WO2020020267A1 - 一种取代的多环性吡啶酮化合物及其前药 - Google Patents

一种取代的多环性吡啶酮化合物及其前药 Download PDF

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Publication number
WO2020020267A1
WO2020020267A1 PCT/CN2019/097614 CN2019097614W WO2020020267A1 WO 2020020267 A1 WO2020020267 A1 WO 2020020267A1 CN 2019097614 W CN2019097614 W CN 2019097614W WO 2020020267 A1 WO2020020267 A1 WO 2020020267A1
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Prior art keywords
compound
deuterium
hydrogen
pharmaceutically acceptable
influenza
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PCT/CN2019/097614
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English (en)
French (fr)
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王义汉
刘志强
李焕银
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深圳市塔吉瑞生物医药有限公司
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Publication of WO2020020267A1 publication Critical patent/WO2020020267A1/zh

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    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • 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
    • 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 invention relates to a substituted polycyclic pyridone compound, a prodrug thereof, a composition containing the compound, and a use thereof. More specifically, the present invention relates to certain deuterium-substituted (((12aR) -12-((11S) -7,8-difluoro-6,11-dihydrodibenzo (B, E) thioheptin -11-yl) -6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H- (1,4) oxazine (3,4-C) pyrido (2, 1-F) (1,2,4) triazin-7-yl) oxy) methyl carbonate and their parent drugs, these deuterium-substituted compounds and their compositions exhibit cap-dependent endonucleases ( Cap-dependent endonuclease), and these deuterated compounds have more excellent pharmacokinetic properties.
  • deuterium-substituted (
  • Influenza or flu for short is an acute respiratory infectious disease caused by the infection of the influenza virus, and has become the most lethal viral infectious disease. Elderly people over 65 years of age, children under 2 years of age, and people with chronic respiratory and cardiovascular diseases are more likely to have flu complications, so they are at high risk for influenza.
  • the Spanish flu 1918, the Asian flu of 1957, and the Hong Kong flu of 1968.
  • the Spanish flu H1N1 was devastating, with more deaths than during World War I, infecting 30% of the world's population and causing at least 20 million deaths.
  • the other two influenza outbreaks were caused by the H2N2 and H3N2 influenza viruses. Although smaller, they also caused hundreds of deaths.
  • H1N1 influenza virus A new type of H1N1 influenza virus that appeared in 2009 caused the first influenza pandemic in the 21st century. Studies have found that the gene of this virus contains the genetic sequences of various influenza viruses such as human, pig, and poultry. Recombinant virus. In just a few months, the virus spread quickly worldwide, causing great panic. The World Health Organization has upgraded the alert from three levels to several levels up to the highest level.
  • Influenza viruses are classified into three types: A, B, and C (also known as A, B, and C) according to the different characteristics of nuclear proteins and matrix protein antigens.
  • Influenza A virus has the widest range of hosts, can infect humans, pigs, horses, and poultry, and is highly pathogenic, can cause the world's influenza pandemic, and is most harmful to humans; influenza B virus mainly infects humans and pigs, causing The disease ability is low, which can cause local outbreaks of influenza; influenza C virus only infects infants and young children and people with low immunity, and rarely causes epidemics, and the harm is relatively small.
  • anti-influenza drugs the main known ones are: (1) Amantadine and Rimantadine are two anti-influenza virus drugs in the morning market, mainly by blocking the M2 ion channel of the virus, Inhibits virus husking and exerts antiviral effect. (2) Oseltamivir Phosphate (trade name: Tamiflu, manufactured by Roche), Zanamivir (trade name: Relenza, manufactured by GlaxoSmithKline), is Neuraminidase inhibitors have higher efficacy and better safety and tolerability, and are currently the first choice drugs for anti-flu.
  • Cap-dependent endonucleases which are enzymes derived from influenza viruses, are considered essential for virus proliferation and have virus-specific enzymatic activity not possessed by the host. Endoenzymes are suitable targets for anti-influenza drugs.
  • the cap-dependent endonuclease of influenza virus is a fragment that uses a host mRNA precursor as a substrate and contains 9 to 13 bases (cap bases are not included in the above number of bases). Endonuclease activity. This fragment functions as a primer for viral RNA polymerase and is used to synthesize mRNA encoding viral proteins. That is, it is thought that a substance that inhibits a cap-dependent endonuclease inhibits the synthesis of viral proteins by inhibiting the synthesis of viral mRNA, and consequently inhibits the proliferation of the virus.
  • Baloxavir Marboxil also known as S-033188, chemical name is (((12aR) -12-((11S) -7,8-difluoro-6,11-dihydrodibenzo (B, E) thioheptin- 11-yl) -6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H- (1,4) oxazine (3,4-C) pyrido (2,1 -F) (1,2,4) triazin-7-yl) oxy) methyl carbonate, which has the following structure) is a pioneer developed by Shionogl & Co., Ltd.
  • ADME absorption, distribution, metabolism, and / or excretion
  • the present invention discloses a novel deuterium-substituted polycyclic pyridone derivative, a prodrug thereof, a composition containing the compound, and a use thereof, which have better inhibition of cap-dependent endonucleases. Enzyme activity, especially with better pharmacokinetic properties and / or oral bioavailability.
  • P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 );
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from hydrogen or deuterium;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each independently selected from hydrogen Or deuterium;
  • the additional condition is that the above compound contains at least one deuterium atom
  • the invention provides a compound of the invention or a tautomer, stereoisomer, prodrug, pharmaceutically acceptable salt, crystalline form, hydrate or solvent compound thereof, and a pharmaceutically acceptable Pharmaceutical composition of excipients.
  • a compound of the present invention or a tautomer, stereoisomer, prodrug, pharmaceutically acceptable salt, crystalline form, hydrate or solvent compound thereof is provided in the pharmaceutical composition in an effective amount. in.
  • a compound of the invention or a tautomer, stereoisomer, prodrug, pharmaceutically acceptable salt, crystalline form, hydrate or solvent compound thereof is provided in a therapeutically effective amount.
  • a compound of the invention or a tautomer, stereoisomer, prodrug, pharmaceutically acceptable salt, crystalline form, hydrate or solvent compound thereof is provided in a prophylactically effective amount.
  • the present invention provides a pharmaceutical composition as described above or a tautomer, stereoisomer, prodrug, pharmaceutically acceptable salt, crystalline form, hydrate or solvent compound thereof
  • the preparation method comprises the steps of: mixing a pharmaceutically acceptable excipient with a compound of the present invention or a pharmaceutically acceptable salt, crystal form, hydrate or solvent compound thereof to form a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate, or solvent thereof.
  • the invention provides a compound of the invention or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent compound thereof for use in the preparation of a treatment And the use in a medicament for preventing a disease caused by a virus having a cap-dependent endonuclease.
  • the invention also relates to a method of treating and / or preventing a disease caused by a virus having a cap-dependent endonuclease in a subject, the method comprising administering to the subject A therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, crystalline form, hydrate or solvent compound or pharmaceutical composition thereof.
  • the compound is administered orally, subcutaneously, intravenously, or intramuscularly.
  • the compound is administered chronically.
  • the present invention further provides a method for treating or preventing influenza infectious diseases using a prodrug compound, and the aforementioned compound having an anti-influenza effect.
  • the present invention further provides a parent compound of a prodrug compound.
  • the parent compound is used as an anti-influenza agent or an intermediate of the prodrug compound.
  • the compounds of the present invention have the activity of inhibiting cap-dependent endonucleases.
  • a more preferred compound is a prodrug, and it is useful as a therapeutic and / or preventive agent against influenza infectious diseases because it becomes a parent compound having a cap-dependent endonuclease inhibitory activity in vivo after administration. .
  • deuterated refers to the replacement of one or more hydrogens in a compound or group with deuterium; deuteration may be mono-, di-, poly- or fully substituted.
  • deuteration may be mono-, di-, poly- or fully substituted.
  • deuteration may be mono-, di-, poly- or fully substituted.
  • deuteration may be mono-, di-, poly- or fully substituted.
  • deuterated and “one or more deuterated” are used interchangeably.
  • non-deuterated compound means a compound containing a deuterium atomic proportion not higher than the natural deuterium isotope content (0.015%).
  • pharmaceutically acceptable salt means, within the scope of sound medical judgment, suitable for contact with human and lower animal tissues without excessive toxicity, irritation, allergies, etc., and with reasonable benefits / dangers Proportion of those salts.
  • Pharmaceutically acceptable salts are well known in the art. For example, the pharmaceutically acceptable salts detailed in Berge et al., J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include salts derived from suitable inorganic and organic acids and bases.
  • the compounds of the invention may be in amorphous or crystalline form.
  • the compounds of the invention may exist in one or more crystalline forms.
  • the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • crystalline form refers to the different arrangements of chemical drug molecules, which generally appear as the existing form of the drug substance in a solid state.
  • a drug can exist in multiple crystalline substance states, and different crystal forms of the same drug may have different dissolution and absorption in the body, which will affect the dissolution and release of the preparation.
  • crystalline form refers to the different arrangements of chemical drug molecules, which generally appear as the existing form of the drug substance in a solid state.
  • a drug can exist in multiple crystalline substance states, and different crystal forms of the same drug may have different dissolution and absorption in the body, which will affect the dissolution and release of the preparation.
  • the term "subject” includes, but is not limited to: a human (ie, a male or female of any age group, for example, a pediatric subject (eg, infant, child, adolescent) or an adult subject (eg, Young adults, middle-aged adults or older adults)) and / or non-human animals, such as mammals, for example, 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.
  • treatment includes the effect of a subject having a specific disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder, or condition. Or development of a condition ("therapeutic treatment”), and also includes effects that occur before a subject begins to suffer from a particular disease, disorder, or disease (“prophylactic treatment”).
  • an "effective amount" of a compound refers to an amount sufficient to elicit a biological response of interest.
  • the effective amount of a compound of the invention may vary depending on factors such as the biological objective, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age of the subject. Health conditions and symptoms. Effective amounts include therapeutically and prophylactically effective amounts.
  • a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit during the treatment of a disease, disorder, or condition, or to cause one or more to be associated with the disease, disorder, or condition. Symptoms are delayed or minimized.
  • a therapeutically effective amount of a compound refers to the amount of a therapeutic agent used alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder, or condition.
  • the term "therapeutically effective amount” may include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of other therapeutic agents.
  • a prophylactically effective amount of a compound used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent a disease , The number of recurrences of a disorder or condition.
  • a prophylactically effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other agents, that provides a preventative benefit in the prevention of a disease, disorder, or condition.
  • the term “prophylactically effective amount” may include an amount that improves overall prevention, or an amount that enhances the preventive efficacy of other preventive agents.
  • Combination and related terms refer to the simultaneous or sequential administration of a therapeutic agent of the invention.
  • a compound of the invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or simultaneously in a single unit dosage form with another therapeutic agent.
  • prodrug in the present specification refers to a compound represented by the formula (II) or a pharmaceutically acceptable salt thereof in the following reaction formula, and means that the drug is metabolized by a drug metabolizing enzyme under physiological conditions in the body, A compound that exhibits a cap-dependent endonuclease (CEN) inhibitory activity and / or a CPE inhibitory effect by a decomposition reaction caused by a hydrolase, gastric acid, intestinal bacteria, etc. .
  • CEN cap-dependent endonuclease
  • the prodrug represented by the formula (II) more preferably represents: bioavailability and / or AUC (area enclosed by blood concentration curve versus time axis) and / or C max (after administration
  • the compound with the highest plasma concentration) is a compound which is higher than the compound represented by formula (III).
  • the prodrug is efficiently absorbed into the body in the stomach and / or intestine, etc. after being administered to a living body (for example, oral administration), and thereafter converted into a compound represented by the formula (III), so it is preferable It exhibits a higher therapeutic and / or preventive effect than the compound represented by the formula (III).
  • the present invention provides a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent compound thereof:
  • P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 );
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 and Y 8 are each independently selected from hydrogen or deuterium;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each independently selected from hydrogen Or deuterium;
  • the additional condition is that the above compounds contain at least one deuterium atom.
  • the deuterium isotope content of deuterium at the deuterated position is at least 0.015% greater than the natural deuterium isotope content, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably Ground is greater than 95%, more preferably greater than 99%.
  • the deuterium isotope content in each deuterated position is at least 5%, more preferably greater than 10%, more preferably More than 15%, more preferably more than 20%, more preferably more than 15%, more preferably more than 25%, more preferably more than 30%, more preferably more than 35%, more preferably more than 40%, more preferably more than 45%, more preferably more than 50%, more preferably more than 55%, more preferably more than 60%, more preferably more than 65%, more preferably more than 70%, more preferably more than 75%, more preferably more than 80 %, More preferably more than 85%,
  • the compound of formula (I) contains at least one deuterium atom, more preferably contains two deuterium atoms, more preferably contains three deuterium atoms, more preferably contains four deuterium atoms, more preferably
  • the ground contains five deuterium atoms, more preferably six deuterium atoms, more preferably seven deuterium atoms, more preferably eight deuterium atoms, more preferably nine deuterium atoms, and more preferably ten deuteriums.
  • Atoms preferably containing eleven deuterium atoms, more preferably twelve deuterium atoms, more preferably thirteen deuterium atoms, more preferably fourteen deuterium atoms, and more preferably fifteen deuterium atoms Atoms, preferably containing sixteen deuterium atoms, more preferably containing seventeen deuterium atoms, more preferably containing eighteen deuterium atoms, more preferably containing nineteen deuterium atoms, and more preferably containing twenty deuterium atoms
  • the atom more preferably contains 21 deuterium atoms, more preferably contains 22 deuterium atoms, and more preferably contains 23 deuterium atoms.
  • Y 1, Y 2, Y 3, Y 4, Y 5, Y 6, Y 7 and Y 8 are each independently selected from hydrogen or deuterium
  • Y 1 is selected from hydrogen or deuterium
  • Y 2 It is selected from hydrogen or deuterium
  • Y 3 is selected from hydrogen or deuterium
  • Y 8 is selected from hydrogen or deuterium. More specifically, including Y 1 is hydrogen or Y 1 is deuterium, Y 2 is hydrogen or Y 2 is deuterium, Y 3 is hydrogen or Y 3 is deuterium, and so on, until Y 8 is hydrogen or Y 8 is deuterated.
  • R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14 And R 15 are each independently selected from hydrogen or deuterium "includes R 1 selected from hydrogen or deuterium, R 2 selected from hydrogen or deuterium, R 3 selected from hydrogen or deuterium, and so on, until R 15 is selected from hydrogen or deuterium Technical solutions. More particularly, comprising R 1 is R 1 is hydrogen or deuterium, R 2 is R 2 is hydrogen or deuterium, R 3 is R 3 is hydrogen or deuterium, and so on, until R 15 is R 15 is hydrogen or deuterium, Technical solutions.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or solvent thereof
  • a compound wherein P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 is hydrogen, and R 1 -R 15 are as defined above, with the additional Provided that the compound contains at least one deuterium atom.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or A solvent compound, wherein P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 is hydrogen, and R 1 -R 15 are as defined above,
  • P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 )
  • Y 1 -Y 8 is hydrogen
  • R 1 -R 15 are as defined above
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or A solvent compound, wherein P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 are hydrogen, R 1 and R 2 are hydrogen, and R 3- R 15 is each independently selected from hydrogen or deuterium, with the proviso that the compound contains at least one deuterium atom.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or A solvent compound, wherein P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 are hydrogen, R 1 and R 2 are hydrogen, and R 3 -R 15 are each independently selected from hydrogen or deuterium, with the proviso that R 7 -R 15 is at least one of deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 are hydrogen, R 1 -R 2 and R 4 -R 6 is hydrogen, and R 3 and R 7 -R 15 are each independently selected from hydrogen or deuterium, with the proviso that the compound contains at least one deuterium atom.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 are hydrogen, R 1 -R 2 and R 4 -R 6 is hydrogen, and R 3 and R 7 to R 15 are each independently selected from hydrogen or deuterium, with the proviso that at least one of R 7 to R 15 is deuterium.
  • P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 )
  • Y 1 -Y 8 are hydrogen
  • R 1 -R 2 and R 4 -R 6 is hydrogen
  • R 3 and R 7 to R 15 are each independently selected from hydrogen or deuterium, with the proviso that at least one of R 7 to R 15 is deuterium.
  • R 7 -R 10 are the same.
  • R 7 -R 10 are deuterium.
  • R 7 -R 10 are hydrogen.
  • R 11 -R 12 are the same.
  • R 11 -R 12 are deuterium.
  • R 11 -R 12 are hydrogen.
  • R 13 -R 15 are the same.
  • R 13 -R 15 are deuterium.
  • R 13 -R 15 are hydrogen.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 are hydrogen, R 1 -R 2 and R 4 -R 6 is hydrogen, R 3 is deuterium, and R 7 to R 15 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 are hydrogen, R 1 -R 2 and R 4 -R 6 is hydrogen, R 3 is deuterium, and R 7 to R 15 are each independently selected from hydrogen or deuterium, with the proviso that at least one of R 7 to R 15 is deuterium.
  • P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 )
  • Y 1 -Y 8 are hydrogen
  • R 1 -R 2 and R 4 -R 6 is hydrogen
  • R 3 is deuterium
  • R 7 to R 15 are each independently selected from hydrogen or deuterium, with the proviso that at least one of R 7 to R 15 is
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 is hydrogen, R 1 -R 2 and R 4 -R 6 are Hydrogen, R 3 is deuterium, and R 7 to R 15 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 is hydrogen, R 1 -R 2 and R 4 -R 6 are Hydrogen, R 3 is deuterium, and R 7 to R 15 are each independently selected from hydrogen or deuterium, with the proviso that at least one of R 7 to R 15 is deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 are hydrogen, R 1 -R 2 and R 4 -R 6 is hydrogen, R 7 to R 10 are deuterium, and R 3 and R 11 to R 15 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 is hydrogen, R 1 -R 2 and R 4 -R 6 are Hydrogen, R 7 -R 10 are deuterium, and R 3 , R 11 -R 15 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 are hydrogen, R 1 -R 2 and R 4 -R 6 is hydrogen, R 3 and R 7 -R 10 are deuterium, and R 11 -R 15 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 is hydrogen, R 1 -R 2 and R 4 -R 6 are Hydrogen, R 3 and R 7 -R 10 are deuterium, and R 11 -R 15 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 are hydrogen, R 1 -R 2 and R 4 -R 6 is hydrogen, R 13 to R 15 are deuterium, and R 3 and R 7 to R 12 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 are hydrogen, R 1 -R 2 and R 4 -R 6 is hydrogen, R 3 and R 13 -R 15 are deuterium, and R 7 -R 12 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 is hydrogen, R 1 -R 2 and R 4 -R 6 are Hydrogen, R 13 -R 15 are deuterium, and R 3 , R 7 -R 12 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 is hydrogen, R 1 -R 2 and R 4 -R 6 are Hydrogen, R 3 and R 13 -R 15 are deuterium, and R 7 -R 12 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 are hydrogen, R 1 -R 2 and R 4 -R 6 is hydrogen, R 7 -R 10 and R 13 -R 15 are deuterium, and R 3 and R 11 -R 12 are each independently selected from hydrogen or deuterium.
  • P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 )
  • Y 1 -Y 8 are hydrogen
  • R 1 -R 2 and R 4 -R 6 is hydrogen
  • R 7 -R 10 and R 13 -R 15 are deuterium
  • R 3 and R 11 -R 12 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 is hydrogen, R 1 -R 2 and R 4 -R 6 are Hydrogen, R 7 -R 10 and R 13 -R 15 are deuterium, and R 3 and R 11 -R 12 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from H or -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 are hydrogen, R 1 -R 2 and R 4 -R 6 is hydrogen, R 3 , R 7 -R 10 and R 13 -R 15 are deuterium, and R 11 -R 12 are each independently selected from hydrogen or deuterium.
  • the invention relates to a compound of formula (I), or a tautomer, stereoisomer, prodrug, crystalline form, pharmaceutically acceptable salt, hydrate or Solvent compound, wherein P is selected from -C (R 11 R 12 ) OC (O) OC (R 13 R 14 R 15 ), Y 1 -Y 8 is hydrogen, R 1 -R 2 and R 4 -R 6 are Hydrogen, R 3 , R 7 -R 10 and R 13 -R 15 are deuterium, and R 11 -R 12 are each independently selected from hydrogen or deuterium.
  • the compound has any one of the following structures, or a pharmaceutically acceptable salt thereof, but is not limited to the following structures:
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in multiple stereoisomeric forms, for example, enantiomeric and / or diastereomeric forms.
  • the compounds of the invention may be individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, Includes racemic mixtures and mixtures rich in one or more stereoisomers.
  • Isomers can be separated from a mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be obtained by Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • organic compounds can form complexes with solvents that react in the solvent or precipitate or crystallize from the solvent. These complexes are called “solvates”. When the solvent is water, the complex is called a "hydrate”. The invention encompasses all solvates of the compounds of the invention.
  • solvate refers to the form of a compound or a salt thereof that is generally combined by a solvolysis reaction with a solvent. This physical association may include hydrogen bonding.
  • Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, and the like.
  • the compounds described herein can be prepared, for example, in crystalline form, and can be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • the "solvate” includes a solvate in a solution state and a separable solvate. Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined.
  • a hydrate of a compound may be represented, for example, by the general formula R ⁇ x H 2 O, where R is the compound, and x is a number greater than 0.
  • a given compound can 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)).
  • 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)
  • 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 an amorphous or crystalline form (polymorphic form).
  • the compounds of the invention may exist in one or more crystalline forms.
  • the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • polymorph refers to a crystalline form (or a salt, hydrate, or solvate) of a compound in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to a crystalline form prevailing.
  • Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present invention also includes isotopically-labeled compounds, which are equivalent to those described in formula (I), but one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature.
  • isotopes that can be introduced 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 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
  • Compounds of the present invention containing the aforementioned isotopes and / or other isotopes of other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention.
  • Certain isotopically-labeled compounds of the invention such as those incorporating radioisotopes (such as 3 H and 14 C), can be used in drug and / or substrate tissue distribution assays.
  • Thallium, i.e. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect.
  • An isotope-labeled compound of the formula (I) of the present invention and a prodrug thereof can generally be prepared in such a manner that, when performing the processes disclosed in the following schemes and / or examples and preparation examples, non-isotope-labeled reagents are replaced with readily available isotopically-labeled reagents. Labeled reagent.
  • compositions preparations and kits
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of an active ingredient.
  • the pharmaceutical composition comprises a therapeutically effective amount of an active ingredient.
  • the pharmaceutical composition comprises a prophylactically effective amount of an active ingredient.
  • a pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compounds formulated together.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin ), Buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides 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 substance, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-embedded
  • kits eg, pharmaceutical packaging.
  • the 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 Suitable container).
  • the provided kit may also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and / or other therapeutic agent.
  • a compound of the invention and other therapeutic agents are provided in a first container and a second container to form a unit dosage form.
  • parenteral administration includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, and sternum , Cerebrospinal spinal membrane administration, intralesional 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 .
  • a compound provided herein is administered to a subject at risk of developing the condition, typically based on a doctor's recommendation and under the supervision of a doctor, at a dosage level as described above.
  • Subjects at risk for developing a particular disorder typically include subjects with a family history of the disorder, or those subjects that have been determined by genetic testing or screening to be particularly sensitive to the development of the disorder.
  • the pharmaceutical composition may be administered by bolus, for example, to rapidly increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active ingredient, for example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, whereas a bolus delivered directly to a vein (e.g., by IV intravenous drip) can be more Rapid delivery allows the concentration of the active ingredient in the blood to rise rapidly to an effective level.
  • the pharmaceutical composition may be administered in the form of a continuous infusion, for example, by IV drip infusion, thereby providing a steady state concentration of the active ingredient in the subject's body.
  • a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
  • Oral compositions can take the form of a liquid solution or suspension in bulk or a powder in bulk. However, more generally, in order to facilitate accurate dosage administration, the composition is provided in unit dosage form.
  • unit dosage form means a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined number of active substances and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect.
  • Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions.
  • the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remainder is each useful for forming a desired administration form A carrier or excipient and processing aid.
  • a representative regimen is one oral dose per day. Using these dosing modes, each dose provides about 0.01 to about 50 mg / kg of a compound of the invention, and preferred doses each provide about 10 to about 40 mg / kg, especially about 10 to about 30 mg / kg.
  • transdermal doses are usually 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 about 0.5 to about 15% by weight.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous vehicles and buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may include, for example, any of the following components, or compounds having similar properties: a binder, such as microcrystalline cellulose, tragacanth, or gelatin; an excipient, such as starch or lactose, a disintegrant, For example, alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as mint, water Methyl salicylate or orange flavor.
  • a binder such as microcrystalline cellulose, tragacanth, or gelatin
  • an excipient such as starch or lactose, a disintegrant, 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.
  • 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 a topical ointment or cream containing an active ingredient.
  • the active ingredient When formulated as an ointment, the active ingredient is typically combined with a paraffin or a 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 generally include other components for enhancing the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by the present invention.
  • transdermal administration can be achieved using a reservoir or porous membrane type, 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 Remington's Pharmaceuticals, Science, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, and are incorporated herein by reference.
  • the compounds of the invention may also be administered in a sustained release form or from a sustained release delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention also relates to a pharmaceutically acceptable formulation of a compound of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ -, and ⁇ -cyclodextrin consisting of 6, 7, and 8 ⁇ -1,4-linked glucose units, respectively, which optionally include one on the linked sugar moiety Or more substituents, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted.
  • the cyclodextrin is a sulfoalkyl ether ⁇ -cyclodextrin, for example, a sulfobutyl ether ⁇ -cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation includes hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • compound of the present invention refers to a compound represented by formula (I).
  • the term also includes tautomers, stereoisomers, prodrugs, crystalline forms, pharmaceutically acceptable salts, hydrates or solvent compounds of the compound of formula (I).
  • the compounds of the present invention are anti-influenza virus drugs and have inhibitory activity on dependent endonucleases, so they can be used to treat and / or prevent epidemic infectious diseases.
  • Influenza viruses are negative-sense single-stranded RNA viruses and are members of the orthomyxoviridae family. There are currently three influenza viruses: influenza virus A, influenza virus B, and influenza virus C.
  • Influenza virus A has a host-derived lipid membrane that contains hemagglutinin, neuraminidase, and M2 proteins protruding from the surface of the virus. Influenza virus A has been further classified based on hemagglutinin (H or HA) and neuraminidase (N). There are approximately 16 H antigens (H1 to H16) and 9 N antigens (N1 to N9).
  • Influenza virus A includes several subtypes, including H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N7, H7N9, H9N2, and H10N7.
  • Influenza virus polymerase is a heterotrimer composed of the following three subunits: polymerase acid (PA), polymerase base 1 (PB1), and polymerase base 2 (PB2). In the nucleus of infected cells, this polymerase is responsible for the replication and transcription of viral RNA.
  • the PA subunit contains an endonuclease active site. The endonuclease activity of PA cleaves the cellular mRNA, which is then used as a primer by the PB1 subunit for viral mRNA synthesis.
  • an effective amount of a compound of the invention or a pharmaceutical composition described herein can be used to treat and / or ameliorate an influenza virus infection. In other embodiments, an effective amount of a compound of the invention or a pharmaceutical composition described herein can be used to prevent influenza virus infection.
  • an effective amount of a compound of the invention or a pharmaceutical composition described herein can be used to inhibit the replication of an influenza virus. In other embodiments, an effective amount of a compound of the invention or a pharmaceutical composition described herein can be used to inhibit the influenza polymerase complex. In other embodiments, an effective amount of a compound of the invention or a pharmaceutical composition described herein can be used to inhibit and / or reduce the activity of a cap-dependent endonuclease. In other embodiments, an effective amount of a compound of the invention or a pharmaceutical composition described herein can be used to inhibit and / or reduce the ability of an endonuclease to cleave mRNA.
  • influenza virus infection may be an influenza A virus infection.
  • influenza virus infection may be an influenza B virus infection.
  • influenza virus infection may be an influenza C virus infection.
  • compounds of the invention are useful for treating and / or alleviating one or more subtypes of influenza.
  • the compounds of the invention can be used to treat H1N1 and / or H3N2.
  • the compounds of the invention can be used to treat H2N2, H5N1 and / or H7N9.
  • the compounds of the invention are effective against more than one subtype of influenza.
  • the compounds of the invention are effective against 2, 3, 4, and / or 5 or more subtypes of influenza.
  • an effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention can be used to treat and / or alleviate upper respiratory tract infection due to (direct and / or indirect) influenza virus infection. In some embodiments, an effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention can be used to treat and / or alleviate a lower respiratory virus infection due to (direct and / or indirect) influenza virus infection.
  • an effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention can be used to treat and / or alleviate one or more symptoms of an influenza virus infection (e.g., cough, sore throat, headache, nasal congestion, Fever or chills, muscles or joints to pain, fatigue, etc.).
  • an effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention can be used to treat and / or alleviate bronchiolitis and / or tracheobronchitis due to an influenza virus infection.
  • an effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention can be used to treat and / or alleviate pneumonia due to an influenza virus infection.
  • an effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention can be used to reduce the severity of one or more symptoms of an influenza infection.
  • symptoms include, but are not limited to, the following, fever, chills, cough, sore throat, runny nose, stuffy nose, muscle soreness, physical pain, headache, fatigue, vomiting, and / or diarrhea.
  • an effective amount of a compound of the invention is an amount effective to reduce the viral load compared to the viral load prior to administration of a compound of formula (I). For example, where the viral load is detected before the compound of formula (I) is administered, and again after the start of a treatment regimen using the compound of formula (I) (eg, 1-2 days after the start of treatment).
  • an effective amount of a compound of the invention may be an amount effective to reduce viral load to less than about 10E4TCID50 / mL. In some embodiments, an effective amount of a compound of the present invention is effective to achieve a virus titer in a nasal / pharyngeal or nasal rinse sample of an individual compared to the viral load prior to administration of a compound of formula (I) Decreased amount: about 1.5-log to about 2.5-log, or about 3-log to about 4-log.
  • the viral load is detected prior to administering a compound of formula (I)
  • the viral load is detected prior to using a compound of formula (I)
  • a treatment regimen using a compound of formula (I) is started (e.g., , 1-2 days after the start of treatment).
  • the compounds of the invention can produce one or more overall quality of life health compared to untreated individuals, such as a greatly reduced duration of disease and reduced severity of disease compared to untreated individuals , Reduced time to return to normal health and normal activity, and reduced time to relieve one or more symptoms of a viral infection.
  • a compound of the invention can cause a reduction in the length and / or severity of one or more symptoms associated with a viral infection compared to an untreated individual.
  • the compounds of the invention can cause one or more of the following related to viral infections, including but not limited to otitis media (ear inflammation) sinusitis, bronchitis, and pneumonia, compared to untreated individuals. Reduced complications.
  • a compound of the invention can cause a decrease in viral replication by at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 75, 100 or more times relative to the pre-treatment levels of the individual, As determined after the start of the treatment regimen.
  • drug resistance refers to a virus strain that exhibits a delay, reduction, and / or zero response to one or more therapeutic agents.
  • drug resistance refers to a virus strain that exhibits a delay, reduction, and / or zero response to one or more therapeutic agents.
  • the viral load of an individual infected with a drug-resistant virus can be reduced to a lesser extent than the amount of viral load shown by an individual infected with a non-resistant strain.
  • a compound of the invention may be administered to an individual infected with an influenza virus that is resistant to one or more different anti-influenza agents (eg, amantadine and / or oseltamivir).
  • a compound of the invention can be administered to an individual infected with an influenza virus that is anti-M2 protein inhibitor.
  • the development of drug-resistant influenza strains is delayed compared to the development of influenza strains against other influenza drugs, but when individuals are treated with a compound of the invention.
  • a compound of the invention can reduce the percentage of individuals experiencing complications from an influenza virus infection compared to the percentage of individuals experiencing complications using oseltamivir treatment.
  • the percentage of individuals treated with a compound of formula (I) experiencing complications is 10%, 20%, 30%, 40%, 60%, 70%, 80%, and 90% of individuals treated with oseltamivir.
  • a compound of the invention can reduce the percentage of individuals experiencing complications from an influenza virus infection compared to the percentage of individuals experiencing complications using Baloxavir marboxil treatment.
  • the percentage of individuals treated with a compound of formula (I) experiencing complications is 10%, 20%, 30%, 40%, 60%, 70%, 80%, and 90% of individuals treated with Baloxavir® marboxil.
  • a compound of the invention can be used in combination with one or more additional agents.
  • a compound of the invention can be used in combination with one or more agents currently used in routine care standards for the treatment of influenza.
  • the additional agent may be amantadine (adamantan-1-amine, Symmetrel), amantadine (Flumadine), zanamivir (Relenza), and oseltamivir (Tamiflu).
  • additional agents include but are not limited to: neuraminidase inhibitors, M2 protein inhibitors, polymerase inhibitors, PB2 inhibitors, paramivir, laninamivir, fapilavir, laninami Vesinate, influenza enzyme (DAS181, NexBio), ADS-8902 (amantadine HCl / oseltamivir / ribavirin, Adamas Pharmaceuticals), immunomodulators (e.g., type I interferon), beprost Vegetarian, ribavirin, etc.
  • a compound of the invention may be administered in a single pharmaceutical composition with one or more additional agents.
  • a compound of the invention can be administered with one or more additional agents as two or more separate pharmaceutical compositions.
  • a compound of the invention can be administered in one pharmaceutical composition, and at least one additional agent can be administered in a second pharmaceutical composition. If there are at least two additional agents, one or more of the additional agents may be present in the first pharmaceutical composition comprising a compound of the invention, and at least one of the other additional agents may be present in the first In two pharmaceutical compositions.
  • the order of administration of a compound of the invention with one or more additional agents may vary. In some embodiments, a compound of the invention may be administered before all additional agents.
  • a compound of the invention may be administered before at least one additional agent. In still other embodiments, a compound of the invention may be administered simultaneously with one or more additional agents. In still other embodiments, a compound of the invention may be administered after administration of at least one additional agent. In some embodiments, a compound of the invention may be administered after all additional agents have been administered.
  • a combination of a compound of the invention in combination with one or more additional agents can cause additive effects.
  • a combination of a compound of the invention in combination with one or more additional agents may result in a synergistic effect.
  • a combination of a compound of the invention in combination with one or more additional agents can result in a strong synergistic effect.
  • the combination of a compound of the invention in combination with one or more additional agents is not antagonistic.
  • the term “antagonistic” means that the activity of a combination of compounds is lower when the activity of each compound is measured individually (ie, as a single compound) compared to the sum of the activities of the compounds in the combination.
  • the term “synergistic effect” means that when the activity of each compound is measured individually, the activity of a combination of compounds is greater than the sum of the individual activities of the compounds in the combination.
  • the term “cumulative effect” means that when the activity of each compound is measured individually, the activity of a combination of compounds is approximately equal to the sum of the individual activities of the compounds in the combination.
  • a potential advantage of using a compound of the invention in combination with one or more additional agents as described above, including pharmaceutically acceptable salts and prodrugs thereof, may be: when combined with compounds of formula (I) or Pharmacologically acceptable salts thereof are effective in treating one or more additional agents (including their pharmaceutically acceptable salts and prodrugs) when the same is required to achieve the same therapeutic results when administered as disclosed herein.
  • the required amount of one or more additional agents, including their pharmaceutically acceptable salts and prodrugs, for a disease state e.g., influenza
  • the additional agents can be present in smaller amounts when administered in combination with a compound of the invention.
  • Another potential advantage of using a compound of the present invention in combination with one or more additional agents as described above, including its pharmaceutically acceptable salts and prodrugs, is the barrier phase when the compound is administered as a monotherapy In contrast, the use of two or more compounds with different mechanisms of action can establish a higher barrier to drug-resistant virus strains.
  • the compounds of the invention can be prepared using known organic synthesis techniques, and can be synthesized according to any of a number of possible synthetic routes, such as those in the schemes below.
  • the reaction for preparing the compound of the present invention can be performed in a suitable solvent, and a person skilled in the art of organic synthesis can easily select a solvent.
  • Suitable solvents may be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is performed (e.g., a temperature ranging from the solvent freezing temperature to the solvent boiling point temperature).
  • a given reaction may be performed in one solvent or a mixture of more than one solvent.
  • the skilled person can select a solvent for a specific reaction step depending on the specific reaction step.
  • the preparation of the compounds of the invention may involve the protection and removal of different chemical groups. Those skilled in the art can easily determine whether protection and removal of protection are needed and the choice of an appropriate protecting group.
  • the chemical properties of the protecting groups can be found, for example, in Wuts and Greene, Protective Groups, Organic Synthesis, 4th Edition, John Wiley & Sons: New Jersey, (2006), which is incorporated herein by reference in its entirety.
  • the compound of the present invention can be prepared into a single stereo by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. isomer.
  • Enantiomeric resolution can be performed using diastereomeric derivatives of the compounds of the present invention, with preferentially dissociable complexes (e.g., crystalline diastereomeric salts).
  • Diastereomers have significantly different physical properties (eg, melting points, boiling points, solubility, reactivity, etc.) and can be easily separated by the advantages of these dissimilarities.
  • Diastereomers can be separated by chromatography, preferably by separation / resolution techniques based on differences in solubility. The optically pure enantiomers are then recovered by any practical means without racemization, along with the resolving reagents.
  • a more detailed description of techniques suitable for resolution of stereoisomers of compounds starting from racemic mixtures can be found in Jean Jacques, Andre Collet, Samue1H. Wilen, "Enantiomers, Racemates and Resolution” ("Enantiomers, Racemates and Resolutions "), John Wiley And Sons, Inc., 1981.
  • the reaction can be monitored according to any suitable method known in the art.
  • it may be by spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g. 1 H or 13 C), infrared (IR) spectroscopy, spectrophotometry (e.g. UV-visible light), mass spectrometry (MS)) or by chromatography Methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) to monitor product formation.
  • NMR nuclear magnetic resonance
  • IR infrared
  • spectrophotometry e.g. UV-visible light
  • MS mass spectrometry
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • T3P propylphosphonic anhydride
  • PPT P-toluenesulfonic acid pyridine salt
  • the compound of formula (I) of the present invention can be prepared by the following reaction scheme 1:
  • R 3 and R 7 -R 15 are each independently selected from hydrogen or deuterium, and R 3 and R 7 -R 15 are not all hydrogen.
  • the compound of formula (C) can be obtained by using a compound of formula (A) and a compound of formula (B) in a suitable condensing agent DMF, DMA, NMP, THF, ethyl acetate, butyl acetate, dioxane and other solvents or a mixture of these solvents) and a suitable base (for example, sodium carbonate, potassium carbonate, cesium carbonate, etc.) are reacted.
  • a suitable condensing agent for example, sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • the reaction is carried out in a temperature range of about 10 ° C to 80 ° C, and may be completed in about 1-24 hours.
  • the compound of the formula (I-1) can be synthesized by removing the protective group Bn from the compound of the formula (C) (for example, it can be carried out by using Protective Groups Organic Science, Theodora W Green (the general method described in John Wiley & Sons, etc.).
  • the compound (I-2) can be converted into an ether group by a general method (e.g., a compound of the formula (I-1) and a compound of the formula (D) in the presence of a suitable base (e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.) (e.g., , Can be obtained using the methods described in Protective Groups, Organics, Theodora, Green (John Wiley & Sons), Prog. Med, 5: 2157-2161 (1985), and Supplementary Library-"The The Word's Knowledge", etc.) Compound of formula (I-2).
  • a suitable base e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • the compound of formula (A-1) can be prepared by the following reaction scheme 2:
  • the compound of formula (A-2) can be prepared by the following reaction scheme 3:
  • the preparation route and synthesis method of the compound of the formula (A-2) are the same as those of the compound of the formula (A-1), except that the deuterated compound F-2 is used instead of the compound F-1.
  • the preparation route and synthetic method of the compound of formula (B-1) have been disclosed in WO2017 / 221869A1.
  • the contract method of the compound of formula (B-2) differs from that of the compound of formula (B-1) in that the last step replaces NaBH 4 with a deuterated metal reducing agent.
  • the synthetic route is as follows:
  • the synthetic route is as follows:
  • LiAlD 4 (7.2 g, 170.9 mmol) was slowly added to a solution of compound 10 (10.0 g, 85.6 mmol) in tetrahydrofuran (150 ml). After the addition, the reaction solution was heated to reflux for 10 h. After the reaction was completed, the temperature was lowered to 0 ° C, and then the reaction was quenched by adding water. The diatomite was filtered, and the filtrate was directly spin-dried to obtain 4.4 g of a liquid, which was directly used in the next step.
  • the synthetic route is as follows:
  • NaBH 4 (0.4 g, 11.5 mmol) was added to a solution of compound 22 (2.0 g, 7.6 mmol) in isopropanol (20 ml), and then the reaction was continued for 1 h. The reaction was then quenched with 1M hydrochloric acid, extracted with dichloromethane (30 ml x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain 1.8 g of a gray solid product.
  • NaBD 4 (0.5 g, 11.5 mmol) was added to a solution of compound 22 (2.0 g, 7.6 mmol) in isopropanol (20 ml), and the reaction was continued for 1 h. The reaction was then quenched with 1M hydrochloric acid, extracted with dichloromethane (30 ml x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and spin-dried to obtain 1.8 g of a gray solid product.
  • HLM Human liver microsome
  • RLM Rat liver microsome
  • NADPH NADH
  • Preparation of stock solution Weigh out a certain amount of the powder of the example compound and the reference compound, and dissolve them to 5mM with DMSO.
  • NADPH regeneration system solution (containing 6.5mM NADP, 16.5mM G-6-P, 3U / mL G-6-PD, 3.3mM magnesium chloride), and place on wet ice before use.
  • stop solution acetonitrile solution containing 50ng / mL propranolol hydrochloride and 200ng / mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer solution (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg / mL.
  • phosphate buffer solution pH 7.4
  • Determination of metabolic stability 300 ⁇ L of pre-cooled stop solution was added to each well of a 96-well deep well plate, and placed on ice as a stop plate. Place the 96-well incubation plate and NADPH regeneration system in a 37 ° C water bath, shake at 100 rpm, and pre-incubate for 5 minutes. Take 80 ⁇ L of the incubation solution from each well of the incubation plate and add it to the termination plate, mix well, and add 20 ⁇ L of the NADPH regeneration system solution as a 0min sample. Add 80 ⁇ L of NADPH regeneration system solution to each well of the incubation plate, start the reaction, and start timing.
  • the reaction concentration of the corresponding compound was 1 ⁇ M, and the protein concentration was 0.5 mg / mL.
  • 100 ⁇ L of each reaction solution was taken, added to the stop plate, and the reaction was stopped by vortexing for 3 minutes.
  • the stop plate was centrifuged at 5000 ⁇ g for 10 min at 4 ° C. Take 100 ⁇ L of the supernatant into a 96-well plate pre-added with 100 ⁇ L of distilled water, mix well, and use LC-MS / MS for sample analysis.
  • the compounds of the present invention and the compounds without deuteration were tested and compared simultaneously to evaluate their metabolic stability in human and rat liver microsomes.
  • the undeuterated compound Baloxavir marboxil was used as a reference.
  • the compounds of the present invention can significantly improve metabolic stability by comparison with the undeuterated compound Baloxavir marboxil.
  • Table 1 The results of liver microsomal experiments with the compounds of the representative examples are shown in Table 1 below.
  • Rats were raised on a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide.
  • Orbital blood was collected at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were anesthetized briefly after inhaling ether, and 300 ⁇ L of blood samples were collected in test tubes.
  • the test tube contained 30 ⁇ L of a 1% heparin salt solution. Prior to use, test tubes were dried at 60 ° C overnight. After blood samples were collected at the last time point, rats were sacrificed after ether anesthesia.
  • the blood sample was centrifuged at 5000 rpm at 4 ° C for 5 minutes to separate the plasma from the red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube with the name and time point of the compound. Plasma was stored at -80 ° C before analysis. LC-MS / MS was used to determine the concentration of a compound of the invention in plasma. Pharmacokinetic parameters were calculated based on the blood drug concentration of each animal at different time points.
  • CPE cytopathic
  • MDCK cells were seeded in a 384-well plate at a density of 2000 cells / well, and cultured at 37 ° C, 5% CO 2 overnight. Compounds and virus were added the next day, and cells (no virus infection) and virus infection controls were set. The final cell culture DMSO concentration was 0.5%. The cells were cultured at 37 ° C and 5% CO 2 for 5 days until the disease rate of virus control wells reached 80-95%. The cytotoxicity test was the same as the antiviral test, but there was no virus infection. Cell viability was measured using CCK-8 reagents, and raw data was used to calculate antiviral activity and cytotoxicity of the compounds. GraphPad Prism software application Compound dose response curve analysis and calculation of EC 50 values of 50 and CC.
  • the compounds of the present invention and the compounds without deuteration were tested and compared at the same time to evaluate their antiviral activity and cytotoxicity.
  • the results show that the compound of the present invention exhibits a higher CPE inhibitory effect than the non-deuterated compound Baloxavir marboxil, and therefore the compound of the present invention can more effectively inhibit the cap-dependent endonuclease (CDE) in influenza virus, Thereby play a role in inhibiting virus replication.
  • CDE cap-dependent endonuclease

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Abstract

本发明提供了一种氘取代的多环性吡啶酮化合物及其前药及包含该化合物的组合物及其用途，所述的氘取代的多环性吡啶酮化合物如式(I)所示化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物。本发明化合物和组合物表现出帽依赖性核酸内切酶抑制活性且具有更优良的药代动力学性质。

Description

一种取代的多环性吡啶酮化合物及其前药 技术领域
本发明涉及一种取代的多环性吡啶酮化合物及其前药及包含该化合物的组合物及其用途。更具体而言，本发明涉及某些氘取代的(((12aR)-12-((11S)-7,8-二氟-6,11-二氢二苯并(B,E)噻庚英-11-基)-6,8-二氧代-3,4,6,8,12,12a-六氢-1H-(1,4)噁嗪(3,4-C)吡啶并(2,1-F)(1,2,4)三嗪-7-基)氧基)甲基碳酸甲酯及其母药，这些氘取代的化合物及其组合物表现出帽依赖性核酸内切酶(Cap-dependent endonuclease)抑制活性，且这些氘取代的化合物具有更优良的药代动力学性质。
背景技术
流行性感冒简称为流感(influenza或flu)是由流行性感冒病毒的感染引起的急性呼吸道传染病，已经成为致死率最高的病毒性传染疾病。65岁以上的老人、2岁以下的儿童及患有慢性呼吸道疾病及心血管疾病的人群更容易发生流感并发症，因此是流感的高危人群。在20世纪，有三次大规模流感爆发，1918年西班牙流感，1957年亚洲流感和1968年香港流感。其中，西班牙流感(H1N1)是毁灭性的，死亡人数超过了第一次世界大战，感染了世界30％的人口，造成了至少2000万人死亡。其它两次流感爆发分别是H2N2和H3N2型流感病毒引起的，虽然规模较小，但也导致了上百人死亡。2009年出现的一株新型的甲型H1N1流感病毒引起了21世纪的第一次流感大流行，研究发现这种病毒的基因含有人类、猪以及禽类等多种流感病毒的基因序列，是一种重组病毒。在短短几个月时间内，该病毒迅速蔓延到全球，引起了极大的恐慌。世界卫生组织将警戒由三级，多次提升，直至为最高的六级。
流感病毒根据核蛋白和基质蛋白抗原特性的不同，分为甲、乙、丙(也称为A、B、C)三种类型。甲型流感病毒的宿主范围最广，能够感染人、猪、马和禽类，且致病力强，能够引起世界流感大流行，对人类的危害最大；乙型流感病毒主要感染人和猪，致病能力较低，能引起流感局部爆发；丙型流感病毒仅感染婴幼儿和免疫力低下的人群，很少引起流行，危害相对较小。
作为抗流行性感冒药，公知的主要有：(1)金刚烷胺(Amantadine)和金刚乙胺(Rimantadine)是较早上市的两种抗流感病毒药物，主要通过阻断病毒的M2离子通道，抑制病毒脱壳而发挥抗病毒作用。(2)磷酸奥司他韦(Oseltamivir Phosphate，商品名：达菲(Tamiflu)，罗氏研制)，扎那米韦(Zanamivir，商品名：依乐韦(Relenza)，葛兰素史克研制)，是神经氨酸酶抑制剂，具有较高的疗 效及较好的安全性和耐受性，是目前抗流感的首选药物。然而，有耐药性菌株的出现、副作用的问题，又有病原性或致死性较高的新型流行性感冒病毒世界大流行等顾虑，因此期望开发出新机理的抗流行性感冒药。
关于作为源自流行性感冒病毒的酶的帽依赖性核酸内切酶，由于其对于病毒增殖而言是必须的，且具有宿主所不具有的病毒特异性酶活性，故而认为该帽依赖性核酸内切酶适于抗流行性感冒药的目标物。流行性感冒病毒的帽依赖性内切酶是生成以宿主mRNA前体为底物且包含帽结构的9～13个碱基(帽结构的碱基并不包含于上述碱基数量中)的片段的核酸内切酶活性。该片段作为病毒RNA聚合酶的引子发挥功能，用于编码病毒蛋白质的mRNA的合成。即，认为抑制帽依赖性核酸内切酶的物质通过抑制病毒mRNA的合成而抑制病毒蛋白质的合成，结果抑制病毒增殖。
Baloxavir Marboxil(又名S-033188，化学名称为(((12aR)-12-((11S)-7,8-二氟-6,11-二氢二苯并(B,E)噻庚英-11-基)-6,8-二氧代-3,4,6,8,12,12a-六氢-1H-(1,4)噁嗪(3,4-C)吡啶并(2,1-F)(1,2,4)三嗪-7-基)氧基)甲基碳酸甲酯，其具有以下结构)是日本盐野义制药株式会社(Shionogl&Co.,Ltd)开发一款首创(first-in-class)、单剂量实验性口服药物，旨在抑制流感病毒中帽依赖性核酸内切酶，起到抑制病毒复制的作用。2016年2月，盐野义将日本和台湾以外地区的开发权转让给了罗氏。Baloxavir Marboxil已于2018年2月23日在日本通过加速审批并成功上市用于治疗成人和儿童患者的甲型和乙型流感，商品名为Xofluza。2018年6月，罗氏宣布美国FDA已受理Baloxavir Marboxil的新药申请并授予了优先审查资格，预计将在2018年12月24日作出审查决定。临床试验表明Baloxavir Marboxil只需单剂量(每次40或80mg，一天一次，服用1天)给药，就能减少流感症状的持续时间，并在一天内显著减少病毒脱落，相比奥司他韦(每次75mg，一天二次，服用5天)具有更强大的抗病毒疗效，在接受治疗后的第一天，50％以上的患者(包括儿童)体内的病毒滴度下降至检测限以下，除此之外，对甲流(H5N1或H7N9)也非常有效。
Figure PCTCN2019097614-appb-000001
已知较差的吸收、分布、代谢和/或排泄(ADME)性质是导致许多候选药物临床试验失败的主要原因。当前上市的许多药物也由于较差的ADME性质限制了它们的应用范围。药物的快速代谢会导致许多本来可以高效治疗疾病的药物由于过快的从体内代谢清除掉而难以成药。频繁或高剂量服 药虽然有可能解决药物快速清除的问题，但该方法会带来诸如病人依从性差、高剂量服药引起的副作用及治疗成本上升等问题。另外，快速代谢的药物也可能会使患者暴露于不良的毒性或反应性代谢物中。
虽然Baloxavir Marboxil可有效治疗流行性感冒，但是该领域仍存在严重的临床未满足需求，发现具有具有很好的口服生物利用度且有成药性的新型化合物还是具有挑战性的工作。因此，本领域仍需开发具有抑制帽依赖性核酸内切酶活性和/或更好地药代动力学的化合物，本发明提供了这样的化合物。
发明内容
针对以上技术问题，本发明公开了一种新型的氘取代的多环性吡啶酮衍生物及其前药及包含该化合物的组合物及其用途，其具有更好地抑制帽依赖性核酸内切酶活性，特别是具有更好地药代动力学性能和/或口服生物利用度。
对此，本发明采用以下技术方案：
本发明的第一方面，提供了式(I)化合物：
Figure PCTCN2019097614-appb-000002
其中，
P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)；
Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢或氘；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15各自独立地选自氢或氘；
附加条件是，上述化合物至少含有一个氘原子；
或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物。
在另一方面，本发明提供了含有本发明化合物或其互变异构体、立体异构体、前药、药学上可接受的盐、晶型、水合物或溶剂化合物和药学上可接受的赋形剂的药物组合物。在具体实施方案中，本发明化合物或其互变异构体、立体异构体、前药、药学上可接受的盐、晶型、水合物或溶剂化合物以有效量提供在所述药物组合物中。在具体实施方案中，本发明化合物或其互变异构体、立体异构体、前药、药学上可接受的盐、晶型、水合物或溶剂化合物以治疗有效量提供。在具体实施方案中，本发明化合物或其互变异构体、立体异构体、前药、药学上可接受的盐、晶型、水合物或溶剂化合物以预防有效量提供。
在另一方面，本发明提供了一种如上所述的药物组合物或其互变异构体、立体异构体、前药、药学上可接受的盐、晶型、水合物或溶剂化合物的制备方法，包括以下步骤：将药学上可接受的赋形剂与本发明化合物或其药学上可接受的盐、晶型、水合物或溶剂化合物进行混合，从而形成药物组合物。
在另一方面，本发明提供了一种药物组合物，其包含本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，与神经胺酸酶抑制剂、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、或免疫作用药的组合。
在另一方面，本发明提供了一种本发明化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物在用于制备治疗以及预防与由具有帽依赖性核酸内切酶的病毒引起的疾病的药物中的用途。
在另一方面，本发明还涉及提供一种在受试者中治疗和/或预防与由具有帽依赖性核酸内切酶的病毒引起的疾病的方法，该方法包括向该受试者给药治疗有效量的本发明化合物或其药学上可接受的盐、晶型、水合物或溶剂化合物或药物组合物。在具体实施方案中，口服、皮下、静脉内或肌肉内给药所述化合物。在具体实施方案中，长期给药所述化合物。
本发明进一步提供一种使用前药化合物的流行性感冒传染病的治疗法或预防法、以及具有抗流行性感冒作用的上述化合物。本发明进一步提供一种前药化合物的母化合物。该母化合物系作为抗流行性感冒剂、或该前药化合物的中间体。
本发明的化合物具有抑制帽依赖性核酸内切酶的活性。更优选的化合物是前药，由于其在给药后在体内成为具有对帽依赖性核酸内切酶的抑制活性的母化合物，因此作为流行性感冒传染病的治 疗剂和/或预防剂而有用。
由随后的具体实施方式、实施例和权利要求，本发明的其它目的和优点将对于本领域技术人员显而易见。
定义
本文中，如无特别说明，“氘代”指化合物或基团中的一个或多个氢被氘所取代；氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
本文中，如无特别说明，“非氘代的化合物”是指含氘原子比例不高于天然氘同位素含量(0.015％)的化合物。
术语“药学上可接受的盐”是指，在可靠的医学判断范围内，适合与人和低等动物的组织接触而没有过度毒性、刺激性、变态反应等等，并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。例如，Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述的药学上可接受的盐。本发明化合物的药学上可接受的盐包括衍生自合适无机和有机酸和碱的盐。
本发明化合物可以是无定形或结晶形式。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“晶型”是指化学药物分子的不同排列方式，一般表现为药物原料在固体状态下的存在形式。一种药物可以多种晶型物质状态存在，同一种药物的不同晶型，在体内的溶解和吸收可能不同，从而会对制剂的溶出和释放产生影响。
术语“晶型”是指化学药物分子的不同排列方式，一般表现为药物原料在固体状态下的存在形式。一种药物可以多种晶型物质状态存在，同一种药物的不同晶型，在体内的溶解和吸收可能不同，从而会对制剂的溶出和释放产生影响。
如本文所用，术语“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在另一些实施方案中，受试者是非人动物。
“疾病”、“障碍”和“病症”在本文中可以互换地使用。
除非另作说明，否则，本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用，它降低疾病、障碍或病症的严重程度，或延迟或减缓疾病、障碍或病症的发展(“治疗性治 疗”)，还包括受试者开始患有具体疾病、障碍或疾病之前发生的作用(“预防性治疗”)。
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药物动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗和预防性治疗有效量。
除非另作说明，否则，本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗有益处的数量，或使与疾病、障碍或病症有关的一或多种症状延迟或最小化。化合物的治疗有效量是指单独使用或与其他疗法联用的治疗剂的数量，它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其他治疗剂的治疗效能的数量。
除非另作说明，否则，本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的数量，或足以预防与疾病、障碍或病症有关的一或多种症状的数量，或防止疾病、障碍或病症复发的数量。化合物的预防有效量是指单独使用或与其它药剂联用的治疗剂的数量，它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的数量，或增强其它预防药剂的预防效能的数量。
“组合”以及相关术语是指同时或依次给药本发明的治疗剂。例如，本发明化合物可以与另一治疗剂以分开的单位剂型同时或依次给药，或与另一治疗剂一起呈单一单位剂型同时给药。
具体实施方式
化合物
本说明书中的所谓“前药”，是指以下的反应式中的式(II)所示的化合物或其药学上可接受的盐，表示的是在体内的生理条件下通过由药物代谢酶、水解酶、胃酸、肠内细菌等所引起的分解反应而转化为式(III)所示的化合物，从而表现出帽依赖性核酸内切酶(CEN)抑制活性、和/或CPE抑制效果的化合物。
Figure PCTCN2019097614-appb-000003
(式中，各符号与上述含义相同)
该式(II)所示的前药更优选表示的是：体内给药时的生物利用度和/或AUC(血药浓度曲线对时间轴所包围的面积)和/或C max(给药后出现的血药浓度最高值)较式(III)所示的化合物得到提高的化合物。
因此，该前药在给药至活体(例如，口服给药)后在胃和/或肠等中被高效地吸收至体内，其后被转化为式(III)所示的化合物，因此可优选地表现出较式(III)所示化合物更高的治疗和/或预防效果。
本发明提供式(I)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物：
Figure PCTCN2019097614-appb-000004
其中，
P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)；
Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢或氘；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15各自独立地选自氢或氘；
附加条件是，上述化合物至少含有一个氘原子。
作为本发明的优选实施方案，氘在氘代位置的氘同位素含量至少是大于天然氘同位素含量0.015％，较佳地大于30％，更佳地大于50％，更佳地大于75％，更佳地大于95％，更佳地大于99％。
具体地说，在本发明中Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7、Y 8、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15，各氘代位置中氘同位素含量至少是5％，更佳地大于10％，更佳地大于15％，更佳地大于20％，更佳地大于15％，更佳地大于25％，更佳地大于30％，更佳地大于35％，更佳地大于40％，更佳地大于45％，更佳地大于50％，更佳地大于55％，更佳地大于60％，更佳地大于65％，更佳地大于70％，更佳地大于75％，更佳地大于80％，更佳地大于85％，更佳地大于90％，更佳地大于95％，更佳地大于99％。
作为本发明的优选实施方案，式(I)的化合物中至少含有一个氘原子，更佳地含有二个氘原子，更佳地含有三个氘原子，更佳地含有四个氘原子，更佳地含有五个氘原子，更佳地含有六个氘原子，更佳地含有七个氘原子，更佳地含有八个氘原子，更佳地含有九个氘原子，更佳地含有十个氘原子，更佳地含有十一个氘原子，更佳地含有十二个氘原子，更佳地含有十三个氘原子，更佳地含有十四个氘原子，更佳地含有十五个氘原子，更佳地含有十六个氘原子，更佳地含有十七个氘原子，更佳地含有十八个氘原子，更佳地含有十九个氘原子，更佳地含有二十个氘原子，更佳地含有二十一个氘原子，更佳地含有二十二个氘原子，更佳地含有二十三个氘原子。
在具体实施方案中，“Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢或氘”包括Y 1选自氢或氘，Y 2选自氢或氘，Y 3选自氢或氘，以此类推，直至Y 8选自氢或氘的技术方案。更具体地，包括Y 1为氢或Y 1为氘，Y 2为氢或Y 2为氘，Y 3为氢或Y 3为氘，以此类推，直至Y 8为氢或Y 8为氘的技术方案。
在另一具体实施方案中，“R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15各自独立地选自氢或氘”包括R 1选自氢或氘，R 2选自氢或氘，R 3选自氢或氘，以此类推，直至R 15选自氢或氘的技术方案。更具体地，包括R 1为氢或R 1为氘，R 2为氢或R 2为氘，R 3为氢或R 3为氘，以此类推，直至R 15为氢或R 15为氘的技术方案。
在一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，且R 1-R 15如上所定义，附加条件是所述化合物至少含有一个氘原子。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，且R 1-R 15如上所定义，附加条件是R 7-R 15中至少一者是氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1和R 2为氢，且R 3-R 15各自独立地选自氢或氘，附加条件是所述化合物至少含有一个氘原子。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1和R 2为氢，且R 3-R 15各自独立地选自氢或氘，附加条件是R 7-R 15中至少一者是氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，且R 3、R 7-R 15各自独立地选自氢或氘，附加条件是所述化合物至少含有一个氘原子。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，且R 3、R 7-R 15各自独立地选自氢或氘，附加条件是R 7-R 15中至少一者是氘。
在另一更优选地实施方案中，R 7-R 10是相同的。
在另一更优选地实施方案中，R 7-R 10是氘。
在另一更优选地实施方案中，R 7-R 10是氢。
在另一更优选地实施方案中，R 11-R 12是相同的。
在另一更优选地实施方案中，R 11-R 12是氘。
在另一更优选地实施方案中，R 11-R 12是氢。
在另一更优选地实施方案中，R 13-R 15是相同的。
在另一更优选地实施方案中，R 13-R 15是氘。
在另一更优选地实施方案中，R 13-R 15是氢。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 3为氘，且R 7-R 15各自独立地选自氢或氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 3为氘，且R 7-R 15各自独立地选自氢或氘，附加条件是R 7-R 15中至少一者是氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 3为氘，且R 7-R 15各自独立地选自氢或氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 3为氘，且R 7-R 15各自独立地选自氢或氘，附加条件是R 7-R 15中至少一者是氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 7-R 10为氘，且R 3、R 11-R 15各自独立地选自氢或氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 7-R 10为氘，且R 3、R 11-R 15各自独立地选自氢或氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 3和R 7-R 10为氘，且R 11-R 15各自独立地选自氢或氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 3和R 7-R 10为氘，且R 11-R 15各自独立地选自氢或氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 13-R 15为氘，且R 3、R 7-R 12各自独立地选自氢或氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 3和R 13-R 15为氘，且R 7-R 12各自独立地选自氢或氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 13-R 15为氘，且R 3、R 7-R 12各自独立地选自氢或氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 3和R 13-R 15为氘，且R 7-R 12各自独立地选自氢或氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 7-R 10和R 13-R 15为氘，且R 3和R 11-R 12各自独立地选自氢或氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 7-R 10和R 13-R 15为氘，且R 3和R 11-R 12各自独立地选自氢或氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 3、R 7-R 10和R 13-R 15为氘，且R 11-R 12各自独立地选自氢或氘。
在另一个优选地实施方案中，本发明涉及一种式(I)的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，其中，P选自-C(R 11R 12)OC(O)OC(R 13R 14R 15)，Y 1-Y 8为氢，R 1-R 2和R 4-R 6为氢，R 3、R 7-R 10和R 13-R 15为氘，且R 11-R 12各自独立地选自氢或氘。
作为本发明的优选实施方案，所述化合物为如下任一结构，或其药学上可接受的盐，但不限于下列结构：
Figure PCTCN2019097614-appb-000005
Figure PCTCN2019097614-appb-000006
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
本领域技术人员将理解，有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R·x H 2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R·0.5H 2O))和多水合物(x为大于1的数，例如，二水合物(R·2H 2O)和六水合物(R·6H 2O))。
本发明化合物可以是无定形或结晶形式(多晶型)。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。
本发明还包括同位素标记的化合物，它们等同于式(I)所述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如 3H和 14C)的那些可用于药物和/或底物组织分布测定。氚、即 3H和碳-14、即 14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即 2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(I)化合物及其前体药物一 般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。
药物组合物、制剂和试剂盒
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的活性组分。在一些实施方案中，所述药物组合物包含治疗有效量的活性组分。在一些实施方案中，所述药物组合物包含预防有效量的活性组分。
用于本发明的药学上可接受的赋形剂是指不会破坏一起配制的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括但不限于，离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的 受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度快速提高至有效水平。推注剂量取决于活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组合物，而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量，代表性的方案是，每天一个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约50mg/kg的本发明化合物，优选的剂量各自提供大约10至大约40mg/kg，尤其是大约10至大约30mg/kg。
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％ 重量，剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中，本文以引用的方式引入该文献。
本发明化合物还可以以持续释放形式给予，或从持续释放给药系统中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。
适应症
如本文所用，术语“本发明化合物”指式(I)所示的化合物。该术语还包括及式(I)化合物的互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物。
本发明化合物是抗流感病毒药物，具有对依赖性核酸内切酶的抑制活性，所以可以用于治疗和/或预防流行性传染病。
流感病毒是负义单链RNA病毒，并且是正粘病毒科家族的一员。目前有3中流感病毒：流感病毒A、流感病毒B和流感病毒C。流感病毒A具有源自宿主细胞的脂质膜，其包含从病毒表面突出的血凝素、神经氨酸酶和M2蛋白质。根据血凝素(H或HA)和神经氨酸酶(N)已将流感病毒A进一步分类。大约有16种H抗原(H1至H16)和9种N抗原(N1至N9)。流感病毒A包括若干亚型，包括H1N1、H1N2、H2N2、H3N1、H3N2、H3N8、H5N1、H5N2、H5N3、H5N8、H5N9、 H7N1、H7N2、H7N3、H7N7、H7N9、H9N2和H10N7。流感病毒聚合酶是由以下3种亚基组成的异三聚体：聚合酶酸(PA)、聚合酶碱1(PB1)和聚合酶碱2(PB2)。在受感染细胞的细胞核中，这种聚合酶负责病毒RNA的复制和转录。PA亚基包含核酸内切酶活性部位。PA的核酸内切酶活性切割细胞mRNA，随后细胞mRNA被PB1亚基用作引物用于病毒mRNA合成。
在一些实施方案中，有效量的本发明化合物或本文所述的药物组合物可用于治疗和/改善流感病毒感染。在另一些实施方案中，有效量的本发明化合物或本文所述的药物组合物可用于预防流感病毒感染。
在一些实施方案中，有效量的本发明化合物或本文所述的药物组合物可用于抑制流感病毒的复制。在另一些实施方案中，有效量的本发明化合物或本文所述的药物组合物可用于抑制流感聚合酶复合体。在另一些实施方案中，有效量的本发明化合物或本文所述的药物组合物可用于抑制和/或降低帽依赖性核酸内切酶的活性。在另一些实施方案中，有效量的本发明化合物或本文所述的药物组合物可用于抑制和/或降低核酸内切酶切割mRNA的能力。
在一些实施方案中，所述流感病毒感染可以是流感A病毒感染。在另一些实施方案中，所述流感病毒感染可以是流感B病毒感染。在另一些实施方案中，所述流感病毒感染可以是流感C病毒感染。在一些实施方案中，本发明化合物可用于治疗和/或缓解流感的一种或多种亚型。例如，本发明化合物可用于治疗H1N1和/或H3N2。此外或替代地，本发明化合物可用于治疗H2N2、H5N1和/或H7N9。在一些实施方案中，本发明化合物可有效抵抗超过1种亚型的流感。例如，本发明化合物可有效抵抗2、3、4和/或5种或更多亚型的流感。
在一些实施方案中，有效量的本发明化合物或包含本发明化合物的药物组合物可用于治疗和/或缓解由于(直接和/或间接)流感病毒感染导致的上呼吸道感染。在一些实施方案中，有效量的本发明化合物或包含本发明化合物的药物组合物可用于治疗和/或缓解由于(直接和/或间接)流感病毒感染导致的下呼吸道病毒感染。在一些实施方案中，有效量的本发明化合物或包含本发明化合物的药物组合物可用于治疗和/或缓解流感病毒感染的一种或多种症状(例如，咳嗽、喉咙疼痛、头痛、鼻塞、发热或恶寒、肌肉或关节至疼痛、疲劳等)。在一些实施方案中，有效量的本发明化合物或包含本发明化合物的药物组合物可用于治疗和/或缓解由于流感病毒感染导致的细支气管炎和/或气管支气管炎。在一些实施方案中，有效量的本发明化合物或包含本发明化合物的药物组合物可用于治疗和/或缓解由于流感病毒感染导致的肺炎。
在一些实施方案中，有效量的本发明化合物或包含本发明化合物的药物组合物可用于减轻流感感染的一种或多种症状的严重程度。症状的实例包括，但不限于下列，发烧、寒战、咳嗽、咽喉痛、 流鼻涕、鼻塞、肌肉酸痛、身体疼痛、头痛、疲劳、呕吐和/或腹泻。
在一些实施方案中，本发明化合物的有效量可有效地使病毒滴度降低至较低水平的量，例如，约10E4TCID50/mL(TCID＝组织培养感染剂量)至约10E3TCID50/mL、或至约100TCID50/mL、或至约10TCID50/mL。在一些实施方案中，本发明化合物的有效量为：与给予式(I)化合物之前的病毒载量相比，有效地降低病毒载量的量。例如，其中在给予式(I)的化合物之前检测病毒载量，并在使用式(I)的化合物的治疗方案开始后再次检测(例如，治疗开始后1-2天)。在一些实施方案中，本发明化合物的有效量可以是有效地使病毒载量降低至低于约10E4TCID50/mL的量。在一些实施方案中，本发明化合物的有效量为：与在给予式(I)的化合物之前的病毒载量相比，有效实现个体的鼻/咽或鼻腔冲洗样本中的病毒滴度如下范围的降低的量：降低约1.5-log至约2.5-log、或降低约3-log至约4-log。例如，其中在给予式(I)的化合物之前检测病毒载量，并在使用式(I)的化合物之前检测病毒载量，并在使用式(I)的化合物的治疗方案开始后再次检测(例如，治疗开始后1-2天)。
在一些实施方案中，与未经治疗的个体相比，本发明化合物可产生一种或多种生活整体质量健康，如与未经治疗的个体相比，疾病持续时间大大减少、疾病严重程度降低、恢复到正常健康和正常活动的时间减少、以及减轻病毒感染的一种或多种症状的时间减少。在一些实施方案中，与未经治疗的个体相比，本发明化合物可引起与病毒感染有关的一种或多种症状的长度和/或严重程度的降低。在一些实施方案中，与未经治疗的个体相比，本发明化合物可引起与病毒感染有关的、包括但不限于中耳炎(耳部炎症)窦炎、支气管炎和肺炎的一种或多种继发并发症的减少。
在一些实施方案中，相对于个体的治疗前水平，本发明化合物可引起病毒复制减少至少1、2、3、4、5、10、15、20、25、75、100倍或更多倍，如在治疗方案开始之后所测定的。
一段时间后，传染原可发展对一种或多种治疗及的抗药性。如本文使用的术语“抗药性”是指对一种或多种治疗剂显示延迟、减少和/或零反应的病毒菌株。例如，在使用抗病毒剂治疗后，与感染非抗药性菌株的个体所显示的病毒载量减少的量相比，感染抗药性病毒的个体的病毒载量可减少至更小程度。在一些实施方案中，可向感染了抗一种或多种不同抗流感药剂(例如，金刚烷胺和/或奥司他韦)的流感病毒的个体给予本发明化合物。在一些实施方案中，可向感染了抗M2蛋白抑制剂的流感病毒的个体给予本发明化合物。在一些实施方案中，与流感菌株抗其他流感药物的发展相比，但使用本发明化合物治疗个体时，抗药性流感菌株的发展延迟。
在一些实施方案中，与经历使用奥司他韦治疗的并发症的个体百分比相比，本发明化合物可降低经历来自流感病毒感染的并发症的个体百分比。例如，使用式(I)的化合物治疗的个体经历并发症的百分比使用奥司他韦治疗的个体少10％、20％、30％、40％、60％、70％、80％和90％。
在一些实施方案中，与经历使用Baloxavir marboxil治疗的并发症的个体百分比相比，本发明化合物可降低经历来自流感病毒感染的并发症的个体百分比。例如，使用式(I)的化合物治疗的个体经历并发症的百分比使用Baloxavir marboxil治疗的个体少10％、20％、30％、40％、60％、70％、80％和90％。
联合疗法
在一些实施方案中，本发明化合物，或包括本文所述化合物的药物组合物可与一种或多种额外的药剂组合使用。在一些实施方案中，本发明化合物可与一种或多种目前在治疗流感的常规护理标准中使用的药剂组合使用。例如，所述额外的药剂可为金刚烷胺(金刚烷-1-胺、Symmetrel)、金刚烷乙胺(Flumadine)、扎那米韦(Relenza)和奥司他韦(Tamiflu)。对于流感的治疗，额外的药剂包括但不限于：神经氨酸酶抑制剂、M2蛋白抑制剂、聚合酶抑制剂、PB2抑制剂、帕拉米韦、拉尼娜米韦、法匹拉韦、拉尼娜米韦辛酸酯、流感酶(DAS181,NexBio)、ADS-8902(金刚烷胺HCl/奥司他韦/利巴韦林,Adamas Pharmaceuticals)、免疫调节剂(例如，I型干扰素)、贝前列素、利巴韦林等。
在一些实施方案中，本发明化合物可以与一种或多种额外的药剂以单一药物组合物一起给药。在一些实施方案中，本发明化合物可以与一种或多种额外的药剂作为两种或更多种单独的药物组合物给药。例如，本发明化合物能够以一种药物组合物给药，以及至少一种额外的药剂能够以第二种药物组合物给药。如果有至少两种额外的药剂，则所述额外的药剂的一种或多种可存在于包含本发明化合物的第一种药物组合物中，以及其他额外的药剂的至少一种可存在于第二种药物组合物中。本发明化合物与一种或多种额外的药剂的给药顺序可变化。在一些实施方案中，可在所有额外的药剂之前给予本发明化合物。在其他实施方案中，可在至少一种额外的药剂之前给予本发明化合物。仍是在其他实施方案中，本发明化合物可以与一种或多种额外的药剂同时给药。仍还是在其他实施方案中，可在给予至少一种额外的药剂之后给予本发明化合物。在一些实施方案中，可在给予所有额外的药剂之后给予本发明化合物。
在一些实施方案中，本发明化合物联合一种或多种额外的药剂的组合可导致累加效应。在一些实施方案中，本发明化合物联合一种或多种额外的药剂的组合可导致协同效应。在一些实施方案中，本发明化合物联合一种或多种额外的药剂的组合可导致强烈的协同效应。在一些实施方案中，本发明化合物联合一种或多种额外的药剂的组合不是拮抗的。
如本文所使用，术语“拮抗的”意为：与组合中化合物活性的总和相比，当单独地测定每个化合物的活性时(即作为单一化合物)，化合物组合的活性更低。如本文所使用，术语“协同效应”意为：当 单独测定每个化合物的活性时，化合物组合的活性大于组合中化合物单独活性的总和。如本文所使用，术语“累加效应”意为：当单独测定每个化合物的活性时，化合物组合的活性约等于组合中化合物单独活性的总和。
利用与一种或多种如上所述的额外的药剂(包括其药学上可接受的盐和前药)组合的本发明化合物的潜在优点可以是：与当在不含式(I)的化合物或其药学上可接受的盐的情况下给予一种或多种额外的药剂(包括其药学上可接受的盐和前药)时实现相同治疗结果所需要的量相比，有效治疗本文所公开的疾病状态(例如，流感)的一种或多种额外的药剂(包括其药学上可接受的盐和前药)所需要的量有所降低。例如，与以单一疗法给药时实现相同的病毒载量减少所需要的额外的药剂(包括其药学上可接受的盐和前药)的量相比，如上所述的额外的药剂(包括其药学上可接受的盐和前药)当与本发明化合物组合给药时的量可以更少。利用与一种或多种如上所述的额外的药剂(包括其药学上可接受的盐和前药)组合的本发明化合物的另一个潜在的优点是：与以单一疗法给予化合物时的屏障相比，使用两种或更多种具有不同作用机制的化合物能够建立形成抗药性病毒菌株的更高屏障。
制备本发明化合物的方法
本发明化合物(包括其盐)可使用已知有机合成技术来制备，且可按照多种可能合成途径中的任一种(诸如下文方案中的那些)来合成。用于制备本发明化合物的反应可在合适的溶剂中进行，有机合成领域的技术人员可容易地选择溶剂。合适的溶剂可在进行反应的温度(例如，在溶剂结冻温度至溶剂沸点温度范围内的温度)下与起始物质(反应物)、中间体或产物实质上不反应。既定反应可在一种溶剂或一种以上溶剂的混合物中进行。技术人员可依据具体反应步骤来选择用于具体反应步骤的溶剂。
本发明化合物的制备可涉及不同化学基团的保护和去除保护。本领域技术人员可容易地判定是否需要保护和去除保护以及适当保护基的选择。保护基的化学性质可参见例如Wuts和Greene，Protective Groups in Organic Synthesis，第4版，John Wiley&Sons：New Jersey，(2006)，其通过引用整体并入本文中。
本发明化合物可通过化合物的消旋混合物与光学活性的拆分剂反应形成一对非对映异构体化合物、分离非对映异构体并回收光学纯度的対映体，制备成其单个立体异构体。对映体拆分时可使用本发明化合物的非对映体衍生物进行，优先可解离的复合物(例如，结晶非对映体盐)。非对映体具有显著不同的物理性质(例如，熔点、沸点、溶解度、反应性等)，并可通过这些不相似性的优势容易地得到分离。非对映体可通过色谱，优选通过基于溶解度的差异的分离/拆分技术进行分离。然后 通过不会消旋化的任何实际手段，回收光学纯对映体，连同拆分试剂。适用于从消旋混合物开始拆分得到化合物立体异构体的技术的更详细的描述可见于Jean Jacques，Andre Collet，Samue1H.Wilen，“对映体、消旋体和拆分”(“Enantiomers，Racemates and Resolutions”)，John Wiley And Sons，Inc.,1981。
可按照本领域已知任何合适的方法来监测反应。例如，可通过光谱手段(诸如核磁共振(NMR)光谱法(例如 1H或 13C)、红外(IR)光谱法、分光光度法(例如，UV-可见光)、质谱(MS))或通过色谱方法(诸如高效液相色谱法(HPLC)或薄层色谱法(TLC))来监测产物形成。
在通常的合成方法以及实施例中，各缩写的含义如下所述。
Boc：叔丁氧基羰基
DBU：二氮杂双环十一烯
DMA：N,N-二甲基乙酰胺
DMF：N,N-二甲基甲酰胺
NMP：N-甲基吡咯烷酮
THF：四氢呋喃
OBn：苄氧基
T3P：丙基膦酸酐
PPT：对甲苯磺酸吡啶盐
MSA：甲磺酸
ACN：乙腈
MTBE：甲基叔丁基醚
本发明式(I)化合物可通过像以下反应路线1那样进行制备：
反应路线1
Figure PCTCN2019097614-appb-000007
其中R 3、R 7-R 15各自独立地选自氢或氘，且R 3、R 7-R 15不全为氢。
式(C)化合物可通过式(A)化合物和式(B)化合物在适宜的缩合剂(例如，丙基磷酸酐(T3P)、甲磺酸或对甲苯磺酸)，适宜的溶剂(例如，DMF、DMA、NMP、THF、乙酸乙酯、乙酸丁酯、二氧六 环等溶剂或这些的混合溶剂)和适宜的碱(例如碳酸钠、碳酸钾、碳酸铯等)存在下反应。反应在约10℃至80℃的温度范围进行，可需约1-24小时内完成。式(I-1)化合物可通过保护基团Bn从式(C)化合物离去进行合成(例如，可利用protective Groups in Organic Synthesis,Theodora W Green(John Wiley&Sons等所记载的通常方法进行)。式(I-2)化合物可通过式(I-1)化合物和式(D)化合物在适宜的碱(例如碳酸钠、碳酸钾、碳酸铯等)存在下利用羟基转化为醚基的通常方法(例如，可应用Protective Groups in Organic Synthesis,Theodora W Green(John Wiley&Sons)、Prog.Med,5:2157-2161(1985)、及Supplied by The British Library–“The word’s Knowledge”等所记载的方法)而获得式(I-2)化合物。
式(A-1)化合物可通过以下反应路线2进行制备：
反应路线2
Figure PCTCN2019097614-appb-000008
式(A-1)化合物和式(E-1)的制备路线和合成方法已在WO2017/221869A1中揭露。
式(A-2)化合物可通过以下反应路线3进行制备：
反应路线3
Figure PCTCN2019097614-appb-000009
式(A-2)化合物的制备路线和合成方法同式(A-1)化合物，不同之处用氘代化合物F-2代替化合物F-1。
式(B-1)化合物和式(B-2)化合物可通过以下反应路线4进行制备：
反应路线4
Figure PCTCN2019097614-appb-000010
式(B-1)化合物的制备路线和合成方法已在WO2017/221869A1中揭露。式(B-2)化合物的合同方法与式(B-1)化合物的不同之处在于最后一步用氘代的金属还原剂替代NaBH 4。
中间体化合物9的制备
Figure PCTCN2019097614-appb-000011
合成路线如下：
Figure PCTCN2019097614-appb-000012
步骤1化合物3的合成
将化合物1(2.0g，1.05mmol)和化合物2(2.3g，1.7mmol)加入到DMA(20ml)溶液中，将溶液加热至40℃，然后慢慢加入叔丁醇钠(1.6g，1.6mmol)，40℃下搅拌反应3小时，反应完全后冷却至室温，然后缓慢滴加乙酸调pH值约为7，加入10ml水，用二氯甲烷(50ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝10:1)，得到白色固体2.1g，收率72％。
步骤2化合物4的合成
将化合物3(2.0g，7.2mmol)加入到乙醇(10ml)和水(10ml)中，将溶液加热至60℃，然后加入水合肼(0.7g，14.3mmol)，60℃下搅拌反应4小时，反应完全后再慢慢加20％氢氧化钠水溶液调pH约为13，用二氯甲烷(100ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩，浓缩液直接投下一步。
步骤3化合物6的合成
依次将化合物5(5.0g，20.5mmol)、碘甲烷(3.5g，24.4mmol)，DBU(6.3g，40.7mmol)加入至DMF(20ml)液中，该反应液在室温下反应20h，然后加入80ml水，再用乙酸乙酯(60ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝5:1)，得到黄色固体3.6g，收率69％。
步骤4化合物7的合成
依次将化合物6(0.5g，1.8mmol)、对甲苯磺酸吡啶盐(1.38g，5.5mmol)，NH 2NHBoc(0.36g，2.7mmol)加入至DMA(10ml)液中，在60℃下反应15h，然后加入20ml水，再用乙酸乙酯(30ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝4:1)，得到黄色固体0.6g，收率80％。
步骤5化合物8的合成
依次将化合物7(1.0g，2.7mmol)、化合物4(0.8g，5.3mmol)，加入至THF(20ml)液中，然后滴加2滴DBU，该溶液在60℃下反应20h，然后旋干反应液，加入20ml水，再用乙酸乙酯(30ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝4:1)，得到固体0.7g，收率54％。
步骤6化合物9的合成
依次将化合物8(1.5g，3.1mmol)、甲磺酸(0.43g，4.5mmol)加入至乙腈(20ml)液中，该溶液在60℃下反应5h，然后旋干反应液，加入20ml水，再用乙酸乙酯(30ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1:2)，得到固体0.5g，收率51％。
中间体化合物17的制备
Figure PCTCN2019097614-appb-000013
合成路线如下：
Figure PCTCN2019097614-appb-000014
步骤1化合物11的合成
在0℃条件下，将LiAlD 4(7.2g，170.9mmol)慢慢加入至化合物10(10.0g，85.6mmol)的四氢呋喃(150ml)溶液中，加完后再将反应液升温至回流反应10h。反应完全后降温至0℃，然后加水淬灭反应，硅藻土过滤，直接旋干滤液，得到液体4.4g，直接投下一步。
步骤2化合物13的合成
依次将化合物12(5.0g，34.0mmol)、化合物11(4.4g，68.0mmol)，九水硝酸铁(1.3g，3.4mmol)加入至甲苯(40ml)液中，该反应液在115℃下反应15h，然后加入20ml水，再用乙酸乙酯(50ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝5:1)，得到白色固体3.9g，收率59％。
步骤3化合物14的合成
将化合物13(4.0g，21.0mmol)和化合物2(4.6g，34mmol)加入到DMA(20ml)溶液中，将溶液加热至40℃，然后慢慢加入叔丁醇钠(3.2g，3.2mmol)，40℃下搅拌反应3小时，反应完全后再慢慢滴加乙酸调pH值约为7，加入10ml水，用二氯甲烷(50ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝10:1)，得到白色固体3.7g，收率63％。
步骤4化合物15的合成
将化合物14(2.0g，7.2mmol)加入到乙醇(10ml)和水(10ml)中，将溶液加热至60℃，然后加入水合肼(0.7g，14.3mmol)，60℃下搅拌反应4小时，反应完全后再慢慢加20％氢氧化 钠水溶液调pH值约为13，用二氯甲烷(100ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩，浓缩液直接投下一步。
步骤5化合物16的合成
依次将化合物7(1.0g，2.7mmol)和化合物15(0.8g，5.3mmol)加入至THF(20ml)液中，然后滴加2滴DBU，该溶液在60℃下反应20h，然后旋干反应液，加入20ml水，再用乙酸乙酯(30ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝4:1)，得到固体0.8g，收率60％。
步骤6化合物17的合成
依次将化合物16(1.0g，2.1mmol)和甲磺酸(0.3g，3.0mmol)加入至乙腈(20ml)液中，该溶液在60℃下反应5h，然后旋干反应液，加入20ml水，再用乙酸乙酯(30ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1:2)，得到固体0.45g，收率68％。
中间体化合物23的制备
Figure PCTCN2019097614-appb-000015
合成路线如下：
Figure PCTCN2019097614-appb-000016
步骤1化合物19的合成
氮气保护下，将化合物LDA(35ml，70mmol)加入至无水THF(50ml)液中，该溶液降至-40℃后，然后再滴加化合物18(5g，31.6mmol)的四氢呋喃溶液中，加完后在该温度下继续反应1.5h，然后再慢慢加入DMF(5.74g，78.5mmol)至上述反应液中，加完后再加入盐酸(34ml,6 mol/L)，再搅拌十分钟，再用乙酸乙酯(50ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩得到黄色液体6g。
步骤2化合物20的合成
将苯硫酚(3.9g,35.4mmol)和右旋樟脑磺酸(1.6g,5.0mmol)加入到上述化合物6的甲苯溶液中，然后在60℃下搅拌反应4h,反应完全后，冷却时0℃，然后加入氢氧化钠(10ml,2mol/L),然后用甲苯萃取(20ml×3)萃取，在用水洗，合并有机相，无水硫酸钠干燥，浓缩，浓缩液直接投下一步。
步骤3化合物21的合成
将三氯化铝(5.52g，41.4mmol)加入到甲苯(30ml)中，将溶液降温至0℃，然后将四甲基二硅氧烷(5.56g，41.4mmol)慢慢滴加入上述溶液中，然后在室温下将化合物20再慢慢加入到上述溶液中，加完后室温下反应3h，反应完全后再慢慢加15％硫酸(35ml),然后用乙酸乙酯(50ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩干，再用石油醚打浆，得到白色固体7g，79％。
步骤4化合物22的合成
将化合物21(7.0g，25.0mmol)加入到多聚磷酸(30ml)中，将溶液升温至120℃，该温度下反应3h，反应完全后再慢慢将反应液倒入冰水中，然后用乙酸乙酯(60ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩干，再用石油醚打浆，得到白色固体5g，77％。
步骤5化合物23的合成
在40℃条件下，将NaBH 4(0.4g，11.5mmol)加入至化合物22(2.0g，7.6mmol)的异丙醇醇(20ml)溶液中，然后继续反应1h。然后用1M的盐酸淬灭反应，二氯甲烷(30ml×2)萃取，合并有机相，无水硫酸钠干燥，过滤旋干，得到灰色固体产物1.8g。
中间体化合物24的合成
Figure PCTCN2019097614-appb-000017
采用如下合成路线：
Figure PCTCN2019097614-appb-000018
在40℃条件下，将NaBD 4(0.5g，11.5mmol)加入至化合物22(2.0g，7.6mmol)的异丙醇醇(20ml)溶液中，然后继续反应1h。然后用1M的盐酸淬灭反应，二氯甲烷(30ml×2)萃取，合并有机相，无水硫酸钠干燥，过滤旋干，得到灰色固体产物1.8g。
实施例1(((12aR)-12-((11S)-7,8-二氟-6,11-二氢二苯并(B,E)噻庚英-11-基-11-d)-6,8-二氧代 -3,4,6,8,12,12a-六氢-1H-(1,4)噁嗪(3,4-C)吡啶并(2,1-F)(1,2,4)三嗪-7-基)氧基)甲基碳酸甲酯(化合物 T-1)的制备
Figure PCTCN2019097614-appb-000019
合成路线如下
Figure PCTCN2019097614-appb-000020
步骤1化合物25的合成
依次将化合物9(0.5g，1.5mmol)、化合物24(0.45g，1.5mmol)和T3P(0.73g，2.3mmol)加入至乙酸乙酯(6ml)液中，然后再加入甲磺酸(0.29g，3.0mmol)，该反应液在,70℃下反应6h，然后加入10ml水，再用乙酸乙酯(20ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1:2)，得到白色固体0.6g，收率69％。
步骤2化合物26的合成
将化合物25(0.6g，1.0mmol)和氯化锂(0.23g，5.0mmol)加入到DMA(10ml)中，将溶液升温至80℃，该温度下反应3h，反应完全后再缓慢将反应液倒入冰水中，然后用乙酸乙酯(20ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩干，再用MTBE打浆，得到白色固体0.4g，收率81％。
步骤3化合物27的合成
依次将化合物26(0.3g，0.61mmol)、碳酸甲基氯甲酯(0.15g，1.3mmol)，碳酸钾(0.2g，1.22mmol)，碘化钾(0.1g，0.61mmol)加入至DMA(6ml)液中，该反应液在,50℃下反应6h，然后加入10ml水，再用乙酸乙酯(20ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：DCM/MeOH(v/v)＝20:1)，得到白色固体0.21g。
步骤4化合物T-1的合成
将0.21g的化合物27溶于20mL甲醇中，采用如下条件进行制备(仪器：SFC-80(Thar,Waters)；手性柱：OJ-H 20*250mm,10um(Daicel)；柱温：35℃；流动性：CO 2/甲醇(含0.2％氨甲醇)＝87/13；流速：80g/min；柱压：100bar；检测波长：214nm；循环时间：6.0min；每次进样体积：1.0mL)，得到四个异构体，采用如下条件进行手性分析(仪器：Agilent 1200；手性柱：IG 4.6×250mm,5um(Decial)；柱温：25℃；流动相：正己烷(含0.1二乙胺)：乙醇(含0.1％二乙胺)＝60:40；流速：1.0mL/min；检测波长：214nm；进样量：15uL),其中保留时间＝35.65min即为化合物T-1,白色化合物45mg。LC-MS:m/z＝573.2(M+1) +,UV 214； 1H NMR(500MHz,CDCl 3)δ/ppm:7.14-7.08(m,4H),7.03-7.00(m,1H),6.89-6.87(m,1H),6.83-6.81(m,1H),5.99(s,2H),5.87(d,J＝7.5Hz,1H),5.27(dd,J＝14.0Hz,J＝2.5Hz,1H),4.63(dd,J＝14.0Hz,J＝2.5Hz,1H),4.51(dd,J＝10.0Hz,J＝2.5Hz,1H),4.06(d,J＝14.0Hz,1H),3.93(dd,J＝11.0Hz,J＝3.0Hz,1H),3.86(s,3H),3.76(dd,J＝11.0Hz,J＝3.0Hz,1H),3.55(t,J＝10.5Hz,1H),3.46-3.41(m,1H),2.96-2.91(m,1H).
实施例2(((12aR)-12-((11S)-7,8-二氟-6,11-二氢二苯并(B,E)噻庚英-11-基-11-d)-6,8-二氧代 -3,4,6,8,12,12a-六氢-1H-(1,4)噁嗪(3,4-C)吡啶并(2,1-F)(1,2,4)三嗪-7-基-3,3,4,4-d 4)氧基)甲基碳酸甲酯 (化合物T-2)的制备
Figure PCTCN2019097614-appb-000021
合成路线如下
Figure PCTCN2019097614-appb-000022
步骤1化合物28的合成
依次将化合物17(0.5g，1.5mmol)、化合物24(0.45g，1.5mmol)和T3P(0.73g，2.3mmol)加入至乙酸乙酯(6ml)溶液中，然后再加入甲磺酸(0.29g，3.0mmol)，该反应液在,70℃下反应6h，然后加入10ml水，再用乙酸乙酯(20ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1:2)，得到白色固体0.55g，收率60％。
步骤2化合物29的合成
将化合物28(0.5g，0.86mmol)和氯化锂(0.2g，4.3mmol)加入到DMA(10ml)中，将溶液升温至80℃，该温度下反应3h，反应完全后再缓慢将反应液倒入冰水中，然后用乙酸乙酯(20ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩干，再用MTBE打浆，得到白色固体0.33g，78％。
步骤3化合物30的合成
依次将化合物29(0.33g，0.67mmol)、碳酸甲基氯甲酯(0.20g，1.4mmol)、碳酸钾(0.25g，1.4mmol)和碘化钾(0.1g，0.67mmol)加入至DMA(6ml)溶液中，该反应液在,50℃下反应6h，然后加入10ml水，再用乙酸乙酯(20ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：DCM/MeOH(v/v)＝20:1)，得到白色固体0.25g。
步骤4化合物T-2的合成
将0.25g的化合物30溶于25mL甲醇中，采用如下条件进行制备(仪器：SFC-80(Thar,Waters)；手性柱：OJ-H 20*250mm,10um(Daicel)；柱温：35℃；流动性：CO 2/甲醇(含0.2％氨甲醇)＝87/13；流速：80g/min；柱压：100bar；检测波长：214nm；循环时间：6.0min；每次进样体积：1.0mL)，得到四个异构体，采用如下条件进行手性分析(仪器：Agilent 1200；手性柱：IG 4.6×250mm,5um(Decial)；柱温：25℃；流动相：正己烷(含0.1二乙胺)：乙醇(含0.1％二乙胺)＝60:40；流速：1.0mL/min；检测波长：214nm；进样量：15uL),其中保留时间＝36.53min即为化合物T-2,白色化合物50mg。LC-MS:m/z＝577.3(M+1) +,UV 214； 1H NMR(500MHz,CDCl 3)δ/ppm:7.14-7.08(m,4H),7.03-7.00(m,1H),6.89-6.87(m,1H),6.83-6.81(m,1H),5.99(s,2H),5.87(d,J＝7.5Hz,1H),5.27(dd,J＝14.0Hz,J＝2.5Hz,1H),4.51(dd,J＝10.0Hz,J＝2.5Hz,1H),4.06(d,J＝14.0Hz,1H),3.93(dd,J＝11.0Hz,J＝3.0Hz,1H),3.86(s,3H),3.55(t,J＝10.5Hz,1H),3.12-3.08(m,1H).
实施例3(((12aR)-12-((11S)-7,8-二氟-6,11-二氢二苯并(B,E)噻庚英-11-基)-6,8-二氧代 -3,4,6,8,12,12a-六氢-1H-(1,4)噁嗪(3,4-C)吡啶并(2,1-F)(1,2,4)三嗪-7-基)氧基)甲基碳酸(甲基-d 3)酯(化 合物T-3)的制备
Figure PCTCN2019097614-appb-000023
合成路线如下
Figure PCTCN2019097614-appb-000024
步骤1化合物碳酸(甲基-d 3)氯甲酯的合成
将氘代甲醇(1.0g，28.7mmol)和三乙胺(3.4g，34.2mmol)加入到二氯甲烷(30ml)中，将溶液降温至0℃，然后将氯甲酸氯甲酯(3.7g，28.7mmol)慢慢滴加到上述溶液中，然后在室温下反应3h，反应完全后水(10ml)淬灭,，DCM(20ml)萃取，合并有机相，无水硫酸钠干燥，浓缩干，得到液体2.8g，收率78％。
步骤2化合物31的合成
依次将化合物9(0.8g，2.45mmol)、化合物23(0.65g，2.45mmol)和T3P(1.2g，3.7mmol)加入至乙酸乙酯(6ml)溶液中，然后再加入甲磺酸(0.45g，4.9mmol)，该反应液在70℃下反应6h，然后加入10ml水，再用乙酸乙酯(20ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：石油醚/乙酸乙酯(v/v)＝1:2)，得到白色固体0.9g，收率64％。
步骤3化合物32的合成
将化合物31(0.9g，1.57mmol)和氯化锂(0.33g，7.85mmol)加入到DMA(10ml)中，将溶液升温至80℃，该温度下反应3h，反应完全后再慢慢将反应液倒入冰水中，然后用乙酸乙酯(20ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩干，再用MTBE打浆，得到白色固体0.6g，79％。
步骤4化合物33的合成
依次将化合物32(0.6g，1.2mmol)、碳酸(甲基-d 3)氯甲酯(0.3g，2.4mmol)、碳酸钾(0.4g，2.4mmol)和碘化钾(0.2g，1.2mmol)加入至DMA(6ml)液中，该反应液在50℃下反应6h， 然后加入10ml水，再用乙酸乙酯(20ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：DCM/MeOH(v/v)＝20:1)，得到白色固体0.55g。
步骤5化合物T-3的合成
将0.55g化合物33溶于50mL甲醇中，采用如下条件进行制备(仪器：SFC-80(Thar,Waters)；手性柱：OJ-H 20*250mm,10um(Daicel)；柱温：35℃；流动性：CO 2/甲醇(含0.2％氨甲醇)＝87/13；流速：80g/min；柱压：100bar；检测波长：214nm；循环时间：6.0min；每次进样体积：1.0mL)，得到四个异构体，采用如下条件进行手性分析(仪器：Agilent 1200；手性柱：IG 4.6×250mm,5um(Decial)；柱温：25℃；流动相：正己烷(含0.1二乙胺)：乙醇(含0.1％二乙胺)＝60:40；流速：1.0mL/min；检测波长：214nm；进样量：15uL),其中保留时间＝37.24min即为化合物T-3,白色固体100mg。LC-MS:m/z＝575.0(M+1) +,UV 214； 1H NMR(500MHz,CDCl 3)δ/ppm:7.14-7.08(m,4H),7.03-7.00(m,1H),6.89-6.87(m,1H),6.83-6.81(m,1H),5.99(s,2H),5.87(d,J＝7.5Hz,1H),5.33(s,1H),5.27(dd,J＝14.0Hz,J＝2.5Hz,1H),4.63(dd,J＝14.0Hz,J＝2.5Hz,1H),4.51(dd,J＝10.0Hz,J＝2.5Hz,1H),4.06(d,J＝14.0Hz,1H),3.93(dd,J＝11.0Hz,J＝3.0Hz,1H),3.76(dd,J＝11.0Hz,J＝3.0Hz,1H),3.55(t,J＝10.5Hz,1H),3.46-3.41(m,1H),2.96-2.91(m,1H).
实施例4(((12aR)-12-((11S)-7,8-二氟-6,11-二氢二苯并(B,E)噻庚英-11-基-11-d)-6,8-二氧代 -3,4,6,8,12,12a-六氢-1H-(1,4)噁嗪(3,4-C)吡啶并(2,1-F)(1,2,4)三嗪-7-基)氧基)甲基碳酸(甲基-d 3)酯(化 合物T-4)的制备
Figure PCTCN2019097614-appb-000025
合成路线如下
Figure PCTCN2019097614-appb-000026
步骤1化合物34的合成
依次将化合物26(0.5g，1.01mmol)、碳酸(甲基-d 3)氯甲酯(0.26g，2.06mmol)、碳酸钾(0.28g，2.06mmol)和碘化钾(0.1g，1.01mmol)加入至DMA(6ml)液中，该反应液在,50℃下反应6h，然后加入10ml水，再用乙酸乙酯(20ml×3)萃取，合并有机相，无水硫酸钠干燥，浓缩液进行柱分离(洗脱剂：DCM/MeOH(v/v)＝20:1)，得到白色固体0.4g。
步骤2化合物T-4的合成
将0.4g化合物34溶于40mL甲醇中，采用如下条件进行制备(仪器：SFC-80(Thar,Waters)；手性柱：OJ-H 20*250mm,10um(Daicel)；柱温：35℃；流动性：CO 2/甲醇(含0.2％氨甲醇)＝87/13；流速：80g/min；柱压：100bar；检测波长：214nm；循环时间：6.0min；每次进样体积：1.0mL)，得到四个异构体，采用如下条件进行手性分析(仪器：Agilent 1200；手性柱：IG 4.6×250mm,5um(Decial)；柱温：25℃；流动相：正己烷(含0.1二乙胺)：乙醇(含0.1％二乙胺)＝60:40；流速：1.0mL/min；检测波长：214nm；进样量：15uL),其中保留时间＝33.77min即为化合物T-4,白色固体80mg。LC-MS:m/z＝576.3(M+1) +,UV 214； 1H NMR(500MHz,CDCl 3)δ/ppm:7.14-7.08(m,4H),7.03-7.00(m,1H),6.89-6.87(m,1H),6.83-6.81(m,1H),5.99(s,2H),5.87(d,J＝7.5Hz,1H),5.27(dd,J＝14.0Hz,J＝2.5Hz,1H),4.63(dd,J＝14.0Hz,J＝2.5Hz,1H),4.51(dd,J＝10.0Hz,J＝2.5Hz,1H),4.06(d,J＝14.0Hz,1H),3.93(dd,J＝11.0Hz,J＝3.0Hz,1H),3.76(dd,J＝11.0Hz,J＝3.0Hz,1H),3.55(t,J＝10.5Hz,1H),3.46-3.41(m,1H),2.96-2.91(m,1H).
生物活性测试。
(1)代谢稳定性评价
微粒体实验：人肝微粒体(Human liver microsome,HLM)：0.5mg/mL，Xenotech；大鼠肝微粒体(Rat liver microsome,RLM)：0.5mg/mL，Xenotech；辅酶(NADPH/NADH)：1mM，Sigma Life Science； 氯化镁：5mM，100mM磷酸盐缓冲剂(pH为7.4)。
储备液的配制：精密称取一定量的实施例化合物和对照品化合物的粉末，并用DMSO分别溶解至5mM。
磷酸盐缓冲液(100mM，pH＝7.4)的配制：取预先配好的150mL的0.5M磷酸二氢钾和700mL的0.5M磷酸氢二钾溶液混合，再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4，使用前用超纯水稀释5倍，加入氯化镁，得到磷酸盐缓冲液(100mM)，其中含100mM磷酸钾，3.3mM氯化镁，pH为7.4。
配制NADPH再生系统溶液(含有6.5mM NADP，16.5mM G-6-P，3U/mL G-6-P D，3.3mM氯化镁)，使用前置于湿冰上。
配制终止液：含有50ng/mL盐酸普萘洛尔和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL人肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中，分别加入812.5μL SD大鼠肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。
样品的孵育：用含70％乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM，作为工作液，备用。分别取398μL的人肝微粒体或者大鼠肝微粒体稀释液加入96孔孵育板中(N＝2)，分别加入2μL0.25mM的的工作液中，混匀。
代谢稳定性的测定：在96孔深孔板的每孔中加入300μL预冷的终止液，并置于冰上，作为终止板。将96孔孵育板和NADPH再生系统置于37℃水浴箱中，100转/分钟震荡，预孵5min。从孵育板每孔取出80μL孵育液加入终止板，混匀，补充20μL NADPH再生系统溶液，作为0min样品。再向孵育板每孔加入80μL的NADPH再生系统溶液，启动反应，开始计时。相应化合物的反应浓度为1μM，蛋白浓度为0.5mg/mL。分别于反应10、30、90min时，各取100μL反应液，加入终止板中，涡旋3min终止反应。将终止板于5000×g，4℃条件下离心10min。取100μL上清液至预先加入100μL蒸馏水的96孔板中，混匀，采用LC-MS/MS进行样品分析。
数据分析：通过LC-MS/MS系统检测相应化合物及内标的峰面积，计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率，并根据以下公式计算t 1/2和CL int，其中V/M即等于1/蛋白浓度。
Figure PCTCN2019097614-appb-000027
对本发明化合物及其没有氘代的化合物同时测验比较，评价其在人和大鼠肝微粒体的代谢稳定 性。采用未经氘代的化合物Baloxavir marboxil作为对照品。在人和大鼠肝微粒体实验中，通过与未经氘代的化合物Baloxavir marboxil对照，本发明化合物可以明显改善代谢稳定性。代表性实施例化合物的肝微粒体实验结果如下表1所示。
表1：
Figure PCTCN2019097614-appb-000028
(2)大鼠药代动力学实验
6只雄性Sprague-Dawley大鼠，7-8周龄，体重约210g，分成2组，每组3只，经静脉或口服单个剂量的化合物(口服10mg/kg)，比较其药代动力学差异。
大鼠采用标准饲料饲养，给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血，采血的时间点为给药后0.083小时，0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时和24小时。
大鼠吸入乙醚后短暂麻醉，眼眶采集300μL血样于试管。试管内有30μL 1％肝素盐溶液。使用前，试管于60℃烘干过夜。在最后一个时间点血样采集完成之后，大鼠乙醚麻醉后处死。
血样采集后，立即温和地颠倒试管至少5次，保证混合充分后放置于冰上。血样在4℃5000rpm离心5分钟，将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中，标明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进计算。
实验表明，本发明化合物在动物体内具有更好的药代动力学性质，因此具有更好的药效学和治疗效果。
(3)体外抗流感病毒活性病毒株：流感病毒A/WSN/33(H1N1)，细胞：MDCK；
应用细胞病变(CPE)法测试受试化合物对流感病毒株的抗病毒活性，同时测定细胞毒性。化合物测试8个浓度，双复孔。使用CCK-8试剂检测细胞活力。化合物起始浓度为500nM,，终浓度为0.229nM,3倍梯度稀释。
MDCK细胞以2000个/孔的密度接种于384孔板内，于37℃、5％CO 2培养过夜。第二天加入化合物和病毒，设置细胞(无病毒感染)和病毒感染对照。细胞培养DMSO终浓度为0.5％。细胞于37℃、5％CO 2培养5天至病毒对照孔细胞病变率达80-95％。细胞毒性实验与抗病毒实验相同，但无病毒感染。使用CCK-8试剂检测细胞活力，原始数据用于化合物抗病毒活性和细胞毒性计算。应用GraphPad Prism软件分析化合物剂量反应曲线并计算EC 50和CC 50值。
对本发明化合物及其没有氘代的化合物同时测验比较，评价其抗病毒活性和细胞毒性。结果表明，与未经氘代的化合物Baloxavir marboxil相比，本发明化合物表现出更高的CPE抑制效果，因此本发明化合物可更高效地抑制流感病毒中帽依赖性核酸内切酶(CDE)，从而起到抑制病毒复制的作用。代表性实施例化合物的抗病毒活性和细胞毒性的结果如下表2所示。
表2
实施例化合物 EC 50(nM) CC 50(nM)
Baloxavir marboxil 10.11 >500
T-1 10.05 >500
T-2 3.54 >500
T-3 6.11 >500
T-4 5.94 >500
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。

Claims (12)

  1. 一种式(I)化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物：
    Figure PCTCN2019097614-appb-100001
    其中，
    P选自H或-C(R 11R 12)OC(O)OC(R 13R 14R 15)；
    Y 1、Y 2、Y 3、Y 4、Y 5、Y 6、Y 7和Y 8各自独立地选自氢或氘；
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15各自独立地选自氢或氘；
    附加条件是，上述化合物至少含有一个氘原子。
  2. 权利要求1所述的化合物，其中，R 7、R 8、R 9、R 10、R 11、R 12、R 13、R 14和R 15中至少一者为氘。
  3. 权利要求1或2所述的化合物，其中，R 3是氘。
  4. 权利要求1-3任一项所述的化合物，其中，R 7、R 8、R 9和R 10是氘。
  5. 权利要求1-4任一项所述的化合物，其中，R 11和R 12是氘。
  6. 权利要求1-5任一项所述的化合物，其中，R 13、R 14和R 15是氘。
  7. 权利要求1所述的化合物，其选自下式化合物：
    Figure PCTCN2019097614-appb-100002
    Figure PCTCN2019097614-appb-100003
    或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物。
  8. 一种药物组合物，其含有药学上可接受的赋形剂和权利要求1-7中任一项所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物。
  9. 权利要求1-7中任一项所述的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，或权利要求8所述的药物组合物在用于制备治疗和/或预防与由具有帽依赖性核酸内切酶的病毒引起的疾病的药物中的用途。
  10. 权利要求9所述的用途，其中，由具有帽依赖性核酸内切酶的病毒引起的疾病选自甲型流感、乙型流感或丙型流感。
  11. 一种在受试者中治疗和/或预防与由具有帽依赖性核酸内切酶的病毒引起的疾病的方法，所述方法包括向所述受试者给药权利要求1-7中任一项所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化合物，或者权利要求8所述的药物组合物。
  12. 权利要求11所述的方法，其中，由具有帽依赖性核酸内切酶的病毒引起的疾病选自甲型流感、乙型流感或丙型流感。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3778608A4 (en) * 2018-04-11 2021-06-23 Andikang (Wuxi) Biological Technology Co., Ltd. POLYCYCLIC CARBAMOYL PYRIDONE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND THEIR USES

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111825699B (zh) * 2019-04-15 2023-02-21 上海复星星泰医药科技有限公司 含硫杂环化合物及其制备方法
CN112707862B (zh) * 2019-10-24 2022-09-27 广东东阳光药业有限公司 一种并环吡啶酮化合物的制备方法
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
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
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
CN111808069B (zh) * 2020-07-21 2022-05-17 中国药科大学 一种巴洛沙韦关键中间体的制备方法及其中间体
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
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
CN113527119A (zh) * 2021-06-30 2021-10-22 和鼎（南京）医药技术有限公司 一种巴洛沙韦中间体的制备方法
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
CN113549088B (zh) * 2021-08-25 2022-10-04 北京理工大学 一种巴洛沙韦关键中间体的制备方法
CN116284048B (zh) * 2023-05-18 2023-08-15 长沙晶易医药科技股份有限公司 一种化合物及其制备方法、药物组合物和用途

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 (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL2620436T3 (pl) * 2010-09-24 2018-10-31 Shionogi & Co., Ltd. Prolek podstawionej policyklicznej pochodnej karbamoilopirydonowej

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 (1)

* Cited by examiner, † Cited by third party
Title
WANG, SHIZHEN: "Molecular Nuclear Medicine (2nd Edition)", 30 April 2004, article "Part VI Research of Nuclear Medicine", pages: 417 - 418 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3778608A4 (en) * 2018-04-11 2021-06-23 Andikang (Wuxi) Biological Technology Co., Ltd. POLYCYCLIC CARBAMOYL PYRIDONE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND THEIR USES

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