒感染的药物。优选地，其中所述病毒感染是人冠状病毒、新冠病毒SARS-CoV-2、SARS冠状病毒和MERS冠状病毒。
在各个不同的实施方案中，所述化合物优选具有以下表1中所示的结构之一。
表1代表性氘代内酰胺类化合物
Figure PCTCN2022097751-appb-000003
Figure PCTCN2022097751-appb-000004
Figure PCTCN2022097751-appb-000005
Figure PCTCN2022097751-appb-000006
在某些实施方案中，本发明考虑了包含药学上可接受的赋形剂和本文公开的化合物的药物组合物。在某些实施方案中，药物组合物为片剂、胶囊剂、丸剂或含水缓冲剂，例如盐水或磷酸盐缓冲剂的形式。
在某些实施方案中，公开的药物组合物可包含本文公开的化合物和推进剂。在某些实施方案中，推进剂是气溶胶化推进剂，例如压缩空气、乙醇、氮气、二氧化碳、一氧化二氮、氢氟烷烃(HFA)、1,1,1,2-四氟乙烷、l,1,l,2,3,3,3-七氟丙烷或其组合。
在某些实施方案中，本发明考虑了包含本文所述的化合物或药物组合物的加压容器或非加压容器。在某些实施方案中，容器是手动泵喷雾器、吸入器、计量吸入器、干粉吸入器、喷雾器、振动筛网喷雾器、喷射喷雾器或超声波喷雾器。
在某些实施方案中，化合物或药物组合物口服施用、静脉内施用或通过肺部，即肺部施用。
在某些实施方案中，本发明涉及本文所述的化合物在制备用于治疗或预防病毒感染的药物中的用途，所述病毒感染例如为新冠病毒SARS-CoV-2、SARS冠状病毒和MERS冠状病毒感染。
在某些实施方案中，本发明涉及通过在形成本文公开的化合物的条件下混合本文公开的起始材料和试剂来制备化合物的方法。
本发明设计、公开了新型氘代内酰胺类化合物，具有很好的抗病毒活性和药代动力学性质，可用于治疗冠状病毒的感染。此外，相较于对应的非氘代化合物，本发明化合物的半衰期更长，在体内暴露情况更佳，具有疗效和安全性高等优点。
具体实施方式
以下详细的说明都仅是示例性和解释性的，而非限制性的。
以下实施例，除非另外指出，否则使用的所有溶剂和试剂都是商购得到并且以原样使用。
本文采用了以下缩写:
HATU：2-(7-氮杂苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯
ACN：乙腈
THF：四氢呋喃
DMF：N,N-二甲基甲酰胺
DIEA：N,N-二异丙基乙胺
EtOAc：乙酸乙酯
PE：石油醚
Burgess试剂：N-(三乙基铵磺酰)氨基甲酸甲酯
制备实施例
实施例1：化合物M-D的合成
Figure PCTCN2022097751-appb-000007
1)化合物M-E-1的合成
向250ml三颈瓶中加入原料M-F-1(11.5g,53.5mmol)、HATU(20.3g,53.5mmol)和DMF100ml，冷却至-10℃下，先滴加DIEA(6.9g,53.5mmol)，再分4批加入M-G(10g,48.6mmol)，投毕，升至室温25℃，搅拌24h。TLC监控终点，加入甲基叔丁基醚(300ml)，有机相经水洗后，经减压浓缩后，得黄色油状物粗品。经柱层析(PE:EtOAc＝1:1)纯化，制得化合物M-E-1(15.3g，收率78％)，淡黄色油状物。
2)化合物M-D-1的合成
向500ml三颈瓶中加入原料M-E-1(5.2g,14.2mmol)、四氢呋喃25ml和水5ml，冷却至10℃下，加入氢氧化锂(1.8g,42.6mmol)，投毕，10℃搅拌4h。TLC监控终点，加入水(500g)和甲基叔丁基醚(100ml)，有机相分别经水、1M盐酸溶液、食盐水洗涤，有机相经减压浓缩后，得黄色油状物粗品。经柱层析(PE:EtOAc＝2:1)纯化，制得化合物M-D-1(4.0g，收率80％)，类白色固体。
化合物M-D结构式汇总：
Figure PCTCN2022097751-appb-000008
化合物M-D-2～M-D-9的制备方法，同M-D-1(使用不同原料M-F)。
实施例2：化合物M的合成
Figure PCTCN2022097751-appb-000009
1)化合物M-B-1的合成
向100ml三颈瓶中加入原料M-D-1(3.0g,8.5mmol)、HATU(3.2g,8.5mmol)和DMF30ml，冷却至-10℃下，先滴加DIEA(1.1g,8.5mmol)，再分4批加入 M-C(1.9g,8.5mmol)，投毕，升至室温25℃，搅拌24h。TLC监控终点，加入甲基叔丁基醚(100ml)，有机相经水洗后，经减压浓缩后，得淡黄色油状物粗品。经柱层析(PE:EtOAc＝2:1)纯化，制得化合物M-B-1(3.3g，收率74％)，类白色固体。
2)化合物M-A-1的合成
向50ml反应瓶中加入原料M-B-1(2.0g,3.8mmol)、氨甲醇溶液150ml(3.5ml,7M)和甲醇10ml，40℃下，搅拌48h。TLC监控终点，反应液减压浓缩后，得淡黄色固体粗品。经柱层析(PE:EtOAc＝3:1)纯化，制得化合物M-A-1(1.5g，收率77％)，类白色固体。
3)化合物M-1的合成
向50ml反应瓶中加入原料M-A-1(1.0g,2.0mmol)和二氯甲烷20ml，冷却至0℃下，缓慢滴加Burgess试剂(1.5g,6mmol)，投毕，升至25℃，搅拌4h。TLC监控终点，0℃下，，缓慢滴加碳酸氢钠溶液(5ml)，有机相分别经水、食盐水洗涤，有机相经减压浓缩后，得淡黄色固体粗品。经柱层析(PE:EtOAc＝1:1)纯化，制得化合物M-1(0.83g，收率85％)，白色固体。
化合物M结构式汇总：
Figure PCTCN2022097751-appb-000010
化合物M-2～M-7的制备方法，同M-1(使用不同中间体M-D-2～M-D-7)。
1H NMR(400MHz,DMSO-d6)δH(ppm):8.97(d,1H),7.72(s,1H),6.92(d,1H),4.90-5.02(m,1H),4.45(s,1H),4.15(s,1H),3.73-3.91(m,2H),2.35-2.47(m,1H),2.01-2.22(m,2H),1.49-1.78(m,3H),1.33(d,1H),1.05(s,9H),1.01(s,3H),0.90(s,9H),0.80(s,3H)。MS(ESI):490([M+H] +)。
Figure PCTCN2022097751-appb-000011
化合物M-2的合成
化合物M-2的制备方法，同M-1(使用反应原料M-D-2)。
1H NMR(400MHz,DMSO-d6)δH(ppm):8.95(d,1H),7.82(d,1H),7.66(s,1H),4.91-5.01(m,1H),4.38(d,1H),4.13(s,1H),3.74-3.90(m,2H),2.56(m,1H),2.35-2.45(m,1H),1.98-2.22(m,2H),1.50-1.79(m,3H),1.34(d,1H),1.03(s,3H),0.90-1.01(s,15H),0.79(s,3H)。MS(ESI):462([M+H] +)。
Figure PCTCN2022097751-appb-000012
化合物M-3的合成
化合物M-3的制备方法，同M-1(使用反应原料M-D-3)。
1H NMR(400MHz,DMSO-d6)δH(ppm):8.97(d,1H),7.85(d,1H),7.68(s,1H),4.92-5.01(m,1H),4.38(d,1H),4.15(s,1H),3.74-3.92(m,2H),2.34-2.45(m,1H),1.99-2.22(m,4H),1.50-1.82(m,3H),1.34(d,1H),1.10(m,9H),1.03(s,3H),0.93(s,9H),0.81(s,3H)。MS(ESI):462([M+H] +)。
Figure PCTCN2022097751-appb-000013
化合物M-4的合成
化合物M-4的制备方法，同M-1(使用反应原料M-D-4)。
1H NMR(400MHz,DMSO-d6)δH(ppm):8.98(d,1H),7.89(d,1H),7.68(s,1H),4.93-5.00(m,1H),4.39(d,1H),4.14(s,1H),3.75-3.92(m,2H),2.33-2.44(m,1H),1.97-2.20(m,2H),1.90(s,3H),1.51-1.82(m,3H),1.33(d,1H),1.02(s,3H),0.96(s,9H),0.76(s,3H)。MS(ESI):448([M+H] +)。
Figure PCTCN2022097751-appb-000014
化合物M-5的合成
化合物M-5的制备方法，同M-1(使用反应原料M-D-5)。
1H NMR(400MHz,DMSO-d6)δH(ppm):8.99(d,1H),8.15(d,1H),7.70(s,1H),7.12-7.31(m,6H),4.86-5.03(m,1H),4.38(d,1H),4.12(s,1H),3.94-3.82(m,1H),3.75(d,1H),3.42-3.55(m,2H),2.02-2.25(m,3H),1.47-1.77(m,4H),1.34(d,1H),1.02(s,3H),0.94(s,9H),0.77(s,3H)。MS(ESI):524([M+H] +)。
Figure PCTCN2022097751-appb-000015
化合物M-6的合成
化合物M-6的制备方法，同M-1(使用反应原料M-D-6)。
1H NMR(400MHz,DMSO-d6)δH(ppm):9.00(d,1H),7.63-7.77(m,2H),4.88-5.04(m,1H),4.39(d,1H),4.13(s,1H),3.94-3.78(m,2H),2.85-2.65(m,1H),2.35-2.48(m,1H),2.03-2.22(m,2H),1.44-1.77(m,11H),1.32(d,1H),1.02(s,3H),0.95(s,9H),0.82(s,3H)。MS(ESI):502([M+H] +)。
Figure PCTCN2022097751-appb-000016
化合物M-7的合成
化合物M-7的制备方法，同M-1(使用反应原料M-D-7)。
1H NMR(400MHz,DMSO-d6)δH(ppm):9.03(d,1H),7.61-7.75(m,2H),4.88-5.01(m,1H),4.37(d,1H),4.13(s,1H),3.95-3.80(m,4H),2.25-2.50(m,2H),2.04-2.23(m,2H),1.45-1.78(m,8H),1.23-1.08(m,4H),1.03(s,3H),0.95(s,9H),0.83(s,3H)。MS(ESI):516([M+H] +)。
Figure PCTCN2022097751-appb-000017
实施例3：化合物N的合成
Figure PCTCN2022097751-appb-000018
1)化合物M-B-8的合成
向100ml三颈瓶中加入原料M-D-8(2.8g,8.5mmol)、HATU(3.2g,8.5mmol)和DMF30ml，冷却至-10℃下，先滴加DIEA(1.1g,8.5mmol)，再分4批加入M-C(1.9g,8.5mmol)，投毕，升至室温25℃，搅拌24h。TLC监控终点，加入甲基叔丁基醚(100ml)，有机相经水洗后，经减压浓缩后，得淡黄色油状物粗品。经柱层析(PE:EtOAc＝2:1)纯化，制得化合物M-B-8(3.0g，收率72％)，类白色固体。
2)化合物N-A-1的合成
向100ml三颈瓶中加入原料M-B-8(3.0g,6.0mmol)和四氢呋喃30ml，冷却至-10℃下，分4批加入硼氢化锂(0.56g,25.5mmol)，投毕，升至室温25℃，搅拌2h。TLC监控终点，冷却至0℃下，缓慢滴加0.5M盐酸(15ml)，再加入醋酸乙酯(100ml)，有机相经水洗后，经减压浓缩后，得淡黄色油状物粗品。经柱层析(PE:EtOAc＝2:1)纯化，制得化合物N-A-1(2.4g，收率85％)，白色固体。
3)化合物N-1的合成
向50ml反应瓶中加入原料N-A-1(2.0g,4.3mmol)和二氯甲烷20ml，降温至0℃下，加入Dess-Martin试剂(2.7g,6.5mmol)，0℃下搅拌2h。TLC监控终点，0℃下缓慢滴加硫代硫酸钠溶液，有机相经水洗，减压浓缩后，得淡黄色固体粗品。经柱层析(PE:EtOAc＝1:1)纯化，制得化合物N-1(1.6g，收率78％)，白色固体。
化合物N结构式汇总：
Figure PCTCN2022097751-appb-000019
化合物N-2的制备方法，同N-1(使用不同中间体M-D-9)。
1H NMR(400MHz,DMSO-d6)δH(ppm):9.88(s,1H),9.57(s,1H),8.46(s,1H),7.24(d,1H),7.06(s,1H),6.43-6.85(m,3H),5.91(s,1H),4.69(s,1H),4.38(s,1H),4.26(m,1H),3.85(m,1H),3.78(s,3H),3.45(s,1H),3.02(s,1H),2.88(s,1H),2.52(s,1H),2.36(m,1H),1.43-2.08(m,17H)。MS(ESI):469([M+H] +)。
Figure PCTCN2022097751-appb-000020
化合物N-2的合成
化合物N-2的制备方法，同N-1(使用反应原料M-D-9)。
1H NMR(400MHz,DMSO-d6)δH(ppm):9.87(s,1H),9.55(s,1H),8.45(s,1H),7.25(d,1H),7.21(m,1H),7.03(s,1H),6.45-6.88(m,3H),5.92(s,1H),4.69(s,1H),4.36(s,1H),4.27(m,1H),3.83(m,1H),3.47(s,1H),3.03(s,1H),2.89(s,1H),2.55(s,1H),2.32(m,1H),1.45-2.10(m,17H)。MS(ESI):505([M+H] +)。
Figure PCTCN2022097751-appb-000021
实施例4：化合物O的合成
Figure PCTCN2022097751-appb-000022
1)化合物M-B-8的合成
向100ml三颈瓶中加入原料M-D-8(2.8g,8.5mmol)、HATU(3.2g,8.5mmol)和DMF30ml，冷却至-10℃下，先滴加DIEA(1.1g,8.5mmol)，再分4批加入M-C(1.9g,8.5mmol)，投毕，升至室温25℃，搅拌24h。TLC监控终点，加入甲基叔丁基醚(100ml)，有机相经水洗后，经减压浓缩后，得淡黄色油状物粗品。经柱层析(PE:EtOAc＝2:1)纯化，制得化合物M-B-8(3.0g，收率72％)，类白色固体。
2)化合物O-B的合成
向100ml三颈瓶中加入原料M-B-8(3.0g,6.0mmol)、氯代碘甲烷(6.3g,36mmol)和DMF30ml，室温下，加入碳酸钾(4.1g,30mmol)，投毕，升温至50℃，搅拌6h。TLC监控终点，冷却至室温，加入醋酸乙酯(150ml)，有机相经水洗后，经减压浓缩后，得淡黄色油状物粗品。经柱层析(PE:EtOAc＝2:1)纯化，制得化合物O-B(2.5g，收率82％)，淡黄色固体。
3)化合物O的合成
向50ml反应瓶中加入原料O-B(2.0g,3.9mmol)、2,6-二氯苯甲酸(1.1g,5.9mmol)和DMF30ml，室温下，加入碳酸钾(4.1g,30mmol)，投毕，升温至50℃，搅拌8h。TLC监控终点，冷却至室温，加入醋酸乙酯(120ml)，有机相经水洗后，经减压浓缩后，得淡黄色油状物粗品。经柱层析(PE:EtOAc＝1:1)纯化，制得化合物O(2.0g，收率76％)，淡黄色固体。
Figure PCTCN2022097751-appb-000023
1H NMR(400MHz,DMSO-d6)δH(ppm):9.85(s,1H),9.56(s,1H),8.45(s,1H),7.75(d,1H),7.43(s,2H),7.25(d,1H),7.06(s,1H),6.43-6.85(m,3H),5.91(s,1H),5.52(s,2H),4.67(s,1H),4.35(s,1H),4.27(m,1H),3.88(m,1H),3.76(s,3H),3.43(s,1H),3.01(s,1H),2.86(s,1H),2.55(s,1H),2.38(m,1H),1.45-2.06(m,17H)。MS(ESI):672([M+H] +)。
实施例5：化合物P的合成
Figure PCTCN2022097751-appb-000024
1)化合物M-B-8的合成
向100ml三颈瓶中加入原料M-D-8(2.8g,8.5mmol)、HATU(3.2g,8.5mmol)和DMF30ml，冷却至-10℃下，先滴加DIEA(1.1g,8.5mmol)，再分4批加入M-C(1.9g,8.5mmol)，投毕，升至室温25℃，搅拌24h。TLC监控终点，加入甲基叔丁基醚(100ml)，有机相经水洗后，经减压浓缩后，得淡黄色油状物粗品。经柱层析(PE:EtOAc＝3:1)纯化，制得化合物M-B-8(3.0g，收率72％)，类白色固体。
2)化合物P-A-1的合成
向100ml三颈瓶中加入原料M-B-8(3.0g,6.0mmol)、环己基异氰基(2.6g, 24.0mmol)和二氯甲烷30ml，室温下，加入醋酸(5ml)，投毕，升温至40℃，搅拌10h。TLC监控终点，冷却至室温，加入醋酸乙酯(150ml)，有机相经碳酸氢钠溶液、食盐水洗后，经减压浓缩后，得淡黄色固体粗品。经柱层析(PE:EtOAc＝3:1)纯化，制得化合物P-A-1(3.0g，收率80％)，淡黄色固体。
3)化合物P-1的合成
向50ml反应瓶中加入原料P-A-1(2.0g,3.2mmol)和二氯甲烷30ml，0℃下，加入Dess-Martin试剂(2.7g,6.5mmol)，0℃下搅拌2h。TLC监控终点，0℃下缓慢滴加硫代硫酸钠溶液，有机相经水洗，减压浓缩后，得淡黄色固体粗品。经柱层析(PE:EtOAc＝2:1)纯化，制得化合物P-1(1.5g，收率73％)，淡黄色固体。
化合物P结构式汇总：
Figure PCTCN2022097751-appb-000025
化合物P-1
1H NMR(400MHz,DMSO-d6)δH(ppm):9.85(s,1H),9.58(s,1H),8.46(s,1H),7.24(d,1H),7.23(m,1H),7.03(s,1H),6.44-6.89(m,3H),5.95(s,1H),4.67(s,1H),4.33(s,1H),4.28(m,1H),3.83(m,1H),3.56(m,1H),3.47(s,1H),3.03(s,1H),2.89(s,1H),2.55(s,1H),2.32(m,1H),1.43-2.10(m,23H),1.10-1.25(m,4H)。 MS(ESI):630([M+H] +)。
化合物P-2的合成
化合物P-2的制备方法，同P-1(使用反应原料M-D-9)。
1H NMR(400MHz,DMSO-d6)δH(ppm):9.87(s,1H),9.56(s,1H),8.45(s,1H),7.24(d,1H),7.23(s,1H),6.46-6.86(m,3H),5.92(s,1H),4.67(s,1H),4.35(s,1H),4.25(m,1H),3.82(m,1H),3.77(s,3H),3.45(s,1H),3.03(s,1H),2.89(s,1H),2.55(s,1H),2.33(m,1H),1.45-2.10(m,23H),1.10-1.26(m,4H)。MS(ESI):594([M+H] +)。
Figure PCTCN2022097751-appb-000026
化合物N-2的合成
化合物P-3的制备方法，同P-1(使用反应原料R 2CN:苯基异氰基)。
1H NMR(400MHz,DMSO-d6)δH(ppm):9.88(s,1H),9.54(s,1H),8.45(s,1H),7.56(m,2H),7.25(d,1H),7.28(m,2H),7.21(m,1H),7.10(s,1H),7.05(s,1H),6.46-6.88(m,3H),5.92(s,1H),4.69(s,1H),4.38(s,1H),4.25(m,1H),3.85(m,1H),3.45(s,1H),3.03(s,1H),2.92(s,1H),2.53(s,1H),2.33(m,1H),1.45-2.12(m,17H)。MS(ESI):624([M+H] +)。
Figure PCTCN2022097751-appb-000027
效果实施例：
实施例6:
本实施例为靶向SARS-CoV-2病毒M Pro蛋白酶活性抑制检测
检测原理:3-胰凝乳蛋白酶样蛋白酶(3-chymotrypsin-like Protease)，即主要蛋白酶(M Pro,也称为3CL Pro)，由ORF1编码(定位于nsp5)，位于复制酶基因中心区域,是新型冠状病毒RNA复制时的一个关键蛋白质。其作用机制为:新冠病毒入侵细胞后，会利用宿主细胞合成自身复制必需的两条超长复制酶多肽(ppla和pplab)。复制酶多肽需进一步被剪切成多个蛋白(如RdRp、helicase等)，进一步组装成用于病毒启动自身遗传物质复制所需的复制转录机器。M Pro在复制酶多肽上存在至少11个切割位点，只有当复制酶多肽上这些位点被正常切割后，组装成复制转录机器，启动病毒复制。鉴于M Pro蛋白酶在病毒复制过程中至关重要，且人体中并无类似的蛋白质，因此主蛋白酶M Pro成为一个抗新冠病毒的潜在关键药物靶点。利用荧光共振能量转移方法评价氘代三嗪类化合物对SARS-CoV-2-M Pro蛋白酶的抑制活性。
具体检测方法：酶促反应体系的体积为120μL，蛋白酶的终浓度为30nM，底物终浓度为20μM，反应体系的缓冲液包括50mM Tris、pH 7.3 1mM EDTA。在96孔板中加入SARS-CoV-2-M Pro蛋白酶和不同浓度的目标化合物，在30℃孵育10min，加入底物并迅速放入酶标仪中读数。激发光和发射光分别为340nm 和405nm。测试时间为10min，每隔30s读一次荧光值。最终结果取前2min的读值拟合反应速率，并与对照组(DMSO)比较，计算抑制率。以Graghpad prism7作图，计算抗SARS-CoV-2病毒化合物对应时间点IC 50值，具体数值见表2。
表2：SARS-CoV-2-M Pro蛋白酶的IC 50值
化合物 IC 50(μΜ)
化合物M-1 ＜0.1μΜ
化合物M-2 ＜0.1μΜ
化合物M-3 ＜0.1μΜ
化合物M-4 ＜0.1μΜ
化合物M-5 ＜0.1μΜ
化合物M-6 ＜0.1μΜ
化合物M-7 ＜0.1μΜ
化合物N-1 ＜0.1μΜ
化合物N-2 ＜0.1μΜ
化合物O ＜0.1μΜ
化合物P-1 ＜0.1μΜ
化合物P-2 ＜0.1μΜ
化合物P-3 ＜0.1μΜ
由表2可知，本发明所述氘代化合物具有很好的抗病毒活性，其对SARS-CoV-2-M Pro蛋白酶的IC50值均小于＜0.1μΜ。
实施例7
本实施例为化合物(M-1、P-1、化合物1和化合物2)在大鼠上的药代动力学研究
在7-10周龄，雄性Wistar-Hannover大鼠进行药代动力学研究。在药代动力 学研究期间，所有动物都单独饲养。自由摄取食物和水(动物在进食状态下给药)。动物禁食过夜并在给药后4小时进食。在灌胃给药(30mg/kg)后的预定时间点通过颈静脉插管收集血样。在研究完成时，通过过量吸入麻醉随后放血对动物实施安乐死。将血样收集到含有K 2EDTA的试管中并储存在冰上，直至离心获得血浆，将其储存在-20℃冰箱。
血浆样品的LC-MS/MS分析：血浆样品使用蛋白质沉淀法进行处理，使用含有500:50的乙腈:甲醇，含有propranolol(50ng/ml)作为内标，然后根据空白血浆中制备的标准曲线(0.1-2500ng/ml)进行定量。使用LC-MS/MS对血浆样品中的分析物进行定量。简而言之，使用与配备Sciex 6500三重四极杆质谱仪联用的Waters ACQUITY超高效液相色谱系统。使用Waters Acquity UPLC BEH C18柱(1.7m，2.1 50mm)完成色谱分离。优化流动相以实现分析物之间的良好分离。通常，溶剂A由0.025％甲酸和1mM乙酸铵的水/乙腈溶液(95:5v/v)组成，溶剂B包括0.025％甲酸和1mM乙酸铵的水/乙腈溶液(5:95v/v)。梯度一般从3-30％B开始，直到大约1.2分钟，然后增加到50-65％B到1.6分钟，然后降低到10-30％B，直到约1.7-1.9分钟。Analyst 1.7软件用于峰积分和标准曲线回归。
药代动力学分析：使用非房室分析(Watson v.7.5，Thermo Scientific)计算药代动力学参数。
其中，化合物1是对应化合物M-1的非氘代化合物，其结构式为：
Figure PCTCN2022097751-appb-000028
(参照WO2022/020242A1公开的方法合成得到)。
化合物2是对应化合物P-1的非氘代化合物，其结构式为：
Figure PCTCN2022097751-appb-000029
(参照WO2022/020242A1公开的方法合成得到)。
如表3所示，从结果看出，相比于非氘代化合物1和化合物2，氘代化合物M-1，化合物P-1在动物体内具有更优的药动学性质，其半衰期更长，在体内暴露情况更佳，具有安全性高、降低药物毒副作用等优点。
表3：化合物的药代动力学参数
化合物 T 1/2(h)
化合物1 4.0±1.2
化合物M-1 5.5±1.4
化合物2 4.25±1.5
化合物P-1 6.0±1.5
应用实施例
实施例8:
对于氘代化合物的口服片剂制备方法(以化合物M-1为例)
口服片剂所用的药用载体有调节剂、填充剂、粘合剂、崩解剂、添加剂、助流剂、润滑剂、膜衣材料、增塑剂、着色剂等。
组分 作用 含量(mg/片)
化合物M-1 活性成分 150
淀粉 填充剂、崩解剂 90
磷酸氢钙 填充剂 23
预胶化淀粉 填充剂 45
枸橼酸 调节剂 3
亚硫酸氢钠 添加剂 0.8
10％淀粉浆 粘合剂 适量
硬脂酸镁 润滑剂 1.7
白色欧巴代 包衣预混料 约4
水、乙醇 溶剂 适量
操作方法：
按上述配方将化合物M-1分别磨粉过筛,然后与填充剂、崩解剂以及经磨粉过筛处理的调节剂、添加剂混合均匀,加入10％的淀粉浆在搅拌机中制成软材,软材在摇摆机上制成湿粒,置烘箱中干燥,再与润滑剂混合均匀,压制成片芯。片芯用欧巴代包制薄膜衣片。
对于氘代化合物的胶囊剂制备方法(以化合物M-1为例)
胶囊剂所用的药用载体有填充剂、粘合剂、崩解剂、添加剂、润滑剂等。
组分 作用 含量(mg/粒)
化合物M-1 活性成分 150
乳糖一水合物 填充剂 76
预胶化淀粉 填充剂、粘合剂 41
羧甲基淀粉钠 崩解剂 13.1
硬脂酸镁 润滑剂 1.7
操作方法：
按上述配方将化合物M-1和各辅料分别磨粉过筛，与填充剂、粘合剂和崩解剂等以一定比例混合均匀，加入干法制粒机中压制成条带，后经破碎机破碎制成颗粒。颗粒与适量润滑剂和崩解剂混合均匀后填充胶囊。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对公开专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (10)

  1. 一种如式1-13所示的氘代内酰胺类化合物，或其药学上可接受的盐、异构体、前药或共晶物：
    Figure PCTCN2022097751-appb-100001
    其中：
    R 1～R 2各自独立地为氢或氘，且R 1～R2中至少一个是氘。
  2. 根据权利要求1所述的化合物，其特征在于，R 1～R2均为氘。
  3. 根据权利要求1所述的化合物，其特征在于，所述化合物选自下组的化合物或其药学上可接受的盐：
    Figure PCTCN2022097751-appb-100002
  4. 一种权利要求1-3任一项所述式I化合物的制备方法，其为以下线路1-线路4中的一种：
    Figure PCTCN2022097751-appb-100003
    上述路线1-4中的化合物的基团定义与权利要求1-3中所述化合物相一致。
  5. 一种药物组合物，其特征在于，其含有药学上可接受载体和权利要求1-3任一所述化合物，或其药学上可接受的盐、异构体、前药或共晶物。
  6. 根据权利要求5所述的药物组合物，其特征在于，它还包含另外的治疗药物，所述的另外的治疗药物为抗病毒药物。
  7. 一种如权利要求1-3所述的化合物或其药学上可接受的盐，或如权利要求5-6所述的药物组合物的用途，其特征在于，用于制备3CL蛋白酶抑制剂类药物组合物。
  8. 根据权利要求7所述的用途，其特征在于，所述药物组合物用于制备治疗 和预防病毒感染的药物。
  9. 根据权利要求8所述的用途，其中所述病毒感染是新冠病毒SARS-CoV-2、SARS冠状病毒和MERS冠状病毒。
  10. 根据权利要求8所述的用途，其中所述病毒感染是新冠病毒SARS-CoV-2。
PCT/CN2022/097751 2022-03-07 2022-06-09 氘代内酰胺类化合物及其制备方法、组合物和用途 WO2023168844A1 (zh)

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