WO2022105669A1 - 含Se大环类化合物 - Google Patents

含Se大环类化合物 Download PDF

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WO2022105669A1
WO2022105669A1 PCT/CN2021/130114 CN2021130114W WO2022105669A1 WO 2022105669 A1 WO2022105669 A1 WO 2022105669A1 CN 2021130114 W CN2021130114 W CN 2021130114W WO 2022105669 A1 WO2022105669 A1 WO 2022105669A1
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compound
pharmaceutically acceptable
acceptable salt
reaction solution
compounds
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PCT/CN2021/130114
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English (en)
French (fr)
Inventor
陈新海
熊剑
王晶晶
姜明
胡国平
刘金鑫
尧中升
黎健
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2022105669A1 publication Critical patent/WO2022105669A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • C07D517/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms

Definitions

  • the present invention relates to a class of Se-containing macrocyclic compounds and applications thereof, in particular to compounds represented by formula (II) 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.
  • the synthesis of influenza virus proteins utilizes the host cell translation mechanism, and even the virus can suspend the translation of host proteins and speed up 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".
  • cap a process known as "cap" snatching"
  • 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 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. Wherein WO2016175224 reported the following compounds and their prodrugs:
  • anti-influenza virus drugs with a new mechanism of action are urgently needed in clinical practice.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R a ;
  • R 1 and R 2 are attached to the carbon atom to which they are attached to form a C 3-5 cycloalkyl or 3-5 membered heterocycloalkyl;
  • R 3 is selected from H and
  • each R 4 is independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R 5 is selected from C 1-3 alkyl and The C 1-3 alkyl and each independently optionally substituted with 1, 2 or 3 R;
  • each R a is independently selected from F, Cl, Br, I and OH;
  • each R b is independently selected from F, Cl, Br, I and OH;
  • n is selected from 0, 1, 2, 3 and 4;
  • the "3-5 membered heterocycloalkyl” contains 1 or 2 heteroatoms independently selected from O, S, N and NH.
  • R 1 and R 2 are selected from H, and other variables are as defined in the present invention.
  • R 1 and R 2 are attached to the carbon atoms to which they are attached to form a cyclopropyl, cyclobutyl, oxetanyl or azetidinyl group, other variables being as defined in the present invention definition.
  • R1 and R2 are attached to the carbon atom to which they are attached to form a cyclobutyl group, other variables are as defined herein.
  • R 5 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 R b , other variables are as defined in the present invention.
  • R 5 is selected from CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 and Other variables are as defined in the present invention.
  • R 3 is selected from H, Other variables are as defined in the present invention.
  • R above is selected from H and Other variables are as defined in the present invention.
  • each of the above R 4 is independently selected from F, and other variables are as defined in the present invention.
  • the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 , R 2 and R 3 are as defined in the present invention.
  • the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 and R 2 are each independently selected from H;
  • R 1 and R 2 are attached to the carbon atom to which they are attached to form a C 3-5 cycloalkyl or 3-5 membered heterocycloalkyl;
  • the "3-5 membered heterocycloalkyl” contains 1 or 2 heteroatoms independently selected from O and NH.
  • the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 and R 2 are as defined in the present invention.
  • the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 and R 2 are as defined in the present invention.
  • the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 and R 2 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 and R 2 are selected from H;
  • R 1 and R 2 are attached to the carbon atoms to which they are attached to form C 3-5 cycloalkylcyclobutyl or 3-5 membered heterocycloalkyl;
  • the "3-5 membered heterocycloalkyl” contains 1 or 2 heteroatoms independently selected from O and NH.
  • the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof
  • the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from,
  • the above-mentioned compounds or their pharmaceutically acceptable salts are used in the preparation of medicines for the treatment of influenza virus-related diseases.
  • the present invention also provides a method for testing the stability of liver microsomes:
  • test article stock solution (10 mM DMSO solution) with 495 microliters of acetonitrile (intermediate working solution concentration: 100 ⁇ M, 99% acetonitrile).
  • NADPH powder NADPH ⁇ 4Na, ⁇ -nicotinamide adenine dinucleotide phosphate reduced tetrasodium salt, supplier: Chem-Impex International, Cat.No.00616.
  • HLM Human liver microsomes, supplier: Corning, Cat No. 452117, Lot No. 38295.
  • NADPH powder was weighed and diluted into a 10 mM magnesium chloride solution (concentration of working solution: 10 mM; final concentration of reaction system: 1 mM).
  • liver microsome solution was diluted to 1 mg/mL with 100 mM potassium phosphate buffer.
  • test compound in dimethyl sulfoxide (100 ⁇ M) to the “incubation” plate (T60 and NCF60) containing microsomes and mix thoroughly 3 times;
  • NCF60 plate For NCF60 plate, add 50 ⁇ L of buffer and mix well 3 times. Start the timer; the plate will be shaken at 37°C for 60 minutes;
  • the compound of the present invention shows a positive effect in the test of inhibiting the replication of influenza virus at the cellular level, and has excellent pharmacokinetic properties, excellent metabolic stability and good liver microsome stability, and exhibits excellent in vivo pharmacodynamic model in animals weight protection.
  • 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 provided herein also exist in prodrug forms.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • 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.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • 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.
  • 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 located, 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 the connected chemical bond. 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;
  • the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2)
  • the following formula (B) indicates that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or exists in two forms of formula (B-1) and formula (B-2) exists as a mixture of isomers.
  • the following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2) exists in the form of a mixture.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • 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.
  • 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.
  • the term "3-5 membered heterocycloalkyl” by itself or in combination with other terms denotes a saturated monocyclic group consisting of 3 to 5 ring atoms, 1, 2, 3 or 4 ring atoms, respectively are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen atom is optionally oxidized (ie, NO).
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 3-5 membered heterocycloalkyl includes 4-5 membered, 4 membered, and 5 membered heterocycloalkyl and the like.
  • Examples of 3-5 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) or tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.) and the like.
  • 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 present invention adopts the following abbreviations: DMAC: N,N-dimethylacetamide, PG: propylene glycol, HP- ⁇ -CD: hydroxypropyl- ⁇ -cyclodextrin.
  • 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 diffractometry (SXRD), using Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultivated single crystal, the light source is CuK ⁇ radiation, scanning mode: ⁇ / ⁇ scanning, after collecting the relevant data, further adopt the direct method (Shelxs97) analysis of the crystal structure, the absolute configuration can be confirmed.
  • SXRD single crystal X-ray diffractometry
  • Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultivated single crystal
  • the light source is CuK ⁇ radiation
  • scanning mode: ⁇ / ⁇ scanning after collecting the relevant data
  • the absolute configuration can be confirmed.
  • reaction solution was quenched by adding hydrochloric acid solution (10%, 200 mL), and extracted with ethyl acetate (100 mL ⁇ 3). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the crude product obtained was stirred with petroleum ether (100 mL) for 10 minutes, filtered, and the filter cake was dried under reduced pressure to obtain BB-1 -2 was used directly in the next reaction.
  • BB-1-3 (5 g, 24.73 mmol) was dissolved in dichloromethane (50 mL), oxalyl chloride (3.77 g, 29.68 mmol, 2.60 mL) and a catalytic amount of N,N-dichloromethane were added dropwise Methylformamide (90.39 mg, 1.24 mmol), the reaction solution was stirred at 20°C for 2 hours, the reaction solution was concentrated under reduced pressure, the obtained crude product was dissolved in ethanol (50 mL), and then stirred at 20°C for 1 hour. The reaction solution was concentrated to dryness under reduced pressure.
  • BB-1-4 (3.5 g, 15.20 mmol) was dissolved in carbon tetrachloride (50 mL), azobisisobutyronitrile (124.83 mg, 760.18 ⁇ mol) and N-bromosuccinimide (2.98 g) were added , 16.72 mmol), the reaction solution was stirred at 80 °C overnight. The reaction solution was diluted with water (50 mL), and extracted with dichloromethane (100 mL ⁇ 2). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product BB-1-5, which was directly used in the next reaction.
  • BB-1-5 (4.2 g, 10.87 mmol, 80% purity) was dissolved in a mixed solvent of acetonitrile (60 mL) and water (20 mL), zinc powder (1.42 g, 21.74 mmol), sodium dihydrogen phosphate (6.52 mL) were added. g, 54.35 mmol), diphenyl diselenide (2.04 g, 6.52 mmol), the reaction solution was stirred at 25°C for 2 hours. The reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (100 mL ⁇ 2).
  • BB-1-6 (3.6 g, 9.34 mmol) was dissolved in ethanol (50 mL), sodium hydroxide aqueous solution (2 M, 25.05 mL, 50.1 mmol) was added, and the reaction solution was stirred at 80° C. for 12 hours.
  • BB-1-7 (0.05 g, 139.97 ⁇ mol) was dissolved in 1,2-dichlorobenzene (1 mL), polyphosphoric acid (1 mL) was added, and the reaction solution was stirred at 130° C. for 2 hours.
  • the reaction solution was poured into ice water (10 mL), and extracted with ethyl acetate (30 mL ⁇ 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 8 Synthesis of Compound BB-1-9
  • BB-1-8 (0.05g, 147.41 ⁇ mol) was dissolved in dichloromethane (1mL), and a solution of boron tribromide (92.32mg, 368.52 ⁇ mol) in dichloromethane (1mL) was added dropwise, The reaction solution was stirred at 25°C for 2 hours. The reaction solution was poured into ice water (10 mL) to quench, and extracted with ethyl acetate (30 mL ⁇ 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product BB-1-9, which was directly used in the next reaction.
  • Step 9 Synthesis of Compound BB-1-10
  • BB-1-10 (0.05 g, 136.90 ⁇ mol) was dissolved in a mixed solvent of dichloromethane (1 mL) and methanol (0.5 mL), and sodium borohydride (15.54 mg, 410.70 ⁇ mol) was added to react. The solution was stirred at 25°C for 12 hours, additional sodium borohydride (15.54 mg, 410.70 ⁇ mol) was added, and the reaction solution was further stirred at 25°C for 2 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL), and then extracted with dichloromethane (20 mL ⁇ 2).
  • BB-1-11 (0.05g, 136.15 ⁇ mol) was dissolved in dichloromethane (1mL), thionyl chloride (32.40mg, 272.30 ⁇ mol) was added, and the reaction solution was heated to 25°C and continued to stir for 1 Hour. The reaction solution was concentrated under reduced pressure to obtain crude product BB-1, which was directly used in the next reaction.
  • the trifluoroacetate salt of compound 1-3 (0.9 g, crude product) was dissolved in ethanol (5 mL), sodium hydroxide aqueous solution (1 M, 2.61 mL) and formalin solution (353.39 mg, 4.35 mmol, 324.21 ⁇ L, 37%) were added purity), the reaction solution was stirred at 25°C for 20 minutes.
  • the reaction solution was extracted with dichloromethane (30 mL ⁇ 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • compound 1-4 (0.16 g, 513.92 ⁇ mol) was dissolved in N,N-dimethylformamide (3 mL), sodium hydrogen (61.66 mg, 1.54 mmol, 60% purity) was added, and the reaction was The solution was stirred at 0°C for 0.5 hours, a solution of BB-1 (0.23 g, 596.33 ⁇ mol) in N,N-dimethylformamide (2 mL) was added to the reaction solution, and the reaction solution was further stirred at 25°C for 1 hour.
  • Step 6 Synthesis of Compounds 1-6A, 1-6B, 1-6C and 1-6D
  • compound 2-1 (10 g, 27.75 mmol) was dissolved in N,N-dimethylformamide (100 mL), and benzotriazole-N,N,N',N'-tetramethylene Biurea hexafluorophosphate (12.66g, 33.30mmol) and N,N-diisopropylethylamine (17.93g, 138.75mmol, 24.17mL) were added to the reaction solution, and the reaction solution was reacted at 25°C for 0.5 hours, and then 1-Vinylcyclobutylamine hydrochloride (4.45 g, 33.30 mmol) was added to the reaction solution, and the reaction solution was continued to react at 25° C.
  • 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 2000 cells per well, and then placed in a 37°C, 5% CO 2 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 a 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 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.
  • TCID90 tissue culture infectious dose
  • the cytotoxicity assay and the antiviral activity assay of the compounds were performed in parallel, except that no virus was added, the other experimental conditions were the same as the antiviral activity experiments.
  • 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 male BALB/c mice, 7-9 weeks old, weighing 17-23 grams;
  • injection administration i.v.
  • the dose is 1 mpk
  • the concentration is 0.50 mg/mL
  • the vehicle is 40% DMAC+40% PG+20% (20% HP- ⁇ -CD in water)
  • oral administration pro : The dose is 10 mpk, the concentration is 1 mg/mL, and the vehicle is 3% DMSO+10% solutol HS+87% water.
  • mice pharmacokinetic study show that the compound of the present invention has a low clearance rate and a high oral plasma exposure of its prodrug, and has good pharmacokinetic properties.
  • mice Male SD rats, 6-8 weeks old, weighing 200-300 grams;
  • 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.
  • body weight loss rate on day N (body weight on day N-body weight on day 0)/body weight on day 0*100%.
  • Table 4 The results are shown in Table 4.
  • Compound 3 can achieve a maximum weight loss rate of -9.22% in protected animals on the 4th day, and then begins to recover, and the survival rate of mice is 100% at the end of the experiment.
  • the maximum weight loss rate of the animals in the vehicle group was over -35% on the 8th day, and all the animals died on the 9th day.
  • the compounds of the present invention show excellent body weight protection and early recovery time in an animal pharmacodynamic model.

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Abstract

一类含Se大环类化合物及其应用，具体公开了式(II)所示化合物及其药学上可接受的盐。

Description

含Se大环类化合物
本发明主张如下优先权：
CN202011288166.X，申请日2020年11月17日。
技术领域
本发明涉及一类含Se大环类化合物及其应用，具体涉及式(II)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。流感病毒蛋白的合成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”。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。
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。其中WO2016175224报道了如下化合物及其前药：
Figure PCTCN2021130114-appb-000001
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。
发明内容
本发明提供了式(II)所示化合物或其药学上可接受的盐，
Figure PCTCN2021130114-appb-000002
其中，
R 1和R 2分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
或者，R 1和R 2与它们相连的碳原子连接形成C 3-5环烷基或3-5元杂环烷基；
R 3选自H和
Figure PCTCN2021130114-appb-000003
各R 4分别独立地选自H、F、Cl、Br、I、OH和NH 2；
R 5选自C 1-3烷基和
Figure PCTCN2021130114-appb-000004
所述C 1-3烷基和
Figure PCTCN2021130114-appb-000005
分别独立地任选被1、2或3个R b取代；
各R a分别独立地选自F、Cl、Br、I和OH；
各R b分别独立地选自F、Cl、Br、I和OH；
n选自0、1、2、3和4；
所述“3-5元杂环烷基”包含1或2个分别独立地选自O、S、N和NH的杂原子。
在本发明的一些方案中，上述R 1和R 2选自H，其他变量如本发明所定义。
在本发明的一些方案中，上述R 1和R 2与它们相连的碳原子连接形成环丙基、环丁基、氧杂环丁烷基或氮杂环丁烷基，其他变量如本发明所定义。
在本发明的一些方案中，上述R 1和R 2与它们相连的碳原子连接形成环丁基，其他变量如本发明所定义。
在本发明的一些方案中，上述R 5选自CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和
Figure PCTCN2021130114-appb-000006
所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和
Figure PCTCN2021130114-appb-000007
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，上述R 5选自CH 3、CH 2CH 3、CH(CH 3) 2和
Figure PCTCN2021130114-appb-000008
其他变量如本发明所定义。
在本发明的一些方案中，上述R 3选自H、
Figure PCTCN2021130114-appb-000009
Figure PCTCN2021130114-appb-000010
其他变量如本发明所定义。
在本发明的一些方案中，上述R 3选自H和
Figure PCTCN2021130114-appb-000011
其他变量如本发明所定义。
在本发明的一些方案中，上述各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，上述结构单元
Figure PCTCN2021130114-appb-000012
选自
Figure PCTCN2021130114-appb-000013
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2021130114-appb-000014
选自
Figure PCTCN2021130114-appb-000015
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2021130114-appb-000016
其中，R 1、R 2和R 3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，上述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2021130114-appb-000017
其中，
R 1和R 2分别独立地选自H；
或者，R 1和R 2与它们相连的碳原子连接形成C 3-5环烷基或3-5元杂环烷基；
所述“3-5元杂环烷基”包含1或2个分别独立地选自O和NH的杂原子。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2021130114-appb-000018
其中，R 1和R 2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，上述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2021130114-appb-000019
其中，R 1和R 2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，上述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2021130114-appb-000020
Figure PCTCN2021130114-appb-000021
其中，R 1和R 2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 PCTCN2021130114-appb-000022
其中，
R 1和R 2选自H；
或者，R 1和R 2与它们相连的碳原子连接形成C 3-5环烷基环丁基或3-5元杂环烷基；
所述“3-5元杂环烷基”包含1或2个分别独立地选自O和NH的杂原子。
本发明还有一些方案，由上述变量任意组合而来。
本发明还提供了下式化合物或其药学上可接受的盐
Figure PCTCN2021130114-appb-000023
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2021130114-appb-000024
在本发明的一些方案中，上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药物中的应用。
本发明还提供了肝微粒体稳定性测试方法：
实验目的：检测化合物肝微粒体稳定性
实验方法：
1.测试化合物和工作液的配制
用495微升乙腈稀释5微升供试品储备液(10mM DMSO溶液)(中间工作液浓度：100μM,99％乙腈)。
2材料
NADPH粉末：NADPH·4Na，β-烟酰胺腺嘌呤二核苷酸磷酸还原式四钠盐，供应商：Chem-Impex International,Cat.No.00616。
HLM：人源肝微粒体，供应商：Corning，Cat No.452117，Lot No.38295。
3.NADPH再生体系工作液的制备
称取适量NADPH粉末，稀释成10mM氯化镁溶液(工作液浓度：10mM；反应体系终浓度：1mM)。
4.肝微粒体的制备
用100mM磷酸钾盐缓冲液将肝微粒体溶液稀释到1mg/mL。
5.淬灭溶液制备
用含有200ng/mL甲苯磺丁脲和200ng/mL拉贝洛尔作为内标物(IS)的冷(4℃)乙腈作为淬灭溶液。
6.试验步骤
1)将空“孵育”板T60和NCF60预热10分钟；
2)用100mM磷酸盐缓冲液将肝微粒体稀释至0.56mg/mL；
3)将445μL微粒体工作溶液(0.56mg/mL)转移到预热的“孵育”板T60和NCF60中，然后在37℃下持续摇动将“孵育”板T60和NCF60预孵育10分钟。将54μL肝微粒体转移到空白板上，然后在空白板上添加6μL NAPDH辅因子，然后在空白板上添加180μL淬灭液；
4)向含有微粒体的“孵育”板(T60和NCF60)中添加5μL检测化合物的二甲亚砜溶液(100μM)，并充分混合3次；
5)对于NCF60板，添加50μL缓冲液并充分混合3次。开始计时；平板将在37℃下摇动60分钟；
6)在“淬火”板T0中，添加180μL淬火溶液和6μL NAPDH辅因子。确保冷却盘子以防止蒸发；
7)对于T60板，彻底混合3次，并立即在0分钟时间点将54μL混合物移到“淬火”板。然后向培养板(T60)中添加44μL NAPDH辅因子。开始计时；平板将在37℃下摇动60分钟；
8)在5、15、30、45和60min时，将180μL淬火溶液添加到“淬火”板中，混合一次，并在每个时间点将60μL样品从T60板连续转移到“淬火”板中；
9)对于NCF60：混合一次，并在60分钟的时间点将60μL样品从NCF60培养皿转移到含有淬火溶液的“淬火”平板上；
10)将所有取样板摇晃10分钟，然后在4℃下以4000rpm离心20分钟；
11)将80μL上清液移入240μL高效液相色谱仪水中，用平板摇动器搅拌10分钟；
12)在LC-MS/MS分析之前，将每个生物分析板密封并摇晃10分钟。
技术效果
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，且药代动力学性质优良，具有优秀的代谢稳定性和良好的肝微粒体稳定性，在动物体内药效模型中表现出优异的体重保护。
定义和说明
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。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
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。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2021130114-appb-000025
和楔形虚线键
Figure PCTCN2021130114-appb-000026
表示一个立体中心的绝对构型，用直形实 线键
Figure PCTCN2021130114-appb-000027
和直形虚线键
Figure PCTCN2021130114-appb-000028
表示立体中心的相对构型，用波浪线
Figure PCTCN2021130114-appb-000029
表示楔形实线键
Figure PCTCN2021130114-appb-000030
或楔形虚线键
Figure PCTCN2021130114-appb-000031
或用波浪线
Figure PCTCN2021130114-appb-000032
表示直形实线键
Figure PCTCN2021130114-appb-000033
或直形虚线键
Figure PCTCN2021130114-appb-000034
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。
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 PCTCN2021130114-appb-000035
直形虚线键
Figure PCTCN2021130114-appb-000036
或波浪线
Figure PCTCN2021130114-appb-000037
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 PCTCN2021130114-appb-000038
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 PCTCN2021130114-appb-000039
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 PCTCN2021130114-appb-000040
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 PCTCN2021130114-appb-000041
Figure PCTCN2021130114-appb-000042
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2021130114-appb-000043
仍包括
Figure PCTCN2021130114-appb-000044
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。
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用
Figure PCTCN2021130114-appb-000045
表示，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2021130114-appb-000046
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。
Figure PCTCN2021130114-appb-000047
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备， 其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
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，“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，术语“3-5元杂环烷基”本身或者与其他术语联合分别表示由3至5个环原子组成的饱和单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮原子可任选被氧化(即NO)。此外，就该“3-5元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-5元杂环烷基包括4-5元、4元、和5元杂环烷基等。3-5元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)或四氢呋喃基(包括四氢呋喃-2-基等)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。
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。
本发明采用下述缩略语：DMAC：N,N-二甲基乙酰胺，PG：丙二醇，HP-β-CD：羟丙基-β-环糊精。
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：φ/ω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。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2021130114-appb-000048
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：片段BB-1的合成
Figure PCTCN2021130114-appb-000049
合成路线：
Figure PCTCN2021130114-appb-000050
步骤1：化合物BB-1-2的合成
将金属镁(8.4g,345.61mmol)和碘(432.40mg,1.70mmol)加入三口烧瓶，加热反应瓶，使碘蒸汽充满整个反应瓶，再将甲醇(60mL)和甲苯(200mL)加入反应瓶中，然后升温至80℃直到镁屑溶解。反应液减压蒸馏去除甲醇，加入甲苯(200mL)，然后加入BB-1-1(30g,170.36mmol)，反应液在110℃下搅拌12小时。将反应液加入盐酸溶液(10％,200mL)淬灭，用乙酸乙酯(100mL×3)萃取。合并有机相，用饱和食盐水(300mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品用石油醚(100mL)搅拌10分钟，过滤，滤饼减压干燥，得到BB-1-2直接用于下一步反应。
步骤2：化合物BB-1-3的合成
在氮气保护下，将四甲基乙二胺(37.06g,318.93mmol)溶于四氢呋喃(200mL)中，在-60℃下滴加仲丁基锂(1.4M,227.81mL,318.93mmol)，然后缓慢滴加BB-1-2(20g,106.31mmol)的四氢呋喃(200mL)溶液，反应液在-60℃下搅拌2小时。加入碘甲烷(61.38g,432.44mmol,26.92mL)，反应液缓慢升温至20℃，继续搅拌2小时。向反应液中分别加入水(200mL)和氢氧化钠水溶液(1N,100mL)，用甲基叔丁醚(200mL×2)萃取，合并有机相，用1N的氢氧化钠水溶液(100mL×2)洗涤，合并2次萃取的碱性水相，用6N盐酸调节pH至3-4，用乙酸乙酯(100mL×3)萃取，合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品BB-1-3，直接用于下一步反应。
步骤3：化合物BB-1-4的合成
在冰浴下，将BB-1-3(5g,24.73mmol)溶于二氯甲烷(50mL)中，滴加草酰氯(3.77g,29.68mmol,2.60mL)和催化量的N,N-二甲基甲酰胺(90.39mg,1.24mmol)，反应液在20℃下搅拌2小时，将反应液减压浓缩，所得粗品用乙醇(50mL)溶解，然后在20℃下继续搅拌1小时。反应液减压浓缩干。所得粗品经硅胶柱(石油醚：乙酸乙酯＝100:1至50:1)纯化得化合物BB-1-4。 1HNMR(400MHz,氘代氯仿)δppm6.23-6.58(m,1H)，4.39(q,J＝7.06Hz,2H)，3.79(s,3H)，2.25(d,J＝2.4Hz,3H)，1.23(t,J＝7.20Hz,3H)。
步骤4：化合物BB-1-5的合成
将BB-1-4(3.5g,15.20mmol)溶于四氯化碳(50mL)，加入偶氮二异丁腈(124.83mg,760.18μmol)和N-溴代丁二酰亚胺(2.98g,16.72mmol)，反应液在80℃搅拌过夜。将反应液加水(50mL)稀释，用二氯甲烷(100mL×2)萃取。合并有机相，用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品BB-1-5，直接用于下一步反应。 1HNMR(400MHz,氘代氯仿)δppm 6.74-6.80(m,1H)，4.51(s,2H)，4.41-4.46(m,2H)，3.82(s,3H)，1.39-1.46(m,3H)。
步骤5：化合物BB-1-6的合成
将BB-1-5(4.2g,10.87mmol，80％纯度)溶于乙腈(60mL)和水(20mL)的混合溶剂中，加入锌粉(1.42g,21.74mmol)，磷酸二氢钠(6.52g,54.35mmol)，二苯基联硒(2.04g,6.52mmol)，反应液在25℃搅拌2小时。反应液加水(50mL)稀释，用乙酸乙酯(100mL×2)萃取。合并有机相，用饱和食盐水(200mL)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(石油醚：乙酸乙酯＝50:1至20:1)纯化得BB-1-6。 1HNMR(400MHz,氘代二甲亚砜)δppm 7.46-7.49(m,2H)，7.30-7.31(m,3H)，7.18-7.29(m,1H)，4.17-4.27(m,2H)，4.14(s,2H)，3.77(s,3H)，1.25(q,J＝7.20Hz,3H)。
步骤6：化合物BB-1-7的合成
将BB-1-6(3.6g,9.34mmol)溶于乙醇(50mL)，加入氢氧化钠水溶液(2M,25.05mL，50.1mmol)，反应液在80℃搅拌12小时。反应液减压浓缩，加入水(20mL)稀释，用1N盐酸调节pH＝2-3，用乙酸乙酯(50mL×3)萃取，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得到粗品BB-1-7，直接用于下一步反应。MS(ESI)m/z:357.0(M-H) +。
步骤7：化合物BB-1-8的合成
将BB-1-7(0.05g，139.97μmol)溶于1,2-二氯苯(1mL)，加入多聚磷酸(1mL)，反应液在130℃搅拌2小时。将反应液倒入冰水(10mL)中，用乙酸乙酯(30mL×2)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。所得粗品经制备型薄层层析板(石油醚：乙酸乙酯＝10:1)纯化得BB-1-8。 1HNMR(400MHz,氘代氯仿)δppm 7.89-7.91(m,1H)，7.30-7.36(m,3H)，6.60-6.65(m,1H)，4.07(s,2H)，3.74(s,3H)。
步骤8：化合物BB-1-9的合成
在冰浴下，将BB-1-8(0.05g,147.41μmol)溶于二氯甲烷(1mL)中，滴加三溴化硼(92.32mg,368.52μmol)的二氯甲烷(1mL)溶液，反应液在25℃搅拌2小时。将反应液倒入冰水(10mL)中淬灭，用乙酸乙酯(30mL×2)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，滤液减压浓缩得粗品BB-1-9，直接用于下一步反应。 1HNMR(400MHz,氘代氯仿)δppm 12.79(s,1H)，8.07-8.10(m,1H)，7.62-7.65(m,1H)，7.30-7.40(m,1H)，6.72-6.76(m,1H)，4.11(s,2H)。
步骤9：化合物BB-1-10的合成
在冰浴下，将BB-1-9(0.38g,1.17mmol)溶于乙腈(6mL)，加入碳酸钾(484.55mg,3.51mmol)和烯丙基溴(424.14mg,3.51mmol)，反应液在50℃搅拌12小时。反应液加水(10mL)稀释，用乙酸乙酯(30mL×2)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，滤液减压浓缩到粗品BB-1-10，直接用于下一步反应。MS(ESI)m/z:367.0(M+H) +。
步骤10：化合物BB-1-11的合成
在冰浴下，将BB-1-10(0.05g,136.90μmol)溶于二氯甲烷(1mL)和甲醇(0.5mL)的混合溶剂中，加入硼氢化钠(15.54mg,410.70μmol)，反应液在25℃搅拌12小时，补加硼氢化钠(15.54mg,410.70μmol)，反应液在25℃继续搅拌2小时。将反应液用饱和氯化铵水溶液(10mL)淬灭，然后用二氯甲烷(20mL×2)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。所得粗品经过柱硅 胶柱(石油醚：乙酸乙酯＝20:1至10:1)纯化得到BB-1-11。 1HNMR(400MHz,氘代氯仿)δppm 7.49-7.51(m,1H)，7.10-7.23(m,3H)，6.60-6.63(m,1H)，6.28-6.30(m,1H)，6.05-6.10(m,1H)，5.38-5.46(m,2H)，4.74-4.77(m,1H)，4.15-4.51(m,3H)。
步骤11：化合物BB-1的合成
在冰浴下，将BB-1-11(0.05g,136.15μmol)溶于二氯甲烷(1mL)中，加入二氯亚砜(32.40mg,272.30μmol)，反应液升温至25℃继续搅拌1小时。将反应液减压浓缩得到粗品BB-1，直接用于下一步反应。
实施例1
Figure PCTCN2021130114-appb-000051
步骤1：化合物1-2的合成
在冰浴下，将1-1(3g,8.32mmol)加入二氯甲烷(30mL)中，加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(3.80g,9.99mmol)和N,N-二异丙基乙胺(2.15g,16.65mmol,2.90mL)，反应液在25℃反应0.5小时，将丙烯胺(0.85g,14.89mmol)加入反应液中，继续在25℃反应12小时。将加水(30mL)加入反应 液,然后溶液用二氯甲烷(50mL×3)萃取。合并有机相，用饱和食盐水(100mL)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(二氯甲烷：甲醇＝50:1至20:1)纯化，得到化合物1-2。MS(ESI)m/z:399.9(M+H) +。
步骤2：化合物1-3的合成
将化合物1-2(0.9g,2.25mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(6.16g,54.03mmol,4mL)，反应液在25℃搅拌3小时。反应液减压浓缩得到粗品1-3的三氟乙酸盐，直接用于下一步反应。
步骤3：化合物1-4的合成
将化合物1-3的三氟乙酸盐(0.9g,粗品)溶于乙醇(5mL)，加入氢氧化钠水溶液(1M,2.61mL)和甲醛水溶液(353.39mg,4.35mmol,324.21μL,37％纯度)，反应液在25℃搅拌20分钟。反应液用二氯甲烷(30mL×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。所得粗品经硅胶柱(二氯甲烷：甲醇＝50:1至20:1)纯化得化合物1-4。MS(ESI)m/z:312.0(M+H) +。
步骤4：化合物1-5的合成
在冰浴下，将化合物1-4(0.16g,513.92μmol)溶于N,N-二甲基甲酰胺(3mL)中，加入钠氢(61.66mg,1.54mmol,60％纯度)，将反应液在0℃搅拌0.5小时，将BB-1(0.23g,596.33μmol)的N,N-二甲基甲酰胺(2mL)溶液加入反应液中，反应液在25℃继续搅拌1小时。反应液倒入冰水(10mL)中淬灭，用乙酸乙酯(30mL×2)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。所得粗品经硅胶柱(二氯甲烷：甲醇＝100:1至50:1)纯化得到化合物1-5。MS(ESI)m/z:662.1(M+H) +。
步骤5：化合物1-6的合成
将化合物1-5(60mg,90.83μmol)溶于二氯乙烷(8mL)中，加入[1,3-双(2,4,6-三甲基苯基)咪唑啉-2-基]-二氯-[(2-异丙氧基苯基)亚甲基]钌(11.38mg,18.17μmol)，反应液在80℃搅拌3小时。将反应液减压浓缩。所得粗品经制备薄层层析板(二氯甲烷：甲醇＝10:1)纯化2次，得到化合物1-6。MS(ESI)m/z:634.1(M+H) +。
步骤6：化合物1-6A、1-6B、1-6C和1-6D的合成
化合物1-6经超临界流体色谱检测(柱子型号:Chiralcel OJ-3(100mm*4.6mm,3μm)；流动相:[A：二氧化碳，B：0.05％二乙胺/乙醇]；梯度：5％～40％(B％),4min；40％(B％),2.5min,5％(B％)1.5min)为4个峰的混合物，混合物经超临界流体色谱(柱子型号:DAICEL CHIRALCEL OJ-H(250mm*30mm,5μm)；流动相:A：二氧化碳，B:[0.1％氨水/乙醇]；梯度：B％:35％-35％)分离得到4个异构体：1-6A(保留时间3.300min，手性纯度＝90.2％)、1-6B(保留时间3.459min，手性纯度＝75.0％)、1-6C(保留时间3.781min，手性纯度＝97.0％)和1-6D(保留时间4.146min，手性纯度＝99.0％)。
步骤7：化合物1A的合成
将化合物1-6A(20mg,31.62μmol)加入到N,N-二甲基乙酰胺(0.5mL)中，加入氯化锂(13.40mg,316.20μmol)，反应液在80℃下搅拌12小时。反应液经制备型高效液相分离纯化(柱子型号:Boston Green ODS 150*30mm*5μm；流动相:[A:水(0.075％三氟乙酸)-B:乙腈]；梯度：B％:38％-68％)得化合物1A。 1H NMR(400MHz,氘代甲醇)δ7.72(d,J＝7.53Hz,1H),7.22(d,J＝8.03Hz,1H),7.04-7.18(m,2H),6.83-6.94(m,2H),6.29-6.42(m,1H),5.93-6.03(m,2H),5.60(dd,J＝2.76,12.55Hz,1H),5.54(s,1H),5.22(d,J＝14.05Hz,1H),5.01(dd,J＝5.14,14.43Hz,1H),4.75-4.80(m,1H),4.54(d,J＝13.80Hz,1H),4.39(br t,J＝10.04Hz,1H),4.13(d,J＝12.55Hz,1H),3.16(dd,J＝7.65,14.18Hz,1H)。MS(ESI)m/z:544.0(M+H) +。
步骤8：化合物1B的合成
将化合物1-6B(8mg,12.65μmol)加入到N,N-二甲基乙酰胺(0.5mL)中，加入氯化锂(5.36mg,126.48μmol)，反应液在80℃下搅拌12小时。反应液经制备型高效液相分离纯化(柱子型号:Boston Green ODS 150*30mm*5μm；流动相:[A:水(0.075％三氟乙酸)-B:乙腈]；梯度：B％:38％-68％)得化合物1B。 1H NMR(400MHz,氘代甲醇)δ7.61(d,J＝7.53Hz,1H),7.23-7.30(m,1H),7.04-7.19(m,2H),6.83-6.93(m,1H),6.69(d,J＝6.78Hz,1H),6.47-6.56(m,1H),6.26-6.39(m,2H),6.00-6.08(m,1H),5.64(dd,J＝2.89,12.92Hz,1H),5.09(d,J＝13.55Hz,1H),4.75-4.80(m,1H),4.51-4.60(m,2H),4.41(dd,J＝7.53,13.80Hz,1H),4.01(d,J＝12.80Hz,1H),3.77(dd,J＝8.53,13.55Hz,1H)。MS(ESI)m/z:544.0(M+H) +。
步骤9：化合物1C的合成
将化合物1-6C(8mg,12.65μmol)加入到N,N-二甲基乙酰胺(0.5mL)中，然后加入氯化锂(5.36mg,126.48μmol)，反应液在80℃下搅拌12小时。反应液经制备型高效液相分离纯化(柱子型号:Boston Green ODS 150*30mm*5μm；流动相:[A:水(0.075％三氟乙酸)-B:乙腈]；梯度：B％:38％-68％)得化合物1C。 1H NMR(400MHz,氘代甲醇)δ7.63(d,J＝7.28Hz,1H),7.22-7.28(m,1H),7.07-7.18(m,2H),6.87(t,J＝6.90Hz,1H),6.70(d,J＝6.78Hz,1H),6.47-6.57(m,1H),6.27-6.40(m,2H),6.07(d,J＝7.53Hz,1H),5.65(dd,J＝2.89,12.92Hz,1H),5.09(d,J＝13.55Hz,1H),4.75-4.80(m,1H),4.51-4.63(m,2H),4.42(dd,J＝7.53,13.80Hz,1H),4.02(d,J＝12.80Hz,1H),3.78(dd,J＝8.78,13.80Hz,1H)。MS(ESI)m/z:544.0(M+H) +。
步骤10：化合物1D的合成
将化合物1-6D(20mg,31.62μmol)加入到N,N-二甲基乙酰胺(0.5mL)中，加入氯化锂(13.40mg,316.20μmol)，反应液在80℃下搅拌12小时。反应液经制备型高效液相分离纯化(柱子型号:Boston Green ODS 150*30mm*5μm；流动相:[A:水(0.075％三氟乙酸)-B:乙腈]；梯度：B％:38％-68％)得化合物1D。 1H NMR(400MHz,氘代甲醇)δ7.73(d,J＝7.53Hz,1H),7.22(d,J＝7.78Hz,1H),7.05-7.18(m,2H),6.85-6.95(m,2H),6.35(td,J＝7.72,15.18Hz,1H),5.93-6.04(m,2H),5.60(dd,J＝2.51,12.80Hz,1H),5.54(s,1H),5.22(d,J＝14.05 Hz,1H),5.01(dd,J＝4.77,14.81Hz,1H),4.75-4.80(m,1H),4.54(d,J＝13.80Hz,1H),4.39(br t,J＝10.16Hz,1H),4.13(d,J＝12.55Hz,1H),3.16(dd,J＝7.65,14.43Hz,1H)。MS(ESI)m/z:544.0(M+H) +。
实施例2
Figure PCTCN2021130114-appb-000052
步骤1：化合物2-2的合成
在冰浴下，将化合物2-1(10g,27.75mmol)溶于N,N-二甲基甲酰胺(100mL)，将苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(12.66g,33.30mmol)和N,N-二异丙基乙胺(17.93g,138.75mmol,24.17mL)加到反应液中，反应液在25℃反应0.5小时，后将1-乙烯基环丁胺盐酸盐(4.45g,33.30mmol)加入反应液中，反应液在25℃继续反应12小时。将反应液中加入水(100mL)稀释，用二氯甲烷(100mL×3)萃取。有机相合并用饱和食盐水(400mL×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(二氯 甲烷：甲醇＝50:1至20:1)纯化得化合物2-2。MS(ESI)m/z:440.1(M+H) +。
步骤2：化合物2-3的合成
将化合物2-2(4g,9.10mmol)溶于二氯甲烷40mL)中，加入三氟乙酸(11.20g,98.20mmol,7.27mL)，反应液在25℃搅拌2小时。反应液减压浓缩得到粗品2-3的三氟乙酸盐，直接用于下一步反应。MS(ESI)m/z:340.1(M+H) +。
步骤3：化合物2-4的合成
将化合物2-3的三氟乙酸盐(4g,粗品)溶于乙醇(40mL)，加入氢氧化钠水溶液(3M,3.53mL)和甲醛水溶液(859.22mg,10.59mmol,788.27μL,37％纯度)，反应液在25℃搅拌1小时。反应液用二氯甲烷(50mL×3)萃取，合并有机相，用饱和食盐水(100mL)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(二氯甲烷：甲醇＝50:1至20:1)纯化得化合物2-4。MS(ESI)m/z:352.1(M+H) +。
步骤4：化合物2-5的合成
在冰浴下，将化合物2-4(0.8g,2.28mmol)溶于乙腈(15mL)中，加入碳酸钾(943.92mg,6.83mmol)和BB-1(1.05g,2.73mmol)，反应液在25℃继续搅拌12小时。反应液加入水(50mL)中淬灭，用乙酸乙酯(50mL×2)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。所得粗品经硅胶柱(二氯甲烷：甲醇＝100:1至50:1)纯化得到化合物2-5。MS(ESI)m/z:702.1(M+H) +。
步骤5：化合物2-6的合成
将化合物2-5(0.47g,670.82μmol)溶于二氯乙烷(240mL)中，加入[1,3-双(2,4,6-三甲基苯基)咪唑啉-2-基]-二氯-[(2-异丙氧基苯基)亚甲基]钌(84.07mg,134.16μmol)，反应液在80℃搅拌12小时。反应液加硫硅胶(500mg)，搅拌1小时，过滤，将滤液减压浓缩。所得粗品经硅胶柱(二氯甲烷：甲醇＝100:1至50:1)纯化得到化合物2-6。。MS(ESI)m/z:674.1(M+H) +。
步骤6：化合物2-6A和2-6B的合成
化合物2-6经超临界流体色谱检测(柱子型号:Chiralcel OJ-3(100mm*4.6mm,3μm)；流动相:[A：二氧化碳，B：0.05％二乙胺/乙醇]；梯度：5％～40％(B％),4min；40％(B％),2.5min,5％(B％)1.5min)为2个峰的混合物，混合物经超临界流体色谱(柱子型号:DAICEL CHIRALCEL OJ-H(250mm*30mm,5μm)，流动相:[A：二氧化碳，B：0.1％氨水/乙醇]；梯度：B％:25％-25％)分离得到2个异构体：化合物2-6A(保留时间3.295min，手性纯度＝100％)和化合物2-6B(保留时间3.931min，手性纯度＝99.3％)。
步骤7：化合物2A的合成
将化合物2-6A(90mg,133.81μmol)加入到二氯甲烷(2mL)中，加入氯化镁(63.70mg,669.07μmol)，反应液在25℃下搅拌12小时。反应液过滤，滤液减压浓缩，所得粗品经制备型高效液相分离纯化(柱子型号:Welch Xtimate C18 100*40mm*3μm；流动相:[A:水(0.075％三氟乙酸)-B:乙腈]；梯度：B％:58％-88％)得化 合物2A。 1H NMR(400MHz,氘代甲醇)δ7.78(d,J＝7.53Hz,1H),7.14-7.25(m,2H),7.06(t,J＝6.90Hz,1H),6.85-6.94(m,1H),6.78-6.84(m,1H),6.48(br d,J＝15.81Hz,1H),6.23-6.33(m,1H),5.93(d,J＝7.53Hz,1H),5.67(dd,J＝2.38,12.92Hz,1H),5.55(s,1H),5.17(d,J＝13.80Hz,1H),4.75-4.81(m,1H),4.62(br dd,J＝7.03,11.04Hz,1H),4.19(d,J＝13.80Hz,1H),4.11(d,J＝12.55Hz,1H),2.93-3.08(m,1H),2.53-2.64(m,1H),2.17-2.27(m,1H),2.07-2.16(m,1H),1.81-1.91(m,1H),1.69-1.80(m,1H)。MS(ESI)m/z:584.0(M+H) +。
步骤8：化合物2B的合成
将化合物2-6B(90mg,133.81μmol)加入到二氯甲烷(1mL)中，加入氯化锂(127.41mg,1.34mmol)，反应液在25℃下搅拌12小时。反应液过滤，滤液减压浓缩，所得粗品经制备型高效液相分离纯化(柱子型号:Welch Xtimate C18 100*40mm*3μm；流动相:[A:水(0.075％三氟乙酸)-B:乙腈]；梯度：B％:45％-75％)得化合物2B。 1H NMR(400MHz,氘代甲醇)δ7.80(br d,J＝7.28Hz,1H),7.14-7.30(m,2H),7.06(br t,J＝7.53Hz,1H),6.76-6.95(m,2H),6.48(br d,J＝15.81Hz,1H),6.23-6.37(m,1H),5.97(d,J＝7.53Hz,1H),5.66(br d,J＝14.56Hz,1H),5.56(s,1H),5.18(br d,J＝13.80Hz,1H),4.78(br d,J＝8.28Hz,1H),4.58-4.67(m,1H),4.18-4.24(m,1H),4.11(br d,J＝12.55Hz,1H),2.95-3.08(m,1H),2.54-2.65(m,1H),2.09-2.25(m,2H),1.73-1.88(m,2H)。MS(ESI)m/z:584.0(M+H) +。
实施例3
Figure PCTCN2021130114-appb-000053
步骤1：化合物3的合成
将化合物2B(180.00mg,309.04μmol)加入到丙酮(4mL)中，然后加入氯甲基碳酸甲酯(150.83mg,618.07μmol)和碳酸铯(503.45mg,1.55mmol)，反应液在室温下搅拌1小时。将反应液减压浓缩至干，所 得粗品经硅胶柱(二氯甲烷:甲醇＝100:1至50:1)纯化得化合物3。 1H NMR(400MHz,氘代二甲基亚砜)δ7.84(br d,J＝7.78Hz,1H),7.13-7.25(m,2H),7.01-7.11(m,1H),6.85-6.98(m,2H),6.50(br d,J＝15.81Hz,1H),6.23-6.39(m,1H),5.99(br d,J＝7.53Hz,1H),5.63-5.81(m,3H),5.53(s,1H),5.10(br d,J＝13.80Hz,1H),4.71-4.80(m,1H),4.54-4.66(m,1H),4.10(br dd,J＝9.66,12.92Hz,2H),3.85(s,3H),2.79(q,J＝10.54Hz,1H),2.57(br s,1H),2.07-2.20(m,2H),1.68-1.92(m,2H)；MS(ESI)m/z:672.2[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(Influenza 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2000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 PCTCN2021130114-appb-000054
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1。
表1 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)
1C 7.5
1D 2.9
2B 1.9
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：小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BALB/c小鼠体内血浆药代动力学。
实验动物：雄性BALB/c小鼠，7-9周龄，体重17-23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的水溶液)；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：从隐静脉穿刺采集血液后，血浆基质当中添加敌敌畏做稳定剂(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，迅速至于干冰中，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2。
表2 本发明化合物的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2B(i.v.) 20 3.6 / 1386
化合物3(po) / 4.2 681 4379
注：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。
实验结论：小鼠药代动力学研究结果显示，本发明化合物的清除率低，其前药的口服血浆暴露量高，具有良好的药代动力学性质。
实验例3：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+H 2O)；口服给药(po)，剂量为10mpk，浓度为1mg/mL，溶媒为3％DMSO+10％solutol HS+87％H 2O)。
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(血浆：敌敌畏溶液(40mM，乙腈：水＝1:1)为40:1)，在半小时内，于4℃、3000g离心10分钟吸取上清血浆，迅速至于干冰中，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3。
表3 本发明化合物的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2B(i.v.) 12.9 5.7 / 1948
化合物3(po) / 4.3 490 4089
注：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。
实验结论：大鼠药代动力学研究结果显示，本发明化合物清除率低，其前药口服血浆暴露量高，具有良好的药代动力学性质。
实验例4：体内药效研究
实验目的：评价本发明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，计算公式：第N天的体重下降率＝(第N天的体重-第0天的体重)/第0天的体重*100％。结果如表4所示，化合物3在第4天可以实现保护动物体重最大下降率为-9.22％，然后开始恢复，至实验结束小鼠存活率为100％。溶媒组第8天动物体重最大下降率超过-35％，第9天动物全部死亡。
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)
溶媒组 超过-35％(第8天) 0％
化合物3 -9.22％(第4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。

Claims (16)

  1. 式(II)所示化合物或其药学上可接受的盐，
    Figure PCTCN2021130114-appb-100001
    其中，
    R 1和R 2分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
    或者，R 1和R 2与它们相连的碳原子连接形成C 3-5环烷基或3-5元杂环烷基；
    R 3选自H和
    Figure PCTCN2021130114-appb-100002
    各R 4分别独立地选自H、F、Cl、Br、I、OH和NH 2；
    R 5选自C 1-3烷基和
    Figure PCTCN2021130114-appb-100003
    所述C 1-3烷基和
    Figure PCTCN2021130114-appb-100004
    分别独立地任选被1、2或3个R b取代；
    各R a分别独立地选自F、Cl、Br、I和OH；
    各R b分别独立地选自F、Cl、Br、I和OH；
    n选自0、1、2、3和4；
    所述“3-5元杂环烷基”包含1或2个分别独立地选自O、S、N和NH的杂原子。
  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，R 1和R 2分别独立地选自H。
  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 1和R 2与它们相连的碳原子连接形成环丙基、环丁基、氧杂环丁烷基或氮杂环丁烷基。
  4. 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 5选自CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和
    Figure PCTCN2021130114-appb-100005
    所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和
    Figure PCTCN2021130114-appb-100006
    任选被1、2或3个R b取代。
  5. 根据权利要求4所述化合物或其药学上可接受的盐，其中，R 5选自CH 3、CH 2CH 3、CH(CH 3) 2和
    Figure PCTCN2021130114-appb-100007
  6. 根据权利要求1或5所述化合物或其药学上可接受的盐，其中，R 3选自H和
    Figure PCTCN2021130114-appb-100008
  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，各R 4分别独立地选自F。
  8. 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 PCTCN2021130114-appb-100009
    选自
    Figure PCTCN2021130114-appb-100010
  9. 根据权利要求7或8所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2021130114-appb-100011
    选自
    Figure PCTCN2021130114-appb-100012
  10. 根据权利要求1～9任意一项所述化合物或其药学上可接受的盐，其选自，
    Figure PCTCN2021130114-appb-100013
    其中，
    R 1、R 2和R 3如权利要求1～9任意一项所定义；
    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。
  11. 根据权利要求1所述化合物或其药学上可接受的盐，其选自，
    Figure PCTCN2021130114-appb-100014
    其中，
    R 1和R 2分别独立地选自H；
    或者，R 1和R 2与它们相连的碳原子连接形成C 3-5环烷基或3-5元杂环烷基；
    所述“3-5元杂环烷基”包含1或2个分别独立地选自O和NH的杂原子。
  12. 根据权利要求10或11所述化合物或其药学上可接受的盐，其选自，
    Figure PCTCN2021130114-appb-100015
    其中，
    R 1和R 2如权利要求10或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10所述化合物或其药学上可接受的盐，其选自，
    Figure PCTCN2021130114-appb-100016
    其中，
    R 1和R 2如权利要求10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 PCTCN2021130114-appb-100017
    Figure PCTCN2021130114-appb-100018
    其中，
    R 1和R 2如权利要求13所定义。
  15. 下式化合物或其药学上可接受的盐，
    Figure PCTCN2021130114-appb-100019
  16. 根据权利要求15所述化合物或其药学上可接受的盐，其选自，
    Figure PCTCN2021130114-appb-100020
    Figure PCTCN2021130114-appb-100021
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