WO2022148434A1 - 吡啶酮多并环类衍生物及其应用 - Google Patents

吡啶酮多并环类衍生物及其应用 Download PDF

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WO2022148434A1
WO2022148434A1 PCT/CN2022/070733 CN2022070733W WO2022148434A1 WO 2022148434 A1 WO2022148434 A1 WO 2022148434A1 CN 2022070733 W CN2022070733 W CN 2022070733W WO 2022148434 A1 WO2022148434 A1 WO 2022148434A1
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compound
pharmaceutically acceptable
acceptable salt
compounds
added
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PCT/CN2022/070733
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English (en)
French (fr)
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陈新海
熊剑
王晶晶
胡国平
刘金鑫
韩宇
黎健
陈曙辉
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辉诺生物医药科技（杭州）有限公司
南京明德新药研发有限公司
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Priority to CN202280009275.4A priority Critical patent/CN116670135A/zh
Priority to KR1020237026759A priority patent/KR20230131237A/ko
Priority to JP2023541778A priority patent/JP2024502198A/ja
Priority to EP22736595.4A priority patent/EP4276099A1/en
Priority to US18/271,162 priority patent/US20240025921A1/en
Priority to AU2022205484A priority patent/AU2022205484A1/en
Publication of WO2022148434A1 publication Critical patent/WO2022148434A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D517/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D517/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms in which the condensed system contains three hetero rings
    • C07D517/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D517/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D517/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms in which the condensed system contains two hetero rings
    • C07D517/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a class of pyridone polycyclic derivatives and applications thereof, in particular to compounds represented by formula (VI) and pharmaceutically acceptable salts thereof.
  • Influenza virus namely influenza virus (IFV) is a segmented single-stranded antisense RNA virus that can cause influenza in humans and animals. Influenza viruses can cause very high morbidity and mortality, especially influenza A viruses can cause global pandemics, such as "Spanish flu” (H1N1 subtype) in 1918-1920, "Asian flu” in 1957-1958 “(H2N2 subtype), 1968 to 1969 "Asian flu” (H3N2 subtype), 1977 to 1978 "Hong Kong flu” (H1N1 subtype) and the first outbreak of influenza A H1N1 in Mexico in March 2009. Influenza outbreaks killed thousands of people, caused huge social panic and increased social instability.
  • IMV influenza virus
  • Influenza A virus is a single negative-stranded RNA virus with a genome of 8 segments encoding 8 proteins.
  • the 5' and 3' ends of influenza virus genome fragments are highly conserved, and the sequences of the two ends are complementary to form a handle loop structure, which plays an important role in initiating viral RNA replication.
  • the proteins encoded by each gene segment of the virus are different in size and play different roles in the life cycle of influenza virus.
  • the basic functions of several main proteins are introduced as follows.
  • HA of influenza virus is a ligand for influenza virus to recognize host receptors, bind to virus-specific receptors on the cell surface, mediate the fusion of the viral outer membrane and the intracellular body membrane, and release the viral nucleocapsid into the cytoplasm.
  • the receptor of influenza virus is specific, and the receptor of influenza A virus is sialoglycoprotein.
  • the NA protein of influenza virus can remove sialic acid on the surface of virus particles during replication, so that virus particles cannot continue to aggregate on the surface of host cells, which is conducive to the release of virions and further infection of more host cells.
  • M2 protein of influenza virus binds to sialic acid, and influenza virus is endocytosed by host cells.
  • the acidity and alkalinity in phagosomes play a crucial role in virus uncoating.
  • the ion channel of M2 protein on the viral membrane can gradually reduce the pH of phagosomes. When the pH value drops to 5.0-6.0, HA2
  • the protein allosteric shifts the fusion peptide located at the amino terminus of the HA2 protein, which activates the fusion process, resulting in the fusion of the double lipid membrane of the virus and the cell membrane, releasing the RNPs inside the virus particle to the host cytoplasm.
  • the M2 protein is a transmembrane ion channel found only in influenza A virus, and it partially extends to the surface of the viral outer membrane.
  • influenza virus proteins also utilizes the host cell translation mechanism, and even the virus can suspend the translation of host proteins and accelerate the synthesis of its own proteins.
  • the polyadenylation of host cell mRNA is completed by a specific adenylase, unlike the adenylate tail of viral mRNA, which is formed by the transcription of 5-7 consecutive uracils on the negative-strand vRNA. of.
  • mRNAs viral individual messenger RNAs
  • PA and PB2 proteins grab the 5' capping primer of the host pre-mRNA transcript and in turn initiate viral mRNA synthesis, a process known as "cap” snatching", which is mainly accomplished by the virus' RNA-dependent RNA polymerase (RdRp), whose PA subunit has RNA endonuclease activity and is responsible for severing host mRNA.
  • RdRp virus' RNA-dependent RNA polymerase
  • the mRNA of the virus exits the nucleus, enters the cytoplasm, and is translated like the mRNA of the host cell.
  • the nuclear export of the viral vRNA fragment is mediated by the M1 and NS2 proteins of the virus.
  • M1 protein when M1 protein can interact with vRNA and NP protein, it also interacts with nuclear export protein NS2; thus, nuclear export protein NS2 mediates the export of M1-RNP as a nuclear protein into the cytoplasm of host cells.
  • Influenza has direct costs due to lost productivity and associated healthcare resources and indirect costs of preventive measures.
  • influenza cumulatively costs approximately $10 billion annually, and future influenza pandemics are estimated to have direct and indirect costs in the hundreds of billions of dollars.
  • Prevention costs are also very high, with governments around the world spending billions of dollars to prepare for and plan for a possible H5N1 avian influenza pandemic, costs associated with purchasing drugs and vaccines, and developing strategies for disaster drills and improved border controls.
  • Influenza vaccine against influenza is often recommended for high-risk groups, such as children and the elderly, or people with asthma, diabetes, or heart disease, but even vaccination does not completely prevent the flu. Vaccines for some specific influenza strains are recreated each season, but it is impossible to cover the various strains that actively infect people globally during that season. In addition, because influenza viruses undergo a certain degree of antigenic drift, if more than one virus infects a single cell, the 8 separate vRNA segments in the genome mix or reassort, resulting in rapid changes in viral genetics that can produce The antigenic shift enables the virus to infect new host species and rapidly overcome protective immunity.
  • Antiviral drugs can also be used to treat influenza.
  • neuraminidase inhibitors such as oseltamivir (Tamiflu)
  • Tamiflu oseltamivir
  • Drug-resistant virus strains have emerged.
  • anti-influenza virus there is an urgent need for anti-influenza virus drugs with a new mechanism of action, which can support the use of single drugs for the treatment of influenza A, or can be used in combination with other anti-influenza virus drugs with other mechanisms of action that have been marketed for influenza A.
  • Influenza prevention and treatment Among them, WO2016175224 reported RNA polymerase PA subunit inhibitors, such as S-033447 and its prodrug S-033188:
  • the present invention provides a compound represented by formula (VI) or a pharmaceutically acceptable salt thereof,
  • R 7 is selected from H and
  • R 8 is selected from C 1-3 alkyl and The C 1-3 alkyl and optionally substituted with 1, 2 or 3 Ra ;
  • R 9 is selected from H
  • E 1 is selected from Se
  • X 1 is selected from CR 10 R 11 , R 10 and R 11 together with the atoms to which they are commonly attached form a C 3-5 cycloalkyl
  • X1 and R9 are formed together with the atoms to which they are attached p is selected from 0 and 1, one of E 1 and E 2 is selected from Se, and the other is selected from S and O;
  • R 12 is selected from H, F, Cl, Br, I, OH, NH 2 , -COOH, C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino, the C 1-3 Alkyl, C 1-3 alkoxy and C 1-3 alkylamino are each independently optionally substituted with 1 , 2 or 3 R b ;
  • T 1 , T 2 , T 3 and T 4 are each independently selected from CH and N;
  • q is selected from 0 and 1;
  • t is selected from 0, 1, 2, 3 and 4;
  • each R a and R b are independently selected from H, F, Cl, Br and I;
  • each R12 is independently selected from OH and NH2 .
  • each R 12 is independently selected from F, and other variables are as defined in the present invention.
  • the R 8 is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and The CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and Optionally substituted with 1, 2 or 3 Ra , other variables are as defined herein.
  • the R 8 is selected from CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and Other variables are as defined in the present invention.
  • the R8 is selected from CH3 and Other variables are as defined in the present invention.
  • the R is selected from H, Other variables are as defined in the present invention.
  • the R is selected from H, Other variables are as defined in the present invention.
  • the R is selected from H and Other variables are as defined in the present invention.
  • the E 1 is selected from Se
  • E 2 is selected from O
  • other variables are as defined in the present invention.
  • the structural unit selected from R 5 and R 6 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , -COOH, C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino,
  • the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino groups are each independently optionally substituted with 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • said R5 is selected from F, and other variables are as defined herein.
  • said R6 is selected from F, and other variables are as defined herein.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 5 and R 6 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R 7 is selected from H and
  • R 8 is selected from C 1-3 alkyl and The C 1-3 alkyl and optionally substituted with 1, 2 or 3 Ra ;
  • R 9 is selected from H
  • E 1 is selected from Se
  • X 1 is selected from CR 10 R 11 , R 10 and R 11 together with the atoms to which they are commonly attached form a C 3-5 cycloalkyl
  • X1 and R9 are formed together with the atoms to which they are attached
  • One of E 1 and E 2 is selected from Se, and the other is selected from S and O;
  • T 1 is selected from CH and N;
  • p and q are independently selected from 0 and 1, respectively;
  • each R a is independently selected from H, F, Cl, Br and I;
  • T1 is selected from CH
  • E1 is selected from Se
  • E2 is selected from O
  • p is selected from 1
  • q is selected from 1
  • R5 and R6 are independently selected from OH and NH2 , respectively ;
  • the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from,
  • the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from,
  • the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from,
  • the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • n is selected from 0 and 1;
  • R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
  • said R 1 and R 2 are each independently selected from F, and other variables are as defined in the present invention.
  • said R 5 and R 6 are each independently selected from F, and other variables are as defined in the present invention.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 , R 2 , R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • n and m are independently selected from 0 and 1, respectively;
  • R 1 and R 2 are independently selected from OH and NH 2 respectively; q, R 5 , R 6 and R 8 as defined in the present invention.
  • said R 1 and R 2 are each independently selected from F, and other variables are as defined in the present invention.
  • said R 3 and R 4 are each independently selected from F, and other variables are as defined in the present invention.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
  • the present invention provides a compound represented by formula (V) or a pharmaceutically acceptable salt thereof,
  • R 5 and R 6 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R 7 is selected from H and
  • R 8 is selected from C 1-3 alkyl and The C 1-3 alkyl and optionally substituted with 1, 2 or 3 Ra ;
  • R is selected from H;
  • X 1 is selected from CR 10 R 11 , R 10 and R 11 together with the atoms to which they are commonly attached form a C 3-5 cycloalkyl;
  • E 1 is selected from S and Se;
  • E 2 is selected from O and Se, and at least one of E 1 and E 2 is selected from Se;
  • T 1 is selected from CH and N;
  • p and q are independently selected from 0 and 1, respectively;
  • each R a is independently selected from H, F, Cl, Br and I;
  • T1 is selected from CH
  • E1 is selected from Se
  • E2 is selected from O
  • p is selected from 1
  • q is selected from 1
  • R5 and R6 are independently selected from OH and NH2 , respectively ;
  • the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • the present invention provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from CH and N;
  • E 1 is selected from S and Se;
  • E 2 is selected from O and Se, and at least one of E 1 and E 2 is selected from Se;
  • R 5 and R 6 are each independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R 7 is selected from H and
  • R 8 is selected from C 1-3 alkyl and The C 1-3 alkyl and optionally substituted with 1, 2 or 3 Ra ;
  • p and q are independently selected from 0 and 1, respectively;
  • each R a is independently selected from H, F, Cl, Br and I;
  • T 1 is selected from CH, and E 1 is selected from Se, E 2 is selected from O, p is selected from 1, and q is selected from 1, R 5 and R 6 are independently selected from OH and NH 2 respectively;
  • the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from,
  • the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • T 1 is selected from CH and N;
  • R 1 is selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R 2 is selected from H, F, Cl, Br, I, OH and NH 2 ;
  • n is selected from 0 and 1;
  • the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • R3 is selected from H, F, Cl, Br, I, OH and NH2 ;
  • R4 is selected from H, F, Cl, Br, I, OH and NH2 ;
  • n is selected from 0 and 1;
  • the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 and m are as defined in the present invention.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R 2 is selected from H, F, Cl, Br, I, OH and NH 2 ;
  • n is selected from 0 and 1;
  • the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • said R1 is selected from F , and other variables are as defined herein.
  • said R 2 is selected from F, and other variables are as defined herein.
  • said R3 is selected from F, and other variables are as defined herein.
  • said R4 is selected from F, and other variables are as defined herein.
  • the present invention provides a compound of the formula or a pharmaceutically acceptable salt thereof,
  • the present invention also provides the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating influenza virus-related diseases.
  • the compound of the present invention exhibits a positive effect in the test of inhibiting influenza virus replication at the cellular level, and exhibits excellent body weight protection in an animal in vivo pharmacodynamic model, and has an early recovery time.
  • the plasma protein binding rate test The results show that the compound of the present invention has a moderate plasma protein binding rate in plasma, and the PK results show that it has good pharmacokinetic properties and good drug-forming properties.
  • FIG. 1 3D binding mode of S-033447 to the protein (PDB ID: 6FS6).
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • the direction of attachment is arbitrary, for example,
  • the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • connection method of the chemical bond is not positioned and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to the corresponding valence. the group.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
  • a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
  • Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-3 alkylamino groups include C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • Examples of C 1-3 alkylamino include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH 2 (CH 3 ) 2 and the like.
  • C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, said C 3-5 cycloalkyl including C 3 -4 and C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
  • Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membere
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
  • a substitution reaction eg, a nucleophilic substitution reaction
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (eg acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the present invention adopts the following abbreviations: DMAC: N,N-dimethylacetamide, PG: propylene glycol, HP- ⁇ -CD: hydroxypropyl- ⁇ -cyclodextrin, Solutol HS-15 stands for polyethylene glycol (15)-Hydroxystearate.
  • the solvent used in the present invention is commercially available.
  • Compounds are named according to conventional nomenclature in the art or are used Software naming, commercially available compounds use supplier catalog names.
  • the low-energy conformation of S-033447 was calculated by the Macromodel module of the Maestro software of Schrodinger Company.
  • the dihedral angle (dehidal 1) of pyridohexahydropyrimidine hereinafter referred to as the parent nucleus
  • the dihedral angle between the parent nucleus and 2,5-dihydrothiophene is 56.8° ( See Figure 3).
  • the smaller the energy barrier difference between the lowest energy barrier conformation (low energy conformation) of a small molecule and its binding mode conformation in the protein (active conformation) the smaller the energy barrier difference means that the small molecule switches from the low energy conformation to binding to the protein.
  • Dihedral 1 is the dihedral angle of pyridohexahydropyrimidine
  • Dihedral 2 is the dihedral angle of pyridohexahydropyrimidine and 2,5-dihydrothiophene
  • ⁇ E is the protein binding mode from the low-energy conformation transition to S-033447 The energy barrier required to consume the active conformation (-153.7° for Dihedral 1 and 55.0° for Dihedral 2).
  • Dihedral 1 is the dihedral angle of pyridohexahydropyrimidine
  • Dihedral 2 is the dihedral angle of pyridohexahydropyrimidine and 2,5-dihydroselenothiophene.
  • the reaction solution was filtered, the filter cake was washed with ethyl acetate (10 mL ⁇ 2), the layers were separated, the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2), the organic phases were combined, washed with saturated brine (20 mL), anhydrous sulfuric acid Dry over sodium, filter, and concentrate the filtrate to dryness under reduced pressure.
  • the crude product reaction solution was separated and purified by preparative high performance liquid chromatography (column: Xtimate C18 100*30mm*3 ⁇ m; mobile phase: [A: water (0.225% formic acid); B: acetonitrile]; gradient: acetonitrile%: 40%-60 %, 8 minutes) to obtain compound 2 (retention time 3.205 minutes) and compound 2' (retention time 3.301 minutes).
  • the obtained crude product was added with dichloromethane (460 mL), triethylamine (77.60 g, 766.87 mmol, 106.74 mL) and N,O-dimethylhydroxylamine hydrochloride (37.40 g, 383.43 mmol, ) were added under stirring, and the reaction solution was Stir at 20°C for 1 hour. Water (100 mL) was added, the layers were separated, and the aqueous phase was extracted with dichloromethane (50 mL ⁇ 2).
  • the reaction solution was cooled to room temperature, water (10 mL) was added, extracted with ethyl acetate (10 mL ⁇ 2), the organic phase was washed with saturated brine (10 mL ⁇ 4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure .
  • Compound 6-9 was detected by supercritical fluid chromatography (analysis method: column model: CHIRALCEL OD-3 (100mm ⁇ 4.6mm, 3 ⁇ m); mobile phase: [A: carbon dioxide, B: 0.05% diethylamine/ethanol]; Gradient: B%: increase from 5% to 40% in 4min, then hold for 2.5min; then hold 5% for 1.5min) analysis as a racemic compound by chiral separation (column type: DAICEL CHIRALCEL OD-H (25mm x 30mm) , 5 ⁇ m); mobile phase: [A: carbon dioxide, B: 0.1% ammonia water/ethanol]; gradient: B%: 40%-40%) to obtain compound 6-9A (retention time 4.024min) and compound 6-9B (retention time 4.024min) time 4.447min).
  • the antiviral activity of the compounds against Influenza virus (IFV) was evaluated by determining the half effective concentration (EC 50 ) value of the compounds. Cytopathic assays are widely used to measure the protective effect of compounds on virus-infected cells to reflect the antiviral activity of compounds.
  • MDCK cells were seeded in black 384-well cell culture plates at a density of 2,000 cells per well, and then placed in a 37°C, 5% CO2 incubator overnight. Compounds were diluted by Echo555 non-contact nanoliter sonic pipetting system and added to cell wells (4-fold dilution, 8 test concentration points). Influenza virus A/PR/8/34 (H1N1) strain was then added to cell culture wells at 1-2 90% tissue culture infectious dose (TCID90) per well at a final concentration of 0.5% DMSO in the medium. Virus control wells (DMSO added and virus added, no compound added), cell control wells (DMSO added, no compound and virus added) and medium control wells (medium only, no cells) were set up.
  • the cytotoxicity assay and the antiviral activity assay of the compounds were performed in parallel, except that no virus was added, other experimental conditions were the same as the antiviral activity assay.
  • Cell plates were placed in a 37°C, 5% CO2 incubator for 5 days. After 5 days of culture, the cell viability was detected using the cell viability detection kit CCK8. Raw data were used for compound antiviral activity and cytotoxicity calculations.
  • the antiviral activity and cytotoxicity of the compounds were expressed by the inhibition rates (%) of the compounds against virus-induced cellular viral effects, respectively. Calculated as follows:
  • the compounds of the present invention exhibited positive effects in the assay of inhibiting influenza virus replication at the cellular level.
  • mice were infected with influenza A virus A/PR/8/34 (H1N1) by intranasal instillation, and were treated with compounds starting 48 hours after infection and administered orally for 7 consecutive days, twice a day.
  • the anti-influenza A virus H1N1 effect of the compound in this model was evaluated by observing the changes in body weight and survival rate of mice.
  • mice of SPF grade, 6-7 weeks old, female were selected for the experiment.
  • the mice were acclimated for at least 3 days after arriving in the BSL-2 animal room to start the experiment.
  • the day of infection was set as day 0 of the experiment.
  • Mice were anesthetized by intraperitoneal injection of pentobarbital sodium (75 mg/kg, 10 mL/kg). After the animals entered deep anesthesia, they were infected with A/PR/8/34 (H1N1) virus by intranasal infusion, and the infection volume was 50 ⁇ L. From day 2 to day 8, the test compound was orally administered at 5 mg/kg (administration volume 10 mL/kg) twice a day. The first dose was 48 hours after infection. The state of the mice was observed every day, and the body weight and survival rate of the mice were recorded. On day 14, all surviving animals were euthanized.
  • the results are shown in Table 4: Compound 5 can protect the animals with a maximum weight loss rate of 13.77% on the 7th day, and then began to recover, and the mouse survival rate was 100% at the end of the experiment; Compound 4 can protect the animals on the 3rd day. The maximum weight loss rate was 7.03%, and then began to recover, and the mouse survival rate was 100% by the end of the experiment.
  • the compounds of the present invention show excellent body weight protection and early recovery time in the animal in vivo pharmacodynamic model.
  • MDCK cells were seeded in 96-well cell culture plates at a density of 15,000 cells per well and cultured overnight in a 37°C, 5% CO2 incubator.
  • Compound solution (3-fold serial dilution, 8 concentration points, triple wells) and Baloxavir-resistant A/PR/8/34 (H1N1) influenza virus strain were added the next day, and the final concentration of DMSO in cell culture medium was 0.5%.
  • Cells were cultured in a 5% CO2 , 37°C incubator for 5 days until 80-95% cytopathic effect was achieved in virus-infected control wells without compound. Cell viability in each well was then assayed with CCK8. If the cell viability of the compound-containing wells is higher than that of the virus-infected control wells, that is, the CPE is weakened, it indicates that the compound has an inhibitory effect on the tested virus.
  • the antiviral activity of the compound was expressed by the inhibitory activity (%) of the compound against the virus-induced cellular viral effect. Calculated as follows:
  • the inhibitory activity and cell viability of the compounds were analyzed by nonlinear fitting of EC 50 using GraphPad Prism (version 5) software, and the fitting method was "log(inhibitor) vs.response--Variable slope".
  • the experimental results are shown in Table 5.
  • the compounds of the present invention show a positive effect in the assay of inhibiting the replication of Baloxavir-resistant A/PR/8/34 (H1N1) influenza virus strain at the cellular level.
  • mice were infected with influenza A virus Baloxavir-resistant A/PR/8/34(H1N1) I38T strain by intranasal infusion, treated with compound starting 2 hours before infection, and administered orally for 7 consecutive days, twice a day .
  • the anti-influenza A virus H1N1 effect of the compound in this model was evaluated by observing the changes in body weight and survival rate of mice.
  • mice of SPF grade, 6-7 weeks old, female were selected for the experiment.
  • the mice were acclimated for at least 3 days after arriving in the BSL-2 animal room to start the experiment.
  • the day of infection was set as day 0 of the experiment.
  • Mice were deeply anesthetized by intraperitoneal injection of sutai 50/xylazine hydrochloride, and then infected with Baloxavir-resistant A/PR/8/34(H1N1) I38T virus strain by intranasal infusion, and the infection volume was 50 ⁇ L.
  • test compounds were administered orally at 15 mg/kg or 50 mg/kg (administration volume 10 mL/kg) twice a day.
  • the first dose was 2 hours before infection.
  • the state of the mice was observed every day, and the body weight and survival rate of the mice were recorded. On day 14, all surviving animals were euthanized.
  • the experimental results are shown in Table 6 below. When compound 4 was administered at a dose of 50 mg/kg, the body weight of mice hardly decreased, and the survival rate of mice was 100% at the end of the experiment.
  • the compounds of the present invention show excellent body weight protection and early recovery time in an animal pharmacodynamic model.
  • Test protocol The test compounds were diluted into the plasma of the above five species with dialysis buffer, respectively, to prepare a sample with a final concentration of 2 ⁇ M, and then the sample was added to a 96-well equilibrium dialysis device with phosphate at 37 °C. The buffer solution was dialyzed for 4 hours. Warfarin was used as a control compound in the experiment. The concentrations of test compounds and warfarin in plasma and buffer were determined by LC-MS/MS method.
  • H stands for human
  • R stands for rat
  • M stands for mouse
  • D stands for dog
  • C stands for cynomolgus monkey
  • the compounds of the present invention have moderate plasma protein binding rates in the plasma of the five species, indicating that in the plasma of the above five species, the free drug concentration ratio of the tested compounds is moderate and has good drug properties.
  • mice Male SD rats, 6-8 weeks old, weighing 200-300 grams;
  • mice male beagle, ⁇ 6 months old, weighing 6-12 kg;
  • Plasma: dichlorvos solution 40:1, and the dichlorvos solution was 40mM dichlorvos in acetonitrile/water (1:1) solution, within half an hour, at 4°C, 3000g After centrifugation for 10 minutes, the supernatant plasma was aspirated, quickly placed in dry ice, and stored in a -80°C refrigerator for LC-MS/MS analysis.
  • the compound of the present invention has low clearance rate, long half-life time, high oral plasma exposure and good pharmacokinetic properties.

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Abstract

提供了一类吡啶酮多并环类衍生物及其应用，具体提供了式(VI)所示化合物及其药学上可接受的盐。

Description

吡啶酮多并环类衍生物及其应用
本发明主张如下优先权：
CN 202110024885.9，申请日2021年01月08日；
CN 202110264686.5，申请日2021年03月11日；
CN 202110513447.9，申请日2021年05月11日。
技术领域
本发明涉及一类吡啶酮多并环类衍生物及其应用，具体涉及式(VI)所示化合物及其药学上可接受的盐。
背景技术
流行性感冒病毒，即流感病毒(influenza virus,IFV)，是一种能够导致人和动物患流行感冒的分节状单链反义RNA病毒。流感病毒可引起非常高的发病率和死亡率，尤其A型流感病毒还能够导致全球性的大流行，比如1918～1920年的“西班牙流感”(H1N1亚型)、1957～1958年“亚洲流感”(H2N2亚型)、1968～1969年“亚洲流感”(H3N2亚型)、1977～1978年“香港流感”(H1N1亚型)以及2009年3月在墨西哥首先暴发的甲型H1N1流感。流感大爆发导致成千上万人死亡，引起巨大社会恐慌并增加社会不稳定因素。
A型流感病毒为单负链RNA病毒，基因组分为8个片段，编码8个蛋白。流感病毒基因组片段5’末端和3’末端高度保守，该两个末端的序列互补而形成柄环状结构，该结构在启动病毒RNA复制时发挥重要作用。病毒各个基因片段编码的蛋白大小不同，而且在流感病毒的生命周期中发挥着不同的作用，先将几种主要的蛋白的基本功能介绍如下。流感病毒的HA是流感病毒识别宿主受体的配体，与细胞表面病毒特异性受体结合，介导病毒外膜与细胞内小体膜融合释放病毒核衣壳进入胞浆。流感病毒的受体具有特异性，A型流感病毒的受体为唾液酸糖蛋白。流感病毒的NA蛋白在复制过程中可除去病毒颗粒表面的唾液酸，使病毒颗粒不能继续在宿主细胞表面聚集，从而有利于病毒子的释放并进一步感染更多的宿主细胞。
流感病毒的M2蛋白的作用：流感病毒的HA蛋白和唾液酸结合，流感病毒被宿主细胞内吞。吞噬泡中的酸碱性对于病毒脱衣壳起着至关重要的作用，病毒膜上的M2蛋白的离子通道可以使吞噬泡的pH值逐步降低，当pH值降至5.0-6.0时，导致HA2蛋白的发生变构，位于HA2蛋白氨基末端的融合肽移位，进而激活融合过程，导致病毒的双层类脂膜与细胞膜融合，释放出病毒颗粒内部的RNPs到宿主细胞浆。M2蛋白是一个跨膜的离子通道，仅在A型流感病毒中被发现，它有一部分延伸至病毒外膜表面。
流感病毒蛋白的合成也是利用宿主细胞翻译机制，甚至病毒可以暂停宿主蛋白的翻译，加快自身蛋白 的合成。宿主细胞mRNA的多聚腺苷酸化是通过特异的腺苷酸化酶完成的，与之不同的是，病毒mRNA的腺苷酸尾是由负链的vRNA上连续的5-7个尿嘧啶转录形成的。病毒各个信使RNA(mRNA)的加帽是以相似的方式完成的：PA和PB2蛋白攫取宿主pre-mRNA转录体的5’加帽引物，并进而启动病毒mRNA合成，这个过程被称为“cap snatching”，主要通过病毒的RNA依赖性RNA聚合酶(RdRp)来完成，其PA亚基具有RNA内切酶活性，负责切断宿主mRNA。在完成了多聚腺苷酸化过程和加帽过程，病毒的mRNA即出核，进入细胞质，并像宿主细胞的mRNA一样进行翻译，病毒vRNA片段的核输出是由病毒的M1蛋白和NS2蛋白介导的，M1蛋白可以与vRNA和NP蛋白相互作用时，同时也与核输出蛋白NS2作用；由此，核输出蛋白NS2介导M1-RNP以核蛋白形式出核进入宿主细胞的细胞质。
流感会产生由于丧失生产力和相关医疗资源的直接成本以及预防措施的间接成本。在美国，流感累计每年大约造成100亿美元的损失，据估计未来的流感大流行可引起数千亿美元的直接和间接成本。预防成本也非常高，全球各国政府已花费数十亿美元为可能的H5N1禽流感大流行做准备和计划，成本和购买药物和疫苗，以及发展灾难演练和提高边境管制的策略相关。
目前的流感治疗选择包括接种疫苗和用抗病毒药物进行化疗和化学预防。经常向高危群体，例如儿童和老年人，或有哮喘、糖尿病或心脏病的人推荐接种抗流感的流感疫苗，但是，即使接种疫苗也不能完全避免患流感。每个季节重新制备一些特定流感株的疫苗，但不可能涵盖该季节时全球主动感染人的各种病毒株。另外，由于流感病毒会发生一定程度的抗原漂移，如果超过一种病毒感染了单个细胞，则基因组中8个单独的vRNA片段发生混合或重配，所导致的病毒遗传学上的快速变化可产生抗原转变并使得病毒能感染新宿主物种并迅速克服保护性免疫。
抗病毒药物也可以用于治疗流感，其中神经氨酸酶抑制剂，如奥司他韦(达菲)，对于甲型流感病毒效果明显，但是经过临床观察发现，对于该类神经氨酸酶抑制剂已经出现了耐药的病毒株。在抗流感病毒领域，临床上亟需全新作用机制的抗流感病毒药物，能够支持单药使用治疗甲型流感，或者通过和已上市的其他作用机制的抗流感病毒药物联用，用于甲型流感的预防和治疗。其中WO2016175224报道了RNA聚合酶PA亚基抑制剂，如S-033447及其前药S-033188：
Figure PCTCN2022070733-appb-000001
前药：
Figure PCTCN2022070733-appb-000002
发明内容
本发明提供了式(VI)所示化合物或其药学上可接受的盐，
Figure PCTCN2022070733-appb-000003
其中，
R 7选自H和
Figure PCTCN2022070733-appb-000004
R 8选自C 1-3烷基和
Figure PCTCN2022070733-appb-000005
所述C 1-3烷基和
Figure PCTCN2022070733-appb-000006
任选被1、2或3个R a取代；
R 9选自H，E 1选自Se，X 1选自CR 10R 11，R 10和R 11与其共同连接的原子一起形成C 3-5环烷基；
或者，X 1和R 9与其连接的原子一起形成
Figure PCTCN2022070733-appb-000007
p选自0和1，E 1和E 2其中一个选自Se，另一个选自S和O；
R 12选自H、F、Cl、Br、I、OH、NH 2、-COOH、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基，所述C 1-3烷基、C 1- 3烷氧基和C 1-3烷氨基分别独立地任选被1、2或3个R b取代；
T 1、T 2、T 3和T 4分别独立地选自CH和N；
q选自0和1；
t选自0、1、2、3和4；
各R a和R b分别独立地选自H、F、Cl、Br和I；
条件是，当T 1选自CH，且E 1选自Se，且E 2选自O，p选自1，q选自1时，各R 12分别独立地选自OH和NH 2。
在本发明的一些方案中，所述各R 12分别独立地选自F，其他变量如本发明所定义。
在本发明的一些方案中，所述R 8选自CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和
Figure PCTCN2022070733-appb-000008
所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和
Figure PCTCN2022070733-appb-000009
任选被1、2或3个R a取代，其他变量如本发明所定义。
在本发明的一些方案中，所述R 8选自CH 3、CH 2CH 3、CH(CH 3) 2和
Figure PCTCN2022070733-appb-000010
其他变量如本发明所定义。
在本发明的一些方案中，所述R 8选自CH 3和
Figure PCTCN2022070733-appb-000011
其他变量如本发明所定义。
在本发明的一些方案中，所述R 7选自H、
Figure PCTCN2022070733-appb-000012
Figure PCTCN2022070733-appb-000013
其他变量如本发明所定义。
在本发明的一些方案中，所述R 7选自H、
Figure PCTCN2022070733-appb-000014
其他变量如本发明所定义。
在本发明的一些方案中，所述R 7选自H和
Figure PCTCN2022070733-appb-000015
其他变量如本发明所定义。
在本发明的一些方案中，所述E 1选自Se，E 2选自O，其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
Figure PCTCN2022070733-appb-000016
选自
Figure PCTCN2022070733-appb-000017
R 5和R 6分别独立地选自H、F、Cl、Br、I、OH、NH 2、-COOH、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基，所述C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基分别独立地任选被1、2或3个R b取代，其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
Figure PCTCN2022070733-appb-000018
选自
Figure PCTCN2022070733-appb-000019
Figure PCTCN2022070733-appb-000020
其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
Figure PCTCN2022070733-appb-000021
选自
Figure PCTCN2022070733-appb-000022
其他变量如本发明所定义。
在本发明的一些方案中，所述R 5选自F，其他变量如本发明所定义。
在本发明的一些方案中，所述R 6选自F，其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
Figure PCTCN2022070733-appb-000023
选自
Figure PCTCN2022070733-appb-000024
Figure PCTCN2022070733-appb-000025
其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
Figure PCTCN2022070733-appb-000026
选自
Figure PCTCN2022070733-appb-000027
Figure PCTCN2022070733-appb-000028
其他变量如本发明所定义。
在本发明的一些方案中，所述结构单元
Figure PCTCN2022070733-appb-000029
选自
Figure PCTCN2022070733-appb-000030
其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2022070733-appb-000031
其中，
R 5和R 6分别独立地选自H、F、Cl、Br、I、OH和NH 2；
R 7选自H和
Figure PCTCN2022070733-appb-000032
R 8选自C 1-3烷基和
Figure PCTCN2022070733-appb-000033
所述C 1-3烷基和
Figure PCTCN2022070733-appb-000034
任选被1、2或3个R a取代；
R 9选自H，E 1选自Se，X 1选自CR 10R 11，R 10和R 11与其共同连接的原子一起形成C 3-5环烷基；
或者，X 1和R 9与其连接的原子一起形成
Figure PCTCN2022070733-appb-000035
E 1和E 2其中一个选自Se，另一个选自S和O；
T 1选自CH和N；
p和q分别独立地选自0和1；
各R a分别独立地选自H、F、Cl、Br和I；
条件是，当T 1选自CH，且E 1选自Se，且E 2选自O，p选自1，q选自1时，R 5和R 6分别独立地选自OH和NH 2；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2022070733-appb-000036
其中，
p、q、E 1、E 2、T 1、R 5、R 6和R 7如本发明所定义；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2022070733-appb-000037
其中，
p、q、E 1、E 2、R 5、R 6和R 7如本发明所定义；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2022070733-appb-000038
其中，
p、q、E 1、E 2、R 5、R 6和R 7如本发明所定义；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2022070733-appb-000039
其中，
R 1和R 2分别独立地选自H、F、Cl、Br、I、OH和NH 2；
m选自0和1；
q、R 5、R 6、R 7和R 8如本发明所定义。
在本发明的一些方案中，所述R 1和R 2分别独立地选自F，其他变量如本发明所定义。
在本发明的一些方案中，所述R 5和R 6分别独立地选自F，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2022070733-appb-000040
Figure PCTCN2022070733-appb-000041
其中，R 1、R 2、R 5、R 6、R 7和R 8如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2022070733-appb-000042
其中，
R 1、R 2、R 3和R 4分别独立地选自H、F、Cl、Br、I、OH和NH 2；
n和m分别独立地选自0和1；
条件是，式(I-1)和式(I-2)中，当m选自1时，R 1和R 2分别独立地选自OH和NH 2；q、R 5、R 6和R 8如本发明所定义。
在本发明的一些方案中，所述R 1和R 2分别独立地选自F，其他变量如本发明所定义。
在本发明的一些方案中，所述R 3和R 4分别独立地选自F，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2022070733-appb-000043
Figure PCTCN2022070733-appb-000044
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8如本发明所定义。
本发明提供了式(V)所示化合物或其药学上可接受的盐，
Figure PCTCN2022070733-appb-000045
其中，
R 5和R 6分别独立地选自H、F、Cl、Br、I、OH和NH 2；
R 7选自H和
Figure PCTCN2022070733-appb-000046
R 8选自C 1-3烷基和
Figure PCTCN2022070733-appb-000047
所述C 1-3烷基和
Figure PCTCN2022070733-appb-000048
任选被1、2或3个R a取代；R 9选自H；
X 1选自CR 10R 11，R 10和R 11与其共同连接的原子一起形成C 3-5环烷基；
或者，X 1和R 9连接在一起形成
Figure PCTCN2022070733-appb-000049
E 1选自S和Se；
E 2选自O和Se，且E 1和E 2至少有一个选自Se；
T 1选自CH和N；
p和q分别独立地选自0和1；
各R a分别独立地选自H、F、Cl、Br和I；
条件是，当T 1选自CH，且E 1选自Se，且E 2选自O，p选自1，q选自1时，R 5和R 6分别独立地选自OH和NH 2；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明提供了式(IV)所示化合物或其药学上可接受的盐，
Figure PCTCN2022070733-appb-000050
其中，
T 1选自CH和N；
E 1选自S和Se；
E 2选自O和Se，且E 1和E 2至少有一个选自Se；
R 5和R 6分别独立地选自H、F、Cl、Br、I、OH和NH 2；
R 7选自H和
Figure PCTCN2022070733-appb-000051
R 8选自C 1-3烷基和
Figure PCTCN2022070733-appb-000052
所述C 1-3烷基和
Figure PCTCN2022070733-appb-000053
任选被1、2或3个R a取代；
p和q分别独立地选自0和1；
各R a分别独立地选自H、F、Cl、Br和I；
条件是，当T 1选自CH，且E 1选自Se，E 2选自O，p选自1，q选自1时，R 5和R 6分别独立地选自OH和NH 2；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2022070733-appb-000054
其中，
p、q、E 1、E 2、R 5、R 6和R 7如本发明所定义；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明提供了式(III)所示化合物或其药学上可接受的盐，
Figure PCTCN2022070733-appb-000055
其中，
T 1选自CH和N；
R 1选自H、F、Cl、Br、I、OH和NH 2；
R 2选自H、F、Cl、Br、I、OH和NH 2；
m选自0和1；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明提供了式(II)所示化合物或其药学上可接受的盐，
Figure PCTCN2022070733-appb-000056
其中，
R 3选自H、F、Cl、Br、I、OH和NH 2；
R 4选自H、F、Cl、Br、I、OH和NH 2；
n选自0和1；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2022070733-appb-000057
其中，R 1、R 2和m如本发明所定义。
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2022070733-appb-000058
其中，
R 1选自H、F、Cl、Br、I、OH和NH 2；
R 2选自H、F、Cl、Br、I、OH和NH 2；
m选自0和1；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
在本发明的一些方案中，所述R 1选自F，其他变量如本发明所定义。
在本发明的一些方案中，所述R 2选自F，其他变量如本发明所定义。
在本发明的一些方案中，所述R 3选自F，其他变量如本发明所定义。
在本发明的一些方案中，所述R 4选自F，其他变量如本发明所定义。
本发明还有一些方案是由所述变量任意组合而来。
本发明提供了下式化合物或其药学上可接受的盐，
Figure PCTCN2022070733-appb-000059
本发明还提供了所述化合物或其药学上可接受的盐在制备治疗与流感病毒相关疾病的药物中的应用。
技术效果
本发明化合物作为一种RNA聚合酶抑制剂，在细胞水平抑制流感病毒复制试验中展示出积极效应，在动物体内药效模型中表现出优异的体重保护，并且恢复时间早，血浆蛋白结合率测试结果显示本发明化合物在血浆中具中等的血浆蛋白结合率，PK结果显示具有良好的药代动力学性质，具有良好的成药性质。
附图说明
图1.S-033447与蛋白(PDB ID:6FS6)的3D结合模式。
图2.S-033447与氨基酸和金属离子相互作用展示。
图3.S-033447低能构象两个二面角。
图4.S-033447的两个二面角在转动过程中能量的变化。
图5.化合物A(深色)与S-033447(浅色)低能构象比较。
图6.化合物A的两个二面角在转动过程中能量的变化
图7.化合物B(深色)与S-033447(浅色)低能构象比较。
图8.化合物B的两个二面角在转动过程中能量的变化。
相关定义
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘 代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2022070733-appb-000060
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2022070733-appb-000061
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2022070733-appb-000062
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2022070733-appb-000063
直形虚线键
Figure PCTCN2022070733-appb-000064
或波浪线
Figure PCTCN2022070733-appb-000065
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2022070733-appb-000066
中的直形虚线键表示通过该基团中的氮原子的 两端与其他基团相连；
Figure PCTCN2022070733-appb-000067
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2022070733-appb-000068
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2022070733-appb-000069
Figure PCTCN2022070733-appb-000070
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022070733-appb-000071
仍包括
Figure PCTCN2022070733-appb-000072
这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，术语“C 1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氨基包括C 1-2、C 3和C 2烷氨基等。C 1-3烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2等。
除非另有规定，“C 3-5环烷基”表示由3至5个碳原子组成的饱和环状碳氢基团，其为单环体系，所述C 3-5环烷基包括C 3-4和C 4-5环烷基等；其可以是一价、二价或者多价。C 3-5环烷基的实例包括，但不限于，环丙基、环丁基、环戊基等。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、 对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2022070733-appb-000073
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明采用下述缩略词：DMAC：N,N-二甲基乙酰胺，PG：丙二醇，HP-β-CD：羟丙基-β-环糊精，Solutol HS-15代表聚乙二醇(15)-羟基硬脂酸酯。
本发明所使用的溶剂可经市售获得。化合物依据本领域常规命名原则或者使用
Figure PCTCN2022070733-appb-000074
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
参考例1
Figure PCTCN2022070733-appb-000075
合成方法：
Figure PCTCN2022070733-appb-000076
参考例2
Figure PCTCN2022070733-appb-000077
合成方法：
Figure PCTCN2022070733-appb-000078
Figure PCTCN2022070733-appb-000079
以盐野义公司的抗流感药物S-033447作为参照化合物，通过薛定谔公司Maestro软件的Macromodel模块计算S-033447的低能构象。在低能构象中吡啶并六氢嘧啶(以下称为母核)的二面角(dehidal 1)为-146.6°，母核与2,5-二氢噻吩二面角(dehidal 2)为56.8°(见附图3)。S-033447从其低能构象变换到其蛋白结合模式活性构象(母核从-146.6°旋转到-153.7°，2,5-二氢噻吩与母核二面角从56.8°旋转到55.0°)需要克服0.8kcal/mol的能垒(见附图4)。S-033447与蛋白(PDB ID:6FS6)的3D结合模式见附图1，S-033447与氨基酸和金属离子相互作用展示见附图2。
实施例1
通过观察S-033447和6FS6蛋白的活性构象结合模式，我们发现S-033447的苯并2,5-二氢噻吩并二氟苄基片段在自由旋转的同时，与吡啶并六氢嘧啶母核间形成的最低能垒构象(低能构象)，与S-033447和6FS6蛋白共晶中的蛋白结合模式构象(活性构象)较为吻合，这解释了S-033447和6FS6蛋白的高结合活性。一般地，小分子的最低能垒构象(低能构象)与其在该蛋白中的结合模式构象(活性构象)间的能垒差越小，意味着该小分子从低能构象变换到与该蛋白的结合活性构象时损失的能量就越小，化合物越容易与蛋白相结合，其结合活性将较高。
为了锁定S-033447的活性构象，进一步降低其旋转能垒，我们通过原子的替换将S-033447的四氢吡喃片段和2,5-二氢噻吩片段的O与S替换为Se，得到了不同的环硒戊烷片段和环硒己烷片段，并探索了这些Se代分子的最低能垒构象与S-033447和6FS6蛋白共晶中的活性构象间的能垒差别。
(1)经Macromodel模块计算化合物A和化合物B的低能构象旋转二面角和旋转能垒，结果如表1所示。化合物A(深色)与S-033447(浅色)低能构象比较见附图5，化合物A的两个二面角在转动过程中能量的变化见附图6，化合物B(深色)与S-033447(浅色)低能构象比较见附图7，化合物B的两个二面角在转动过程中能量的变化见附图8。
表1.本发明化合物低能构象旋转二面角和旋转能垒
化合物 Dihedral 1(度) Dihedral 2(度) E(Kcal/mol) ΔE(Kcal/mol)
S-033447(活性构象) -153.7 55.0 67.6 0
S-033447(低能构象) -146.6 56.8 66.8 0.8
化合物A(低能构象) 163.5 51.4 39.6 28
化合物B(低能构象) -147.1 53.8 56.8 10.8
注：Dihedral 1为吡啶并六氢嘧啶的二面角，Dihedral 2为吡啶并六氢嘧啶和2,5-二氢噻吩的二面角，ΔE为从低能构象变换到S-033447的蛋白结合模式活性构象(Dihedral 1为-153.7°，Dihedral 2为55.0°)需要消耗的能垒。
结论：化合物B的低能构象与S-033447的活性构象叠合好。本发明化合物在6FS6蛋白结构中的结合最低能垒，与参照化合物在该蛋白结构中的活性构象下的能垒，具有较小的能量差异，因此本发明化合物较容易与该蛋白结合，在与该蛋白的实际结合中有可能展现与参照化合物相似的或更优的结合活性。
(2)经Macromodel模块计算化合物B的低能构象旋转二面角，结果如表2所示。
表2.本发明化合物低能构象旋转二面角
化合物 Dihedral 1(度) Dihedral 2(度)
化合物B(低能构象) -147.1 53.8
注：Dihedral 1为吡啶并六氢嘧啶的二面角，Dihedral 2为吡啶并六氢嘧啶和2,5-二氢硒代噻吩的二面角。结论：化合物B的低能构象与S-033447的低能构象基本一致。
实施例2
Figure PCTCN2022070733-appb-000080
Figure PCTCN2022070733-appb-000081
步骤1：化合物2-2的合成
将磷酸二氢钠(13.58g,113.19mmol)加入到水(20mL)中，加入乙腈(10mL)，二苯基二硒醚(1.18g,3.77mmol)，分批加入锌粉(986.83mg,15.09mmol)，反应液在室温下搅拌1小时，然后加入化合物2-1(2g,7.55mmol)，反应液在室温下搅拌过夜。将反应液过滤，滤饼用乙酸乙酯(10mL×2)洗涤，分液，水相用乙酸乙酯(10mL×2)萃取，合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干。所得粗品经硅胶柱纯化(石油醚:乙酸乙酯＝1:0至10:1)得化合物2-2。MS m/z:343.0[M+H] +。
步骤2：化合物2-3的合成
将化合物2-2(1.5g,4.40mmol)加入到甲醇(10mL)和水(5mL)中，加入氢氧化钠(527.53mg,13.19mmol)，反应液在60℃下搅拌2小时。将反应液冷却到室温，反应液用1N盐酸调至pH＝7，用乙酸乙酯萃取，合并有机相，用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干得化合物2-3，粗品直接用于下一步。
步骤3：化合物2-4的合成
将化合物2-3(1.3g,3.97mmol)加入到多聚磷酸(13mL)中，反应液在120℃下搅拌2小时。反应液冷却至80℃，加入到搅拌下的水(50mL)中，继续搅拌5分钟，用二氯甲烷(20mL×2)萃取，合并有机相，用水(20mL)洗涤，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干。所得粗品经硅胶柱纯化(石油醚:乙酸乙酯＝1:0至10:1)得化合物2-4。MS m/z:310.9[M+H] +。
步骤4：化合物2-5的合成
将化合物2-4(300mg,970.34μmol)加入甲醇(6mL)中，然后加入硼氢化钠(110.13mg,2.91mmol)，反应液在室温下搅拌1小时。反应液用1N盐酸调至pH＝7，然后用二氯甲烷(10mL×2)萃取，合并有机相，用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干。所得粗品经硅胶柱纯化(石油醚:乙酸乙酯＝10:1至2:1)得化合物2-5。
步骤5：化合物2-7的合成
将化合物2-6(50mg,152.75μmol)加入乙酸乙酯(1mL)中，加入化合物2-5(47.53mg,152.75μmol)，然后加入1-丙基磷酸酐(388.82mg,611.00μmol,363.38μL,50％乙酸乙酯溶液)和甲烷磺酸(58.72mg, 611.00μmol,43.50μL)，反应液回流过夜。将反应液冷却到室温，加入水(10mL)，用乙酸乙酯(5mL×2)萃取，合并有机相，用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干。所得粗品经硅胶柱纯化(二氯甲烷:甲醇＝1:0至10:1)得化合物2-7。MS m/z:622.0[M+H] +。
步骤6：化合物2和2’的合成
将化合物2-7(10mg,16.12μmol)加入到N,N-二甲基乙酰胺(0.5mL)中，加入氯化锂(3.42mg,80.58μmol,1.65μL)，反应液在80℃下搅拌3小时。将反应液冷却到室温，用乙腈(2mL)稀释。粗品反应液经制备型高效液相色谱分离纯化(柱子:Xtimate C18 100*30mm*3μm；流动相:[A：水(0.225％甲酸)；B：乙腈]；梯度：乙腈％:40％-60％,8分钟)得到化合物2(保留时间3.205分钟)和化合物2’(保留时间3.301分钟)。
化合物2(保留时间3.205分钟)， 1H NMR(400MHz,氘代甲醇)δ7.49(d,J＝7.53Hz,1H),7.23-7.32(m,2H),7.16-7.22(m,1H),7.07-7.15(m,1H),6.85-6.97(m,2H),5.85(d,J＝7.28Hz,1H),5.69(s,1H),5.39(dd,J＝2.64,12.67Hz,1H),4.73(dd,J＝2.89,10.16Hz,1H),4.62(br d,J＝15.56Hz,1H),4.12(d,J＝12.80Hz,1H),4.07(dd,J＝3.14,11.17Hz,1H),3.77(dd,J＝3.01,11.80Hz,1H),3.65(t,J＝10.54Hz,1H),3.43-3.53(m,1H),3.06-3.17(m,1H).MS m/z:532.1[M+H] +。
化合物2’(保留时间3.301分钟) 1H NMR(400MHz,氘代甲醇)δ7.51(d,J＝7.28Hz,1H),7.35-7.45(m,2H),7.21-7.33(m,2H),6.94-7.04(m,1H),6.82-6.93(m,1H),6.11(d,J＝7.53Hz,1H),5.52-5.68(m,2H),4.42-4.58(m,2H),4.16(d,J＝13.05Hz,1H),4.06(dd,J＝3.14,10.92Hz,1H),3.60-3.78(m,2H),3.39-3.52(m,1H),2.65-2.81(m,1H).MS m/z:532.1[M+H] +。
实施例3
Figure PCTCN2022070733-appb-000082
Figure PCTCN2022070733-appb-000083
步骤1：化合物3-2的合成
将化合物3-1(66g,383.43mmol)溶于二氯甲烷(460mL)中，加入N,N-二甲基甲酰胺(280.27mg,3.83mmol,295.02μL)，向反应液中滴加草酰氯(73.00g,575.15mmol,50.35mL)，滴完后反应液在20℃下搅拌30分钟，然后减压浓缩至干。所得粗品加入二氯甲烷(460mL)，搅拌下加入三乙胺(77.60g,766.87mmol,106.74mL)和N,O-二甲基羟胺盐酸盐(37.40g,383.43mmol,)，反应液在20℃下搅拌1小时。加入水(100mL)，分液，水相用二氯甲烷(50mL×2)萃取。合并有机相，分别用稀盐酸(0.2M，50mL)，饱和碳酸氢钠水溶液(50mL)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干，得化合物3-2。 1H NMR(400MHz,氘代氯仿)δ7.02-7.05(m,2H),3.81(brs,3H),3.49(s,3H),2.28(s,3H)。
步骤2：化合物3-3的合成
将化合物3-2(20g,92.94mmol)溶于四氢呋喃(200mL)中，在0℃下滴加甲基溴化镁(3M,37.18mL)，滴完后反应液升温至20℃搅拌2小时。反应液用1M盐酸淬灭，调节pH至7，用乙酸乙酯(100mL×2)萃取，合并有机相，分别用稀盐酸(0.2M，50mL)，饱和碳酸氢钠溶液(50mL)，饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干得化合物3-3。 1H NMR(400MHz,氘代氯仿)δ7.47-7.50(m,1H),7.03-7.07(m,1H),2.60(s,3H),2.47(s,3H)。
步骤3：化合物3-4的合成
将化合物3-3(15g,88.15mmol)溶于吡啶(90mL)中，加入二氧化硒(19.56g,176.31mmol)，反应液在110℃下搅拌12小时。将反应液冷却至室温，过滤，减压浓缩干。粗品中加入水(50mL)，用1M盐酸调pH至4，用乙酸乙酯(50mL×3)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干得化合物3-4。 1H NMR(400MHz,氘代甲醇)δ7.64-7.68(m,1H),7.30-7.32(m,1H),2.52(s,3H)。
步骤4：化合物3-5的合成
将化合物3-4(15g,74.95mmol)溶于二氯甲烷(60mL)和甲醇(60mL)中，控温0～20℃，滴加三甲基硅基重氮甲烷(2M,44.97mL)，反应液在20℃下搅拌2小时，然后加入乙酸(3mL)，搅拌5分钟。将反应液减压浓缩至干，加入水(50mL)，用二氯甲烷(50mL×2)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干。所得粗品经硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯比例：0～20％)得化合物3-5。 1H NMR(400MHz,氘代氯仿)δ7.51-7.55(m,1H),7.12-7.16(m,1H),3.98(s,3H),2.54(s,3H)。
步骤5：化合物3-6的合成
将化合物3-5(5g,23.35mmol)溶于1,2-二氯乙烷(50mL)中，加入N-溴代丁二酰亚胺(8.31g,46.69mmol)和偶氮二异丁腈(383.37mg,2.33mmol)，反应液在80℃下搅拌12小时。将反应液冷却至室温，分别用饱和亚硫酸钠溶液(20mL)，水(20mL)和饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干。所得粗品经硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯比例：0～5％)得化合物3-6。 1H NMR(400MHz,氘代氯仿)δ7.61-7.64(m,1H),7.26-7.31(m,1H),4.94(s,2H),3.99(s,3H)。
步骤6：化合物3-7的合成
将磷酸二氢钠(11.52g,96.05mmol)溶于水(60mL)中，然后加入乙腈(30mL),加入3-(3-吡啶基二硒基)吡啶(3.62g,11.53mmol)，分批加入锌粉(1.88g,28.82mmol)，反应液在20℃下搅拌30分钟。加入化合物3-6(5.63g,19.21mmol)，反应液在20℃下搅拌3小时。将反应液过滤，滤液用乙酸乙酯(30mL×2)萃取。合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干。所得粗品经硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯比例：0～60％)得化合物3-7。MS(ESI)m/z:373.8[M+H] +。
步骤7：化合物3-8的合成
将化合物3-7(4.2g,11.28mmol)溶于二氯甲烷(80mL)中，加入戴斯-马丁过碘烷(7.18g,16.93mmol)，反应液在20℃下搅拌12小时。反应液中加入饱和亚硫酸钠溶液(30mL)，搅拌5分钟。用二氯甲烷(30mL×2)萃取，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干。 所得粗品经硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯比例：0～50％)得化合物3-8。MS(ESI)m/z:371.9[M+H] +。
步骤8：化合物3-9的合成
将化合物3-8(2.9g,7.83mmol)溶于四氢呋喃(16mL)中，加入氢氧化钠水溶液(626.67mg,15.67mmol，4mL)，反应液在20℃下搅拌1小时。减压浓缩除去大部分四氢呋喃，水相用1N盐酸调节pH至6，固体过滤，滤饼减压抽干得化合物3-9。MS(ESI)m/z:357.9[M+H] +。
步骤9：化合物3-10的合成
将化合物3-9(2.3g,6.46mmol)溶于二甲基亚砜(23mL)中，分别加入过硫酸铵(2.95g,12.91mmol,)，硝酸银(109.69mg,645.74μmol和浓硫酸(633.34mg,6.46mmol)，反应液在50℃下搅拌3小时。向反应液中分别加入饱和碳酸氢钠水溶液(20mL)，水(10mL)和二氯甲烷(20mL)，搅拌5分钟，过滤，滤液分液，水相用二氯甲烷(10mL)萃取。合并有机相，用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干。所得粗品经硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯比例：0～50％)得化合物3-10。MS(ESI)m/z:311.8[M+H] +。
步骤10：化合物3-11的合成
将化合物3-10(390mg,1.26mmol)溶于异丙醇(8mL)中，加入硼氢化钠(95.14mg,2.51mmol)，反应液在20℃下搅拌1小时。加入1N盐酸调节pH至7，用乙酸乙酯(15mL×2)萃取，合并有机相，用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干。所得粗品经硅胶柱纯化(乙酸乙酯/石油醚，乙酸乙酯比例：0～50％)得化合物3-11。MS(ESI)m/z:313.8[M+H] +。
步骤11：化合物3-12的合成
将化合物3-11(330mg,1.06mmol)溶于二氯甲烷(6mL)中，加入二氯亚砜(251.53mg,2.11mmol,153.37μL)，反应液在20℃下搅拌1小时。将反应液减压浓缩至干得化合物3-12，粗品直接用于下一步反应。
步骤12：化合物3-13和3-13’的合成
将化合物2-6(340mg,1.04mmol)溶于乙腈(6mL)中，加入化合物3-12(343.41mg,1.04mmol)和碳酸铯(676.86mg,2.08mmol)，反应液在60℃下搅拌12小时。将反应液冷却到室温，加入水(5mL)，用乙酸乙酯(5mL×3)萃取，合并有机相，用饱和食盐水(5mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干。所得粗品经硅胶柱纯化(甲醇/二氯甲烷，甲醇比例：0～5％)，所得化合物经超临界流体色谱柱检测(分析方法：柱子型号:Chiralpak AD-3(50mm*4.6mm,3μm)；流动相:[A：二氧化碳，B：0.05％二乙胺/乙醇]；梯度：流动相B浓度在2分钟内从5％增加至40％，40％保持1.2分钟，然后5％保持0.8分钟)分析为混合物，使用手性分离(柱子型号:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:[A：二氧化碳，B：0.1％氨水/乙醇]；梯度：流动相B保持40％)分离得到手性异构体化合物3-13(保留时间1.831min，ee＝96.1％)和化合物3-13’(保留时间2.031min，ee＝100％)。
步骤13：化合物3的合成
将化合物3-13(6mg,9.65μmol)加入到N,N-二甲基乙酰胺(1mL)中，加入氯化锂(2.05mg,48.27μmol)，反应液在80℃下搅拌12小时。将反应液冷却到室温，用乙腈(1mL)稀释。粗品反应液经制备型高效液相色谱分离纯化(柱子:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相:[A：水(0.225％甲酸)；B：乙腈]；梯度：乙腈％:30％-53％,5分钟)得到化合物3。 1H NMR(400MHz,氘代甲醇)δ7.98-8.09(m,1H),7.70(dd,J＝1.51,8.03Hz,1H),7.41(d,J＝7.53Hz,1H),7.18-7.31(m,2H),7.13(dd,J＝4.52,8.03Hz,1H),5.75-5.88(m,2H),5.40-5.53(m,1H),4.71(dd,J＝3.01,10.04Hz,1H),4.63(br s,1H),4.17(d,J＝12.55Hz,1H),4.07(dd,J＝3.01,11.04Hz,1H),3.77(dd,J＝3.01,11.54Hz,1H),3.66(t,J＝10.54Hz,1H),3.48(dt,J＝2.51,11.80Hz,1H),3.04-3.18(m,1H)。MS(ESI)m/z:533.1[M+H] +。
步骤14：化合物3’的合成
将化合物3-13’(5mg,8.05μmol)加入到N,N-二甲基乙酰胺(1mL)中，加入氯化锂(1.71mg,40.23μmol)，反应液在80℃下搅拌12小时。将反应液冷却到室温，用乙腈(1mL)稀释。粗品反应液经制备型高效液相色谱分离纯化(柱子:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相：[A：水(0.225％甲酸)；B：乙腈]；梯度：乙腈％：30％-53％，5分钟)得到化合物3’。 1H NMR(400MHz,氘代甲醇)δ8.39-8.49(m,1H),7.83(dd,J＝1.51,8.03Hz,1H),7.26-7.39(m,2H),6.95-7.10(m,1H),6.85(br s,1H),5.92(d,J＝7.53Hz,1H),5.72(s,1H),5.64(br d,J＝13.55Hz,1H),4.50-4.58(m,1H),4.36(br d,J＝7.53Hz,1H),4.16-4.24(m,1H),4.05(dd,J＝3.01,11.04Hz,1H),3.74(dd,J＝3.51,11.54Hz,1H),3.65(t,J＝10.54Hz,1H),3.47(dt,J＝2.51,11.80Hz,1H),2.79-2.91(m,1H)。MS(ESI)m/z:533.1[M+H] +。
实施例4
Figure PCTCN2022070733-appb-000084
Figure PCTCN2022070733-appb-000085
将化合物3(130.00mg,244.65μmol)加入到N,N-二甲基乙酰胺(2mL)中，然后加入氯甲基碳酸甲酯(45.70mg,366.98μmol)，碳酸钾(67.63mg,489.30μmol)和碘化钾(40.61mg,244.65μmol)，反应液在70℃下搅拌3小时。反应液冷却到室温，加入水(10mL)，用乙酸乙酯(10mL×2)萃取，有机相用饱和食盐水(10mL×4)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干。所得粗品经硅胶柱(二氯甲烷:甲醇＝1:0至20:1)纯化得化合物4。 1H NMR(400MHz,氘代氯仿)δ8.03(dd,J＝1.00,4.52Hz,1H),7.44(dd,J＝1.51,8.03Hz,1H),6.99-7.16(m,3H),6.95(dd,J＝4.52,8.03Hz,1H),5.90(d,J＝6.53Hz,1H),5.74-5.85(m,1H),5.22-5.35(m,3H),4.60(dd,J＝2.01,13.55Hz,1H),4.50(dd,J＝3.01,10.04Hz,1H),4.03(d,J＝12.55Hz,1H),3.95(dd,J＝3.01,11.04Hz,1H),3.77-3.83(m,3H),3.73(dd,J＝3.01,12.05Hz,1H),3.54(t,J＝10.54Hz,1H),3.41(dt,J＝2.51,11.80Hz,1H),2.85-2.97(m,1H)；MS(ESI)m/z:621.0[M+H] +。
化合物4经单晶X射线衍射法(SXRD)确证绝对构型为：
Figure PCTCN2022070733-appb-000086
实施例5
Figure PCTCN2022070733-appb-000087
Figure PCTCN2022070733-appb-000088
将化合物2(30.00mg,56.56μmol)加入到N,N-二甲基乙酰胺(1mL)中，然后加入氯甲基碳酸甲酯(14.09mg,113.13μmol)，碳酸钾(15.64mg,113.13μmol)和碘化钾(9.39mg,56.56μmol)，反应液在70℃下搅拌3小时。反应液冷却到室温，加入水(3mL)，用乙酸乙酯(3mL×2)萃取，有机相用饱和食盐水(3mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干。所得粗品经制备型薄层硅胶板纯化(二氯甲烷:甲醇＝10:1)得化合物5。 1H NMR(400MHz,氘代甲醇)δ7.54(d,J＝7.53Hz,1H),7.13-7.28(m,3H),7.07-7.13(m,1H),6.99-7.05(m,1H),6.90-6.97(m,1H),5.92(d,J＝7.78Hz,1H),5.75-5.83(m,2H),5.66(s,1H),5.39(dd,J＝2.64,12.67Hz,1H),4.65(dd,J＝3.01,10.04Hz,1H),4.55(dd,J＝2.13,13.43Hz,1H),4.03-4.15(m,2H),3.80-3.85(m,3H),3.75(dd,J＝3.26,11.54Hz,1H),3.56(t,J＝10.54Hz,1H),3.42(dt,J＝2.51,11.67Hz,1H),2.98-3.08(m,1H)；MS(ESI)m/z:620.1[M+H] +。
实施例6
Figure PCTCN2022070733-appb-000089
Figure PCTCN2022070733-appb-000090
步骤1：化合物6-2的合成
在冰浴下，向化合物6-1(3.35g,13.61mmol)的甲醇(8mL)和四氢呋喃(32mL)溶液中滴加三甲基硅烷重氮甲烷溶液(2M,13.61mL，27.22mmol)，滴加完后将反应液升温至20℃搅拌1小时。向反应液中加入饱和柠檬酸溶液(100mL)，用乙酸乙酯(100mL×3)萃取，合并有机相，依次用饱和碳酸氢钠溶液(100mL)和饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，旋干，得到化合物6-2粗品，直接用于下一步反应。
步骤2：化合物6-3的合成
将化合物6-2(3.98g,15.29mmol)，肼基甲酸叔丁酯(2.02g,15.29mmol)和对甲苯磺酸吡啶盐(3.84g,15.29mmol)加入N,N-二甲基乙酰胺(80mL)，反应液于60℃反应12小时。将反应液冷却至室温，加入水(200mL)，用乙酸乙酯(100mL×3)萃取，合并有机相，分别用水(200mL)和饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，旋干。粗品经硅胶柱层析(石油醚:乙酸乙酯＝3:1至1:2)纯化得到化合物6-3。
步骤3：化合物6-4的合成
将化合物6-3(2.7g,7.21mmol)，丙烯酸甲酯(1.24g,14.42mmol,1.30mL)，N,N-二异丙基乙基胺(2.80g,21.64mmol,3.77mL)溶于乙腈(35mL)，反应液于50℃反应12小时。将反应液浓缩旋干，粗品经硅胶柱层析(石油醚:乙酸乙酯＝4:1至1:2，体积比)纯化得到化合物6-4。
步骤4：化合物6-5的合成
向化合物6-4(1.6g,3.47mmol)的乙酸乙酯(20mL)溶液中加入盐酸乙酸乙酯溶液(4M,10mL)，反应液在25℃搅拌1小时。将反应液减压浓缩得到盐酸盐粗品6-5，直接用于下一步反应。
步骤5：化合物6-6的合成
将化合物6-5(1.18g，盐酸盐)和叔丁醇钾(955.32mg,8.51mmol)加入乙腈(20mL)，反应液于25℃搅拌1小时。加入甲醇(30mL)，浓缩，旋干。粗品经硅胶柱层析(石油醚：乙酸乙酯＝3:1至0:1，体积比，然后二氯甲烷：甲醇＝10:1至0:1)分离纯化，得到化合物6-6。
步骤6：化合物6-7的合成
将化合物6-6(3g,9.14mmol)溶于二甲基亚砜(30mL)和水(3mL)中，加入氯化钠(1.07g,18.27mmol)，反应液在90℃下搅拌12小时。将反应液用水(100mL)稀释，二氯甲烷(100mL×3)萃取，有机相经饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经硅胶柱层析(二氯甲烷：甲醇＝1:0至10:1)纯化得化合物6-7。
步骤7：化合物6-8的合成
将化合物6-7(0.3g,1.11mmol)和二苯基(乙烯基)锍三氟甲磺酸盐(482.68mg,1.33mmol)溶于二甲基亚砜(3.6mL)中，加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(506.93mg,3.33mmol)，反应液在25℃下搅拌1小时。将反应液用水(30mL)稀释，乙酸乙酯(30mL×3)萃取，有机相经饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，滤液减压浓缩，所得粗品经硅胶柱层析(二氯甲烷：甲醇＝1:0至10:1)纯化得化合物6-8。MS(ESI)m/z:297.3[M+H] +。
步骤8：化合物6-9的合成
将化合物6-8(70mg,236.23μmol)和化合物2-5(73.51mg,236.23μmol)加入到乙酸乙酯(2mL)中，然后加入三正丙基环磷酸酐(50％乙酸乙酯溶液，300.66mg,472.46μmol,280.99μL)和甲烷磺酸(22.70mg,236.23μmol,16.82μL)，反应液在77℃下搅拌3小时。反应液冷却到室温，加入水(10mL)，用乙酸乙酯萃取(5mL×2)，有机相合并，用饱和食盐水洗(5mL)，无水硫酸钠干燥，过滤，滤液减压浓缩干得粗品。粗品用快速硅胶柱纯化(二氯甲烷：甲醇＝1:0至10:1)得化合物6-9。MS(ESI)m/z:591.1[M+H] +。
步骤9：化合物6-9A和6-9B的合成
化合物6-9经超临界流体色谱柱检测(分析方法：柱子型号:CHIRALCEL OD-3(100mm×4.6mm,3μm)；流动相:[A:二氧化碳，B：0.05％二乙胺/乙醇]；梯度：B％:4min内从5％增加至40％，然后保持2.5min；然后5％保持1.5min)分析为外消旋化合物，经手性分离(柱子型号:DAICEL CHIRALCEL OD-H(25mm×30mm,5μm)；流动相:[A：二氧化碳，B：0.1％氨水/乙醇]；梯度：B％:40％-40％)得到化合物6-9A(保留时间4.024min)和化合物6-9B(保留时间4.447min)。
步骤10：化合物6的合成
将化合物6-9A(20mg,33.93μmol)加入到N,N-二甲基乙酰胺(1mL)中，然后加入氯化锂(7.19mg,169.64μmol)，反应液在80℃下搅拌12小时。反应液冷却到室温，用乙腈(2mL)稀释。粗品经制备型 高效液相分离纯化(柱子型号:Xtimate C18 100×30mm×3μm；流动相:[水(0.225％甲酸)-乙腈]；乙腈％:50％-70％,5min)得化合物6。 1H NMR(400MHz,氘代甲醇)δ7.59(d,J＝7.53Hz,1H),7.19-7.31(m,2H),7.03-7.19(m,2H),6.90(br s,2H),5.86(d,J＝7.53Hz,1H),5.45-5.61(m,2H),4.26(br d,J＝15.06Hz,1H),4.11(d,J＝12.55Hz,1H),3.07(br d,J＝15.06Hz,1H),1.84-1.97(m,1H),1.60-1.75(m,1H),0.92-1.12(m,2H)；MS(ESI)m/z:501.2[M+H] +。
步骤11：化合物6’的合成
将化合物6-9B(20.00mg,33.93μmol)加入到N,N-二甲基乙酰胺(1mL)中，然后加入氯化锂(7.19mg,169.64μmol,3.47μL)，反应液在80℃下搅拌12小时。反应液冷却到室温，用乙腈(2mL)稀释。粗品经制备型高效液相分离纯化(柱子型号:Xtimate C18 100×30mm×3μm；流动相:[水(0.225％甲酸)-乙腈]；乙腈％:50％-70％,5min)得化合物6’。 1H NMR(400MHz,氘代甲醇)δ7.59(d,J＝7.53Hz,1H),7.19-7.32(m,2H),7.02-7.19(m,2H),6.81-6.96(m,2H),5.86(d,J＝7.53Hz,1H),5.44-5.63(m,2H),4.26(br d,J＝15.06Hz,1H),4.11(d,J＝12.55Hz,1H),3.07(br d,J＝15.06Hz,1H),1.81-1.98(m,1H),1.57-1.73(m,1H),0.90-1.14(m,2H)。MS(ESI)m/z:501.1[M+H] +。
生物测试数据
实验例1：流感病毒细胞病变(CPE)实验
通过测定化合物的半数有效浓度(EC 50)值来评价化合物对流感病毒(Inflμenza virus,IFV)的抗病毒活性。细胞病变实验被广泛用于测定化合物对病毒感染细胞的保护作用来反映化合物的抗病毒活性。
流感病毒CPE实验
将MDCK细胞以2,000细胞每孔的密度种入黑色384孔细胞培养板中，随后置于37℃，5％CO 2培养箱中培养过夜。化合物由Echo555非接触式纳升级声波移液系统进行稀释并加入到细胞孔内(4倍倍比稀释，8个测试浓度点)。流感病毒A/PR/8/34(H1N1)株随后以每孔1-2 90％组织培养感染剂量(TCID90)加入细胞培养孔中，培养基中DMSO终浓度为0.5％。设置病毒对照孔(加入DMSO和病毒，不加化合物)，细胞对照孔(加入DMSO，不加化合物和病毒)和培养基对照孔(只有培养基，不含细胞)。化合物的细胞毒性测定和抗病毒活性测定平行进行，除了不加病毒，其它的实验条件和抗病毒活性实验一致。细胞板置于37℃，5％CO 2培养箱中培养5天。培养5天后使用细胞活力检测试剂盒CCK8检测细胞活性。原始数据用于化合物抗病毒活性和细胞毒性计算。
化合物的抗病毒活性和细胞毒性由化合物分别对病毒引起的细胞病毒效应的抑制率(％)表示。计算公式如下：
Figure PCTCN2022070733-appb-000091
使用GraphPad Prism软件对化合物的抑制率和细胞毒性进行非线性拟合分析，得到化合物的EC 50值。实验结果见表3。
表3化合物对于流感病毒A/PR/8/34(H1N1)的抑制活性
化合物 EC 50(nM)
化合物2 2.0
化合物2’ 54.5
化合物3 2.8
化合物3’ 157
化合物6’ 0.75
结论：本发明化合物在细胞水平抑制流感病毒复制试验中展示出积极效应。
实验例2：体内药效研究
实验目的：评价化合物在甲型流感病毒H1N1小鼠感染模型中的药效
实验方案：小鼠经滴鼻感染甲型流感病毒A/PR/8/34(H1N1)，感染后48小时开始用化合物处理，口服给药，连续7天，每天两次。通过观察小鼠体重变化及存活率，来评价化合物在该模型中的抗甲型流感病毒H1N1作用。
实验选用SPF级别的BALB/c小鼠，6-7周，雌性。小鼠到达BSL-2动物房后适应至少3天后开始实验。将感染当天设为实验第0天。小鼠经戊巴比妥钠腹腔注射麻醉(75mg/kg,10mL/kg)，待动物进入深麻状态后，经滴鼻感染A/PR/8/34(H1N1)病毒，感染体积为50μL。从第2天至第8天，每天口服给予5mg/kg(给药体积10mL/kg)待测化合物，每天两次。首次给药时间为感染后48小时。每天观察小鼠状态，并记录小鼠体重及存活率。在第14天时，将所有存活动物进行安乐死。
实验结果：
检测动物存活率及体重下降率，体重下降率＝(第0天体重–第N天体重)/第0天体重*100％。结果如表4所示：化合物5在第7天可以实现保护动物体重最大下降率为13.77％，然后开始恢复，至实验结束小鼠存活率为100％；化合物4在第3天可以实现保护动物体重最大下降率为7.03％，然后开始恢复，至实验结束小鼠存活率为100％。
表4动物存活率及体重下降率结果
化合物 最大体重下降率(第N天) 存活率(百分比)
化合物5 13.77％(第7天) 100％
化合物4 7.03％(第3天) 100％
结论：本发明化合物在动物体内药效模型中表现出优异的体重保护，并且恢复时间早。
实验例3：对Baloxavir耐药A/PR/8/34(H1N1)I38T流感病毒株细胞病变(CPE)实验
实验目的：通过测定化合物的半数有效浓度(EC 50)值来评价化合物对Baloxavir耐药A/PR/8/34(H1N1)I38T流感病毒株的抗病毒活性。
实验方案：MDCK细胞以每孔15,000个细胞的密度接种于96孔细胞培养板中，并于37℃，5％CO 2培养箱中培养过夜。次日加入化合物溶液(3倍系列稀释、8个浓度点、三复孔)和Baloxavir耐药A/PR/8/34(H1N1)流感病毒株，细胞培养液中DMSO终浓度为0.5％。细胞在5％CO 2、37℃培养箱中培养5天，直至无化合物的病毒感染对照孔内细胞病变达80–95％。然后用CCK8检测每孔细胞活力。如含化合物孔的细胞活力较病毒感染对照孔高，即CPE减弱，则表明化合物对所测病毒有抑制作用。
实验结果：
化合物的抗病毒活性由化合物对病毒引起的细胞病毒效应的抑制活性(％)表示。计算公式如下：
Figure PCTCN2022070733-appb-000092
EC 50使用GraphPad Prism(version 5)软件对化合物的抑制活性和细胞活率进行非线性拟合分析，拟合方法为"log(inhibitor)vs.response--Variable slope"。实验结果见表5。
表5本发明化合物对Baloxavir耐药A/PR/8/34(H1N1)I38T流感病毒株的抑制活性结果
化合物 EC 50(nM)
化合物2 133.7
化合物3 57.5
结论：本发明化合物在细胞水平抑制Baloxavir耐药A/PR/8/34(H1N1)流感病毒株复制试验中展示出积极效应。
实验例4：体内药效研究
实验目的：评价化合物在甲型流感病毒H1N1耐药株中小鼠感染模型中的药效
实验方案：小鼠经滴鼻感染甲型流感病毒Baloxavir耐药A/PR/8/34(H1N1)I38T病毒株，感染前2小时开始用化合物处理，口服给药，连续7天，每天两次。通过观察小鼠体重变化及存活率，来评价化合物在该模型中的抗甲型流感病毒H1N1作用。
实验选用SPF级别的BALB/c小鼠，6-7周，雌性。小鼠到达BSL-2动物房后适应至少3天后开始实验。将感染当天设为实验第0天。小鼠经腹腔注射舒泰50/盐酸赛拉嗪深度麻醉后，经滴鼻感染Baloxavir耐药A/PR/8/34(H1N1)I38T病毒株，感染体积为50μL。从第2天至第8天，每天口服给予15mg/kg或50mg/kg(给药体积10mL/kg)待测化合物，每天两次。首次给药时间为感染前2小时。每天观察小鼠状态，并记录 小鼠体重及存活率。在第14天时，将所有存活动物进行安乐死。
实验结果：
检测动物存活率及体重下降率，体重下降率＝(第0天体重–第N天体重)/第0天体重*100％。实验结果如下表6所示。化合物4在给药剂量50mg/kg时小鼠体重几乎没有下降，至实验结束小鼠存活率为100％。
表6动物存活率及体重下降率结果
Figure PCTCN2022070733-appb-000093
结论：本发明化合物在动物体内药效模型中表现出优异的体重保护，并且恢复时间早。
实验例5 化合物的血浆蛋白结合率测试
实验目的：采用平衡透析法评估本发明化合物在CD-1小鼠、SD大鼠和人血浆中的蛋白结合率。
试验方案：将受试化合物分别用透析缓冲液稀释到上述五个物种的血浆中，配制成终浓度为2μM的样品，然后将样品加入到96孔平衡透析装置中，在37℃下用磷酸盐缓冲溶液透析4小时。实验采用华法林(warfarin)作为对照化合物。血浆和缓冲液中受试化合物与warfarin的浓度用LC-MS/MS法进行测定。
实验结果：结果显示如表7。
表7本发明化合物血浆蛋白结合率结果
化合物 血浆蛋白结合PPB unbound(％)
化合物3 25.9(H),31.3(R),13.7(M),24.6(D),31.6(C)
化合物2 6.7(H),7.9(R),9.5(M),13.6(D),13.6(C)
注：H代表人，R代表大鼠，M代表小鼠,D代表犬,C代表食蟹猴
结论：本发明化合物在五个种属血浆中均具中等的血浆蛋白结合率，预示在上述五个种属的血浆中，受试化合物的游离态药物浓度比例适中，具有良好的成药性质。
实验例6：大鼠药代动力学研究试验
实验目的：考察本发明化合物单次静脉注射和灌胃给药后雄性SD大鼠体内血浆药代动力学。
实验动物：雄性SD大鼠，6-8周龄，体重200-300克；
实验过程：注射给药(i.v.)，剂量为1mpk，浓度为0.50mg/mL，溶媒为40％DMAC+40％PG+20％(20％HP-β-CD+水)；口服给药(po)，剂量为10mpk，浓度为1mg/mL，溶媒为3％DMSO+10％solutol HS+87％水)。
样品采集：实验动物每个时间点从隐静脉穿刺采集血液样本0.03mL，记录实际采血时间。所有血样均加入规格为1.5mL的商品化EDTA-K2抗凝管中。血样采集后，血浆基质当中添加DDV做稳定剂，其 中，血浆：敌敌畏溶液＝40:1，敌敌畏溶液为40mM敌敌畏的乙腈/水(1:1)溶液，在半小时内，于4℃、3000g离心10分钟吸取上清血浆，迅速置于干冰中，于-80℃冰箱保存，用于LC-MS/MS分析。
数据分析：采用Phoenix WinNonlin 6.3药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法方法计算药动学参数：Cl(表观清除率)，T 1/2(清除一半化合物所需时长)，C max(达峰浓度)，AUC 0-last(0-末次取样时间内的浓度积分面积)，结果见表8。
表8本发明化合物的大鼠PK结果
化合物 Cl(mL/Kg/min) T 1/2(h) C max(nM) AUC 0-last(nM·h)
化合物3(i.v.) 178 1.7 / 171
化合物4(po) / 2.9 332 946
实验结论：本发明化合物口服血浆暴露量较高，具有良好的药代动力学性质。
实验例7：比格犬药代动力学研究试验
实验目的：考察本发明化合物单次静脉注射和灌胃给药后雄性比格犬体内血浆药代动力学。
实验动物：雄性比格犬，≥6月龄，体重6～12千克；
实验过程：注射给药(i.v.)，剂量为1mpk，浓度为1mg/mL，溶媒为10％DMAC+90％(20％HP-β-CD+水)；口服给药(po)，剂量为10mpk，浓度为2mg/mL，溶媒为3％DMSO+10％solutol HS+87％水)。
样品采集：实验动物每个时间点从隐静脉穿刺采集血液样本0.8mL，记录实际采血时间。所有血样均加入规格为1.5mL的商品化EDTA-K2抗凝管中。血样采集后，血浆基质当中添加DDV做稳定剂，其中，血浆：敌敌畏溶液＝40:1，敌敌畏溶液为40mM敌敌畏的乙腈/水(1:1)溶液，在半小时内，于4℃、3000g离心10分钟吸取上清血浆，迅速置于干冰中，于-80℃冰箱保存，用于LC-MS/MS分析。
数据分析：采用Phoenix WinNonlin 6.3药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法方法计算药动学参数Cl,T 1/2,C max,AUC 0-last，结果见表9。
表9本发明化合物的比格犬PK结果
化合物 Cl(mL/Kg/min) T 1/2(h) C max(nM) AUC 0-last(nM·h)
化合物3(i.v.) 36.8 3.7 / 830
化合物4(po) / 6.4 1100 3852
实验结论：本发明化合物清除率低，半衰期时间长，口服血浆暴露量高，具有良好的药代动力学性质。

Claims (19)

  1. 式(VI)所示化合物或其药学上可接受的盐，
    Figure PCTCN2022070733-appb-100001
    其中，
    R 7选自H和
    Figure PCTCN2022070733-appb-100002
    R 8选自C 1-3烷基和
    Figure PCTCN2022070733-appb-100003
    所述C 1-3烷基和
    Figure PCTCN2022070733-appb-100004
    任选被1、2或3个R a取代；
    R 9选自H，E 1选自Se，X 1选自CR 10R 11，R 10和R 11与其共同连接的原子一起形成C 3-5环烷基；
    或者，X 1和R 9与其连接的原子一起形成
    Figure PCTCN2022070733-appb-100005
    p选自0和1，E 1和E 2其中一个选自Se，另一个选自S和O；
    各R 12分别独立地选自H、F、Cl、Br、I、OH、NH 2、-COOH、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基，所述C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基分别独立地任选被1、2或3个R b取代；
    T 1、T 2、T 3和T 4分别独立地选自CH和N；
    q选自0和1；
    t选自0、1、2、3和4；
    各R a和R b分别独立地选自H、F、Cl、Br和I；
    条件是，当T 1选自CH，且E 1选自Se，且E 2选自O，p选自1，q选自1时，各R 12分别独立地选自OH和NH 2。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，各R 12分别独立地选自F。
  3. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 8选自CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和
    Figure PCTCN2022070733-appb-100006
    所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和
    Figure PCTCN2022070733-appb-100007
    任选被1、2或3个R a取代。
  4. 根据权利要求3所述化合物或其药学上可接受的盐，其中，R 8选自CH 3、CH 2CH 3、CH(CH 3) 2和
    Figure PCTCN2022070733-appb-100008
  5. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 7选自H、
    Figure PCTCN2022070733-appb-100009
    Figure PCTCN2022070733-appb-100010
  6. 根据权利要求1所述化合物或其药学上可接受的盐，其中，E 1选自Se，E 2选自O。
  7. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022070733-appb-100011
    选自
    Figure PCTCN2022070733-appb-100012
    R 5和R 6分别独立地选自H、F、Cl、Br、I、OH、NH 2、-COOH、C 1-3烷基、C 1- 3烷氧基和C 1-3烷氨基，所述C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基分别独立地任选被1、2或3个R b取代，T 1、E 1、q和R b如权利要求1所定义。
  8. 根据权利要求7所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022070733-appb-100013
    选自
    Figure PCTCN2022070733-appb-100014
  9. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022070733-appb-100015
    选自
    Figure PCTCN2022070733-appb-100016
    Figure PCTCN2022070733-appb-100017
  10. 根据权利要求9所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022070733-appb-100018
    选自
    Figure PCTCN2022070733-appb-100019
    Figure PCTCN2022070733-appb-100020
  11. 根据权利要求1～10任意一项所述化合物或其药学上可接受的盐，其选自，
    Figure PCTCN2022070733-appb-100021
    其中，
    R 5和R 6分别独立地选自H、F、Cl、Br、I、OH和NH 2；
    R 7选自H和
    Figure PCTCN2022070733-appb-100022
    R 8选自C 1-3烷基和
    Figure PCTCN2022070733-appb-100023
    所述C 1-3烷基和
    Figure PCTCN2022070733-appb-100024
    任选被1、2或3个R a取代；
    R 9选自H，E 1选自Se，X 1选自CR 10R 11，R 10和R 11与其共同连接的原子一起形成C 3-5环烷基；
    或者，X 1和R 9与其连接的原子一起形成
    Figure PCTCN2022070733-appb-100025
    E 1和E 2其中一个选自Se，另一个选自S和O；
    T 1选自CH和N；
    p和q分别独立地选自0和1；
    各R a分别独立地选自H、F、Cl、Br和I；
    条件是，当T 1选自CH，且E 1选自Se，且E 2选自O，p选自1，q选自1时，R 5和R 6分别独立地选自OH和NH 2；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  12. 根据权利要求11所述化合物或其药学上可接受的盐，其选自，
    Figure PCTCN2022070733-appb-100026
    其中，
    p、q、E 1、E 2、T 1、R 5、R 6和R 7如权利要求11所定义；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  13. 根据权利要求12所述化合物或其药学上可接受的盐，其选自，
    Figure PCTCN2022070733-appb-100027
    其中，
    p、q、E 1、E 2、R 5、R 6和R 7如权利要求12所定义；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  14. 根据权利要求13所述化合物或其药学上可接受的盐，其选自，
    Figure PCTCN2022070733-appb-100028
    Figure PCTCN2022070733-appb-100029
    其中，
    R 1和R 2分别独立地选自H、F、Cl、Br、I、OH和NH 2；
    m选自0和1；
    q、R 5、R 6、R 7和R 8如权利要求13所定义。
  15. 根据权利要求14所述化合物或其药学上可接受的盐，其中，R 1和R 2分别独立地选自F。
  16. 根据权利要求14所述化合物或其药学上可接受的盐，其中，R 5和R 6分别独立地选自F。
  17. 根据权利要求14所述化合物或其药学上可接受的盐，其选自，
    Figure PCTCN2022070733-appb-100030
    其中，R 1、R 2、R 5、R 6、R 7和R 8如权利要求14所定义。
  18. 下式化合物或其药学上可接受的盐，
    Figure PCTCN2022070733-appb-100031
  19. 根据权利要求1～18任意一项所述的化合物或其药学上可接受的盐在制备治疗与流感病毒相关疾病的药物中的应用。
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115677698A (zh) * 2021-11-01 2023-02-03 南京知和医药科技有限公司 一种高效抗病毒化合物及其用途
CN115947737A (zh) * 2022-01-26 2023-04-11 南京赛弗斯医药科技有限公司 一种含硒化合物及其用途
CN117003771A (zh) * 2022-11-09 2023-11-07 石家庄迪斯凯威医药科技有限公司 一种抗流感病毒衍生物及其用途
WO2024007997A1 (zh) * 2022-07-05 2024-01-11 辉诺生物医药科技（杭州）有限公司 吡啶酮多并环类衍生物的晶型及其制备方法
WO2024074080A1 (zh) * 2022-10-08 2024-04-11 石家庄迪斯凯威医药科技有限公司 一种抗流感病毒衍生物及其用途
WO2024098273A1 (zh) * 2022-11-09 2024-05-16 石家庄迪斯凯威医药科技有限公司 一种抗流感病毒磷酸酯类化合物及其用途

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016175224A1 (ja) 2015-04-28 2016-11-03 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
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
CN109721615A (zh) * 2017-09-18 2019-05-07 广东东阳光药业有限公司 流感病毒复制抑制剂及其用途
CN110300753A (zh) * 2018-01-22 2019-10-01 太景生物科技股份有限公司 帽依赖性核酸内切酶抑制剂
WO2020015669A1 (zh) * 2018-07-17 2020-01-23 南京明德新药研发有限公司 抗流感病毒三并环衍生物
CN111217810A (zh) * 2018-11-23 2020-06-02 维清生物科技(上海)有限公司 一种氮杂环二酮化合物及其制备方法
CN111410661A (zh) * 2019-01-04 2020-07-14 周雨恬 帽依赖性内切核酸酶抑制剂及其用途
WO2021007506A1 (en) * 2019-07-11 2021-01-14 Nanjing Zhengxiang Pharmaceuticals Co., Ltd. Compounds useful to treat influenza virus infections

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016175224A1 (ja) 2015-04-28 2016-11-03 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
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
CN109721615A (zh) * 2017-09-18 2019-05-07 广东东阳光药业有限公司 流感病毒复制抑制剂及其用途
CN109503625A (zh) * 2018-01-19 2019-03-22 赵蕾 一种多环吡啶酮化合物及其药物组合和用途
CN110300753A (zh) * 2018-01-22 2019-10-01 太景生物科技股份有限公司 帽依赖性核酸内切酶抑制剂
WO2020015669A1 (zh) * 2018-07-17 2020-01-23 南京明德新药研发有限公司 抗流感病毒三并环衍生物
CN111217810A (zh) * 2018-11-23 2020-06-02 维清生物科技(上海)有限公司 一种氮杂环二酮化合物及其制备方法
CN111410661A (zh) * 2019-01-04 2020-07-14 周雨恬 帽依赖性内切核酸酶抑制剂及其用途
WO2021007506A1 (en) * 2019-07-11 2021-01-14 Nanjing Zhengxiang Pharmaceuticals Co., Ltd. Compounds useful to treat influenza virus infections

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115677698A (zh) * 2021-11-01 2023-02-03 南京知和医药科技有限公司 一种高效抗病毒化合物及其用途
WO2023072292A1 (zh) * 2021-11-01 2023-05-04 南京知和医药科技有限公司 一种高效抗病毒化合物及其用途
CN115677698B (zh) * 2021-11-01 2024-02-02 南京知和医药科技有限公司 一种高效抗病毒化合物及其用途
CN115947737A (zh) * 2022-01-26 2023-04-11 南京赛弗斯医药科技有限公司 一种含硒化合物及其用途
CN115947737B (zh) * 2022-01-26 2023-11-28 南京赛弗斯医药科技有限公司 一种含硒化合物及其用途
WO2024007997A1 (zh) * 2022-07-05 2024-01-11 辉诺生物医药科技（杭州）有限公司 吡啶酮多并环类衍生物的晶型及其制备方法
WO2024074080A1 (zh) * 2022-10-08 2024-04-11 石家庄迪斯凯威医药科技有限公司 一种抗流感病毒衍生物及其用途
CN117003771A (zh) * 2022-11-09 2023-11-07 石家庄迪斯凯威医药科技有限公司 一种抗流感病毒衍生物及其用途
CN117003771B (zh) * 2022-11-09 2024-02-02 石家庄迪斯凯威医药科技有限公司 一种抗流感病毒衍生物及其用途
WO2024098856A1 (zh) * 2022-11-09 2024-05-16 石家庄迪斯凯威医药科技有限公司 一种抗流感病毒衍生物及其用途
WO2024098273A1 (zh) * 2022-11-09 2024-05-16 石家庄迪斯凯威医药科技有限公司 一种抗流感病毒磷酸酯类化合物及其用途

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