WO2023226679A1 - Inhibiteur de protéase de type 3c - Google Patents

Inhibiteur de protéase de type 3c Download PDF

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Publication number
WO2023226679A1
WO2023226679A1 PCT/CN2023/091287 CN2023091287W WO2023226679A1 WO 2023226679 A1 WO2023226679 A1 WO 2023226679A1 CN 2023091287 W CN2023091287 W CN 2023091287W WO 2023226679 A1 WO2023226679 A1 WO 2023226679A1
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Prior art keywords
compound
active ingredients
pharmaceutically acceptable
compounds
prodrugs
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PCT/CN2023/091287
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English (en)
Chinese (zh)
Inventor
张宏波
杨琪
张伟
孙静
石磊
丁康
王虎庭
许庆博
黄博
赵金存
陈新文
彭伟
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广州国家实验室
北京望石智慧科技有限公司
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Publication of WO2023226679A1 publication Critical patent/WO2023226679A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a new 3C-like protease inhibitor, or its pharmaceutically acceptable salts or esters, their stereoisomers or tautomers, racemates, nitrogen oxides, polymorphs, hydrated forms compounds, solvates, isotopic labels, prodrugs or metabolites.
  • the present invention also relates to methods for preparing the compounds, pharmaceutical compositions containing the compounds, and the effects of the compounds in treating or preventing diseases caused by viral infections.
  • 2019-nCoV The new coronavirus discovered in December 2019 was initially named 2019-nCoV.
  • the World Health Organization (WHO) renamed it COVID-19.
  • WHO World Health Organization
  • 2019-nCoV The virus was named SARS-CoV-2.
  • SARS-CoV-2 can cause severe acute respiratory (SARI) symptoms, including fever, dyspnea, fatigue, and pneumonia.
  • RNA viruses the maximum genome length of coronaviruses ranges from approximately 26 to 32 kb.
  • Mpro main protease
  • 3Cpro picornavirus 3C protease
  • 3CLpro 3C-like protease
  • 3CLpro The function of 3CLpro is to hydrolyze and cleave the expressed peptide chain at the appropriate site, preparing the peptide chain to form a three-dimensional and four-dimensional structure to form the enzyme required for virus proliferation.
  • the enzyme does not change during the catalytic process, but the activation energy of the hydrolysis reaction is reduced, thereby accelerating the rate of the hydrolysis reaction.
  • the sulfhydryl group on cysteine plays a key role in the entire catalytic hydrolysis process, see Thanigaimalai et al.
  • WO2021/250648A1 discloses a compound currently known as Nirmatrelvir (PF-07321332). As one of the active ingredients of Paxlovid, it can be used in combination with ritonavir to reduce the risk of COVID-19. Risk of death and hospitalization from the virus SARS-CoV-2.
  • WO2021/205290A1 also discloses compounds with similar structures, which treat diseases caused by SARS-CoV-2 through a pathway mediated by 3C-like protease inhibitors.
  • Parovide also inhibits the CYP3A4 enzyme, which may interfere with the enzyme's metabolism of other drugs, change the half-life and clearance rate, reduce efficacy, or produce adverse reactions. situation. For example, when a patient takes parovide and terfenadine at the same time, because parovide inhibits the oxidative metabolism of terfenadine by CYP3A4, the concentration of the latter in the patient's body increases abnormally, causing cardiac QT wave prolongation and arrhythmias. .
  • the compounds disclosed in WO2021/205290A1 also face the problem of being ineffective when administered orally.
  • the present invention uses 3C-like protease as a target and develops a new class of small molecule inhibitors, which can be used to treat or prevent viral infections.
  • the compound of the present invention targets 3C-like protease, has excellent inhibitory activity against 3C-like protease with P132H mutation, and can significantly inhibit the proliferation of SARS-CoV-2. At the same time, it also achieves better in vivo stability and lower drug consumption. Side effects, better pharmacokinetic properties, and better biological activity against the main protease of the drug-resistant mutation L50F+E166A+L167F produced under the pressure screening of the peptidomimetic anti-SARS-COV-2 drug ALG-097161.
  • the invention provides compounds of formula (I), or pharmaceutically acceptable salts or esters thereof, their stereoisomers or tautomers, racemates, nitrogen oxides, polymorphs, Hydrates, solvates, isotopic labels, prodrugs or metabolites:
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt or ester thereof, their stereoisomers or tautomers, racemates, nitrogen oxides, etc. substances, polymorphs, hydrates, solvates, isotopic markers, prodrugs or metabolites.
  • the pharmaceutical composition according to the present invention may also optionally comprise at least one physiologically/pharmaceutically acceptable excipient.
  • the pharmaceutical composition according to the present invention may also optionally comprise pharmaceutically acceptable excipients, such as carriers, adjuvants or vehicles.
  • the pharmaceutical compositions according to the invention may also optionally comprise additional active ingredients or therapeutic agents.
  • the additional active ingredient or therapeutic agent is, for example, Remdesivir (Remdesivir or GS-5734), Lopinavir, Molnupiravir, Ritonavir, Chloroquine or Sigma-C6628), hydroxychloroquine and/or alpha-interferon.
  • compositions according to the invention comprise a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or ester thereof, their stereoisomers or tautomers , racemates, nitrogen oxides, polymorphs, hydrates, solvates, isotope markers, prodrugs or metabolites.
  • the pharmaceutical composition according to the invention is an RNA-dependent RNA polymerase inhibitor, a 3CLpro protease inhibitor, a CYP3A4 inhibitor or a host-targeted antiviral drug.
  • the pharmaceutical composition according to the present invention can be formulated into a dosage form suitable for administration by methods known in the art.
  • the invention provides compounds according to the invention or pharmaceutically acceptable salts or esters thereof, their stereoisomers or tautomers, racemates, nitrogen oxides, polymorphs, Use of hydrates, solvates, isotopic labels, prodrugs or metabolites in the preparation of pharmaceuticals.
  • the medicaments prepared according to the invention may also optionally contain additional active ingredients or therapeutic agents.
  • the additional active ingredient or therapeutic agent is, for example, Remdesivir (Remdesivir or GS-5734), Lopinavir, Molnupiravir, Ritonavir, Chloroquine , Sigma-C6628), hydroxychloroquine and/or alpha-interferon.
  • the drug prepared according to the invention is an RNA-dependent RNA polymerase inhibitor, a 3CLpro protease inhibitor, a CYP3A4 inhibitor or a host-targeted antiviral drug.
  • the medicaments prepared according to the present invention are used to prevent or treat diseases, conditions, syndromes and/or disorders selected from the following group, or for alleviating diseases, conditions selected from the following group , symptoms of syndromes and/or disorders: fever, nausea, vomiting, headache, dyspnea, fatigue, respiratory tract infection, pneumonia, smell and taste disorders and their complications, or combinations thereof caused by viral infection; preferably, the The virus is a coronavirus, preferably alphacoronavirus and/or betacoronavirus, more preferably SARS-CoV-2.
  • the medicine prepared according to the present invention can be further formulated into a dosage form suitable for administration by methods known in the art.
  • the present invention provides a method for treating or preventing diseases, conditions, syndromes and/or disorders caused by viral infection in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutical thereof.
  • the compounds or pharmaceutical compositions of the invention inhibit viral proliferation
  • the compound or pharmaceutical composition of the invention inhibits the activity of viral 3CL protease
  • the 3CL protease has a P132H mutation
  • the virus is a coronavirus, preferably an alphacoronavirus and/or a betacoronavirus, more preferably SARS-CoV-2.
  • the diseases, conditions, syndromes and/or disorders caused by the viral infection are selected from: fever, nausea, vomiting, headache, dyspnea, fatigue, respiratory tract infection, pneumonia, olfactory disorder , dysgeusia and its complications, or combinations thereof;
  • the virus is a coronavirus, preferably alphacoronavirus and/or betacoronavirus, more preferably SARS-CoV-2.
  • coronavirus includes, but is not limited to, the following viruses: HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and/or SARSCoV-2.
  • coronavirus is an alphacoronavirus and/or a betacoronavirus, more preferably a betacoronavirus.
  • the alphacoronavirus is selected from HCoV-229E and HCoV-NL63, preferably HCoV-229E.
  • the betacoronavirus is selected from HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2, preferably HCoV-OC43 or SARS-CoV-2, more preferably SARS-CoV- 2.
  • treatment refers to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition.
  • noun “treat” refers to the action of the verb treat, as just defined.
  • the term “treating” any disease or condition in some embodiments thereof, means ameliorating the disease or condition (i.e., slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” or “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be noticeable to the patient.
  • treating refers to modulating a disease or condition physically (eg, stabilizing perceived symptoms) or physiologically (eg, stabilizing body parameters), or both. In other embodiments, “treating” or “treating” refers to preventing or delaying the onset, development, or progression of a disease or disorder.
  • the term "pharmaceutically acceptable salts” means those carboxylate salts and amino acid addition salts of the compounds of the present invention which are suitable for contact with patient tissue within the scope of reliable medical judgment and will not produce undue toxicity, Irritation effects, allergic reactions, etc., commensurate with a reasonable benefit/risk ratio, are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, etc.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
  • Base addition salts of acidic compounds may be prepared in conventional manner by contacting the free acid form with a sufficient amount of the desired base to form the salt.
  • the free acid can be regenerated by contacting the salt form with the acid and isolating the free acid in the usual manner.
  • the free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention the salts are nevertheless equivalent to their respective free acids.
  • the salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates prepared from inorganic acids Salt, chloride, bromide, iodide, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc.
  • Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate Acid, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, Methanesulfonate, glucoheptonate, lactobionate, lauryl sulfonate and isethionate, etc.
  • Salts may also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malonate Lenate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylbenzoate Acid, citrate, lactate, maleate, tartrate, methanesulfonate, etc.
  • Pharmaceutically acceptable salts may include alkali and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethyl Ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also contemplated are salts of amino acids, such as arginates, gluconates, galacturonates, etc. (see, for example, Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1-19 , incorporated by reference).
  • nitrogen oxide means that one or more nitrogen atoms can be oxidized to form N-oxides when the compound contains several nitrogen-containing functional groups.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocyclic rings.
  • the corresponding nitrogen-containing compounds can be treated with oxidizing agents such as hydrogen peroxide or peracids (eg peroxycarboxylic acid) to form N-oxides.
  • oxidizing agents such as hydrogen peroxide or peracids (eg peroxycarboxylic acid) to form N-oxides.
  • N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which the nitrogen-containing compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as methylene chloride. )reaction.
  • MCPBA m-ch
  • esters refers to an in vivo hydrolyzable ester of a compound containing a hydroxyl or carboxyl group. Such esters are, for example, physiologically/pharmaceutically acceptable esters which hydrolyze in humans or animals to yield the parent alcohol or acid.
  • the compound of formula (I) or (II) of the present invention contains a carboxyl group, which can form a hydrolyzable ester in vivo with an appropriate group.
  • groups include, but are not limited to, alkyl, arylalkyl, etc.
  • Subjects for administration include, but are not limited to: humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adults, middle-aged adults or older adults) and/or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human,” “patient,” and “human” are used interchangeably herein. "Subject”.
  • treatment includes an action in a subject suffering from a specific disease, disorder or condition that reduces the severity of the disease, disorder or condition, or delays or slows down the disease, disorder or the development of a condition ("therapeutic treatment”), and also includes effects that occur before a subject begins to suffer from a specific disease, disorder or condition ("preventive treatment").
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material in association with a suitable pharmaceutical excipient.
  • the unit dosage form may be a pill, a tablet, a capsule or a lozenge, etc.
  • an "effective amount" of a compound is an amount sufficient to elicit a target biological response.
  • the effective amount of a compound of the present invention may vary depending on factors such as, for example, the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the condition of the subject. Age health conditions and symptoms.
  • the effective amount includes a therapeutically effective amount and a preventive effective amount.
  • a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in treating a disease, disorder, or condition, or to cause one or more symptoms associated with the disease, disorder, or condition The amount to delay or minimize.
  • a therapeutically effective amount of a compound is that amount of therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition.
  • the term "therapeutically effective amount” may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.
  • a prophylactically effective amount of a compound as used herein is an amount sufficient to prevent a disease, disorder or condition, or to prevent one or more symptoms associated with a disease, disorder or condition, or to prevent a disease , the amount of recurrence of a disorder or condition.
  • a prophylactically effective amount of a compound is that amount of therapeutic agent that, when used alone or in combination with other agents, provides a prophylactic benefit in preventing a disease, disorder, or condition.
  • the term “prophylactically effective amount” may include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents.
  • Combination and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent.
  • the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or with other therapeutic agents in a single unit dosage form.
  • compounds of the present invention refer to the following compounds of formula (I), or pharmaceutically acceptable salts or esters thereof, their stereoisomers or tautomers, racemates, and nitrogen oxides. , polymorphs, hydrates, solvates, isotopic markers, prodrugs or metabolites.
  • the present invention relates to compounds of formula (I), or pharmaceutically acceptable salts or esters thereof, their stereoisomers or tautomers, racemates, nitrogen oxides, polymorphs , hydrates, solvates, isotopic labels, prodrugs or metabolites:
  • the compounds of the present invention may contain one or more asymmetric centers and thus may exist in multiple stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, Includes racemic mixtures and mixtures enriched in one or more stereoisomers.
  • the isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers may be separated by Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • Tautomers are functional group isomers produced by the rapid movement of an atom in a molecule between two positions.
  • a tautomer is a special functional group isomer.
  • a pair of tautomers can interact with each other. conversion, but usually one of the more stable isomers is its main form of existence. The most important examples are the enol and keto tautomers.
  • compounds of the present invention include the following tautomers:
  • solvate refers to a form of a compound or a salt thereof that is combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, etc.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolating, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes both solution solvates and isolable solvates. Representative solvates include hydrates, ethanolates, and methoxides.
  • hydrate refers to a compound combined with water. Generally, the number of water molecules contained in a hydrate of a compound is related to the hydrate The ratio of the number of molecules in the compound is determined. Thus, a hydrate of a compound may be represented, for example, by the general formula R.xH2O , where R is the compound and x is a number greater than zero.
  • a given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1), for example, hemihydrate (R ⁇ 0.5H 2 O) and polyhydrates (x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O).
  • the compounds of the invention may be in amorphous or crystalline forms (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms often have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I), except that one or more atoms are surrounded by atoms having an atomic mass or mass number different from that common in nature. replaced.
  • isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by replacing non-isotopes with readily available isotope-labeled reagents when performing the following processes and/or the processes disclosed in the Examples and Preparation Examples. Labeled reagents.
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” as used herein refers to a compound that is converted in the body to its active form having a medical effect, for example, by hydrolysis in the blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each introduced This article serves as a reference.
  • a prodrug is any covalently bonded compound of the invention that releases the parent compound in the body when administered to a patient.
  • Prodrugs are typically prepared by modifying functional groups in a manner such that the modification can be cleaved by conventional manipulations or in vivo to yield the parent compound.
  • Prodrugs include, for example, compounds of the invention in which a hydroxyl, amino or thiol group is bonded to any group that can be cleaved to form a hydroxyl, amino or thiol group when administered to a patient.
  • representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide derivatives of the hydroxyl, thiol and amino functionality of compounds of formula (I).
  • esters such as methyl ester, ethyl ester, etc. can be used.
  • the ester itself may be reactive and/or hydrolyzable under human body conditions.
  • Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily break down in the human body to release the parent acid or salt thereof.
  • metabolite refers to a product obtained by metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assays as described herein. Such products can be obtained by administering compounds through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, etc.
  • the invention includes metabolites of compounds, including metabolites produced by contacting a compound of the invention with a mammal for a period of time sufficient to do so.
  • the present invention also provides pharmaceutical preparations, comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable salt thereof.
  • acceptable carrier, diluent or excipient All these forms belong to the invention.
  • the invention provides pharmaceutical compositions comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions comprise an effective amount of a compound of the invention.
  • the pharmaceutical compositions comprise a therapeutically effective amount of a compound of the invention.
  • the pharmaceutical compositions comprise a prophylactically effective amount of a compound of the invention.
  • pharmaceutical composition means a mixture containing one or more compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable salts or prodrugs thereof. Accepted carriers and excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
  • physiologically/pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar inappropriate reactions, such as gastrointestinal upset, dizziness, and the like.
  • carrier refers to a diluent, adjuvant, excipient or matrix with which the compound is administered.
  • These pharmaceutical carriers can be sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Water and aqueous solutions, saline solutions and aqueous glucose and glycerol solutions are preferably used as carriers, especially for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • compositions of the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compounds with which they are formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin) protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene- Block polymers, polyethylene glycols, and
  • Substances that can be used as physiologically/pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphate, glycine, sorbate Acids, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate , polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocked polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives Such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc;
  • compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.
  • the dosage form of the medicine of the present invention can be selected according to specific circumstances.
  • Pharmaceutical dosage forms often consist of drug substance, excipients, and a container/closure system.
  • excipients also known as inactive ingredients
  • the type of excipients added to a drug can depend on various factors, such as the physical and chemical properties of the drug, route of administration, and preparation steps.
  • Pharmaceutical excipients exist in the art and include those listed in various pharmacopeias.
  • compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecules into preparations for pharmaceutical use.
  • Appropriate formulation will depend on the desired route of administration. Routes of administration include intravenous injection, transmucosal or nasal administration, oral administration, etc.
  • the compounds may be formulated in liquid or solid dosage forms and as immediate release or controlled/sustained release preparations. Suitable dosage forms for oral ingestion by individuals include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, ointments, suspensions and emulsions.
  • Solid oral dosage forms may be obtained using excipients including fillers, disintegrants, binders (dry and wet), dissolution retarder, lubricants, glidants, anti-adhesive agents, cationic exchangers Resins, humectants, antioxidants, preservatives, colorants and flavoring agents. These excipients may be of synthetic or natural origin.
  • excipients examples include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicic acid Salt, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or its salts, sugar (i.e. dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oil (hydrogenated) and wax. Ethanol and water can be used as granulation aids.
  • tablets In some cases, it is necessary to coat tablets with, for example, a taste-masking film, an acid-resistant film, or a delayed-release film.
  • Natural and synthetic polymers are often used to coat tablets in combination with colorants, sugars and organic solvents or water to produce dragees.
  • their drug powders, suspensions or solutions may be delivered in compatible hard or soft shell capsules.
  • the therapeutically effective dose can first be estimated using various methods well known in the art. Initial dosages for animal studies may be based on established effective concentrations in cell culture assays. Dosage ranges suitable for humans can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention can be prepared as a medicament for oral administration.
  • the correct formulation, route of administration, dosage and interval between administrations can be selected according to methods known in the art, taking into account the particularities of the individual condition.
  • Suitable formulations for administering the compounds of the invention will be apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, lozenges, solutions (especially injections (subcutaneous, intravenous solution for intramuscular administration) and infusion (injection)), elixir, syrup, cachet, emulsion, inhalation or dispersible powder.
  • the content of one or more pharmaceutically active compounds should range from 0.1 to 90% by weight, preferably from 0.5 to 50% by weight of the composition as a whole, ie an amount sufficient to achieve the dosage ranges specified below. If necessary, the specified dose may be administered several times per day.
  • kits eg, pharmaceutical packaging.
  • Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packaging or other) containing the compounds of the invention, other therapeutic agents. suitable container).
  • provided kits may also optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the invention and/or other therapeutic agents.
  • the compound of the invention and the other therapeutic agent provided in the first container and the second container are combined to form a unit dosage form.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intracerebrospinal membrane drug administration, intralesional drug administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of compound actually administered can be determined by the physician depending on the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .
  • a compound provided herein When used to prevent a disorder described herein, a compound provided herein is administered to a subject at risk of developing the disorder, Typically administered based on a physician's advice and supervision, dosage levels are as described above.
  • Subjects at risk of developing a particular condition generally include subjects with a family history of the condition or those who have been determined by genetic testing or screening to be particularly susceptible to developing the condition.
  • compositions provided herein can also be administered over a long period of time ("chronic administration").
  • Long-term administration refers to the administration of a compound or pharmaceutical composition thereof over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration may be continued indefinitely, For example, the remainder of the subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, eg, within a therapeutic window.
  • a pharmaceutical composition may be administered as a bolus injection, eg, in order to increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic levels of the active ingredient through the body, e.g., an intramuscular or subcutaneous bolus dose provides a slow release of the active ingredient, whereas a bolus dose delivered directly into the vein (e.g., via an IV drip) ) can be delivered more quickly, allowing the concentration of active ingredients in the blood to quickly increase to effective levels.
  • the pharmaceutical composition may be administered as a continuous infusion, for example, by IV infusion, thereby providing a steady-state concentration of the active ingredient in the subject's body. Additionally, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.
  • Oral compositions may take the form of bulk liquid solutions or suspensions, or bulk powders. More typically, however, the compositions are provided in unit dosage form to facilitate precise dosing. Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules, and the like in the case of solid compositions. In such compositions, the compound will generally be a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), with the remainder being various components useful in forming the desired administration form. carriers or excipients and processing aids.
  • a typical regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • a transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • Injectable dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour from about 1 to about 120 hours, especially from 24 to 96 hours. To achieve adequate steady state levels, a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be given. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffering agents, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • Solid forms may include, for example, any of the following components, or compounds of similar nature: binders, for example, microcrystalline cellulose, tragacanth, or gelatin; excipients, for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch; lubricant, for example, magnesium stearate; glidant, for example, colloidal silicon dioxide; sweetener, for example, sucrose or saccharin; or flavoring agent, for example, mint, water Methyl glycolate or orange flavoring.
  • binders for example, microcrystalline cellulose, tragacanth, or gelatin
  • excipients for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As stated previously, in such compositions the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredients.
  • the active ingredients When formulated as an ointment, the active ingredients are typically combined with a paraffin or water-miscible ointment base.
  • the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and often include other ingredients for promoting stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by this invention.
  • transdermal administration may be achieved using reservoir or porous membrane types, or a variety of solid matrix patches.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which article is incorporated by reference.
  • the compounds of the present invention may also be administered in sustained release form or from a sustained release drug delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention also relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation includes water.
  • the formulation contains a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ - and ⁇ -cyclodextrins consisting of 6, 7 and 8 ⁇ -1,4-linked glucose units respectively, optionally including a or multiple substituents including, but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, for example, sulfobutyl ether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation includes hexapropyl-beta-cyclodextrin (eg, in water, 10-50%).
  • 3C-like protease inhibitors For diseases caused by viral infections, the development of 3C-like protease inhibitors can provide therapeutic benefits for a large number of patients.
  • the compounds in the present invention exert therapeutic effects by negatively regulating the activity of 3C-like protease in viruses, especially viruses with P132H mutation in the 3C-like protease.
  • the 3C-like protease inhibitors of the present invention can treat various diseases caused by viral infections and their complications.
  • these compounds can be used to treat the following diseases caused by viral infections: fever, nausea, vomiting, headache, dyspnea, fatigue, respiratory tract infection, pneumonia, smell disorder, taste disorder and its complications, etc.
  • these compounds can be used for the above-mentioned diseases or symptoms caused by SARS-CoV-2 infection.
  • the 3C-like protease inhibitor of the present invention can be combined with other drugs to treat cancer, and contains at least one target drug/viral activity modulator, including Remdesivir (Remdesivir or GS-5734), Lopinavir (Lopinavir) ), Molnupiravir, Ritonavir, chloroquine (Chloroquine or Sigma-C6628), hydroxychloroquine and/or alpha-interferon, etc.
  • Remdesivir Remdesivir or GS-5734
  • Lopinavir Lopinavir
  • Molnupiravir Ritonavir
  • chloroquine Chloroquine or Sigma-C6628
  • hydroxychloroquine and/or alpha-interferon etc.
  • control drugs propranolol and Digoxin were purchased from MCE, and Minoxidil was purchased from China Institute of Food and Drug Control.
  • Caco-2 cells were purchased from American Type Culture Collection (ATCC).
  • FBS medium was purchased from Sigma, DMEM was purchased from Corning Company (Cambridge, MA), non-essential amino acids (NEAA), Hank’s balanced salt solution (HBSS) and trypsin/EDTA were purchased from Thermo Fisher. Penicillin and streptomycin were purchased from Soleba.
  • HTS-96-well Transwell plate and other sterile consumables were purchased from Corning Company.
  • Millicell resistance measurement system was purchased from Millipore. Vision was purchased from Nexcelom Bioscience. Infinite 200 PRO microplate reader was purchased from Tecan. The MTS2/4 orbital shaker was purchased from IKA Labortechnik.
  • Caco-2 was cultured in cell culture flasks.
  • the incubator was set to 37°C, 5% CO 2 , and guaranteed relative humidity of 95%. Cells that reach 70-90% confluence can be used to seed Transwells.
  • the process of replacing the culture medium is as follows. Separate the Transwell chamber from the receiving plate. Discard the medium in the receiving plate first and then discard the medium in the Transwell chamber. Finally, add 75 ⁇ L of fresh culture medium to each chamber and 25 mL of fresh culture medium to the receiving plate. .
  • Caco-2 After 14-18 days of culture, Caco-2 should be fully confluent and complete differentiation. At this time, it can be applied to penetration testing.
  • V A is the volume of the receiving end solution (Ap ⁇ Bl is 0.235mL, Bl ⁇ Ap is 0.075mL), Area is the Transwell-96-well plate membrane area (0.143cm 2 ); time is the incubation time (unit: s ).
  • P app(BA) is the apparent permeability coefficient from the basal end to the top
  • P app(AB) is the apparent permeability coefficient from the top to the basal end.
  • DPX 2 a HepG2 cell line stably transfected with PXR and luciferase systems
  • CellTiter-Fluor TM cell viability assay kit and One-Glo luciferase assay system were purchased from Promega Company (Madison, WI).
  • FBS medium was purchased from Avantor
  • DPX 2 cell culture medium and administration medium were purchased from Puracyp.
  • DPX 2 was cultured in T-75 cell culture flask.
  • the incubator was set to 37°C, 5% CO 2 , and guaranteed relative humidity of 95%. Cells can be used for isolation when they reach 80-90% confluence.
  • Solution configuration Prepare 1. DMSO stock solution of 10mM compound to be tested and 10mM positive control drug rifampicin. The final concentrations of the compounds to be tested were 1 and 10 ⁇ M, respectively, and the final concentration of rifampicin was 10 ⁇ M. The DMSO content of the final system was 0.1%. The blank control is DMSO.
  • the cell plate After 48 hours of drug administration and incubation, the cell plate can be used to test PXR activity.
  • Luciferase activity is determined by RLU/RFU, where RLU represents the average relative luminescence value of three parallel samples of the test compound at each concentration, and RFU represents the average relative fluorescence value of the three parallel samples of the test compound at each concentration.
  • Animal feeding control fast overnight before administration, drink water freely, and provide feed 4 hours after administration.
  • the actual dosing volume was calculated based on the animal's body weight.
  • the LC-MS/MS detection method was applied, and the accompanying standard curve was used to determine the blood drug concentration in the plasma sample.
  • WinNonlin 8.3 (Phoenix TM ) or other similar software will be used to calculate pharmacokinetic parameters. Pharmacokinetic parameters will be calculated if applicable plasma drug concentration-time data are available.
  • Pharmacokinetic data were described by descriptive statistics such as mean, standard deviation, and sample size. Calculations were performed using Microsoft Excel 2013. Other pharmacokinetic parameters and statistical analyzes can also be performed and recorded in the data summary.
  • the assay system (120 ⁇ L) contains 108 ⁇ L main protease (WT or P132H) with a final concentration of 150nM.
  • the protein-free small molecule control group is added with 108 ⁇ L protein diluent.
  • the diluent components are 50mM Tris-HCL PH 7.4 and 1mM EDTA;
  • the negative control NC here is to add 2 ⁇ L of 100% DMSO.
  • the fluorescent substrate is MCA-AVLQSGFR-LYS(DNP)-Lys-NH 2 .
  • the reaction process is as follows: first mix 108 ⁇ L of main protease or protein diluent and 2 ⁇ L of small molecules, add them to a 96-well all-black enzyme plate (Corning costar, #3916), and incubate for 30 minutes. After the incubation is completed, add the fluorescent substrate and quickly start detection on the microplate reader.
  • the microplate reader detection method is:
  • the excitation light wavelength is 320nm
  • the emission light wavelength is 405nm
  • the detection interval is about 15s
  • the total detection time is 20min; the fluorescence value of each reaction well at different times under the detection conditions is recorded, and the fluorescence value recorded in the previous 200s is used for calculation ( Typically 7-10 data points).
  • Inhibition rate (%) (RFU 100% enzyme activity control -RFU sample )/(RFU 100% enzyme activity control -RFU blank control ) ⁇ 100%
  • Inhibition rate (%) (NC initial velocity V 0 - sample initial velocity V 0 )/NC initial velocity V 0 ⁇ 100%;
  • NC enzyme activity is determined as 100%, and the inhibition rate is 0%
  • Inhibition rate (%) (NC initial velocity V 0 - (sample initial velocity V 0 - protein-free small molecule control group V 0 )/NC initial velocity V 0 ⁇ 100% is used to eliminate V 0 (slope ) is a negative value.
  • test sample sample and control substance
  • test process generally uses Formula 2 to optimize the calculation of the inhibition rate.
  • PCR 94°C5min, 94°C30s, 66°C20s, 72°C1min, 30cycles, 72°C10min.
  • Nickel column affinity chromatography column treatment Clean the nickel column with ddH2O first, then use equilibrium buffer to equilibrate the column, combine the filtered bacterial supernatant with the nickel column affinity chromatography gel, and wash with 20mM imidazole.
  • the impurity buffer was used to wash the impurities, and the elution buffer containing 500mM imidazole concentration was used for elution.
  • Reaction buffer 50mM Tris pH 7.4, 1mM EDTA, 0.01% tritonX-100.
  • Protein (108uL) main protease (L50F+E166A+L167F), the final concentration is 500nM, add 108uL reaction buffer to the protein-free small molecule control group;
  • Small molecules (2uL): Compound 1, Comparative Compound 1, Comparative Compound 2 (saved at 50mM), use 100% DMSO to dilute the 50mM concentration of small molecules to 0.06mM, so that the final concentration in the reaction system is 1uM.
  • Gradient dilution of small molecules The above small molecules are diluted 2-fold starting from a concentration of 0.06mM (final concentration 1uM) to the 8th well.
  • the negative control NC here is to add 2uL 100% DMSO.
  • the excitation light wavelength is 320nM
  • the emission light wavelength is 405nM
  • the detection interval is about 15s
  • the total detection time is 20min; the fluorescence values in each reaction well at different times under the detection conditions are recorded, and the fluorescence recorded in the previous 200s is used for calculation. value (typically 7-10 data points)
  • P app (BA) is the apparent permeability coefficient from the basal end to the apical end
  • P app (AB) is the apparent permeability coefficient from the apical end to the basal end.
  • AUC last area under the drug-time curve, to evaluate the degree of drug absorption
  • the above data show that while maintaining excellent inhibitory activity, the compound of the present invention also achieves better stability, lower drug side effects, better pharmacokinetic properties, and is effective against peptoids against SARS-COV- 2.
  • the drug resistance mutation L50F+E166A+L167F main protease produced under the pressure screening of drug ALG-097161 has better biological activity than the comparative compound.
  • the Caco2 permeability experiment characterizes the penetration effect of the drug, and P app (BA) represents the penetration effect from the blood to the small intestine.
  • P app (AB) represents the penetration effect from the small intestine into the blood.
  • the penetration effect of the compound of the present invention from the small intestine into the blood is better than that of the other two comparative compounds, and it is less likely to penetrate from the blood into the small intestine, that is, drug penetration Excellent results.
  • PXR represents a drug interaction. Specifically, PXR activation induces metabolic enzymes (such as CYP3A4). Metabolic enzymes can affect the pharmacokinetics of exogenous and endogenous substances. Overactivation of CYP3A4 enzymes can induce CYP3A4-mediated Anti-tumor drugs, analgesics, etc. accelerate metabolism and affect the efficacy of combined drugs.
  • the PXR value of Compound 1 of the present invention at different concentrations is significantly lower than that of Comparative Compounds 1 and 2, and it has a lower risk of drug interaction and toxic metabolism.
  • the biochemical activity of the main protease of the anti-drug resistance mutation L50F+E166A+L167F of compound 1 is more advantageous than that of comparative compounds 1 and 2.

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Abstract

La présente invention concerne un inhibiteur de protéase de type 3C représenté par la formule (I), ou un sel ou ester pharmaceutiquement acceptable de celui-ci, et un stéréoisomère ou un tautomère, un racémate, un oxyde d'azote, un polymorphe, un hydrate, un solvate, un marqueur isotopique, un promédicament ou un métabolite du sel ou ester pharmaceutiquement acceptable. La présente invention concerne en outre un procédé de préparation du composé chimique, une composition pharmaceutique contenant le composé, et l'effet du composé dans le traitement ou la prévention de maladies causées par une infection virale.
PCT/CN2023/091287 2022-05-27 2023-04-27 Inhibiteur de protéase de type 3c WO2023226679A1 (fr)

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