WO2020151252A1 - 含有n杂五元环的衣壳蛋白装配抑制剂、其药物组合物和用途 - Google Patents

含有n杂五元环的衣壳蛋白装配抑制剂、其药物组合物和用途 Download PDF

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Publication number
WO2020151252A1
WO2020151252A1 PCT/CN2019/108483 CN2019108483W WO2020151252A1 WO 2020151252 A1 WO2020151252 A1 WO 2020151252A1 CN 2019108483 W CN2019108483 W CN 2019108483W WO 2020151252 A1 WO2020151252 A1 WO 2020151252A1
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Prior art keywords
compound
formula
capsid protein
pharmaceutically acceptable
pharmaceutical composition
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PCT/CN2019/108483
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English (en)
French (fr)
Inventor
张寅生
敖汪伟
李元
王辉
沈杭州
倪杰
张欢
吴杰
张立
曹凯
陆鹏
刘戌时
汪杰
赵天笑
葛兴枫
卢丹丹
陈硕
马雪琴
施伟
王晓金
徐宏江
Original Assignee
正大天晴药业集团股份有限公司
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Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to KR1020217026389A priority Critical patent/KR20210119452A/ko
Priority to AU2019424375A priority patent/AU2019424375B2/en
Priority to US17/425,701 priority patent/US20220185774A1/en
Priority to CA3127393A priority patent/CA3127393A1/en
Priority to JP2021542370A priority patent/JP7479384B2/ja
Priority to SG11202107774QA priority patent/SG11202107774QA/en
Priority to EP19911146.9A priority patent/EP3915972A4/en
Priority to CN201980090023.7A priority patent/CN113365979B/zh
Publication of WO2020151252A1 publication Critical patent/WO2020151252A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61P31/20—Antivirals for DNA viruses

Definitions

  • This application relates to the compound represented by Formula I or Formula II, its stereoisomers, tautomers, geometric isomers, solvates, active metabolites, hydrates, prodrugs or pharmaceutically acceptable salts,
  • the preparation method thereof, the pharmaceutical composition containing the compound, and the application thereof in the prevention or treatment of diseases for example, prevention or treatment of diseases that benefit from the inhibition of capsid protein assembly, such as the treatment of hepatitis B virus infection).
  • chronic viral hepatitis B is incurable and can only be controlled. At present, it is mainly limited to two types of agents (interferon and nucleoside analog/viral polymerase inhibitors).
  • the low cure rate of HBV is partly due to the presence and persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected liver cells.
  • the current treatment plan cannot eliminate the cccDNA in the reservoir, and some new HBV targets such as core inhibitors, such as viral capsid protein formation or assembly inhibitors, cccDNA inhibitors and interferon-stimulated gene activators It is expected to bring hope to curing hepatitis B (Mayur Brahmania, et al. New therapeutic agents for chronic hepatitis B).
  • HBV capsid is assembled from core protein.
  • HBV reverse transcriptase and pgRNA need to be correctly encapsulated by the capsid protein. Therefore, blocking the assembly of the capsid protein or accelerating the degradation of the capsid protein will block the process of capsid protein assembly, thereby affecting virus replication.
  • researchers have begun to target capsid protein assembly as inhibitors. For example, WO2014184350, WO2015011281, WO2017156255, etc. have disclosed a series of related compounds. However, most of them are in the pre-clinical research stage or the research has been terminated. There is a need for more alternative effective capsid protein assembly inhibitors to treat, improve or prevent HBV infection in this field.
  • This application relates to a compound of formula I, its stereoisomers, tautomers, geometric isomers, solvates, active metabolites, hydrates, prodrugs or pharmaceutically acceptable salts,
  • the application also relates to compounds of formula II, their stereoisomers, tautomers, geometric isomers, solvates, active metabolites, hydrates, prodrugs or pharmaceutically acceptable salts,
  • the application also provides a pharmaceutical composition, which comprises the compound of formula I or formula II of the application or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.
  • this application also provides a method for treating diseases that benefit from capsid protein assembly inhibition, which includes administering a therapeutically effective amount of a compound represented by formula I or formula II to a mammal in need of the treatment, preferably a human , Its pharmaceutically acceptable salt or its pharmaceutical composition.
  • this application also provides the use of the compound of formula I or formula II, its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a medicament for preventing or treating diseases that benefit from capsid protein assembly inhibition use.
  • this application also provides the use of the compound of formula I or formula II, its pharmaceutically acceptable salt, or its pharmaceutical composition in preventing or treating diseases that benefit from capsid protein assembly inhibition.
  • the present application also provides the above-mentioned compound of formula I or formula II, its pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating diseases that benefit from capsid protein assembly inhibition.
  • the application also provides a pharmaceutical composition, which comprises the compound of formula I or formula II of the application, its stereoisomers, tautomers, geometric isomers, solvates, active metabolites, and hydrates , Prodrugs or pharmaceutically acceptable salts.
  • the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.
  • the present application also provides a method for inhibiting capsid protein assembly, including administering to an individual in need a therapeutically effective amount of the compound of formula I or formula II of the present application, its stereoisomers, and tautomers , Geometric isomers, solvates, active metabolites, hydrates, prodrugs or pharmaceutically acceptable salts or pharmaceutical compositions thereof.
  • the individual is a mammal; in some embodiments, the individual is a human.
  • the present application also provides methods for preventing or treating diseases that benefit from capsid protein assembly inhibition, including administering to an individual in need a therapeutically effective amount of the compound of formula I or formula II of the present application, its stereoisomers, Tautomers, geometric isomers, solvates, active metabolites, hydrates, prodrugs or pharmaceutically acceptable salts or pharmaceutical compositions thereof.
  • the individual is a mammal; in some embodiments, the individual is a human.
  • the application also provides the compound of formula I or formula II, its stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmacy.
  • the application also provides the compound of formula I or formula II, its stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmacy.
  • the application also provides the compound of formula I or formula II, its stereoisomer, tautomer, geometric isomer, solvate, active metabolite, hydrate, prodrug or pharmacy.
  • this application also provides the above-mentioned compound of formula I or formula II, its stereoisomers, tautomers, geometric isomers, solvates, active metabolites, hydrates, prodrugs or pharmaceutically acceptable compounds.
  • the present application also provides the compound of formula I or formula II of the present application, its stereoisomers, tautomers, geometric isomers, solvates, and active metabolites for inhibiting capsid protein assembly. , Hydrates, prodrugs or pharmaceutically acceptable salts, or pharmaceutical compositions thereof.
  • the present application also provides compounds of the above formula I or II, stereoisomers, tautomers, geometric isomers, and solvents for the prevention or treatment of diseases that benefit from capsid protein assembly inhibition.
  • the diseases that benefit from capsid protein assembly inhibition refer to diseases caused by hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • the diseases that benefit from capsid protein assembly inhibition refer to liver diseases caused by hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • the treatment of diseases that benefit from capsid protein assembly inhibition refers to the control, reduction or elimination of HBV to prevent, alleviate or cure liver diseases in infected patients.
  • the term “optional” or “optionally” means that the event or situation described later can occur or not occur, and the description includes occurrence of said event or situation and non-occurrence of said event or situation.
  • the ethyl group is "optionally" substituted by halogen, meaning that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), or polysubstituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ).
  • CH 2 CH 3 unsubstituted
  • monosubstituted such as CH 2 CH 2 F
  • polysubstituted such as CHFCH 2 F, CH 2 CHF 2 etc.
  • CF 2 CF 3 completely substituted
  • treatment means administering the compound or formulation described in this application to improve or eliminate a disease or one or more symptoms related to the disease, and includes:
  • prevention means administering the compound or preparation described in this application to prevent a disease or one or more symptoms related to the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, especially when Such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state.
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) reducing, improving or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The dosage of the compound of the present application for the onset of one or more symptoms of a specific disease, condition, or disorder described herein.
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. It is determined by its own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. can be mentioned. .
  • pharmaceutical composition refers to a mixture of one or more of the compounds of the application or their salts and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the application to the organism.
  • solvate refers to a substance formed by combining the compound of the present application with a pharmaceutically acceptable solvent.
  • Pharmaceutically acceptable solvents include water, ethanol, acetic acid and the like.
  • Solvates include stoichiometric solvates and non-stoichiometric solvates.
  • hydrate refers to a solvate that includes the disclosed or claimed compound and stoichiometric or non-stoichiometric amounts of water.
  • the compounds of the present application can also be prepared as prodrugs, such as pharmaceutically acceptable prodrugs. Since prodrugs are known to improve many desired properties of drugs (such as solubility, bioavailability, preparation, etc.), the compounds of this application can be delivered in the form of prodrugs. Therefore, this application is intended to cover prodrugs of currently claimed compounds, their delivery methods and compositions containing prodrugs.
  • prodrug is intended to include any covalently bound carrier that, when administered to a mammalian subject, releases the active parent drug of the application in vivo.
  • the prodrugs of the present application are prepared by modifying the functional groups present in the compound in such a way that the modified substance is broken into the parent compound in conventional operations or in vivo.
  • mammals such as primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, and poultry, etc.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and do not impair the biological activity and performance of the active compound.
  • Suitable auxiliary materials are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also called proton transfer tautomers
  • proton migration such as keto-enol and imine-enamine isomerization.
  • a specific example of a proton tautomer is the imidazole moiety, where protons can migrate between two ring nitrogens.
  • Valence tautomers include interconversion through the recombination of some bonding electrons.
  • Certain compounds of this application may have asymmetric carbon atoms (stereocenters) or double bonds. Therefore, racemates, diastereomers, enantiomers, geometric isomers and individual isomers are all included in the scope of this application.
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms.
  • This application envisages all such compounds, including tautomers, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers , Diastereomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomeric enriched mixtures, All these are within the scope of this application.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of this application.
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of this application, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the present application also includes compounds of the present application that are the same as those described herein, but have one or more atoms replaced by an isotope-labeled atom having an atomic weight or mass number different from those generally found in nature.
  • isotopes that can be bound to the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotope-labeled compounds of the application can be used in compound and/or substrate tissue distribution analysis. Tritiated (i.e. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability.
  • Positron emission isotopes such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • PET positron emission tomography
  • the isotope-labeled compound of the present application can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by replacing the non-isotopically-labeled reagent with an isotope-labeled reagent.
  • substitution with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations
  • the following may be preferred, where the deuterium substitution may be partial or complete.
  • Partial deuterium substitution refers to the substitution of at least one hydrogen with at least one deuterium. All compounds in such forms are included in the scope of the present application.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administering the compound of the present application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These auxiliary materials enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • the solid oral composition can be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or the core of the dragee.
  • suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.
  • the therapeutic dose of the compound of the present application may be determined according to, for example, the following: the specific use of the treatment, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the compound of the present application in the pharmaceutical composition may not be fixed, depending on various factors, including dosage, chemical properties (such as hydrophobicity) and route of administration.
  • the compound of the present application can be provided by a physiological buffer aqueous solution containing about 0.1-10% w/v of the compound for parenteral administration. Some typical dosage ranges are from about 1 ⁇ g/kg to about 1 g/kg body weight/day.
  • the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight/day.
  • the dosage is likely to depend on such variables, such as the type and degree of development of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation and its route of administration.
  • the effective dose can be obtained by extrapolating the dose-response curve derived from the in vitro or animal model test system.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the examples of the present application.
  • EA stands for ethyl acetate
  • MeOH stands for methanol
  • DMF stands for N,N-dimethylformamide
  • HATU stands for 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyl Urea hexafluorophosphate
  • DIPEA stands for N,N-diisopropylethylamine
  • PO stands for oral administration
  • IV stands for intravenous injection
  • DMSO stands for dimethyl sulfoxide.
  • the nuclear magnetic resonance chromatography (NMR) of this application is measured by BRUKER-300 and BRUKER-500 nuclear magnetic resonance instruments.
  • TMS ⁇ 0.00
  • the format of the proton data recording is: Number, peak type (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant (in Hertz Hz).
  • the instrument used for mass spectrometry is AB SCIEX Triple TOF 4600 or AB SCIEX 3200QTRAP.
  • Step A In an ice bath, under N 2 protection, add 2-chloro-2-oxoacetate (40.8g) and zinc oxide (1.22g) to the reaction flask, and then add 2,4-dimethyl- 1H-pyrrole-3-carboxylic acid ethyl ester (5g), after the addition is complete, the mixture is stirred in an ice bath for 10 minutes, the ice bath is removed, and the mixture is stirred at room temperature. At the end of the reaction, the reaction solution was slowly added dropwise to 200 mL of ice-water mixture, EA (200 mL) was added, and the layers were separated.
  • Step B Into the reaction flask, add 5-(2-ethoxy-2-oxoacetyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (3.5g), MeOH in turn (40 mL), a solution of sodium hydroxide (1.05 g) in water (20 mL) was added dropwise under an ice bath, and stirred at room temperature.
  • Step C At room temperature, add 2-(4-(ethoxycarbonyl)-3,5-dimethyl-1H-pyrrol-2-yl)-2-oxoacetic acid (1g) to the reaction flask in turn , DMF (20mL), HATU (2.07g) and DIPEA (1.08g), after the addition is complete, stir at room temperature for 10 minutes, add (S)-1,1,1-trifluoropropan-2-amine hydrochloride (0.63 g).
  • Step D Add (S)-2,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl to the reaction flask ) Ethyl -1H-pyrrole-3-carboxylate (300 mg), MeOH (2 mL), and NaOH (72 mg) in water (1 mL) was added. After the addition, the reaction temperature was heated to 80° C. to react overnight. After the reaction is over, concentrate, add water (20mL) and EA (60mL), separate the water layer, wash the organic phase with water (30mL), separate the layers, combine the water phases, adjust the water phase with 2N hydrochloric acid to make the pH around 3.
  • Step E At room temperature, sequentially add (S)-2,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl) to the reaction flask (Amino)acetyl)-1H-pyrrole-3-carboxylic acid (230mg), DMF (5mL), HATU (428mg) and DIPEA (194mg), after the addition is complete, stir for 10 minutes, then add 5-amino-2-fluorobenzyl Nitrile (123mg), heated to 40°C and stirred for 20 hours.
  • Step A According to Example 1, in Step C, (R)-1,1,1-trifluoropropan-2-amine hydrochloride is used instead of (S)-1,1,1-trifluoropropan-2- Amine hydrochloride to produce (R)-2,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl)amino)acetyl) -1H-pyrrole-3-carboxylic acid ethyl ester.
  • Step B According to Example 1, (R)-2,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl )Amino)acetyl)-1H-pyrrole-3-carboxylic acid ethyl ester instead of (S)-2,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoro Propan-2-yl)amino)acetyl)-1H-pyrrole-3-carboxylic acid ethyl ester to produce (R)-2,4-dimethyl-5-(2-oxo-2-((1 ,1,1-Trifluoroprop-2-yl)amino)acetyl)-1H-pyrrole-3-carboxylic acid.
  • Step C According to Example 1, (R)-2,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoroprop-2-yl )Amino)acetyl)-1H-pyrrole-3-carboxylic acid instead of (S)-2,4-dimethyl-5-(2-oxo-2-((1,1,1-trifluoropropane- 2-yl)amino)acetyl)-1H-pyrrole-3-carboxylic acid to produce (R)-N-(3-cyano-4-fluorophenyl)-2,4-dimethyl-5- (2-oxo-2-((1,1,1-trifluoropropan-2-yl)amino)acetyl)-1H-pyrrole-3-carboxamide.
  • the DMSO-dissolved compound was diluted with a complete medium, a 2-fold gradient, a total of 10 concentrations, and the compound was added.
  • the fresh medium containing the compound was replaced every 72 h, and the compound was treated for 6 days.
  • 300 ⁇ L of lysis buffer (10mM Tris-HCl, 1mM EDTA, 1% NP-40) to each well.
  • DNA is extracted, and the intracellular viral capsid is determined by real-time fluorescent quantitative PCR instrument
  • the inhibition rate is calculated based on the Ct value, and the EC50 value is calculated by the four-parameter method. The results are shown in Table 1 and Table 2.
  • HepG2.2.15 cells (Wuhan Institute of Virology) in good condition in the exponential growth phase, add 5mL PBS to wash it again, and add 2mL pancreatin.
  • a cell incubator for digestion take it out from time to time for observation under the microscope, when the cells just fall off, discard 1mL of trypsin, leaving only the residual liquid, put it in a 37°C incubator for digestion for 8-15 minutes, take it out and observe under the microscope Cells (whether they are single round, no adhesion between cells), add 5mL MEM medium to resuspend the cells.
  • Count using a cell counter dilute the complete medium, and adjust the cell density to 2*10 5 cells/mL.
  • Sample pretreatment 50 ⁇ L incubation sample, add 300 ⁇ L ice acetonitrile precipitation with internal standard, vortex for 5min, centrifuge (12000rpm, 4°C) for 10min. Aspirate 75 ⁇ L of the supernatant, add 75 ⁇ L of ultrapure water, dilute and mix well, and 1 ⁇ L of sample for analysis. The results are shown in Table 4.
  • Plasma sample preparation Draw 495 ⁇ L of blank plasma of corresponding species (mouse, rat, dog, monkey and human) respectively, and add 5 ⁇ L of the corresponding test compound solution or positive control to obtain the plasma sample solution to make the compound plasma drug concentration separately It is 1 ⁇ M, 10 ⁇ M (prepared with acetonitrile).
  • Sample pretreatment 50 ⁇ L plasma side sample, add 450 ⁇ L ice acetonitrile precipitation with internal standard, vortex for 5min, centrifuge (12000rpm, 4°C) for 10min.
  • Aspirate 75 ⁇ L of the supernatant add 75 ⁇ L of ultrapure water to dilute and mix, 1 ⁇ L for sample analysis;
  • 50 ⁇ L of PBS side sample add 250 ⁇ L of ice acetonitrile with internal standard precipitation, vortex for 5min, centrifuge (12000rpm, 4°C) for 10min.
  • Aspirate 75 ⁇ L of the supernatant add 75 ⁇ L of ultrapure water to dilute and mix, and then 2 ⁇ L of sample for analysis. The results are shown in Table 5.
  • the 300 ⁇ L final incubation system contains 30 ⁇ L liver microsomes (protein concentration: 0.15 mg/mL, Corning), 30 ⁇ L NADPH+MgCl 2 , 3 ⁇ L substrate (prepared with acetonitrile), and 237 ⁇ L PBS buffer. Make 2 servings for each species, 0.3mL each. Prepare each tube with a total volume of 270 ⁇ L of substrate and enzyme mixing solution. After pre-incubating with NADPH for 5 minutes at 37°C, add 30 ⁇ L of NADPH+MgCl 2 mixed solution for reaction at 0, 10, 30, and 60 minutes. Take out 50 ⁇ L and terminate the reaction with 300 ⁇ L ice acetonitrile containing internal standard.
  • Sample pretreatment 50 ⁇ L of incubation sample, adding 300 ⁇ L of ice acetonitrile precipitation containing internal standard diazepam, vortexing for 5min, centrifuging (12000rpm, 4°C) for 10min. Pipette 75 ⁇ L of the supernatant into a 96-well plate and dilute and mix with 75 ⁇ L ultrapure water, inject 0.5 ⁇ L, and perform LC-MS/MS analysis. The results are shown in Table 6.
  • mice Take 6-8 week old male C57BL/6 mice (Shanghai Lingchang Biological Technology Co., Ltd.), and inject rAAV8-1.3HBV virus (Beijing Wujiahe, adr subtype) to C57BL at the dose of 1 ⁇ 10 11 vg. /6 In mice.
  • rAAV8-1.3HBV virus Beijing Wujiahe, adr subtype
  • blood was collected from the orbit of the mice, and the serum was separated.
  • the expression levels of HBeAg and HBsAg and the copy number of HBV DNA in the serum were determined to determine whether the model was successfully constructed.
  • mice Combined with the quantitative detection results of serological HBeAg, HBsAg and HBV DNA, the selected mice have HBV DNA expression levels greater than 1 ⁇ 10 4 IU/mL, HBeAg greater than 1 ⁇ 10 3 NCU/mL and HBsAg greater than 1 ⁇ 10 3 ng/mL.
  • Mice were divided into groups, and set up a blank control group, a vehicle control group and a test substance group. The mice in each group were given intragastric administration for 3 weeks, once a day, and the drug was stopped for 1 week. During the experiment, blood was collected from the orbit every other week, the serum was separated, and the DNA content was detected by fluorescence quantitative PCR. The results are shown in Table 7 and Table 8.
  • Table 7 Decreased levels of HBV DNA in serum (log10) (administration dose 10mpk)
  • Table 8 Decreased levels of HBV DNA in serum (log10) (administration dose 1mpk)
  • mice Take 6-8 week old male C57BL/6 mice (Shanghai Lingchang Biotechnology Co., Ltd.), and dissolve the purified recombinant plasmid pAAV/HBV1.2 (10 ⁇ g) in PBS.
  • the injection volume of each mouse is about its body weight 10% of it was injected into mice through the tail vein within 3-8s.
  • blood was collected from the orbit for detection of serum HBV DNA, and the model mice were selected for uniform serum DNA for grouping, and set up a model control group, a vehicle control group, and a test substance group.
  • Each group of mice was given intragastric administration for 10 consecutive days, once a day, at a dose of 3 mg/kg.
  • mice serum was collected at 0, 4, 7, and 10 days after administration. On the 10th day, the mice were sacrificed and liver tissue samples were taken. The fluorescence quantitative PCR method was used to detect the copy number of HBV DNA in the mouse serum and liver. The results are shown in Table 9.
  • Table 9 Decreased levels of HBV DNA in serum (log10) (administration dose 3mpk)
  • SD rats (Shanghai Xipuer-Bike), weighing 180-220g, were used for 3 to 5 days and then randomly divided into groups, 3 rats in each group, and were given a series of compounds at a dose of 20 mg/kg.
  • test animals SD rats were fasted for 12 hours before the administration, and were given food 4 hours after the administration. They were free to drink water before and after the experiment and during the experiment.

Abstract

式I或者式II所示的化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐、其药物组合物及医药用途，包括用于治疗受益于衣壳蛋白装配抑制的疾病的用途，尤其是乙型肝炎病毒感染引起的疾病。

Description

含有N杂五元环的衣壳蛋白装配抑制剂、其药物组合物和用途
相关申请的交叉引用
本申请要求于2019年1月25日向中国国家知识产权局提交的第201910073465.2号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本申请涉及式I或者式II所示的化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，其制备方法，含有该化合物的药物组合物，及其在预防或治疗疾病(例如预防或者治疗受益于衣壳蛋白装配抑制的疾病，诸如作为治疗乙型肝炎病毒感染的药物)中的应用。
背景技术
当前，针对慢性乙型病毒性肝炎不可治愈只能控制，目前主要限于两类药剂(干扰素和核苷类似物/病毒聚合酶的抑制剂)。HBV的治愈率低部分是由于受感染肝细胞的细胞核中共价闭合环状DNA(cccDNA)的存在和持续性。目前治疗方案无法将储存库中的cccDNA清除掉，而一些HBV的新靶点如核心抑制剂(Core inhibitors，例如病毒的衣壳蛋白形成或装配抑制剂和cccDNA抑制剂及干扰素刺激基因激活剂等)有望给治愈乙肝带来希望(Mayur Brahmania,et al.New therapeutic agents for chronic hepatitis B)。
HBV衣壳由核心蛋白装配而成，在逆转录以前，HBV逆转录酶、pgRNA需要被衣壳蛋白正确包裹。因此，阻断衣壳蛋白装配，或加快衣壳蛋白降解，都会阻断衣壳蛋白装配过程，从而影响病毒复制。近年，研究人员开始以衣壳蛋白装配为靶点的抑制剂，例如WO2014184350、WO2015011281、WO2017156255等公开了一系列相关化合物。但是大多数处于前期临床研究阶段或者研究已终止，本领域中需要治疗、改善或预防HBV感染的更多供选择的有效的衣壳蛋白装配抑制剂。
发明详述
本申请涉及式I化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，
Figure PCTCN2019108483-appb-000001
本申请还涉及式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，
Figure PCTCN2019108483-appb-000002
另一方面，本申请还提供药物组合物，其包含本申请的式I或者式II化合物或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料。
另一方面，本申请还提供一种治疗受益于衣壳蛋白装配抑制的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的上述式I或者式II所示的化合物、其药学上可接受的盐或者其药物组合物。
另一方面，本申请还提供了上述式I或者式II化合物、其药学上可接受的盐、或者其药物组合物在制备用于预防或者治疗受益于衣壳蛋白装配抑制的疾病的药物中的用途。
另一方面，本申请还提供了上述式I或者式II化合物、其药学上可接受的盐、或者其药物组合物在预防或者治疗受益于衣壳蛋白装配抑制的疾病中的用途。
另一方面，本申请还提供了用于预防或者治疗受益于衣壳蛋白装配抑制的疾病的上述式I或者式II化合物、其药学上可接受的盐、或者其药物组合物。
另一方面，本申请还提供药物组合物，其包含本申请的式I或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包含药学上可接受的辅料。
另一方面，本申请还提供一种抑制衣壳蛋白装配的方法，包括对有需要的个体给予治疗有效量的本申请的式I或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者其药物组合物。在一些实施方案中，所述个体为哺乳动物；在一些实施方案中，所述个体为人类。
另一方面，本申请还提供预防或治疗受益于衣壳蛋白装配抑制的疾病的方法，包括对有需要的个体给予治疗有效量的本申请的式I或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者其药物组合物。在一些实施方案中，所述个体为哺乳动物；在一些实施方案中，所述个体为人类。
另一方面，本申请还提供了本申请的式I或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者其药物组合物在抑制衣壳蛋白装配中的用途。
另一方面，本申请还提供了本申请的式I或者式II化合物、其立体异构体、互变异构体、几何异构体、 溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者其药物组合物在制备用于抑制衣壳蛋白装配的药物中的用途。
另一方面，本申请还提供了本申请的式I或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，或者其药物组合物在制备用于预防或者治疗受益于衣壳蛋白装配抑制的疾病的药物中的用途。
另一方面，本申请还提供了上述式I或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，或者其药物组合物在预防或者治疗受益于衣壳蛋白装配抑制的疾病中的用途。
另一方面，本申请还提供了用于抑制衣壳蛋白装配的本申请的式I或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，或者其药物组合物。
另一方面，本申请还提供了用于预防或者治疗受益于衣壳蛋白装配抑制的疾病的上述式I或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，或者其药物组合物。
在本申请的一些实施方式中，所述受益于衣壳蛋白装配抑制的疾病指乙型肝炎病毒(HBV)感染引起的疾病。
在本申请的一些实施方式中，所述受益于衣壳蛋白装配抑制的疾病指乙型肝炎病毒(HBV)感染引起的肝脏疾病。
在本申请的部分实施方式中，所述治疗受益于衣壳蛋白装配抑制的疾病指控制、降低或清除HBV以预防、缓解或治愈受感染患者的肝脏疾病。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术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，而应该按照本领域普通的含义去理解。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。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
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。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“溶剂化物”是指本申请化合物与制药上可接受的溶剂结合形成的物质。制药上可接受的溶剂包括水，乙醇，乙酸等。溶剂化物包括化学计算量的溶剂合物和非化学计算量的溶剂合物。
术语“水合物”指的是一种溶剂化物，包括已披露或要求保护的化合物和化学计量或非化学计量数量的水。
本申请的化合物还可以被制备成前药，如药学上可接受的前药。由于已知前药可提高药物的众多期望特性(如溶解性、生物利用度、制备等)，可以以前药的形式递送本申请的化合物。因此，本申请旨在涵盖当前主张的化合物的前药，其递送方法和含有前药的组合物。
术语“前药”旨在包括任何共价结合的载体，当给予哺乳动物受试者这种前药时，该载体在体内释放本申请的活性母体药物。本申请的前药通过以这样一种方式修饰化合物中存在的官能团制备，使得该修饰物在常规操作中或在体内断裂成母体化合物。
本申请中，术语“个体”包括人和动物，例如，哺乳动物(如灵长类动物，牛，马，猪，狗，猫，小鼠，大鼠，兔，山羊，绵羊以及禽类等)。
术语“活性代谢物”是指当化合物被代谢时形成的化合物的生物活性衍生物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及 性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
本申请的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。
本申请的某些化合物可以具有不对称碳原子(立体中心)或双键。因此，外消旋体、非对映异构体、对映异构体、几何异构体和单个异构体都包括在本申请的范围之内。
当本申请的化合物含有烯属双键或其它几何不对称中心时，除非另有规定，它们包括E和Z几何异构体。
本申请的化合物可以存在特定的几何异构体或立体异构体形式。本申请设想所有的这类化合物，包括互变异构体、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，所有这些都属于本申请的范围之内。烷基等取代基中可以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申请的范围之内。
可以通过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。如果想得到本申请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)。
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位 素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代，所有这样的形式的化合物包含于本申请的范围内。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本申请化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本申请化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供本申请化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推，得到有效剂量。
本申请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申请的实施例。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.本申请引用的所有参考文献整体上并入本申请。
本申请采用下述缩略词：
EA代表乙酸乙酯；MeOH代表甲醇；DMF代表N,N-二甲基甲酰胺；HATU代表2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；DIPEA代表N，N-二异丙基乙胺；PO代表口服；IV代表静脉注射；DMSO代表二甲基亚砜。
为清楚起见，进一步用实施例来阐述本申请，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
具体实施方式
本申请核磁共振色谱(NMR)使用BRUKER-300和BRUKER-500核磁共振仪测定，化学位移以四甲基硅烷(TMS＝δ0.00)为内标，核磁共振氢谱数据记录的格式为：质子数，峰型(s，单峰；d，双重峰；t，三重峰；q，四重峰；m，多重峰)，耦合常数(以赫兹Hz为单位)。质谱使用的仪器为AB SCIEX Triple TOF 4600或AB SCIEX 3200QTRAP。
实施例1(S)-N-(3-氰基-4-氟苯基)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019108483-appb-000003
Figure PCTCN2019108483-appb-000004
步骤A：冰浴中，N 2保护下，反应瓶中依次加入2-氯-2-氧代乙酸乙酯(40.8g)和氧化锌(1.22g)，然后加入2,4-二甲基-1H-吡咯-3-羧酸乙酯(5g)，加料完毕，混合物在冰浴下搅拌10分钟，撤去冰浴，室温搅拌。反应结束，将反应液缓慢滴加到200mL冰水混合物中，加入EA(200mL)，分层，有机相用无水硫酸钠干燥，浓缩，柱层析制备得到5-(2-乙氧基-2-氧代乙酰基)-2,4-二甲基-1H-吡咯-3-羧酸乙酯(4.5g)。MS(ESI+,[M+Na] +)m/z：290.07。
步骤B:反应瓶中，依次加入5-(2-乙氧基-2-氧代乙酰基)-2,4-二甲基-1H-吡咯-3-羧酸乙酯(3.5g)、MeOH(40mL)，冰浴下滴加氢氧化钠(1.05g)的水(20mL)溶液，室温下搅拌。反应结束，用2N盐酸水溶液调节水相pH为3-4，加入EA(100mL*2)萃取，有机相用水(30mL)洗涤，浓缩，得到2-(4-(乙氧基羰基)-3,5-二甲基-1H-吡咯-2-基)-2-氧代乙酸(2.7g)。MS(ESI-,[M-H] -)m/z：238.1.
步骤C:室温下，向反应瓶中,依次加入2-(4-(乙氧基羰基)-3,5-二甲基-1H-吡咯-2-基)-2-氧代乙酸(1g)、DMF(20mL)、HATU(2.07g)及DIPEA(1.08g)，加料完毕，室温下搅拌10分钟，加入(S)-1,1,1-三氟丙-2-胺盐酸盐(0.63g)。反应结束，将反应液倒入50mL水中，EA(50mL*3)萃取，有机相用饱和硫酸钠水溶液(50mL*3)洗涤，无水硫酸钠干燥，过滤，收集滤液，浓缩、经柱层析纯化，得到(S)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸乙酯(0.5g)。MS(ESI-,[M-H] -)m/z：333.4.
步骤D:反应瓶中，加入(S)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸乙酯(300mg)、MeOH(2mL)、加入NaOH(72mg)的水(1mL)溶液，加毕，加热反应温度至80℃反应过夜。反应结束，浓缩，然后加入水(20mL)及EA(60mL)，分离水层，有机相加水(30mL)洗涤，分层，合并水相，用2N盐酸调节水相，使pH为3左右，然后加入EA(100mL*2)萃取，分层，浓缩有机相，得到(S)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸(230mg)。MS(ESI-,[M-H] -)m/z：305.4.
步骤E:室温下，向反应瓶中依次加入(S)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸(230mg)、DMF(5mL)、HATU(428mg)及DIPEA(194mg)，加料完毕，搅拌10分钟，再加入5-氨基-2-氟苄腈(123mg)，加热至40℃搅拌反应20小时。反应结束，加入水(20mL)及EA(60mL)，分层， 无水硫酸钠干燥，过滤，收集滤液，旋干，拌样，柱层析纯化得到(S)-N-(3-氰基-4-氟苯基)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺(180mg)。 1H NMR(500MHz,DMSO-d6)δ12.05(s,1H),10.20(s,1H),9.49(d,J＝9.0Hz,1H),8.20(dd,J＝6.0,2.5Hz,1H),7.98-7.91(m,1H),7.53(t,J＝9.0Hz,1H),4.78-4.67(m,1H),2.40(s,3H),2.32(s,3H),1.34(d,J＝7.0Hz,3H)。MS(ESI-,[M-H] -)m/z：423.0。
实施例2(R)-N-(3-氰基-4-氟苯基)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺
Figure PCTCN2019108483-appb-000005
步骤A：根据实施例1，在步骤C中用(R)-1,1,1-三氟丙-2-胺盐酸盐替代(S)-1,1,1-三氟丙-2-胺盐酸盐，制得(R)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸乙酯。MS(ESI-,[M-H] -)m/z：333.2。
步骤B：根据实施例1，在步骤D中用(R)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸乙酯替代(S)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸乙酯，制得(R)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸。MS(ESI-,[M-H] -)m/z：305.4。
步骤C：根据实施例1，在步骤E中用(R)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸替代(S)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-羧酸，制得(R)-N-(3-氰基-4-氟苯基)-2,4-二甲基-5-(2-氧代-2-((1,1,1-三氟丙-2-基)氨基)乙酰基)-1H-吡咯-3-甲酰胺。 1H-NMR(500MHz,DMSO-d6):δ12.03(s,1H),10.19(s,1H),9.48(d,J＝8.5Hz,1H),8.20(dd,J＝6.0,2.5Hz,1H),8.00-7.90(m,1H),7.52(t,J＝9.0Hz,1H),4.90–4.65(m,1H),2.40(s,3H),2.33(s,3H),1.34(d,J＝7.5Hz,3H)。MS(ESI-,[M-H] -)m/z：423.2。
实验例1.体外活性研究
1.1体外细胞HBV DNA抑制活性
取处于指数生长期状态良好的HepG2.2.15(武汉病毒所)或HepAD38细胞一瓶，加入5mL PBS清洗一 遍，加入3mL胰酶。室温消化5min，弃掉2mL胰酶后再放入细胞培养箱中消化10min，取出显微镜下观察(是否为单个圆形，细胞间无粘连)，加入10mL完全培养基终止消化。吹打成单细胞悬液后，取10μL细胞悬液使用细胞计数仪计数，完全培养基进行稀释，调整细胞密度至1*10 5个/mL。使用排枪接种于24孔板上(24孔板提前使用50μg/mL Collagen Ⅰ溶液包被)，1mL/孔，置恒温CO 2培养箱中培养48h。
使用完全培养基将DMSO溶解的化合物稀释，2倍梯度，共10个浓度，进行化合物加样，每72h更换含化合物的新鲜培养基，化合物处理细胞6天。吸去上清后，每孔加入300μL裂解液(10mM Tris-HCl，1mM EDTA，1％NP-40)，室温放置裂解10min后，提取DNA，用实时荧光定量PCR仪测定胞内病毒衣壳中HBV DNA，根据Ct值计算抑制率，四参数法计算EC50值。结果如表1及表2所示。
表1.HepAD38细胞中抗HBV活性实验结果
实施例编号 EC50(nM)
1 24
表2.HepG2.2.15细胞中抗HBV活性实验结果
实施例编号 EC50(nM)
1 17.4
2 10.7
1.2体外细胞毒性
取处于指数生长期状态良好的HepG2.2.15细胞(武汉病毒所)一瓶，加入5mL PBS清洗一遍，加入2mL胰酶。放入细胞培养箱中进行消化，不时取出显微镜下观察，待细胞刚脱落时，弃掉1mL胰酶，仅仅留下残液，放入37℃培养箱中消化8-15min，取出在显微镜下观察细胞(是否为单个圆形，细胞间无粘连)，加入5mL MEM培养基进行细胞重悬。使用细胞计数仪计数，完全培养基进行稀释，调整细胞密度至2*10 5个/mL。使用排枪接种于96孔板上(96孔板提前使用50μg/mL Collagen Ⅰ溶液包被)，100μL/孔，置恒温CO 2培养箱中培养24h，给药处理，每隔3天，更换含化合物的新鲜培养基，对照孔加不含药物的DMSO浓度为0.5％的培养基，并设普通培养基的对照孔，给药处理6天后，加CCK-8，10μL/孔，1-2h后酶标仪450nm处检测其吸光值，计算抑制率，并计算CC50。结果如表3所示。
表3
细胞 CC50(μM) 实施例编号
HepG2.2.15 >100 1
1.3 CYP450酶抑制研究
500μL最终的温孵体系中，含50μL人肝微粒体(蛋白浓度：0.2mg/mL,Corning)，1μL混合的CYP450 特异性底物(CYP1A2、CYP 2B6、CYP 2C9、CYP2C19、CYP 2D6、CYP 3A4)，398μL PBS缓冲液(PH7.4)，1μL特异性阳性抑制剂(阳性对照组)或受试化合物(乙腈配制)，50μL NADPH+MgCl 2。每个CYP450亚型做2份，每份0.5mL。每管先配好总体积为450μL的底物和酶的混匀液及NADPH分别在37℃预温孵5min后，加入50μL NADPH+MgCl 2混合溶液反应，于30min取出50μL用含内标的冰乙腈300μL终止反应。另外平行做2份空白组各500μL，不加NADPH，作为阴性对照组。
样品前处理：50μL温孵样品，加入300μL含内标的冰乙腈沉淀，涡旋震荡5min后，离心(12000rpm，4℃)10min。吸取上清液75μL，加入75μL超纯水，稀释混匀，1μL进样分析。结果如表4所示。
表4
Figure PCTCN2019108483-appb-000006
1.4血浆蛋白结合试验
血浆样品配制：分别吸取495μL相应种属(小鼠、大鼠、犬、猴及人)的空白血浆，加入5μL相应受试化合物溶液或阳性对照，即得血浆样品溶液，使化合物血浆药物浓度分别为1μM、10μM(乙腈配制)。
预处理好的透析膜置于高通量平衡透析装置中，吸取100μL血浆样品溶液及PBS缓冲液，分别加到透析膜的两侧(样品侧及缓冲液侧)(n＝3)，用贴膜将平衡装置封好后，放入37℃温孵过夜(100rpm)，达到透析平衡后，分别从样品侧及缓冲液侧吸取50μL样品，用含内标的冰乙腈终止反应。
样品前处理：50μL血浆侧样品，加入450μL含内标的冰乙腈沉淀，涡旋震荡5min后，离心(12000rpm，4℃)10min。吸取上清液75μL，加入75μL超纯水稀释混匀，1μL进样分析；50μLPBS侧样品，加入250μL含内标的冰乙腈沉淀，涡旋震荡5min后，离心(12000rpm，4℃)10min。吸取上清液75μL，加入75μL超纯水稀释混匀，2μL进样分析。结果如表5所示。
表5
Figure PCTCN2019108483-appb-000007
实验例2体外肝微粒体稳定性
300μL最终的温孵体系中，含30μL肝微粒体(蛋白浓度：0.15mg/mL，Corning)，30μL NADPH+MgCl 2，3μL底物(乙腈配制)，237μL PBS缓冲液。每个种属做2份，每份0.3mL。每管先配好总体积为270μL的底物及酶的混匀液，和NADPH分别在37℃预温孵5min后，加入30μL NADPH+MgCl 2混合溶液反应，分别于0、10、30、60min取出50μL用含内标的冰乙腈300μL终止反应。
样品前处理：50μL温孵样品，加入300μL含内标地西泮的冰乙腈沉淀，涡旋震荡5min后，离心(12000rpm，4℃)10min。吸取上清液75μL至96孔板中用75μL超纯水稀释混匀，进样0.5μL，进行LC-MS/MS分析。结果如表6所示。
表6体外肝微粒体稳定性
Figure PCTCN2019108483-appb-000008
实验例3：体内动物药效
3.1 AAV小鼠模型评价抗病毒效果
取6-8周龄雄性C57BL/6小鼠(上海灵畅生物科技有限公司)，按照1×10 11vg剂量，尾静脉注射rAAV8-1.3HBV病毒(北京五加和，adr亚型)至C57BL/6小鼠体内。注射病毒第2、4周，小鼠眼眶采血，分离血清，测定血清中HBeAg和HBsAg表达水平以及HBV DNA拷贝数，判断模型构建成功与否。结合血清学HBeAg、HBsAg和HBV DNA的定量检测结果，挑选出的小鼠各自HBV DNA表达水平都大于1×10 4IU/mL，HBeAg大于1×10 3NCU/mL和HBsAg大于1×10 3ng/mL。小鼠进行分组，设空白对照组、溶媒对照组、受试物组。每组小鼠以灌胃方式连续给药3周，每日1次，停药1周。实验过程中，隔周分别眼眶采血，分离血清，荧光定量PCR方法检测DNA含量。结果如表7和表8所示。
表7血清中HBV DNA下降水平(log10)(给药剂量10mpk)
实施例编号 第7天 第14天 第21天 第28天
1 2.67 3.80 4.30 3.50
表8血清中HBV DNA下降水平(log10)(给药剂量1mpk)
实施例编号 第7天 第14天 第21天 第28天
1 2.49 3.41 3.65 3.25
3.2 pAAV/HBV模型实验方法
取6-8周龄雄性C57BL/6小鼠(上海灵畅生物科技有限公司)，将纯化的重组质粒pAAV/HBVl.2(10μg)溶解在PBS中，每只小鼠注射体积约为其体重的10％，通过尾静脉在3-8s内注射到小鼠体内。注射质粒3天后眼眶取血检测血清HBV DNA，挑选出模型小鼠血清DNA均一的进行分组，设模型对照组、溶媒对照组、受试物组。每组小鼠以灌胃方式连续给药10天，每日1次，剂量为3mg/kg。分别于给药后的0、4、7、10天取小鼠血清，第10天处死小鼠取肝组织样本，荧光定量PCR方法检测小鼠血清和肝脏中HBV DNA 拷贝数。结果如表9所示。
表9血清中HBV DNA下降水平(log10)(给药剂量3mpk)
实施例编号 第4天 第7天 第10天
1 2.95 4.13 2.71
2 2.92 4.09 2.42
实验例4体内药物代谢动力学
大鼠体内药物代谢动力学(PK)研究
SD大鼠(上海西普尔-必凯)，体重180～220g，适应3～5天后，随机分组，每组3只，按20mg/kg剂量分别灌胃系列化合物。
受试动物(SD大鼠)给药前禁食12h，给药后4h给食物，实验前后和实验过程中均自由饮水。
给药后，于0min、15min、30min、1h、2h、4h、6h、8h、10h、24h、30h、48h于眼眶取血0.2mL左右，EDTA-K2抗凝后，30min内于4℃，4000rpm条件下离心10min分离血浆。收集全部血浆后立即于-20℃保存待测。
吸取50μL待测血浆样品和标曲样品，加入500μL含内标(地西泮20mg/mL)的乙腈溶液，振荡混匀5min，12000rpm离心10min，取上清75μL，加入75μL超纯水稀释，混匀，吸取1μL用于LC/MS/MS测定。结果如表10所示。
表10
Figure PCTCN2019108483-appb-000009
NA表示未检测。

Claims (10)

  1. 式I化合物或式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐，
    Figure PCTCN2019108483-appb-100001
  2. 药物组合物，其包含如权利要求1所述的式I化合物或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐；任选地，所述药物组合物还包含药学上可接受的辅料。
  3. 预防或者治疗受益于衣壳蛋白装配抑制的疾病的方法，包括对有需要的个体给予治疗有效量的如权利要求1所述的式I化合物或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者如权利要求2所述的药物组合物；任选地，所述受益于衣壳蛋白装配抑制的疾病的为乙型肝炎病毒感染引起的疾病。
  4. 如权利要求1所述的式I化合物或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者如权利要求2所述的药物组合物在制备用于预防或者治疗受益于衣壳蛋白装配抑制的疾病的药物中的用途；任选地，所述受益于衣壳蛋白装配抑制的疾病的为乙型肝炎病毒感染引起的疾病。
  5. 如权利要求1所述的式I化合物或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者如权利要求2所述的药物组合物在预防或者治疗受益于衣壳蛋白装配抑制的疾病中的用途；任选地，所述受益于衣壳蛋白装配抑制的疾病的为乙型肝炎病毒感染引起的疾病。
  6. 用于预防或者治疗受益于衣壳蛋白装配抑制的疾病的如权利要求1所述的式I化合物或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者如权利要求2所述的药物组合物；任选地，所述受益于衣壳蛋白装配抑制的疾病的为乙型肝炎病毒感染引起的疾病。
  7. 抑制衣壳蛋白装配的方法，包括对有需要的个体给予治疗有效量的如权利要求1所述的式I化合物或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者如权利要求2所述的药物组合物。
  8. 如权利要求1所述的式I化合物或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化 物、活性代谢物、水合物、前药或药学上可接受的盐或者如权利要求2所述的药物组合物在抑制衣壳蛋白装配中的用途。
  9. 如权利要求1所述的式I化合物或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者如权利要求2所述的药物组合物在制备用于抑制衣壳蛋白装配的药物中的用途。
  10. 用于抑制衣壳蛋白装配的如权利要求1所述的式I化合物或者式II化合物、其立体异构体、互变异构体、几何异构体、溶剂化物、活性代谢物、水合物、前药或药学上可接受的盐或者如权利要求2所述的药物组合物。
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