WO2019196891A1 - 多环氨基甲酰基吡啶酮衍生物、药物组合物及其用途 - Google Patents

多环氨基甲酰基吡啶酮衍生物、药物组合物及其用途 Download PDF

Info

Publication number
WO2019196891A1
WO2019196891A1 PCT/CN2019/082195 CN2019082195W WO2019196891A1 WO 2019196891 A1 WO2019196891 A1 WO 2019196891A1 CN 2019082195 W CN2019082195 W CN 2019082195W WO 2019196891 A1 WO2019196891 A1 WO 2019196891A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
hydrogen
acid
group
polycyclic
Prior art date
Application number
PCT/CN2019/082195
Other languages
English (en)
French (fr)
Inventor
朱孝云
蒋维平
Original Assignee
安帝康（无锡）生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 安帝康（无锡）生物科技有限公司 filed Critical 安帝康（无锡）生物科技有限公司
Priority to US17/044,079 priority Critical patent/US20210093640A1/en
Priority to RU2020136675A priority patent/RU2770096C1/ru
Priority to EP19784679.3A priority patent/EP3778608A4/en
Priority to AU2019252208A priority patent/AU2019252208B2/en
Publication of WO2019196891A1 publication Critical patent/WO2019196891A1/zh

Links

Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to polycyclic carbamoylpyridone derivatives, pharmaceutical compositions and uses thereof.
  • the flu is an acute viral infection that can easily spread in people, especially during the winter months in temperate regions. Because influenza viruses are prevalent worldwide and can infect anyone of any age group, often causing serious complications and deaths in high-risk populations, is currently a serious public health problem. According to statistics, the annual influenza epidemic is estimated to cause 3 to 5 million serious cases, and the death toll is about 250,000 to 500,000.
  • the messenger RNA (mRNA) of influenza virus needs to have both a 5' cap (CAP) structure and a 3'-poly (A) tail structure which are recognized by the host cell translation system.
  • CAP 5' cap
  • A 3'-poly
  • the 5' cap structure is "robbed” from the 5' end of the host cell precursor mRNA by the endonuclease activity of the PA subunit in the influenza virus RNA polymerase complex. This method, called “CAP-snatching”, captures the CAP cap structure of the host mRNA for viral self-mRNA transcription and is required for the transcription initiation of influenza virus.
  • the present invention provides a polycyclic carbamoylpyridone derivative represented by the formula (VII), a stereoisomer, a tautomer, a hydrate, a solvate, an active metabolite, a crystalline form, and a pharmaceutically acceptable form.
  • Acceptable salt or its prodrug :
  • R 1 is hydrogen or helium
  • R 2 is hydrogen or helium
  • R 3 is hydrogen or helium
  • R 1 , R 2 and R 3 are deuterium;
  • R 4 is hydrogen or halogen (preferably chlorine);
  • R 5 is hydrogen or halogen (preferably fluorine);
  • R 6 is hydrogen or halogen (preferably fluorine);
  • A is C or O.
  • R 7 and R 8 are both hydrogen or both methyl; when A is O, R 7 and R 8 are absent;
  • R 9 is hydrogen or methyl
  • R 10 is hydrogen or methyl
  • R 4 , R 5 and R 6 are not hydrogen at the same time.
  • the polycyclic carbamoyl pyridone derivative represented by the formula (VII) preferably satisfies any of the following conditions:
  • R 4 is hydrogen; R 5 is fluorine; R 6 is fluorine; A is O; R 9 is hydrogen; and R 10 is hydrogen.
  • R 4 is hydrogen; R 5 is fluorine; R 6 is hydrogen; A is O; R 9 is hydrogen; R 10 is a methyl group and the carbon atom directly attached to R 10 is (S).
  • R 4 is chlorine; R 5 is hydrogen; R 6 is hydrogen; A is O; R 9 is hydrogen; and R 10 is hydrogen.
  • R 4 is hydrogen; R 5 is fluorine; R 6 is fluorine; A is C; R 7 and R 8 are both methyl; R 9 is hydrogen; and R 10 is hydrogen.
  • R 4 is hydrogen; R 5 is fluorine; R 6 is fluorine; A is C; R 7 and R 8 are both hydrogen; R 9 is hydrogen and the carbon atom directly attached to R 9 is (R) ; R 10 is hydrogen.
  • R 4 is hydrogen; R 5 is fluorine; R 6 is hydrogen; A is C; R 7 and R 8 are both hydrogen; R 9 is hydrogen; and R 10 is hydrogen.
  • the alkyl group is preferably a C 1-4 alkyl group, and further preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group. .
  • the present invention provides a polycyclic carbamoyl pyridone derivative represented by the formula (I), a stereoisomer, a tautomer, a hydrate, a solvate, an active metabolite, a crystalline form, and a pharmaceutically acceptable form.
  • Acceptable salt or its prodrug :
  • R 1 is hydrogen or helium
  • R 2 is hydrogen or helium
  • R 3 is hydrogen or helium
  • R 1 , R 2 and R 3 is deuterium.
  • the polycyclic carbamoyl pyridone derivative represented by the formula (I) is preferably selected from the group consisting of the following compounds:
  • the present invention provides a polycyclic carbamoyl pyridone derivative represented by the formula (II), a stereoisomer, a tautomer, a hydrate, a solvate, an active metabolite, a crystalline form, and a pharmaceutically acceptable form.
  • Acceptable salt or its prodrug :
  • R 1 is hydrogen or helium
  • R 2 is hydrogen or helium
  • R 3 is hydrogen or helium
  • R 1 , R 2 and R 3 is deuterium.
  • the polycyclic carbamoyl pyridone derivative represented by the formula (II) is preferably selected from the group consisting of the following compounds:
  • the present invention provides a polycyclic carbamoyl pyridone derivative represented by the formula (III), a stereoisomer, a tautomer, a hydrate, a solvate, an active metabolite, a crystalline form, and a pharmaceutically acceptable form.
  • Acceptable salt or its prodrug :
  • R 1 is hydrogen or helium
  • R 2 is hydrogen or helium
  • R 3 is hydrogen or helium
  • R 1 , R 2 and R 3 is deuterium.
  • the polycyclic carbamoyl pyridone derivative represented by the formula (III) is preferably selected from the group consisting of the following compounds:
  • the present invention provides a polycyclic carbamoylpyridone derivative represented by the formula (IV), a stereoisomer, a tautomer, a hydrate, a solvate, an active metabolite, a crystalline form, and a pharmaceutically acceptable form.
  • Acceptable salt or its prodrug :
  • R 1 is hydrogen or helium
  • R 2 is hydrogen or helium
  • R 3 is hydrogen or helium
  • R 1 , R 2 and R 3 is deuterium.
  • the polycyclic carbamoyl pyridone derivative represented by the formula (IV) is preferably selected from the group consisting of the following compounds:
  • the present invention provides a polycyclic carbamoyl pyridone derivative represented by the formula (V), a stereoisomer, a tautomer, a hydrate, a solvate, an active metabolite, a crystalline form, and a pharmaceutically acceptable form.
  • Acceptable salt or its prodrug :
  • R 1 is hydrogen or helium
  • R 2 is hydrogen or helium
  • R 3 is hydrogen or helium
  • R 1 , R 2 and R 3 is deuterium.
  • the polycyclic carbamoyl pyridone derivative represented by the formula (V) is preferably selected from the group consisting of the following compounds:
  • the present invention provides a polycyclic carbamoyl pyridone derivative represented by the formula (VI), a stereoisomer, a tautomer, a hydrate, a solvate, an active metabolite, a crystalline form, and a pharmaceutically acceptable form.
  • Acceptable salt or its prodrug :
  • R 1 is hydrogen or helium
  • R 2 is hydrogen or helium
  • R 3 is hydrogen or helium
  • R 1 , R 2 and R 3 is deuterium.
  • the polycyclic carbamoyl pyridone derivative represented by the formula (VI) is preferably selected from the group consisting of the following compounds:
  • alkyl is used to mean a straight or branched saturated hydrocarbon group which may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • the compounds of the invention are generally employed in the form of the free acid or the free base. Alternatively, the compounds of the invention may be used in the form of an acid or base salt.
  • the acid addition salts of the free amino compounds of the present invention can be prepared by methods well known in the art and can be prepared from organic and inorganic acids.
  • Suitable organic acids include maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, Lactic acid, mandelic acid, phenylacetic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, and benzenesulfonic acid.
  • Suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid.
  • the basic salt includes a salt formed with a carboxylate anion, and includes an organic and inorganic cation formed such as an alkali metal ion, an alkaline earth metal ion (for example, lithium, sodium, potassium, magnesium, barium, calcium) and an ammonium ion. a salt, and a substituted derivative thereof (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, etc.). Therefore, the terms "pharmaceutically acceptable salts" of the general formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) shall include and Acceptable salt form.
  • prodrugs are also included in the scope of the present invention.
  • a prodrug is any covalently bound carrier which, when administered to a patient, is released in the body to receive formula (I), formula (II), formula (III), formula (IV), formula (V). a compound of formula (VI) or formula (VII).
  • Prodrugs are typically prepared by modifying the functional groups in such a way that the modifications can be resolved by conventional exchange or in vivo to give the parent compound.
  • Prodrugs include, for example, a compound of the invention in which a hydroxy, amino or thiol group is bonded to any group, wherein the group is detached when administered to a patient to provide a hydroxy, amino or thiol group.
  • prodrugs include, but are not limited to, Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) or Formula (VII) Derivatives of acetates, formates and benzoate salts of alcohol and amine functional groups of the compounds.
  • a carboxylic acid (-COOH) esters such as a methyl ester, an ethyl ester or the like may be included.
  • a mixed acid anhydride such as a methoxy group, an ethoxy group, a propoxy group, a t-butoxy group or the like can be included.
  • compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) may have a chiral center, and It can exist as a racemate, a racemic mixture, and as individual enantiomers or diastereomers. All isomeric forms are included within the invention, including mixtures thereof. Furthermore, certain crystalline forms of the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) may exist in the form of polymorphs, It is also included in the present invention.
  • any compound may contain an unnatural proportion of atomic isotopes at one or more of the atoms that make up the compound.
  • the deuterated means that the atom at the relevant site of the compound contains a ruthenium atom exceeding a natural ratio (ie, exceeding the natural abundance of ruthenium). . Therefore, any polycyclic carbamoylpyridone derivative containing a ruthenium atom in a ratio above the natural abundance of ruthenium at the relevant site is within the scope of the present invention.
  • the corresponding polycyclic amino group having a corresponding deuteration rate or hydrazine content obtained by introducing a ruthenium atom using a commercially available deuteration reagent by the same or similar chemical synthesis means as shown in the examples of the present invention is understood.
  • the acylpyridone derivatives are all within the scope of the present invention.
  • the chemical synthesis means and deuterated reagents herein are not limited to those exemplified in the examples, but it should be understood that all synthetic methods or routes that can be used in the art to obtain the compounds of the present invention, and all may be combined with the aforementioned synthetic methods or A deuterated reagent that introduces a ruthenium atom into a target molecule.
  • the invention further provides a formula (VII), preferably as shown in formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI) Polycyclic carbamoyl pyridone derivatives, stereoisomers, tautomers, hydrates, solvates, active metabolites, crystalline forms, pharmaceutically acceptable salts or prodrugs thereof, in the preparation of 5' caps Use in dependent endonuclease inhibitors.
  • a formula (VII) preferably as shown in formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI)
  • the invention further provides a formula (VII), preferably as shown in formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI) Polycyclic carbamoylpyridone derivatives, stereoisomers, tautomers, hydrates, solvates, active metabolites, crystalline forms, pharmaceutically acceptable salts or prodrugs thereof for the preparation of prophylaxis and treatment And/or use in a medicament for alleviating a disease associated with a 5' cap-dependent endonuclease.
  • a formula (VII) preferably as shown in formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI)
  • the disease associated with the 5′ cap-dependent endonuclease refers to a symptom and/or disease which is prevented, treated and/or alleviated by inhibiting the level of 5′ cap-dependent endonuclease in vivo, specifically Refers to symptoms and/or diseases caused by influenza virus infection. More specifically, the influenza virus includes, but is not limited to, alpha (A), ethyl (B), and ethyl (C).
  • the symptoms include, but are not limited to, for example, cold symptoms such as fever, chills, headache, muscle pain, body burnout, or respiratory tract inflammation, abdominal pain, runny nose, cough, phlegm, etc. Gastrointestinal symptoms such as vomiting and diarrhea, followed by complications of secondary infections such as acute encephalopathy and pneumonia.
  • the invention further provides a method of preventing, treating and/or ameliorating a disease associated with a 5' cap-dependent endonuclease, the method comprising administering to a subject in need thereof a therapeutically effective amount of, as in formula (VII) (preferably, a polycyclic carbamoyl pyridone derivative represented by formula (I), formula (II), formula (III), formula (IV), formula (V), or formula (VI))
  • the diseases associated with the 5' cap-dependent endonuclease are specifically as described above.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a formula (VII) (preferably such as formula (I), formula (II), formula (III), formula (IV), formula (V) Or a polycyclic carbamoylpyridone derivative represented by formula (VI)), a stereoisomer, tautomer, hydrate, solvate, active metabolite, crystalline form thereof, pharmaceutically acceptable a salt or a prodrug thereof, and a pharmaceutically acceptable carrier.
  • a formula (VII) preferably such as formula (I), formula (II), formula (III), formula (IV), formula (V) Or a polycyclic carbamoylpyridone derivative represented by formula (VI)
  • a stereoisomer, tautomer, hydrate, solvate, active metabolite, crystalline form thereof, pharmaceutically acceptable a salt or a prodrug thereof, and a pharmaceutically acceptable carrier a pharmaceutically acceptable carrier.
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising not only a therapeutically effective amount of formula (VII) (preferably, formula (I), formula (II), formula (III), formula (IV), formula (V) Or a polycyclic carbamoyl pyridone derivative represented by formula (VI)), a stereoisomer, tautomer, hydrate, solvate, active metabolite, crystalline form thereof, pharmaceutically acceptable
  • the salt or a prodrug thereof, and a pharmaceutically acceptable carrier further comprise other pharmaceutically active ingredients.
  • the other pharmaceutically active ingredient is selected from the group consisting of a neuraminidase inhibitor (eg, oseltamivir, zanamivir, peramivir, and Inavir, etc.), an RNA-dependent RNA polymerase inhibitor (eg, Favipiravir).
  • a neuraminidase inhibitor eg, oseltamivir, zanamivir, peramivir, and Inavir, etc.
  • an RNA-dependent RNA polymerase inhibitor eg, Favipiravir
  • M2 protein inhibitor amantadine
  • PB2Cap binding inhibitor VX-787
  • anti-HA antibody MHAA4594A
  • immunological drug Naitazoxanide
  • the compounds of the present invention can be used in combination with other pharmaceutical preparations in order to enhance the efficacy of the compound or to reduce the amount of the compound used.
  • a neuraminidase inhibitor eg, oseltamivir, zanamivir, peramivir, and Inavir, etc.
  • an RNA-dependent RNA polymerase inhibitor such as Favipiravir
  • M2 RNA-dependent RNA polymerase inhibitor
  • a protein inhibitor amantadine
  • a PB2Cap binding inhibitor VX-787
  • an anti-HA antibody MHAA4594A
  • an immunologically active drug Neitazoxanide
  • the pure form or suitable pharmaceutical composition of a compound of the present invention or a pharmaceutically acceptable salt thereof can be administered by any acceptable mode of administration of a similarly useful agent.
  • the pharmaceutical compositions of the present invention can be prepared by combining a compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into a solid, semi-solid, liquid or gaseous form, such as a tablet. , capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of the pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal and intranasal administration.
  • parenteral includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the pharmaceutical compositions of the present invention are formulated to allow the cleansing ingredients contained therein to be bioavailable after administration of the composition to a patient.
  • composition to be administered will in any event contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or condition of interest in accordance with the teachings of the present invention.
  • the pharmaceutical compositions of the invention may be in solid or liquid form.
  • the carrier is a microparticle such that the composition is, for example, in the form of a tablet or powder.
  • the carrier can be a liquid, and the composition is, for example, an oral syrup, an injectable liquid, or an aerosol suitable for administration, for example, by inhalation.
  • the pharmaceutical compositions are preferably in solid or liquid form, wherein the semi-solid, semi-liquid, suspension and gel forms are included in the form considered solid or liquid herein.
  • the pharmaceutical compositions can be formulated in the form of powders, granules, compressed tablets, pills, capsules, chewable tablets, powders, and the like.
  • Such solid compositions typically contain one or more inert diluents or edible carriers.
  • binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, huangwa gum or gelatin
  • excipients such as starch, lactose or paste a disintegrating agent such as alginic acid, sodium alginate, Primogel, corn starch, etc.
  • a lubricant such as magnesium stearate or hydrogenated vegetable oil (Sterotex); a glidant such as colloidal silica
  • a sweetener For example, sucrose or saccharin
  • flavoring agents such as peppermint, methyl salicylate or sweet orange flavoring
  • coloring agents such as peppermint, methyl salicylate or sweet orange flavoring.
  • the pharmaceutical composition When the pharmaceutical composition is in the form of a capsule, such as a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.
  • a liquid carrier such as polyethylene glycol or oil.
  • the pharmaceutical compositions may be in liquid form such as elixirs, syrups, solutions, emulsions or suspensions. This liquid can be administered orally, or delivered by injection, as two examples.
  • the composition When intended for oral administration, it is preferred that the composition contains, in addition to the compound of the present invention, one or more of a sweetener, a preservative, a dye/colorant, and a flavor enhancer.
  • One or more of a surfactant, a preservative, a wetting agent, a dispersing agent, a suspending agent, a buffering agent, a stabilizer, and an isotonic agent may be included in the composition to be administered by injection.
  • the liquid pharmaceutical composition of the present invention may comprise one or more of the following adjuvants: a sterile diluent, such as water for injection, a physiological saline solution, preferably physiological saline, Ringer.
  • a sterile diluent such as water for injection
  • a physiological saline solution such as physiological saline, Ringer.
  • Ringer's solution isotonic sodium chloride, fixed oil (such as synthetic mono or diglyceride, which can be used as a solvent or suspension medium), polyethylene glycol, glycerin, propylene glycol and other solvents; antibacterial agents, for example Benzyl or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate or phosphate, and a tension regulating Reagents such as sodium oxide or dextrose.
  • the parenteral formulation can be enclosed in ampoule, disposable syringes or multiple dose vials made of glass or plastic. Saline is the preferred adjuvant.
  • the injectable pharmaceutical compositions are preferably sterile.
  • the liquid pharmaceutical composition of the present invention to be administered parenterally or orally should contain a certain amount of the compound of the present invention so that a suitable dose can be obtained.
  • the pharmaceutical compositions of the invention may be intended for topical administration, in which case the carrier preferably comprises a solution, emulsion, ointment or gel base.
  • the matrix may comprise one or more of the following: paraffinic oil, lanolin, polyethylene glycol, beeswax, mineral oil, diluents (such as water and alcohol), and emulsifiers and stabilizers. Thickeners may be present in the pharmaceutical compositions for topical administration. If transdermal administration is desired, the composition can include a transdermal patch or an iontophoresis device.
  • compositions for rectal administration may be intended for rectal administration, in the form of a suppository, which will melt in the rectum and release the drug.
  • Compositions for rectal administration may contain an oily base as a suitable non-irritating excipient.
  • the matrix includes, but is not limited to, lanolin, cocoa butter, and polyethylene glycol.
  • compositions of the present invention may include various materials that modify the physical form of the solid or liquid dosage unit.
  • the composition can include a substance that forms a coated outer shell around the active ingredient.
  • the material forming the outer envelope is generally inert and may be selected, for example, from sugars, shellac and other enteric coating agents.
  • the active ingredient can be enclosed in a gelatin capsule.
  • compositions of the invention in solid or liquid form may include an agent that binds to a compound of the invention and thereby aids in the delivery of the compound.
  • Suitable agents with this ability include monoclonal or polyclonal antibodies, proteins or liposomes.
  • compositions of this invention may be comprised of dosage units which may be administered in the form of an aerosol.
  • aerosol is used to refer to a variety of systems from colloidal species to systems consisting of pressurized packaging. Delivery can be by liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of the compounds of the invention may be delivered in a single phase, two phase or three phase system to deliver the active ingredient.
  • the side delivery of the aerosol includes the necessary containers, actuators, valves, sub-containers, etc., which together form a kit.
  • One skilled in the art can determine a preferred aerosol without undue experimentation.
  • compositions of the invention can be made using methods well known in the pharmaceutical art.
  • a pharmaceutical composition to be administered by injection can be prepared by combining a compound of the present invention with sterile distilled water to form a solution.
  • Surfactants may be added to facilitate the formation of a homogeneous solution or suspension.
  • Surfactants are compounds that non-covalently interact with the compounds of the invention, thereby promoting the dissolution or uniform suspension of the compound in an aqueous delivery system.
  • a compound of the invention, or a pharmaceutically acceptable salt thereof, is administered in a therapeutically effective amount which will vary depending on a variety of factors, including the activity of the particular compound employed, the metabolic stability of the compound, and the length of action, the patient Age, weight, general state of health, gender and diet, mode of administration and timing, rate of excretion, combination of drugs, severity of a particular condition or condition, and the individual receiving the therapy.
  • the compounds of the invention, or pharmaceutically acceptable derivatives thereof, may also be administered simultaneously with, before or after administration of one or more additional therapeutic agents.
  • the combination therapy comprises administering a single pharmaceutical formulation containing a compound of the invention and one or more additional active agents, as well as a separate pharmaceutical formulation for administration of the compound of the invention and each active agent.
  • a compound of the invention may be administered to a patient together with another active agent in a single oral administration composition (e.g., a tablet or capsule), or each agent may be administered as a separate oral administration formulation.
  • the compound of the invention and one or more additional active agents can be administered substantially at the same time (i.e., simultaneously) or at separately staggered times (i.e., sequentially), and combination therapy should be understood as Includes all of these programs.
  • the pharmaceutical composition of the present invention will be adjusted depending on the disease state, the route of administration, the age of the patient or the body weight.
  • oral administration to an adult, it is usually from 0.1 to 100 mg/kg/day, preferably from 1 to 20 mg/kg/day.
  • the suitable dosage for administration of the present invention needs to be set in consideration of the age, body weight, condition, administration route, and the like of the patient, and oral administration is usually in the range of 0.05 to 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day. .
  • the pharmaceutical composition of the present invention is administered in a dose which varies widely depending on the administration route, but is usually in the range of 0.005 to 10 mg/kg/day, preferably 0.01 to 1 mg/kg/day.
  • the dose of the compound of the present invention varies depending on the administration method, the age, body weight, state of the patient, and the type of the disease, but usually, in the case of oral administration, the dose per adult per day is about 0.05 mg to 3000 mg. Preferably, it is about 0.1 mg to 1000 mg, and it can be administered separately as needed. Further, in the case of parenteral administration, the dosage per adult per day is about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg. It will be appreciated that in the present invention, combinations of substituents and/or variables of the formula are permissible only if they result in a stable compound.
  • the present invention relates to a substituted polycyclic carbamoylpyridone derivative having a 5' cap structure (CAP)-dependent endonuclease inhibitory activity, a prodrug thereof, a deuterated compound thereof, and a pharmaceutical composition containing the same And methods of using the composition for inhibiting proliferation of influenza virus.
  • CAP 5' cap structure
  • the compound of the present invention is a prodrug, it has the following advantages: high oral absorption, good bioavailability, good clearance, and high lung metastasis. Therefore, it can form an excellent drug.
  • the parent compound of the compound of the present invention has a high inhibitory activity against a 5' cap structure-dependent endonuclease, and since it is a virus-specific enzyme, it has a high selectivity and can be a drug with reduced side effects. Further, the compound of the present invention and/or the parent compound of the compound of the present invention have the advantages of high metabolic stability, high solubility, high oral absorbability, good bioavailability, good clearance, High lung metastasis, long half-life, high non-protein binding rate, low hERG channel inhibition, low inhibition of liver drug enzymes, inhibition of CytoPathic Effect (CPE) inhibition, and/or in phototoxicity test, Ames test and The genotoxicity test shows negative or no hepatotoxicity, and the like, and therefore the compound of the present invention is preferably pharmaceutically acceptable.
  • CPE CytoPathic Effect
  • the compounds of the invention and/or the compounds of the invention are useful for the symptoms and/or diseases caused by influenza viruses.
  • flu symptoms such as fever, chills, headache, muscle pain, general fatigue, or respiratory symptoms such as sore throat, runny nose, stuffy nose, cough, phlegm, etc., abdominal pain, vomiting, diarrhea
  • respiratory symptoms such as sore throat, runny nose, stuffy nose, cough, phlegm, etc.
  • abdominal pain, vomiting, diarrhea Further, it is effective to treat and/or prevent complications and improve symptoms of secondary infections such as acute encephalopathy and pneumonia.
  • the compounds of the invention are either by hand or Software naming, commercially available compounds using the supplier catalog name.
  • the synthetic route is as follows:
  • Example Compound 1A (5.0 g) was added with DMA (25 ml), and chloromethyl methyl carbonate (2.4 g) and potassium carbonate (2.9 g), and potassium iodide (1.7 g) were added, and the mixture was warmed to 50 ° C and stirred for 6 hours. Additional DMA (5 ml) was added and stirring was continued for 6 hours. The reaction solution was cooled to room temperature, DMA (25 ml) was added, and the mixture was stirred at 50 ° C for 5 minutes and filtered. To the filtered droplets, 1 mol/L hydrochloric acid water (50 ml) and water (15 ml) were added at 0 to 5 ° C and stirred for 1 hour.
  • Example Compound 1A (4.8 g), DMA (30 ml) was added and stirred, and bromohexane (1.7 g) and potassium carbonate (2.9 g), potassium iodide (1.7 g) were added, and the mixture was heated to 50 ° C and stirred for 6 hours. Additional DMA (5 ml) was added and stirring was continued for 6 hours. The reaction solution was cooled to room temperature, DMA (30 ml) was added, and the mixture was stirred at 50 ° C for 5 minutes and filtered. To the filtered droplets, 1 mol/L hydrochloric acid water (50 ml) and water (25 ml) were added at 0 to 5 ° C and stirred for 1 hour. The solid obtained was filtered, dried under reduced pressure at 60 °C, in Example 1C to obtain the compound in a yield 79% .MS: ESI 569.2 [M + H] +.
  • the synthetic route is as follows:
  • intermediate 21 For the preparation process of intermediate 21, refer to the preparation of intermediate 15, except that lithium tetrahydrogen aluminum-D 4 is replaced with lithium aluminum hydride, and intermediate 14 is replaced with intermediate 20.
  • Example Compound 2A (10.0 g), DMA (50 ml) was added and stirred, and chloromethylmethyl carbonate (4.8 g) and potassium carbonate (6.0 g) and potassium iodide (3.4 g) were added, and the mixture was heated to 50 ° C and stirred for 6 hours. Additional DMA (10 ml) was added and stirring was continued for 6 hours. The reaction solution was cooled to room temperature, DMA (50 ml) was added, and the mixture was stirred at 50 ° C for 5 minutes and filtered. To the filtered droplets, 1 mol/L hydrochloric acid water (100 ml) and water (30 ml) were added at 0 to 5 ° C and stirred for 1 hour.
  • the synthetic route is as follows:
  • the following table compounds and their individual enantiomers were prepared to prepare prodrugs of esters corresponding to the following table compounds, such as orally administered, using drug metabolizing enzymes, hydrolases , digestive juice, or bacteria in the digestive tract, etc., and converted into active metabolites with hydroxyl groups.
  • the corresponding ester of the table compound is preferably, but not limited to, methyl methyl carbonate.
  • RNP is prepared from viral particles according to a defined method (Reference: VIROLOGY (1976) 73, pages 327-338. LGA M. ROCHOVANSKY). Specifically, 200 ⁇ L of 1 ⁇ 10 3 PFU/mL A/WSN/33 virus was inoculated into 10-day-old developing chicken eggs, cultured at 37° C. for 2 days, and then the allantoic fluid of chicken eggs was recovered.
  • the virus particles were purified by ultracentrifugation using 20% sucrose, the virions were lysed using Triton X-100 and lysolecithin, and then the RNP fraction was collected by ultracentrifugation using a 30-70% glycerol density gradient ( 50 to 70% glycerol fraction) was used as an enzyme solution (containing about 1 nM of PB1 ⁇ PB2 ⁇ PA complex).
  • enzymatic reaction solution composition: 53 mM Tris hydrochloride (pH 7.8), 1 mM MgCl 2 , 1.25 mM dithiothreitol, 80 mM NaCl, 12.5% glycerol, was dispensed on a 384-well plate made of polypropylene. 0.15 ⁇ L of enzyme solution).
  • DMSO a positive control (PC), and a negative control (NC), and mixed well.
  • the solution after the termination of the reaction was heated at 85 ° C for 5 minutes, quenched on ice for 2 minutes, and then analyzed by an ABIPRIZ M3730 Genetic Analyzer.
  • the peak of the cap-dependent endonuclease product was quantified by the analysis software ABI Genemapper, and the fluorescence intensity of PC and NC was used as 0% inhibition and 100% inhibition, and the CEN reaction inhibition rate (%) of the test compound was determined.
  • the IC 50 values were then determined using curve fitting software.
  • MDBK cells adjusted to the appropriate number of cells (3X 10 5 /mL) with 2% FCS E-MEM.
  • MDCK cells washed twice with HBSS and then adjusted to the appropriate number of cells ( 5 ⁇ 10 5 /mL) with 0.5% BSA E-MEM.
  • Trypsin (SIGMA) from porcine pancreas was dissolved in PBS(-) and filtered through a 0.45 ⁇ m filter.
  • the culture solution 2% FCS E-MEM was used when MDBK cells were used, and 0.5% BSA E-MEM was used when MDCK cells were used.
  • FCS E-MEM 0.5% FCS E-MEM was used when MDCK cells were used.
  • BSA E-MEM 0.5% BSA E-MEM was used when MDCK cells were used.
  • the same culture solution is used for dilution of the virus, cell, and test sample.
  • test sample was diluted with a culture solution to an appropriate concentration in advance, and a 2-5-fold serial dilution series (50 ⁇ L/well) was prepared on a 96-well plate. Two pieces for measuring anti-influenza activity and measuring cytotoxicity were prepared. Triplicate assays were performed for each drug.
  • influenza virus was diluted with the culture solution to an appropriate concentration in advance, and each was dispensed at 50 ⁇ L/well into a 96-well plate to which the test sample was added.
  • the culture solution was dispensed into the cytotoxicity assay plate at 50 ⁇ L/well.
  • the anti-influenza activity assay and the cytotoxicity assay were all cultured for 3 days.
  • the 96-well plate cultured for 3 days was observed under a naked eye and a microscope, and the supernatant was removed from the plate in such a manner that cells were not aspirated.
  • the WST-8 kit was diluted 10-fold with the culture solution, and the WST-8 solution was dispensed into each well at 100 ⁇ L each. Mix with a plate mixer and incubate for 1 to 3 hours in a CO 2 incubator.
  • the absorbance was measured with EnVision at a dual wavelength of 450 nm / 620 nm.
  • the calculation is performed using a Microsoft Excel program based on the following calculation formula.
  • Example 4 The measurement results of Example 4 and Example 5 are shown in Table 2 for the test substance (Example compound) as the parent compound.
  • the compound of the example can prepare a preventive/therapeutic drug for use as a symptom/disease induced by influenza virus infection.
  • Administration of administration amount and grouping Oral administration or intravenous administration is carried out using a predetermined administration amount. Set the group as follows. (The amount of each compound administered varies)
  • Oral administration is suspension and intragastric administration.
  • the intravenous administration is a solution and a tail vein administration.
  • Example Compound Number# Example compound BA% Intravenous administration half-life T 1/2 hour 1A 7.1 4.0 2A 5.0 5.0 3A 7.8 5.2 S-033188A 4.7 3.8 1B 18.4 -- 2B 15.9 -- 3B 19.8 -- S-033188B 15.3 --
  • the prodrugs (1B, 2B, and 3B) have improved bioavailability as compared with the parent compound (1A, 2A, and 3A).
  • the compounds of the examples 1A, 2A, and 3A have a greater degree of improvement than the S-033188A; the compounds of the examples 1B, 2B, and 3B have a greater degree of bioavailability than the S-033188B.
  • Intravenous administration of the elimination half-life of the example compounds also has varying degrees of prolongation.
  • the compound of the present invention is more excellent in oral absorption than S-033188A/S-033188B, and can form a drug for use as a therapeutic and/or prophylactic agent for symptoms and/or diseases caused by infection with influenza virus, indicating a dose to be administered. Can be smaller and have fewer side effects.
  • HEK293 cells expressing the human ether-a-go-go-related gene (hERG) channel were used to study delayed rectifier K + current (I Kr ) , which plays an important role in ventricular repolarization. The role of ).
  • the cells were maintained at a membrane potential of -80 mV by whole-cell patch clamp method, and a depolarization stimulus of +50 mV was given for 2 seconds, and a repolarization of -50 mV was further given for 2 seconds. I Kr caused by stimuli .
  • the extracellular solution of the test substance was dissolved at the target concentration (NaCl: 137 mmol/L, KCl: 4 mmol/L, CaCl 2 : 1.8 mmol/L, MgCl 2 -6H 2 O: 1 mmol/ L, glucose: 10 mmol/L, HEPES: 10 mmol/L, pH 7.4) Apply to cells for 10 minutes at room temperature. From the obtained I Kr , the absolute value of the maximum tail current was measured using the analysis software on the basis of the current value of the static membrane potential. Further, the inhibition rate of the maximum tail current before application of the test substance was calculated, and the influence of the test substance on I Kr was evaluated in comparison with the medium application group (0.1% DMSO solution).
  • mice BALB/cAnNCrlCrlj 6 to 7 week old mice were used for the test.
  • A/WS/33, A/Victoria/3/75 or B/Maryland/1/59 were passaged in the lungs of mice to prepare a mouse domesticated virus.
  • the cryopreserved mouse domesticated virus solution was rapidly thawed and diluted with DPBS to form an infectivity titer (A/WS/33: 800-4000 TC ID501 mice, A/Victoria/3/75). : 750 TCID 50 /mouse, B/Maryland/1/59: 100 TCID 50 / mouse).
  • test sample was suspended in a 0.5% methylcellulose solution at a suitable concentration.
  • mice For the mice immediately after the virus infection or after a certain period of time, 200 ul of the diluted test sample was orally administered.
  • the animals were fed for 14 days, and the dose ED 50 (mg/kg/day) for each day required for 50% lethal inhibition was calculated and compared with the control group, and the virus inhibitory effect was evaluated.
  • Table 5 shows the ED 50 values per administration.
  • the (Invitrogen) kit detects the toxic effects of drugs on cells. It is a redox indicator that produces changes in absorbance and fluorescence signals based on metabolic activity. Soluble in water, its oxidized form enters cells and is reduced by mitochondrial enzymes to produce measurable fluorescence and color changes. It is suitable for quantitative analysis of cell viability and cell proliferation and in vitro cytotoxicity studies. Normal cells with metabolic activity are capable of converting reagents into strong fluorescence and color changes, while damaged or inactive cells have lower natural metabolic activity and corresponding signals are lower. Therefore, the fluorescence signal is strong and can reflect the level of cell activity.
  • MDCK cells were seeded in 96-well cell culture plates, and the cells were allowed to adhere after use.
  • the drug was diluted 8 times in a 3-fold serial gradient from 2 times the highest test concentration in DMEM medium.
  • the drug was added to the cells and cultured in a CO 2 incubator at 37 °C.
  • the drug-induced cytopathic effect (CPE) was observed under a microscope, and the cell survival rate was measured by adding alamarBlue.
  • CPE drug-induced cytopathic effect
  • the drug has a toxic effect on MDCK cells at very high concentrations, and the concentration causing a 50% toxic effect is indicated by CC 50, as shown in the table below.
  • Example Compound 1A was significantly less toxic than S-033188A. It is indicated that compound 1A has higher safety than S-033188A.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一组多环氨基甲酰基吡啶酮衍生物、药物组合物及其用途。本发明的多环氨基甲酰基吡啶酮衍生物的结构如式(VII)所示。本发明的所述多环氨基甲酰基吡啶酮衍生物作为流感病毒5'帽状结构(CAP)依赖性内切酶活性的抑制剂，具有治疗流感病毒引起的感冒的用途。本发明还公开了一种包含该多环氨基甲酰基吡啶酮衍生物以及药学上可接受的载体的药物组合物，以及使用该药物组合物来抑制流感病毒增殖的方法。

Description

多环氨基甲酰基吡啶酮衍生物、药物组合物及其用途
本申请要求申请日为2018年4月11日的中国专利申请CN201810323355.2的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及多环氨基甲酰基吡啶酮衍生物、药物组合物及其用途。
背景技术
流感是一种急性病毒感染，很容易在人群中传播，特别是在温带区域的冬季期间达到高峰。由于流感病毒在世界范围内流行，并可感染任何年龄组的任何人，往往在高危人群中造成严重并发疾病和死亡，目前是一个严重的公共卫生问题。据统计在世界范围内，每年的流感流行估计造成3到5百万次严重病例，死亡人数约25万到50万。
由于流感病毒基因组很小，其所需蛋白质的合成依赖宿主细胞的翻译系统。因此，流感病毒的信使RNA(mRNA)需要同时具备可供宿主细胞翻译体系识别的5′帽状(CAP)结构和3′-poly(A)尾结构。其中，5′帽状结构是通过流感病毒RNA聚合酶复合体中PA亚基的内切酶活性从宿主细胞前体mRNA的5′端剪切“抢来的”。这种被称为“CAP－snatching”的方式，夺取宿主mRNA的CAP帽状结构用于病毒自身mRNA转录，是流感病毒转录起始所必须的。
正因为“CAP-snatching”是流感病毒复制周期中的关键环节，又由于宿主细胞中不存在类似的机制和相应的蛋白酶，因此针对“CAP-snatching”内切酶的抑制剂可以选择性阻断流感病毒的转录过程，同时对宿主细胞不造成影响。于是，这一机理成为潜在的抗流感药物靶点。本发明满足了这些需要，并提供了其它相关的优点。
发明内容
本发明提供了一种如式(VII)所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药：
Figure PCTCN2019082195-appb-000001
其中，
R 1为氢或氘；
R 2为氢或氘；
R 3为氢或氘；
L为氢、烷基、或(甲氧羰基)氧甲基(即-CH 2OC(＝O)OCH 3)；
且R 1、R 2和R 3中至少有一个为氘；
R 4为氢或卤素(优选氯)；
R 5为氢或卤素(优选氟)；
R 6为氢或卤素(优选氟)；
A为C或O，当A为C时，R 7和R 8均为氢或均为甲基；当A为O时，R 7和R 8不存在；
R 9为氢或甲基；R 10为氢或甲基；
且R 4、R 5和R 6不同时为氢。
所述的如式(VII)所示的多环氨基甲酰基吡啶酮衍生物优选满足如下任一条件：
条件1：R 4为氢；R 5为氟；R 6为氟；A为O；R 9为氢；R 10为氢。
条件2：R 4为氢；R 5为氟；R 6为氢；A为O；R 9为氢；R 10为甲基且与R 10直接相连的碳原子构型为(S)。
条件3：R 4为氯；R 5为氢；R 6为氢；A为O；R 9为氢；R 10为氢。
条件4：R 4为氢；R 5为氟；R 6为氟；A为C；R 7和R 8均为甲基；R 9为氢；R 10为氢。
条件5：R 4为氢；R 5为氟；R 6为氟；A为C；R 7和R 8均为氢；R 9为氢且与R 9直接相连的碳原子构型为(R)；R 10为氢。
条件6：R 4为氢；R 5为氟；R 6为氢；A为C；R 7和R 8均为氢；R 9为氢；R 10为氢。
本发明中，当L为烷基时，所述的烷基优选为C 1-4烷基，进一步优选甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基。
本发明提供了一种如式(I)所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药：
Figure PCTCN2019082195-appb-000002
其中：
R 1为氢或氘；
R 2为氢或氘；
R 3为氢或氘；
L为氢、烷基、或(甲氧羰基)氧甲基(即-CH 2OC(＝O)OCH 3)；
且R 1、R 2和R 3中至少有一个为氘。
所述的如式(I)所示的多环氨基甲酰基吡啶酮衍生物优选选自如下化合物：
Figure PCTCN2019082195-appb-000003
本发明提供了一种如式(II)所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药：
Figure PCTCN2019082195-appb-000004
其中：
R 1为氢或氘；
R 2为氢或氘；
R 3为氢或氘；
L为氢、烷基或(甲氧羰基)氧甲基(即-CH 2OC(＝O)OCH 3)；
且R 1、R 2和R 3中至少有一个为氘。
所述的如式(II)所示的多环氨基甲酰基吡啶酮衍生物优选选自如下化合物：
Figure PCTCN2019082195-appb-000005
本发明提供了一种如式(III)所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药：
Figure PCTCN2019082195-appb-000006
其中：
R 1为氢或氘；
R 2为氢或氘；
R 3为氢或氘；
L为氢、烷基或(甲氧羰基)氧甲基(即-CH 2OC(＝O)OCH 3)；
且R 1、R 2和R 3中至少有一个为氘。
所述的如式(III)所示的多环氨基甲酰基吡啶酮衍生物优选选自如下化合物：
Figure PCTCN2019082195-appb-000007
本发明提供了一种如式(IV)所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药：
Figure PCTCN2019082195-appb-000008
其中：
R 1为氢或氘；
R 2为氢或氘；
R 3为氢或氘；
L为氢、烷基或(甲氧羰基)氧甲基(即-CH 2OC(＝O)OCH 3)；
且R 1、R 2和R 3中至少有一个为氘。
所述的如式(IV)所示的多环氨基甲酰基吡啶酮衍生物优选选自如下化合物：
Figure PCTCN2019082195-appb-000009
本发明提供了一种如式(V)所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药：
Figure PCTCN2019082195-appb-000010
其中：
R 1为氢或氘；
R 2为氢或氘；
R 3为氢或氘；
L为氢、烷基或(甲氧羰基)氧甲基(即-CH 2OC(＝O)OCH 3)；
且R 1、R 2和R 3中至少有一个为氘。
所述的如式(V)所示的多环氨基甲酰基吡啶酮衍生物优选选自如下化合物：
Figure PCTCN2019082195-appb-000011
本发明提供了一种如式(VI)所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药：
Figure PCTCN2019082195-appb-000012
其中：
R 1为氢或氘；
R 2为氢或氘；
R 3为氢或氘；
L为氢或(甲氧羰基)氧甲基(即-CH 2OC(＝O)OCH 3)；
且R 1、R 2和R 3中至少有一个为氘。
所述的如式(VI)所示的多环氨基甲酰基吡啶酮衍生物优选选自如下化合物：
Figure PCTCN2019082195-appb-000013
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
本发明的化合物通常以游离酸或游离碱的形式使用。可选择地，本发明化合物可以酸或碱盐的形式使用。可用本领域公知的方法制备本发明的游离氨基化合物的酸加合盐，并可从有机酸和无机酸制备。适合的有机酸包括马来酸、反丁烯二酸、安息香酸、抗坏血酸、琥珀酸、甲磺酸、乙酸、三氟乙酸、草酸、丙酸、酒石酸、水杨酸、柠檬酸、葡萄糖酸、乳酸、扁桃酸、苯乙酸、天冬氨酸、硬脂酸、棕榈酸、乙二醇酸、谷氨酸和苯磺酸。适合的无机酸包括盐酸、氢溴酸、硫酸、磷酸和硝酸。碱式盐包括与羧酸根阴离子形成的盐，并包括与诸如选自碱金属离子、碱土金属离子(例如，锂、钠、钾、镁、钡、钙)以及 铵离子的有机和无机阳离子形成的盐，及其取代的衍生物(例如，二苄基铵、苄基铵、2-羟基乙基铵等)。因此，术语通式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或式(VII)的“药物可接受的盐”应包括和所有可接受的盐形式。
此外，前药也包括在本发明的范固之中。前药是任何共价结合载体，当将该前药对患者进行给药时其在体内释放出接受通式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或式(VII)的化合物。通常通过以某种方式修饰官能团来制备前药，该方式使所述的修饰能够通过常规的交换或在体内分解，得到母体化合物。前药包括，例如羟基、氨基或巯基与任何基团结合的本发明化合物，其中当对患者给药时所述基团脱离从而得到羟基、氨基或巯基。
因此，前药的代表性的例子包括(但不限于)通式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或式(VII)化合物的醇和胺官能团的乙酸盐(酯)、甲酸盐(酯)和安息香酸盐的衍生物。此外，在羧酸(-COOH)的情况下，可以包括诸如甲酯、乙酯等等的酯类。在羟基的情况下，可以包括诸如甲氧基、乙氧基、丙氧基、叔丁氧基等等的混合酸酐类。
对于立体异构体，通式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或式(VII)的化合物可具有手性中心，并能以消旋体、消旋混合物，以及单独的对映异构体或非对映异构体的形式存在。所有同分异构的形式均包括在本发明之内，包括其混合物。此外，通式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或式(VII)的化合物的某些晶形可以多形体的形式存在，其也包括在本发明中。此外，一些所述通式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或式(VII)的化合物也可与水或其它有机溶剂形成溶剂化物。这种溶剂化物也类似地包括在本发明的范围之内。
本领域技术人员应理解，任何化合物都可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。本发明所涉及的多环氨基甲酰基吡啶酮衍生物中，所述的氘代即是指该化合物的相关位点上的原子包含了超过天然比例(即超过氘的天然丰度)的氘原子。因此，任何在相关位点上以高于氘的天然丰度的比例包含氘原子的多环氨基甲酰基吡啶酮衍生物均在本发明的保护范围之内。例如，可以理解，通过相同或类似于本发明实施例中所示的化学合成手段使用市售可得的氘代试剂引入氘原子而获得的具有相应氘代率或氘含量的相应多环氨基甲酰基吡啶酮衍生物，均在本发明保护范围之内。此处的化学合成手段和氘代试剂均不受限于实施例中所例举，而应理解为本领域所有可采用以获得本发明化合物的合成方法或路线，以及所有可配合前述合成方法或路线向目标分子中引入氘原子的氘代试剂。
根据本发明在下文中所公开的具体实施例，本领域技术人员可采用与之相同或相似 的原理和方法，制得本发明的所述通式(I)、式(II)、式(III)、式(IV)、式(V)、式(VI)或式(VII)所示的多环氨基甲酰基吡啶酮衍生物中所涉及的各具体化合物。
本发明进一步还提供了一种如式(VII)(优选如式(I)、式(II)、式(III)、式(IV)、式(V)、或式(VI))所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药在制备5′帽依赖性核酸内切酶抑制剂中的应用。
本发明进一步还提供了一种如式(VII)(优选如式(I)、式(II)、式(III)、式(IV)、式(V)、或式(VI))所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药在制备预防、治疗和/或缓解与5′帽依赖性核酸内切酶相关的疾病的药物中的应用。其中，所述的与5′帽依赖性核酸内切酶相关的疾病是指通过抑制体内5′帽依赖性核酸内切酶的水平来预防、治疗和/或缓解的症状和/或疾病，具体是指由流感病毒感染引发的症状和/或疾病。更具体地，所述的流感病毒包括但不限于甲(A)、乙(B)、丙(C)三型。所述的症状包括但不限于例如对于伴有发热、发冷、头痛、肌肉痛、全身感到倦怠等的类感冒症状、或咽痛、流鼻涕、鼻塞、咳嗽、痰等的呼吸道炎症、腹痛、呕吐、腹泻这样的胃肠症状、进而伴有急性脑病、肺炎等二次感染的并发症。
本发明进一步还提供了一种预防、治疗和/或缓解与5′帽依赖性核酸内切酶相关的疾病的方法，所述的方法包括给予需要其的个体治疗有效量的如式(VII)(优选如式(I)、式(II)、式(III)、式(IV)、式(V)、或式(VI))所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药以抑制其体内的5′帽依赖性核酸内切酶水平。其中，所述的与5′帽依赖性核酸内切酶相关的疾病具体如上所述。
本发明进一步还提供了一种药物组合物，其包含治疗有效量的如式(VII)(优选如式(I)、式(II)、式(III)、式(IV)、式(V)、或式(VI))所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药，和药学上可接受的载体。
本发明进一步还提供了一种药物组合物，其不仅包含治疗有效量的如式(VII)(优选如式(I)、式(II)、式(III)、式(IV)、式(V)、或式(VI))所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药，和药学上可接受的载体，还包含其他药物活性成分。所述的其他药物活性成分选自神经胺酸酶抑制剂(如，奥司他韦、扎那米韦、帕拉米韦、及Inavir等)、RNA 依赖性RNA聚合酶抑制剂(如Favipiravir)、M2蛋白质抑制剂(金刚烷胺)、PB2Cap结合抑制剂(VX-787)、抗HA抗体(MHAA4594A)、或免疫作用药(Nitazoxanide)。
本发明化合物可为了增强该化合物药效或者减少化合物用药剂量，与其他药物制剂组合使用。例如流行感冒时，可与神经胺酸酶抑制剂(如，奥司他韦、扎那米韦、帕拉米韦、及Inavir等)、RNA依赖性RNA聚合酶抑制剂(如Favipiravir)、M2蛋白质抑制剂(金刚烷胺)、PB2Cap结合抑制剂(VX-787)、抗HA抗体(MHAA4594A)、或免疫作用药(Nitazoxanide)等组合使用。
本发明化合物或其药学上可接受的盐的纯净形式或适当药物组合物可通过任何可接受的投予起类似效用的药剂的模式投予。本发明药物组合物可通过将本发明化合物与适当药学上可接受的载剂、稀释剂或赋形剂组合而制成，并且可调配成固体、半固体、液体或气体形式制剂，例如片剂、胶囊、散剂、颗粒剂、软膏、溶液、栓剂、注射剂、吸入剂、凝胶、微球体和气雾剂。投予所述药物组合物的典型途径包括(但不限于)经口、局部、透皮、吸入、不经肠、舌下、颊、直肠、阴道和鼻内投药。如本文中所使用，术语不经肠包括皮下注射、静脉内、肌内、胸骨内注射或输注技术。本发明药物组合物经调配，以允许在对患者投予组合物后，其中所含洁性成分是生物可利用的。将被投予个体或患者的组合物里一种或多种剂量单位的形式，其中，例如片剂可为单一剂量单位，而含气雾剂形式的本发明化合物的容器可容纳多个剂量单位。制备所述剂型的实际方法为所属领域技术人员己知，或将为其所知悉。欲投予的组合物在任何情况下都将含有治疗有效量的本发明化合物或其药学上可接受的盐，以便根据本发明的示教治疗所关注的疾病或病状。
本发明药物组合物可呈固体或液体形式。一方面，载剂为微粒，以致组合物例如呈片剂或散剂形式。载剂可为液体，而组合物为例如口服糖浆、可注射液体，或适用于例如吸入投药的气雾剂。当欲口服时，药物组合物优选自固体或液体形式，其中半固体、半液体、悬浮液和凝胶形式包括在本文中视为固体或液体的形式中。对于口服固体组合物，可将药物组合物调配成散剂、颗粒剂、压缩片剂、丸剂、胶囊、咀嚼片、粉片等形式。此类固体组合物通常含有一种或多种惰性稀释剂或可食用载剂。此外，还可存在一种或多种以下物质:粘合剂，例如羧甲基纤维素、乙基纤维素、微晶纤维素、黄瓦胶或明胶；赋形剂，例如淀粉、乳糖或糊精；崩解剂，例如海藻酸、海藻酸纳、Primogel、玉米淀粉等；润滑剂，例如硬脂酸镁或氢化植物油(Sterotex)；助流剂，例如胶状二氧化硅；甜味剂，例如蔗糖或糖精；调味剂，例如薄荷、水杨酸甲酯或甜橙调味剂；和着色剂。
当药物组合物为胶囊形式，例如为明胶胶囊时，除上述类型的物质以外，其还可含有液体载剂，例如聚乙二醇或油。药物组合物可为液体形式，例如酊剂、糖浆、溶液、乳 液或悬浮液。此液体可口服，或通过注射递送，作为两个实例。当欲口服时，优选组合物除含有本发明化合物以外，还含有甜味剂、防腐剂、染料/着色剂和风味增强剂中的一种或多种。在打算通过注射投予的组合物中，可包括表面活性剂、防腐剂、润湿剂、分散剂、悬浮剂、缓冲剂、稳定剂和等渗剂中的一种或多种。
不管是溶液、悬浮液或是其它类似形式的本发明液体药物组合物，均可包括以下一种或多种佐剂：无菌稀释剂，例如注射用水，生理盐水溶液，优选生理盐水，林格氏溶液(Ringer's solution)、等渗氯化钠、不挥发油(例如合成单或二酸甘油酯，其可用作溶剂或悬浮介质)、聚乙二醇、甘油、丙二醇等溶剂；抗菌剂，例如苯甲醇或对羟基苯甲酸甲酯；抗氧化剂，例如抗坏血酸或亚硫酸氢钠；螯合剂，例如乙二胺四乙酸；缓冲剂，例如乙酸盐、柠檬酸盐或磷酸盐，以及调节张力的试剂，例如氧化钠或右旋糖。不经肠制剂可封装于由玻璃或塑料制成的安剖、一次性注射器或多剂量小瓶中。生理盐水是优选的佐剂。可注射药物组合物优选为无菌的。
欲不经肠投予或口服的本发明液体药物组合物应含有一定量本发明化合物，以致能获得合适剂量。本发明药物组合物可打算经局部投予，在此情况中，载剂宜包含溶液、乳液、软膏或凝胶基质。例如，此基质可包含以下一种或多种:石蜡油、羊毛脂、聚乙二醇、蜂蜡、矿物油，稀释剂(例如水和醇)，以及乳化剂和稳定剂。供局部投予的药物组合物中可存在增稠剂。如果打算透皮投药，则组合物可包括透皮贴片或离子电渗装置。
本发明药物组合物可打算经直肠投予，以栓剂形式为例，其将在直肠中熔融，并释放出药物。供直肠投药的组合物可含有油性基质作为合适的无刺激性赋形剂。所述基质包括(但不限于)羊毛脂、可可脂和聚乙二醇。
本发明药物组合物可包括改变固体或液体剂量单位的物理形式的各种物质。例如，此组合物可包括在活性成分周围形成包覆外壳的物质。形成包覆外壳的物质通常为惰性，并且可选自例如糖、虫胶和其它肠溶衣剂。或者，可将活性成分包入明胶胶囊中。
固体或液体形式的本发明药物组合物可包括一种结合本发明化合物并由此帮助化合物递送的试剂。具有此能力的合适试剂包括单克隆或多克隆抗体、蛋白质或脂质体。
本发明药物组合物可由可以气雾剂形式投予的剂量单位组成。术语气雾剂用于表示从胶状种类到由加压包装组成的系统的多种系统。递送可通过液化或压缩气体进行，或通过分配活性成分的合适泵系统进行。本发明化合物的气雾剂可呈单相、两相或三相系统递送，以递送活性成分。气雾剂的边送包括必要的容器、启动器、阀门、子容器等，其一起可形成套件。所属领域技术人员无需过多实验即可确定优选的气雾剂。
本发明药物组合物可利用制药领域中众所周知的方法制成。例如，可通过将本发明 化合物与无菌蒸馏水组合以形成溶液，来制备欲通过注射投予的药物组合物。可添加表面活性剂，以便利形成均匀溶液或悬浮液。表面活性剂是与本发明化合物非共价相互作用，由此促进化合物在水性递送系统中溶解或均匀悬浮的化合物。
本发明化合物或其药学上可接受的盐是以治疗有效量投予，所述治疗有效量将视多种因素而变化，包括所用特定化合物的活性、化合物的代谢稳定性和作用时间长度、患者的年龄、体重、一般健康状态、性别和饮食、投药模式和时间、排泄速率、药物组合、特定病症或病状的严重程度、以及承受疗法的个体。
本发明化合物或其药学上可接受的衍生物也可在投予一种或多种其它治疗剂的同时、之前或之后投予。此组合疗法包括投予含有本发明化合物和一种或多种其它活性剂的单一药学给药制剂，以及投予本发明化合物与各活性剂自己的单独药学给药制剂。例如，本发明化合物与另一活性剂可以单一口服给药组合物(例如片剂或胶囊)一起投予患者，或各药剂以单独口服给药制剂投予。在使用单独给药制剂的情况下，本发明化合物与一种或多种额外活性剂可基本上在同一时间(即同时)或在单独错开的时间(即相继)投予，组合疗法应理解为包括所有这些方案。
本发明的药用组合根据疾病状态、给药途径、患者年龄或者体重的不同，给药剂量会做调整。对于成人口服给药，通常为0.1-100mg/kg/天，较佳为1-20mg/kg/天。本发明适宜的给药剂量需要考虑患者的年龄、体重、病情、给药途径等进行设定，口服给药通常为0.05-100mg/kg/天，较佳为0.1-10mg/kg/天范围内。非口服给药时，本发明药用组合物给药剂量根据不同给药途径差异较大，但通常为0.005-10mg/kg/天，较佳为0.01-1mg/kg/天范围内。
本发明化合物的给药量根据给药方法、患者的年龄、体重、状态和疾病的种类而不同，但通常对于口服给药的情况，成人每1天的给药量约为0.05mg-3000mg、优选约0.1mg-1000mg，根据需要可以分开给药。另外，对于非口服给药的情况，成人每1天的给药量约为0.01mg-1000mg、优选约0.05mg-500mg。应了解，在本发明中，所述化学式的取代基和/或变量的组合只有在其产生稳定化合物的情况下才是允许的。
本发明涉及具有5′帽状结构(CAP)依赖性内切酶抑制活性的被取代的多环氨基甲酰基吡啶酮衍生物及其前体药物及其氘代化合物、和含有其的药物组合物，以及使用该组合物用来抑制流感病毒增殖的方法。
本发明的化合物为前药，因此具有下述优点：口服吸收性高，具有良好的生物利用度，显示良好的清除率，肺转移性高等。因此其可形成优异的药物。
本发明的化合物的母体化合物对于5′帽结构依赖性内切核酸酶的抑制活性高，由于 为病毒特异性的酶，因此具有选择性高等效果，从而可以成为副作用得到减轻的药物。进一步地，本发明的化合物和/或本发明的化合物的母体化合物具有下述优点，即，代谢稳定性高、溶解度高、口服吸收性高、显示良好的生物利用度、显示良好的清除率、肺转移性高、半衰期长、非蛋白结合率高、hERG通道抑制低、肝药酶抑制低、确认有细胞病变效应(CytoPathic Effect，CPE)抑制效果，和/或在光毒性试验、Ames试验和遗传毒性试验中显示为阴性，或不具有肝毒性等，因此本发明的化合物成药学性较佳。
本发明的化合物和/或本发明的化合物可用于由流感病毒引发的症状和/或疾病。例如对于伴有发热、发冷、头痛、肌肉痛、全身感到倦怠等的类感冒症状、或咽痛、流鼻涕、鼻塞、咳嗽、痰等的呼吸道炎症、腹痛、呕吐、腹泻这样的胃肠症状、进而伴有急性脑病、肺炎等二次感染的并发症的治疗和/或预防、症状改善是有效的。
除非另有规定，本发明所用试剂和原料均市售可得。
除非另有规定，本发明的化合物经手工或者
Figure PCTCN2019082195-appb-000014
软件命名，市售化合物采用供应商目录名称。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
具体实施方式
本发明中的某些优选实施例方案在以下非限制性实施例中说明性示出。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。原料可以从商业途径获得，或者通过本领域已知的方法制备，或根据本文所述方法制备。
实施例1.
合成路线如下：
Figure PCTCN2019082195-appb-000015
中间体15的制备
156g中间体14(购自南京雷正医药科技有限公司，也可参照文献Rajsner等，Collection of Czechoslovak Chemical Communications,1987,vol.47,#1,p.65-71制备)溶解在2.5L THF中，在0℃下，缓慢加入14g四氢锂铝-D 4,升温至室温，搅拌3小时。TLC检测反应完全，向反应液加入2N盐酸，乙酸乙酯萃取，减压浓缩。用环己烷/二氯甲烷，打浆，得到白色固体为中间体15.MS:ESI 266.1[M+1] +.
中间体16的制备
257g中间体13及244.3g中间体15悬浮于50wt％丙基磷酸酐的乙酸乙酯溶液(803g)加入280mL乙酸乙酯。于室温下向反应液添加甲磺酸(109g)，回流搅拌6小时。在冰浴 冷却下向反应液添加水，于室温下搅拌1小时后，添加THF，乙酸乙酯萃取。水洗，8％碳酸氢钠水溶液洗有机层，减压蒸馏。固体溶解在1.4L THF中，加入198g碳酸钾，升温至50℃，滴加60mL苄基溴，60℃下搅拌9小时。在冰浴冷却下向反应液滴加2N盐酸水溶液，室温下搅拌，乙酸乙酯萃取。水洗，8％碳酸氢钠水溶液洗有机层，无水硫酸镁干燥。添加活性炭吸附1小时,硅藻土过滤，于减压蒸馏滤液。浓缩液乙酸乙酯/己烷打浆，固体析出，过滤，干燥，得中间体16，收率45％.MS:ESI 575.2[M+H] +.
实施例化合物1A
Figure PCTCN2019082195-appb-000016
25℃下向中间体16(40g)的120mL DMA溶液中，添加15g氯化锂，于80℃下搅拌3小时。在0-5℃下向反应液添加丙酮、0.5N稀盐酸及水并搅拌1.5小时。析出固体，过滤。氯仿/异丙醚重结晶，过滤，干燥得实施例化合物1A，收率79％.MS:ESI 485.1[M+H] +. 1H-NMR(CDCl 3)δ：3.00-3.51(2H，m)，3.62(1H，t)，3.83(2H，m),4.60(2H,m)，5.28-5.33(2H，m)，5.78-6.72(2H，m)，6.86-6.90(1H，m)，6.70-7.18(5H，m).氘代率：99.6％.
实施例化合物1B
Figure PCTCN2019082195-appb-000017
实施例化合物1A(5.0g)，加入DMA(25ml)搅拌，加入氯甲基碳酸甲酯(2.4g)及碳酸钾(2.9g)，碘化钾(1.7g)，升温至50℃并搅拌6小时。再加DMA(5ml)继续搅拌6小时。将反应液冷却至室温，加入DMA(25ml)，于50℃下搅拌5分钟，过滤。0-5℃下向所滤液滴加1mol/L盐酸水(50ml)及水(15ml)并搅拌1小时。过滤得到固体，于60℃下减压干燥，得实施例化合物1B，收率88％.MS:ESI 573.1[M+H] +. 1H-NMR(DMSO-D 6)δ:2.89-3.28(2H,m)，3.41(1H,t)，3.68(1H,m)，3.70(3H，s)，3.97-4.39(2H，m)，4.42(1H，m)，5.39-5.68(2H，m)，5.71-5.74(3H，m)，6.81-7.00(2H， J＝6.9Hz)，7.08-7.45(5H，m).氘代率：99.6％.
实施例化合物1C
Figure PCTCN2019082195-appb-000018
实施例化合物1A(4.8g)，加入DMA(30ml)搅拌，加入溴己烷(1.7g)及碳酸钾(2.9g)，碘化钾(1.7g)，升温至50℃并搅拌6小时。再加DMA(5ml)继续搅拌6小时。将反应液冷却至室温，加入DMA(30ml)，于50℃下搅拌5分钟，过滤。0-5℃下向所滤液滴加1mol/L盐酸水(50ml)及水(25ml)并搅拌1小时。过滤得到固体，于60℃下减压干燥，得实施例化合物1C，收率79％.MS:ESI 569.2[M+H] +.
实施例2.
合成路线如下：
Figure PCTCN2019082195-appb-000019
中间体20购自南京雷正医药科技有限公司，也可参照文献Rajsner等，Collection of Czechoslovak Chemical Communications,1987,vol.47,#1,p.65-71制备。MS:ESI 265.5[M+H] +。
中间体21的制备工艺参见中间体15的制备，区别在于，把四氢锂铝-D 4替换成四氢锂铝，中间体14替换成中间体20.
中间体22的制备工艺参见中间体16的制备，区别在于，把中间体15替换成中间体 21.
实施例2A的制备
Figure PCTCN2019082195-appb-000020
25℃下向中间体22(40g)的120mL DMA溶液中，添加15g氯化锂，于80℃下搅拌3小时。在0-5℃下向反应液添加丙酮、0.5N稀盐酸及水并搅拌1.5小时。析出固体，过滤。氯仿/异丙醚重结晶，过滤，干燥得实施例化合物2A，收率65％.MS:ESI 486.1[M+H] +. 1H-NMR(CDCl 3)δ:3.01-3.50(2H，m),3.61(1H，t),3.80(2H,m),4.02(1H,m),4.58(2H,m),5.76-6.70(2H,m),6.85-6.8/8(1H,m),6.70-7.20(5H,m).氘代率：98.6％.
实施例化合物2B
Figure PCTCN2019082195-appb-000021
实施例化合物2A(10.0g)，加入DMA(50ml)搅拌，加入氯甲基碳酸甲酯(4.8g)及碳酸钾(6.0g)，碘化钾(3.4g)，升温至50℃并搅拌6小时。再加DMA(10ml)继续搅拌6小时。将反应液冷却至室温，加入DMA(50ml)，于50℃下搅拌5分钟，过滤。0-5℃下向所滤液滴加1mol/L盐酸水(100ml)及水(30ml)并搅拌1小时。过滤得到固体，于60℃下减压干燥，得实施例化合物2B，收率90％.MS:ESI 574.2[M+H] +. 1H-NMR(DMSO-D 6)δ:2.91-3.30(2H,m)，3.44(1H,t)，3.71(1H,m)，3.73(3H，s)，4.02-4.41(3H，m)，4.43(1H，m)，5.43-5.76(2H，m)，5.79(1H，m)，6.84-7.05(2H，J＝6.9Hz)，7.10-7.49(5H，m).氘代率：99.6％.
实施例3.
合成路线如下：
Figure PCTCN2019082195-appb-000022
中间体23的制备工艺参见中间体15的制备，区别在于，中间体14替换成中间体20.
中间体24的制备工艺参见中间体16的制备，区别在于，把中间体15替换成中间体23.
实施例3A的制备
Figure PCTCN2019082195-appb-000023
实施例化合物3A的制备工艺参见化合物1A的制备，区别在于，把中间体16替换成中间体24.MS:ESI 487.1[M+H] +.氘代率：99.5％.
实施例3B的制备
Figure PCTCN2019082195-appb-000024
实施例化合物3B的制备工艺参见化合物1B的制备，区别在于，把化合物1A替换成化 合物3A.MS:ESI 575.2[M+H] +。氘代率：99.6％.
中间体2的制备
50g中间体1溶于1L THF，-78℃，N 2保护下加入305mL正丁基锂-己烷溶液，-78℃下搅拌2小时。向反应液中滴加59.6g氯甲酸烯丙酯的THF(200mL)溶液，在-78℃下搅拌2小时。将反应液于饱和氯化铵水溶液中进行淬灭，升温至室温后，利用乙酸乙酯进行提取。利用饱和盐水洗有机层，干燥后，减压蒸馏溶剂，而得到中间体2，收率76％.
中间体3的制备
20g中间体2溶于200mL THF，-78℃，N 2保护下滴加DIBAL-H己烷溶液，共加入138mL，-78℃搅拌1小时。加入酒石酸钠钾水溶液淬灭，乙酸乙酯萃取。饱和盐水洗有机层，干燥，减压蒸馏溶剂，得到中间体3。
中间体4的制备
向中间体3(12.4g)甲醇(130ml)溶液中，加入对甲苯磺酸一水合物(1.3g)，室温下搅拌8小时。碳酸氢钠水溶液淬灭，浓缩，乙酸乙酯萃取。饱和盐水洗涤机层，干燥后，减压蒸馏溶剂，而得到中间体4，收率88％。MS:ESI 202.2[M+H] +.
中间体6的制备
30g中间体5溶于150mL DMF，溶向溶液中滴加15.2g碘乙烷与27.6mL二氮双环十一烯，并于室温下搅拌整夜。10％氯化铵水溶液淬灭，乙酸乙酯萃取。饱和盐水洗涤有机层，干燥，减压蒸馏，到中间体6。
中间体7的制备
中间体2.5g溶于25mL DMA溶液，加入6.9g甲苯磺酸吡啶鎓与1.8g Boc肼，并于60℃下搅拌15小时。加水，乙酸乙酯萃取。饱和氯化铵水溶液洗，饱和氯化钠溶液洗有机层，干燥，减压蒸馏，快速硅胶管柱层析，得到中间体7。
中间体8的制备
2.5g化合物8溶解于4N盐酸乙酸乙酯溶液(25ml)中，于室温下搅拌1小时，减压蒸馏，饱和碳酸氢钠水溶液洗涤，二氯甲烷萃取。饱和盐水洗涤有机层，干燥，减压蒸馏，得到中间体8。
中间体10的制备
氮气保护，-25℃，化合物4(31g)溶于820ml乙腈，加入40g中间体8，滴加四氯化锡(230ml)，并于-25℃搅拌45分钟。将反应液于碳酸氢钠水溶液中进行骤冷淬灭后，加入二氯甲烷，于室温下进行搅拌，硅藻土过滤，二氯甲烷萃取。饱和盐水洗有机层，干燥，减压蒸馏除，得到中间体9粗品中间体9溶解于800mL THF中，吗啉(115mL)，四 (三苯基膦)钯(150g)，于室温下搅拌2.5小时。向反应液添加甲基叔丁基醚，滤取所析出之固体，使所获得之固体干燥，而得到中间体10。
中间体11的制备
于室温下依序向(R)-四氢呋喃-2-羧酸(855mg，7.36mmol)40g中间体10溶于180mL乙酸乙酯，加入80mL吡啶及50％丙基磷酸酐乙酸乙酯溶液，搅拌8hr，滤取所析出之固体后，乙酸乙酯，乙醇洗涤。于120mL乙醇室温下打浆7小时，过滤悬浮液，用乙醇洗2次，得中间体11粗品。
中间体13的制备
15g中间体11粗品混悬于乙醇(700mL)，加DBU(10.5mL)并搅拌30分钟。加1.3L二异丙基醚，于室温下搅拌30分钟。过滤，乙酸乙酯洗2次，得到中间体13，收率91％.MS:ESI 328.1[M+H] +.
S-033188A的制备
Figure PCTCN2019082195-appb-000025
参照实施例化合物1A的制备方法，制备得到S-033188A。
Ms:ESI 485.1[M+H] +.
S-033188B的制备
Figure PCTCN2019082195-appb-000026
参照实施例化合物1B的制备方法，制备得到S-033188B。
Ms:ESI 572.1[M+H] +.
表格化合物：
使用以上类似方案，制备以下表格化合物及其单一的对映异构体，制备以下表格化合物相对应的酯的前体药物，该类酯在体内，如口服给药，利用药物代谢酶、水解酶、消 化液、或者消化道内的细菌等作用，而转换为带有羟基基团的活性代谢物。表格化合物的相对应酯优选但不限于甲基碳酸甲酯。
表1：表格化合物结构
Figure PCTCN2019082195-appb-000027
Figure PCTCN2019082195-appb-000028
Figure PCTCN2019082195-appb-000029
Figure PCTCN2019082195-appb-000030
实施例4帽依赖性核酸内切酶(CEN)抑制活性的测定
1)底物的制备
购入将5’末端的G进行二磷酸化修饰、且2'位的羟基进行甲氧基化修饰、将自5'末端第6位的U进行Cy3标记、3'末端进行BHQ2标记的30merRNA(5'-pp-[m2'-0]GAA UAU(-Cy3)GCA UCA CUA GUA AGCUUU GCU CUA-BHQ2-3'中国药科大学赠予)，使用ScriptCap系统，附加帽结构(产物为m7G[5']-ppp-[5'][m2'-0]GAA UAU(-Cy3)GCA UCA CUA GUA AGC UUU GCU CUA(-BHQ2)-3')。将其通过改性聚丙烯酷肢凝胶电泳法进行分离、纯化，作为底物使用。
2)酶的制备
RNP是按照规定方法，由病毒颗粒制备(参考文献:VIROLOGY(1976)73，327-338页。LGA M.ROCHOVANSKY)。具体来说，将200μL1x10 3PFU/mL A/WSN/33病毒接种于10日龄发育鸡卵中，在37℃下培养2天，然后回收鸡卵的尿囊液。通过使用了20％庶糖的超速离心分离来纯化病毒颗粒，使用TritonX-100和溶血卵磷脂，使病毒颗粒溶解，然后通过使用了30～70％甘油密度梯度的超速离心分离，收集RNP级分(50～70％甘油级分)，作为酶液(含有约1nM的PB1·PB2·PA复合物)使用。
3)酶促反应
在聚丙烯制的384孔板上分注2.5μL酶促反应液(组成:53mM Tris盐酸盐(pH7.8)、1mM MgCl 2、1.25mM二硫苏糖醇、80mM NaCl、12.5％甘油、0.15μL酶液)。接着在0.5μL用DMSO连续稀释的受试化合物溶液、阳性对照(PC)和阴性对照(NC)中加入0.5μL DMSO，充分混合。接着加入2μL底物溶液(1.4nM底物RNA、0.05％Tween20),引发反应，在室温下孵育60分钟，然后将1μL反应液加入到10μL高纯甲酰胺溶液(含有 GeneScan120LizSize Standard作为尺寸标记(Sizing marker):Applied Biosystem(ABI)公司制造)中，终止反应。NC是在反应开始前，通过加入EDTA(4.5mM)来预先中止反应(标记浓度全部为终浓度)。
4)抑制率(IC 50值)的测定
将反应终止后的溶液在85℃下加热5分钟，在冰上骤冷2分钟，然后用ABIPRIZM3730Genetic Analyzer(基因分析仪)进行分析。通过分析软件ABI Genemapper对帽依赖性核酸内切酶产物的峰进行定量，分别以PC、NC的荧光强度作为0％抑制、100％抑制，求出受试化合物的CEN反应抑制率(％)，然后使用曲线拟合软件求出IC 50值。
实施例5CPE抑制效果确认试验
<材料>
1)2％FCS E-MEM(在MEM(最小必须培养基)中添加卡那霉素和FCS进行调制)
2)0.5％BSA E-MEM(在MEM(最小必须培养基)中添加卡那霉素和BSA进行调制)
3)HBSS(Hanks平衡盐溶液)
4)MDBK细胞:用2％FCS E-MEM调整为适当的细胞数(3X 10 5/mL)。
5)MDCK细胞:用HBSS清洗2次，然后用0.5％BSA E-MEM调整为适当的细胞数(5X 10 5/mL)。
6)胰蛋白酶溶液
将来自猪胰腺的胰蛋白酶(SIGMA)用PBS(-)溶解，用0.45μm的滤器过滤。
7)酶标仪
8)WST-8试剂盒
9)10％SDS溶液
<操作流程>
1)受试样品的稀释、分注
作为培养液，使用MDBK细胞时是使用2％FCS E-MEM，使用MDCK细胞时是使用0.5％BSA E-MEM。以下，对病毒·细胞·受试样品的稀释，使用同样的培养液。
预先将受试样品用培养液稀释为适当的浓度，在96孔板上制作2-5倍连续稀释系列(50μL/孔)。制作抗流感活性测定用、细胞毒性测定用两块。对于各药物实施一式三份测定。
使用MDCK细胞时，只在抗流感活性测定用时，向细胞中添加胰蛋白酶，使终浓度为3μg/mL。
2)流感病毒的稀释、分注
预先将流感病毒用培养液稀释为适当的浓度，各自以50μL/孔分注到加入了受试样品的96孔板中。以50μL/孔将培养液分注到细胞毒性测定用板中。
3)细胞的稀释、分注
以100μL/孔将调整为适当的细胞数目的细胞各自分注到加入了受试样品的96孔板中。
用孔板混合器(plate mixer)混合，在CO2培养箱中培养。抗流感活性测定用、细胞毒性测定用均培养3天。
4)WST-8的分注
将培养了3天的96孔板在肉眼、显微镜下观察，从板上以没有吸走细胞的方式清除上清。
将WST-8试剂盒用培养液稀释10倍，以各100μL将该WST-8溶液分注到各孔中。用孔板混合器混合，然后在CO 2培养箱中培养1～3小时。
对于抗流感活性测定用板，培养后，在各孔中各自分注10μL 10％SDS溶液，使病毒失活。
5)吸光度的测定
对于混合的96孔板，用EnVision、以450nm/620nm的双波长测定吸光度。
<各测定项目值的计算>
基于以下的计算式，使用Microsoft Excel程序进行计算。
50％流感感染细胞死亡抑制浓度(EC50)的计算
EC 50＝10 Z
Z＝(50％-High％)/(High％-Low％)x{log(High conc.)-log(Low conc.)}+log(High conc.)
对于作为母体化合物的受试物质(实施例化合物)，实施例4和实施例5的测定结果示于表2。
表2 CEN抑制活性试验和CPE抑制效果测试结果
Figure PCTCN2019082195-appb-000031
由以上结果可知，化合物1A、2A、3A显示较高的帽依赖性核酸内切酶抑制活性、 和高的CPE抑制效果，尤其化合物1A和化合物3A 的CPE抑制效果是S-033188A的两倍。因此，实施例化合物可以制备用作由流感病毒感染所诱发的症状/疾病的预防/治疗药物。
实施例6生物利用度试验
<口服吸收性的研究实验材料和方法>
(1)使用动物:使用SD大鼠。
(2)饲养条件:使SD大鼠自由摄取固形饲料和纯净水。
(3)施与量、分组的设定:利用规定的给药量进行口服给药、静脉给药。如以下这样设定组。(各化合物的给药量有变化)
口服给药1～30mg/kg(n＝5～6)
静脉给药0.5～10mg/kg(n＝5～6)
(4)给药溶液的制备:口服给药为悬浮液、灌胃给药。静脉给药为溶液、尾静脉给药。
(5)评价项目:经时地采血，使用LC/MS/MS测定血浆中药物浓度。
(6)统计分析:对于血浆中浓度变化，使用非线性最小二乘法程序算出血浆中浓度一时间曲线下面积(AUC)，由口服给药组和静脉给药组的AUC算出生物利用度(BA)，和并统计静脉给药血药浓度消除半衰期T 1/2。
测试结果如表3.
表3实施例化合物生物利用度测定结果
实施例化合物编号# 实施例化合物BA％ 静脉给药半衰期T 1/2小时
1A 7.1 4.0
2A 5.0 5.0
3A 7.8 5.2
S-033188A 4.7 3.8
1B 18.4 --
2B 15.9 --
3B 19.8 --
S-033188B 15.3 --
由表3的结果可知，前药(1B、2B、3B)与母体化合物(1A、2A、3A)相比，生物利用度得到提高。实施例化合物1A、2A、3A较S-033188A有较大程度的提高；实施例化合物1B、2B、3B较S-033188B生物利用度的也有较大程度的提高。静脉给药清除半衰期实施例化合物也有不同程度的延长。
因此，本发明化合物较S-033188A/S-033188B的口服吸收性更加优异，可形成用作由感染流感病毒而引发的症状和/或疾病的治疗和/或预防剂的药物，预示给药剂量可以更小、副作用更低。
实施例7 hERG试验
为了评价心电图QT间期延长的风险，使用表达human ether-a-go-go相关基因(hERG)通道的HEK293细胞，研究对于在心室复极过程中起重要作用的延迟整流K +电流(I Kr)的作用。
使用全自动膜片钳系统，通过全细胞膜片钳法记录将细胞保持在-80mV的膜电位后，给予2秒钟+50mV的除极化剌激、进一步给予2秒钟-50mV的复极化剌激时引发的I Kr。在产生的电流稳定后，使以目的浓度溶解了受试物质的细胞外液(NaCl:137mmol/L、KCl:4mmol/L、CaCl 2:1.8mmol/L,MgCl 2-6H 2O:1mmol/L、葡萄糖:10mmol/L、HEPES:10mmol/L、pH 7.4)在室温条件下适用于细胞10分钟。由所得的I Kr，使用分析软件以静止膜电位的电流值为基准测量最大尾电流的绝对值。进一步地，算出相对于受试物质适用前的最大尾电流的抑制率，与介质适用组(0.1％DMSO溶液)比较，评价受试物质对于I Kr的影响。
表4实施例化合物在0.3-10μmol/L条件下的抑制率
实施例化合物编号# 抑制率％
1A 3.1
2A 7.8
3A 3.5
S-033188A 8.2
由表4抑制率结果可知，实施例化合物1A、2A、3A抑制率显著小于S-033188A，尤其是1A和3A的抑制率不到S-033188A二分之一。试验结果表明1A和3A较化合物S-033188A心脏毒性更低。
实施例8流感病毒感染小鼠致死抑制试验
<小鼠>
BALB/cAnNCrlCrlj 6～7周龄的小鼠用于试验。
<病毒溶液的制备>
将A/WS/33、A/Victoria/3/75或B/Maryland/1/59(ATCC)在小鼠肺内传代，制成小鼠驯化病毒。将冷冻保存的小鼠驯化病毒溶液迅速地解冻，用DPBS稀释，以形成使用的传染性滴度(infectivity titer)(A/WS/33:800-4000TC ID501小鼠，A/Victoria/3/75:750 TCID 50/小鼠，B/Maryland/1/59:100TCID 50/小鼠)。
<感染>
在氯胺酮·赛拉嗪混合液的麻醉下，将调制的病毒溶液100ul经鼻接种，使小鼠肺内直接感染。
<受试样品的配制>
将受试样品以合适的浓度在0.5％甲基纤维素溶液中悬浮。
<对感染小鼠给药>
对于刚感染病毒后或经过一定时间后的小鼠，口服给予稀释了的受试样品200ul。
<药效评价>
病毒感染后，饲养14天，算出对于50％致死抑制所需要的每一天的施与量ED 50(mg/kg/day)与对照组比较，评价病毒抑制效果。
<结果>
表5为单次给药的ED 50值。
表5实施例化合物单次给药的ED 50值
实施例化合物编号# ED 50mg/kg/day
1B 0.41
2B 0.71
3B 0.33
S-033188B 0.78
由以上的结果可知，所有测试化合物均表现出不同程度的体内抑制病毒的效果，尤其化合物1B和化合物3B半数有效剂量显著小于S-033188B。说明实施例化合物在临床应用中的剂量小于S-033188B，或者用药间隔时间更长，相应的毒副作用也更小。
实施例9样品对MDCK细胞的毒性检测
实验采用
Figure PCTCN2019082195-appb-000032
(Invitrogen)试剂盒检测药物对细胞的毒性作用。
实验原理：实验采用
Figure PCTCN2019082195-appb-000033
(Invitrogen)试剂盒检测药物对细胞的毒性作用。
Figure PCTCN2019082195-appb-000034
是一种能根据代谢活性产生吸光度变化和荧光信号的氧化还原指示剂。
Figure PCTCN2019082195-appb-000035
易溶于水，其氧化形式进入细胞后经线粒体酶还原产生可测量的荧光及颜色变化，适用于细胞活性和细胞增殖的定量分析以及体外细胞毒性研究。具有代谢活性的正常细胞能够将试剂转换成较强的荧光和颜色变化，而受损或无活性的细胞具有较低的天然代谢活性，对应的信号也较低。因此荧光信号强弱，可以反映细胞活性的高低。
实验步骤：将MDCK细胞接种于96孔细胞培养板中，细胞贴壁后备用。药物用 DMEM培养基从2倍最高测试浓度起连续3倍梯度稀释8个梯度。将药物加入到细胞中，于37℃的CO 2培养箱中培养。加药培养48h后，显微镜下观察药物引起的细胞病变效应(CPE)，加入alamarBlue检测细胞存活率。药物对细胞的毒性的大小与细胞的活性呈反比，并以细胞活性来反映。
计算公式：细胞活性(％)＝(药物组-空白对照)/(细胞对照-空白对照)*100
药物在很高浓度时对MDCK细胞有毒性效应，引起50％毒性效应的浓度用CC 50所示，具体见下表。
表6实施例化合物对于细胞的毒性作用
实施例化合物编号# CC 50nM
1A 48285
S-033188A 29882
实施例化合物1A毒性显著小于S-033188A。说明化合物1A较S-033188A具有更高的安全性。
对于本领域技术人员，本公开不只局限于前述说明性实施例，在不脱离其必要属性的情况下能以其它特定形式体现。因此期望认为，所有方面均作为说明性而不是限制性、对所附权利要求进行参考的实施例而不是前述实施例，引用文献只是针对附加的权利要求而不是上述的实例，以及落入权利要求等效性的含义和范围之内的所有变化因此预期包含于此。
本说明书中列举的所有专利、专利申请和文献参考均在此以其全部内容引入作为参考。在不一致的情况下，包括定义的本公开将是有说服力的。

Claims (15)

  1. 一种如式(VII)所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药，
    Figure PCTCN2019082195-appb-100001
    其中，
    R 1为氢或氘；
    R 2为氢或氘；
    R 3为氢或氘；
    L为氢、烷基、或(甲氧羰基)氧甲基；
    且R 1、R 2和R 3中至少有一个为氘；
    R 4为氢或卤素；
    R 5为氢或卤素；
    R 6为氢或卤素；
    A为C或O，当A为C时，R 7和R 8均为氢或均为甲基；当A为O时，R 7和R 8不存在；
    R 9为氢或甲基；R 10为氢或甲基；
    且R 4、R 5和R 6不同时为氢。
  2. 如权利要求1所述的如式(VII)所示的多环氨基甲酰基吡啶酮衍生物，其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药，
    其中，所述的如式(VII)所示的多环氨基甲酰基吡啶酮衍生物满足如下任一条件：
    条件1：R 4为氢；R 5为氟；R 6为氟；A为O；R 9为氢；R 10为氢；
    条件2：R 4为氢；R 5为氟；R 6为氢；A为O；R 9为氢；R 10为甲基且与R 10直接相连的碳原子构型为(S)；
    条件3：R 4为氯；R 5为氢；R 6为氢；A为O；R 9为氢；R 10为氢；
    条件4：R 4为氢；R 5为氟；R 6为氟；A为C；R 7和R 8均为甲基；R 9为氢；R 10为氢；
    条件5：R 4为氢；R 5为氟；R 6为氟；A为C；R 7和R 8均为氢；R 9为氢且与R 9直接相连的碳原子构型为(R)；R 10为氢；
    条件6：R 4为氢；R 5为氟；R 6为氢；A为C；R 7和R 8均为氢；R 9为氢；R 10为氢。
  3. 一种如式(I)、式(II)、式(III)、式(IV)、式(V)、或式(VI)所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药，
    Figure PCTCN2019082195-appb-100002
    所述的式(I)、式(II)、式(III)、式(IV)、式(V)、或式(VI)的结构式中，
    R 1各自独立地为氢或氘；
    R 2各自独立地为氢或氘；
    R 3各自独立地为氢或氘；
    L各自独立地为氢、烷基或(甲氧羰基)氧甲基；
    且，所述式(I)、式(II)、式(III)、式(IV)、式(V)、或式(VI)各结构式中，R 1、R 2和R 3中至少有一个为氘。
  4. 如权利要求3所述的如式(I)、式(II)、式(III)、式(IV)、式(V)、或式(VI)所示的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药，其中，
    所述如式(I)所示的多环氨基甲酰基吡啶酮衍生物选自：
    Figure PCTCN2019082195-appb-100003
    或，所述如式(II)所示的多环氨基甲酰基吡啶酮衍生物选自：
    Figure PCTCN2019082195-appb-100004
    或，所述如式(III)所示的多环氨基甲酰基吡啶酮衍生物选自：
    Figure PCTCN2019082195-appb-100005
    或，所述如式(IV)所示的多环氨基甲酰基吡啶酮衍生物选自：
    Figure PCTCN2019082195-appb-100006
    或，所述如式(V)所示的多环氨基甲酰基吡啶酮衍生物选自：
    Figure PCTCN2019082195-appb-100007
    或，所述如式(VI)所示的多环氨基甲酰基吡啶酮衍生物选自：
    Figure PCTCN2019082195-appb-100008
  5. 如权利要求1-4中至少一项所述的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药，其中，
    所述的其药学上可接受的盐为所述的如式(VII)、式(I)、式(II)、式(III)、式(IV)、式(V)、或式(VI)所示的多环氨基甲酰基吡啶酮衍生物与有机酸或无机酸所形成的酸加合盐；其中，所述的有机酸选自马来酸、反丁烯二酸、安息香酸、抗坏血酸、琥珀酸、甲磺酸、乙酸、三氟乙酸、草酸、丙酸、酒石酸、水杨酸、柠檬酸、葡萄糖酸、乳酸、扁桃酸、苯乙酸、天冬氨酸、硬脂酸、棕榈酸、乙二醇酸、谷氨酸和苯磺酸中的一种或多种；所述的无机酸选自盐酸、氢溴酸、硫酸、磷酸和硝酸中的一种或多种；
    或，所述的其药学上可接受的盐为所述的如式(VII)、式(I)、式(II)、式(III)、式(IV)、式(V)、或式(VI)所示的多环氨基甲酰基吡啶酮衍生物与选自碱金属离子、碱 土金属离子、铵离子的有机和无机阳离子中的一种或多种所成的盐；其中，所述的碱金属选自锂、钠、或钾；所述的碱土金属选自镁、钡、或钙。
  6. 一种药物组合物，其包含治疗有效量的如权利要求1-5中至少一项所述的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药，和药学上可接受的载体。
  7. 如权利要求6所述的药物组合物，其还包含其他药物活性成分，所述的其他药物活性成分选自神经胺酸酶抑制剂、RNA依赖性RNA聚合酶抑制剂、M2蛋白质抑制剂、PB2Cap结合抑制剂、抗HA抗体、或免疫作用药。
  8. 如权利要求7所述的药物组合物，所述的神经胺酸酶抑制剂为奥司他韦、扎那米韦、帕拉米韦、或Inavir；所述的RNA依赖性RNA聚合酶抑制剂为Favipiravir；所述的M2蛋白质抑制剂为金刚烷胺；所述的PB2Cap结合抑制剂为VX-787；所述的抗HA抗体为MHAA4594A；所述的免疫作用药为Nitazoxanide。
  9. 一种如权利要求1-5中至少一项所述的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药在制备5′帽依赖性核酸内切酶抑制剂中的应用。
  10. 一种如权利要求1-5中至少一项所述的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药在制备预防、治疗和/或缓解与5′帽依赖性核酸内切酶相关的疾病的药物中的应用。
  11. 如权利要求10所述的应用，其中，所述的与5′帽依赖性核酸内切酶相关的疾病是指由流感病毒感染引发的症状和/或疾病。
  12. 如权利要求11所述的应用，其中，所述的流感病毒选自甲型、乙型、或丙型。
  13. 如权利要求11所述的应用，其中，所述的症状选自伴有发热、发冷、头痛、肌肉痛、全身感到倦怠等的类感冒症状、或咽痛、流鼻涕、鼻塞、咳嗽、痰的呼吸道炎症、腹痛、呕吐、腹泻的胃肠症状、进而伴有急性脑病、肺炎二次感染的并发症。
  14. 一种预防、治疗和/或缓解疾病的方法，所述的方法包括给予需要其的个体治疗有效量的如权利要求1-5中至少一项所述的多环氨基甲酰基吡啶酮衍生物、其立体异构体、互变异构体、水合物、溶剂化物、活性代谢物、结晶形式、药学上可接受的盐或其前药，以抑制该个体体内的5′帽依赖性核酸内切酶水平。
  15. 如权利要求14所述的方法，其中，所述的疾病是指由流感病毒感染引发的症状和/或疾病；具体地，所述的流感病毒选自甲型、乙型、或丙型；所述的症状选自伴有发热、发冷、头痛、肌肉痛、全身感到倦怠等的类感冒症状、或咽痛、流鼻涕、鼻塞、咳嗽、痰 的呼吸道炎症、腹痛、呕吐、腹泻的胃肠症状、进而伴有急性脑病、肺炎二次感染的并发症。
PCT/CN2019/082195 2018-04-11 2019-04-11 多环氨基甲酰基吡啶酮衍生物、药物组合物及其用途 WO2019196891A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US17/044,079 US20210093640A1 (en) 2018-04-11 2019-04-11 Polycyclic Carbamoylpyridone Derivatives, Pharmaceutical Compositions and Use Thereof
RU2020136675A RU2770096C1 (ru) 2018-04-11 2019-04-11 Полициклические производные карбамоилпиридона, фармацевтические композиции и их применение
EP19784679.3A EP3778608A4 (en) 2018-04-11 2019-04-11 POLYCYCLIC CARBAMOYL PYRIDONE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND THEIR USES
AU2019252208A AU2019252208B2 (en) 2018-04-11 2019-04-11 Polycyclic carbamoylpyridone derivatives, pharmaceutical compositions and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810323355.2 2018-04-11
CN201810323355.2A CN108440564B (zh) 2018-04-11 2018-04-11 被取代的多环氨基甲酰基吡啶酮衍生物及其前药

Publications (1)

Publication Number Publication Date
WO2019196891A1 true WO2019196891A1 (zh) 2019-10-17

Family

ID=63199693

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/082195 WO2019196891A1 (zh) 2018-04-11 2019-04-11 多环氨基甲酰基吡啶酮衍生物、药物组合物及其用途

Country Status (6)

Country Link
US (1) US20210093640A1 (zh)
EP (1) EP3778608A4 (zh)
CN (1) CN108440564B (zh)
AU (1) AU2019252208B2 (zh)
RU (1) RU2770096C1 (zh)
WO (1) WO2019196891A1 (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112409379A (zh) * 2020-09-28 2021-02-26 长沙晶易医药科技有限公司 氘代的二氢二苯并硫杂卓化合物以及包含该化合物的药物组合物
CN112778332A (zh) * 2020-12-31 2021-05-11 重庆医科大学 一种巴洛沙韦酯中间体多环氨基甲酰基吡啶酮的合成方法
WO2021093860A1 (zh) * 2019-11-13 2021-05-20 南京知和医药科技有限公司 取代的双三环化合物及其药物组合物和用途

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3008607A1 (en) 2015-12-15 2017-06-22 Shionogi & Co., Ltd. A medicament for treating influenza characterized by combining a cap-dependent endonuclease inhibitor and an anti-influenza drug
WO2018030463A1 (ja) 2016-08-10 2018-02-15 塩野義製薬株式会社 置換された多環性ピリドン誘導体およびそのプロドラッグを含有する医薬組成物
CN109721615B (zh) * 2017-09-18 2020-12-29 广东东阳光药业有限公司 流感病毒复制抑制剂及其用途
CN109503625A (zh) * 2018-01-19 2019-03-22 赵蕾 一种多环吡啶酮化合物及其药物组合和用途
CN108440564B (zh) * 2018-04-11 2019-08-06 安帝康（无锡）生物科技有限公司 被取代的多环氨基甲酰基吡啶酮衍生物及其前药
KR102501180B1 (ko) 2018-04-24 2023-02-21 시오노기세야쿠 가부시키가이샤 안정성이 우수한 고형 제제
WO2020020267A1 (zh) * 2018-07-27 2020-01-30 深圳市塔吉瑞生物医药有限公司 一种取代的多环性吡啶酮化合物及其前药
CN109721585B (zh) * 2018-12-19 2020-09-29 浙江工业大学 一种巴洛沙韦关键中间体的制备方法
CN109516998B (zh) * 2018-12-25 2021-06-25 深圳市华先医药科技有限公司 一种巴洛沙韦中间体的合成方法
CN111410661B (zh) * 2019-01-04 2023-05-05 周雨恬 帽依赖性内切核酸酶抑制剂及其用途
CN110105372B (zh) * 2019-06-05 2022-05-10 南京焕然生物科技有限公司 一种r-7-(苄氧基)-四氢-1h-恶嗪并吡啶并-三嗪-6,8-二酮的制备方法
CN110128366A (zh) * 2019-06-05 2019-08-16 南京焕然生物科技有限公司 一种(r)-3-甲氧基-4-吗啉羧酸-2-丙烯-1-基酯的制备方法
CN111057070A (zh) * 2019-10-30 2020-04-24 浙江工业大学 一种巴洛沙韦关键中间体的合成方法
CN112876510A (zh) * 2020-02-10 2021-06-01 石家庄迪斯凯威医药科技有限公司 一种磷酸酯类多环化合物及其药物组合物和用途
CN111233891B (zh) * 2020-03-04 2021-05-04 江苏柯菲平医药股份有限公司 一种稠环吡啶酮衍生物及其制备方法和用途
CN113527296A (zh) * 2020-03-13 2021-10-22 北京凯因科技股份有限公司 一种流感病毒抑制剂
WO2021180147A1 (zh) * 2020-03-13 2021-09-16 北京凯因科技股份有限公司 一种流感病毒抑制剂
WO2022128934A1 (en) * 2020-12-15 2022-06-23 Synthon B.V. Solid forms of baloxavir, salts of baloxavir and cocrystals of baloxavir
CN112898312B (zh) * 2021-01-29 2021-11-12 湖南南新制药股份有限公司 一种稠合多环吡啶酮衍生物及其用途
CN113717199B (zh) * 2021-08-13 2022-04-01 北京北朋科技有限公司 巴洛沙韦的氘代衍生物及其在抗流感病毒中的应用
CN116082361B (zh) * 2023-04-11 2023-06-13 和鼎（南京）医药技术有限公司 一种制备玛巴洛沙韦中间体和玛巴洛沙韦的方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018030463A1 (ja) * 2016-08-10 2018-02-15 塩野義製薬株式会社 置換された多環性ピリドン誘導体およびそのプロドラッグを含有する医薬組成物
CN107709321A (zh) * 2015-04-28 2018-02-16 盐野义制药株式会社 经取代的多环性吡啶酮衍生物及其前药
CN108440564A (zh) * 2018-04-11 2018-08-24 朱孝云 被取代的多环氨基甲酰基吡啶酮衍生物及其前药
CN109503625A (zh) * 2018-01-19 2019-03-22 赵蕾 一种多环吡啶酮化合物及其药物组合和用途

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2013003139A (es) * 2010-09-24 2013-06-18 Shionogi & Co Profarmaco de derivado de carbamoilpiridona policiclica substituida.
JOP20170169A1 (ar) * 2016-08-29 2019-01-30 Novartis Ag مركبات بيريدازين ثلاثية الحلقة مندمجة تفيد في علاج العدوى بفيروس أورثوميكسو
WO2020020267A1 (zh) * 2018-07-27 2020-01-30 深圳市塔吉瑞生物医药有限公司 一种取代的多环性吡啶酮化合物及其前药

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107709321A (zh) * 2015-04-28 2018-02-16 盐野义制药株式会社 经取代的多环性吡啶酮衍生物及其前药
WO2018030463A1 (ja) * 2016-08-10 2018-02-15 塩野義製薬株式会社 置換された多環性ピリドン誘導体およびそのプロドラッグを含有する医薬組成物
CN109503625A (zh) * 2018-01-19 2019-03-22 赵蕾 一种多环吡啶酮化合物及其药物组合和用途
CN108440564A (zh) * 2018-04-11 2018-08-24 朱孝云 被取代的多环氨基甲酰基吡啶酮衍生物及其前药

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
LGA M.ROCHOVANSKY, VIROLOGY, vol. 73, 1976, pages 327 - 338
RAJ SNER ET AL., COLLECTION OF CZECHOSLOVAK CHEMICAL COMMUNICATIONS, vol. 47, no. 1, 1987, pages 65 - 71
See also references of EP3778608A4
WANG, SHIZHEN: "Part VI Research of Nuclear Medicine", MOLECULAR NUCLEAR MEDICINE (2ND EDITION, 30 April 2004 (2004-04-30), pages 417 - 418, XP009524204 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021093860A1 (zh) * 2019-11-13 2021-05-20 南京知和医药科技有限公司 取代的双三环化合物及其药物组合物和用途
CN115175913A (zh) * 2019-11-13 2022-10-11 南京知和医药科技有限公司 取代的双三环化合物及其药物组合物和用途
CN115175913B (zh) * 2019-11-13 2023-11-28 南京知和医药科技有限公司 取代的双三环化合物及其药物组合物和用途
CN112409379A (zh) * 2020-09-28 2021-02-26 长沙晶易医药科技有限公司 氘代的二氢二苯并硫杂卓化合物以及包含该化合物的药物组合物
WO2022063016A1 (zh) * 2020-09-28 2022-03-31 长沙晶易医药科技有限公司 氘代的二氢二苯并硫杂卓化合物以及包含该化合物的药物组合物
CN112409379B (zh) * 2020-09-28 2023-07-28 长沙晶易医药科技股份有限公司 氘代的二氢二苯并硫杂卓化合物以及包含该化合物的药物组合物
CN112778332A (zh) * 2020-12-31 2021-05-11 重庆医科大学 一种巴洛沙韦酯中间体多环氨基甲酰基吡啶酮的合成方法

Also Published As

Publication number Publication date
AU2019252208A1 (en) 2020-11-19
EP3778608A1 (en) 2021-02-17
RU2770096C1 (ru) 2022-04-14
AU2019252208B2 (en) 2022-03-03
CN108440564B (zh) 2019-08-06
US20210093640A1 (en) 2021-04-01
EP3778608A4 (en) 2021-06-23
CN108440564A (zh) 2018-08-24

Similar Documents

Publication Publication Date Title
WO2019196891A1 (zh) 多环氨基甲酰基吡啶酮衍生物、药物组合物及其用途
CN114426568B (zh) 2-氧代-3-吡咯烷基丙腈类化合物及其药物组合物和用途
JP6516705B2 (ja) Ｈｂｖ感染に対する抗ウイルス剤としてのスルファモイルベンズアミド誘導体
EP3391888B1 (en) Medicine for treating influenza characterized by comprising combination of cap-dependent endonuclease inhibitor with anti-influenza drug
CN111548384A (zh) 用于抗新型冠状病毒治疗的被取代的n4-羟基胞苷衍生物及其前药
WO2020020267A1 (zh) 一种取代的多环性吡啶酮化合物及其前药
TW201542553A (zh) 氮雜吡啶酮化合物及其用途
US20140308282A1 (en) Pharmaceutical compounds
NZ719729A (en) Inhibitors of influenza viruses replication
TW201305163A (zh) 用於治療呼吸道融合病毒感染之化合物
WO2020241759A1 (ja) インフルエンザウイルス感染症またはコロナウイルス感染症の予防および／または治療剤
CN111410661A (zh) 帽依赖性内切核酸酶抑制剂及其用途
US20230233573A1 (en) Treating influenza using substituted polycyclic pyridone derivatives and prodrugs thereof
JP2022507117A (ja) 呼吸器疾患の処理のための新規な化合物
JP2021514967A (ja) ピリジノイミダゾール系化合物の結晶型、塩型及びその製造方法
JP6034960B2 (ja) フッ素置換（３ｒ、４ｒ、５ｓ）−５−グアニジノ−４−アセトアミド−３−（ペンタン−３−イルオキシ）シクロヘキセン−１−カルボン酸、そのエステル及びその使用
CN112771048A (zh) 流感病毒复制抑制剂及其中间体和用途
TW202204337A (zh) 截短側耳素類之醫療用途
TWI821343B (zh) 流感病毒複製之抑制劑
WO2024098856A1 (zh) 一种抗流感病毒衍生物及其用途
CN113979936A (zh) 2-芳脲基-n-[3-(4-吗啉基)丙基]烟酰胺类化合物及其应用
CN113979935A (zh) 2-芳脲基-n-(4-氟苄基)烟酰胺类化合物及其应用
US20230151034A1 (en) Peptidomimetic n5-methyl-n2-(nonanoyl-l-leucyl)-l-glutaminate derivatives, triazaspiro[4.14]nonadecane derivatives and similar compounds as inhibitors of norovirus and coronavirus replication
CN114057635A (zh) 2-芳脲基-n-[2-(2-甲氧基苯氧基)乙基]烟酰胺类化合物及其应用
WO2023137875A1 (zh) 一种药物组合物及其抗病毒用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19784679

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2019252208

Country of ref document: AU

Date of ref document: 20190411

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019784679

Country of ref document: EP

Effective date: 20201111