WO2019154343A1 - 衣壳蛋白装配抑制剂、其药物组合物和用途 - Google Patents

衣壳蛋白装配抑制剂、其药物组合物和用途 Download PDF

Info

Publication number
WO2019154343A1
WO2019154343A1 PCT/CN2019/074527 CN2019074527W WO2019154343A1 WO 2019154343 A1 WO2019154343 A1 WO 2019154343A1 CN 2019074527 W CN2019074527 W CN 2019074527W WO 2019154343 A1 WO2019154343 A1 WO 2019154343A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogen
compound
pharmaceutically acceptable
prodrug
hydrate
Prior art date
Application number
PCT/CN2019/074527
Other languages
English (en)
French (fr)
Inventor
张寅生
敖汪伟
沈杭州
李元
王辉
倪杰
张欢
葛兴枫
卢丹丹
张亚琦
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
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 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 CN201980007896.7A priority Critical patent/CN111601788B/zh
Publication of WO2019154343A1 publication Critical patent/WO2019154343A1/zh

Links

Classifications

    • 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
    • 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
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones

Definitions

  • the present application relates to a compound of the formula I, or a stereoisomer, tautomer, solvate, hydrate, prodrug or pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition containing the compound, And its use as a medicament for the treatment and prevention of hepatitis B virus infection.
  • HBV covalently closed circular DNA
  • Current treatment regimens are unable to remove cccDNA from the repository, and some new targets for HBV are core inhibitors (such as viral capsid protein formation or assembly inhibitors and cccDNA inhibitors and interferon-stimulated gene activators). Etc.) is expected to bring hope to cure hepatitis B (Mayur Brahmania, et al. New therapeutic agents for chronic hepatitis B).
  • HBV capsid is assembled from core proteins, and HBV reverse transcriptase and pregenomic RNA (pgRNA) need to be properly encapsulated by the capsid protein before reverse transcription. Therefore, blocking capsid protein assembly, or accelerating capsid protein degradation, blocks the assembly process of the capsid protein, thereby affecting viral replication.
  • inhibitors targeting capsid protein assembly such as WO2014184350, WO2015011281, WO2017156255, etc., which disclose a series of related compounds. However, most of them are in the early stage of clinical research or the research has been terminated, and there is a need in the art for more alternative effective capsid protein assembly inhibitors for treating, ameliorating or preventing HBV infection.
  • the present invention synthesizes a series of novel derivatives and studies the HBV protein assembly activity.
  • the present application relates to a compound of formula I or a stereoisomer, tautomer, solvate, hydrate, prodrug or pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are each independently selected from hydrogen, hydrazine, -CN, fluoro, chloro, bromo, C 1-3 alkyl or C 3-4 cycloalkyl, said C 1-3 alkyl or C 3- a 4- cycloalkyl group optionally substituted with one or more fluorine or hydrazine;
  • R 3 is selected from hydrogen, C 1-3 alkyl or C 3-4 cycloalkyl, and the C 1-3 alkyl or C 3-4 cycloalkyl is optionally substituted with one or more fluoro or hydrazine;
  • R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, -CHF 2 , -CH 2 F, -CF 3 , -CN, C 1-3 alkyl or C 3-4 A cycloalkyl group, the C 1-3 alkyl group or a C 3-4 cycloalkyl group is optionally substituted with one or more hydrazines.
  • the present application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer, tautomer, solvate, hydrate, prodrug or pharmaceutically acceptable salt thereof, of the present application.
  • the pharmaceutical compositions of the present application also include pharmaceutically acceptable excipients.
  • the present application provides a method of treating a disease which is beneficial for inhibition of capsid protein assembly, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the above formula I or a stereoisomer thereof, an interconversion thereof.
  • a compound of the above formula I or a stereoisomer thereof an interconversion thereof.
  • Isomer, solvate, hydrate, prodrug or pharmaceutically acceptable salt or pharmaceutical composition thereof is administered to a subject in need thereof a therapeutically effective amount of a compound of the above formula I or a stereoisomer thereof, an interconversion thereof.
  • Isomer, solvate, hydrate, prodrug or pharmaceutically acceptable salt or pharmaceutical composition thereof In some embodiments, the individual is a mammal; in some embodiments, the individual is a human.
  • the present application provides a compound of the above formula I, or a stereoisomer, tautomer, solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation Use in the prevention or treatment of a drug that benefits from a disease in which capsid protein assembly is inhibited.
  • the present application provides a compound of the above formula I, or a stereoisomer, tautomer, solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention thereof Or the use in the treatment of a disease that benefits from inhibition of capsid protein assembly.
  • the present application provides a compound of the above formula I, or a stereoisomer, tautomer, solvate, hydrate, prodrug thereof, for use in preventing or treating a disease that benefits from inhibition of capsid protein assembly. Or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • the present application relates to a compound of formula I or a stereoisomer, tautomer, solvate, hydrate, prodrug or pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are each independently selected from hydrogen, hydrazine, -CN, fluoro, chloro, bromo, C 1-3 alkyl or C 3-4 cycloalkyl, said C 1-3 alkyl or C 3- a 4- cycloalkyl group optionally substituted with one or more fluorine or hydrazine;
  • R 3 is selected from hydrogen, C 1-3 alkyl or C 3-4 cycloalkyl, and the C 1-3 alkyl or C 3-4 cycloalkyl is optionally substituted with one or more fluoro or hydrazine;
  • R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, -CHF 2 , -CH 2 F, -CF 3 , -CN, C 1-3 alkyl or C 3-4 A cycloalkyl group, the C 1-3 alkyl group or a C 3-4 cycloalkyl group is optionally substituted with one or more hydrazines.
  • R 4 , R 5 , R 6 are each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, —CHF 2 , —CH 2 F, —CF 3 , —CN, C 1-3 alkane. Or a C 3-4 cycloalkyl group, said C 1-3 alkyl or C 3-4 cycloalkyl group being optionally substituted by one or more hydrazines, and only one of R 4 , R 5 , R 6 It may be selected from fluorine.
  • L is selected from In some embodiments, L is selected from In some embodiments, L is selected from
  • R 1 , R 2 are each independently selected from hydrogen, deuterium, —CN, fluoro, chloro, bromo or C 1-3 alkyl, and the C 1-3 alkyl is optionally taken by one or a plurality of deuterium substitutions; in some embodiments, R 1 , R 2 are each independently selected from hydrogen, deuterium, —CN, chloro, or C 1-3 alkyl, and the C 1-3 alkyl group is optionally Or a plurality of deuterium substitutions; in some embodiments, R 1 , R 2 are each independently selected from hydrogen, deuterium, chlorine or C 1-3 alkyl, and the C 1-3 alkyl is optionally one or more In some embodiments, R 1 , R 2 are each independently selected from hydrogen, chloro, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or isopropyl The radical is optionally substituted by one or more deuteriums; in some embodiments
  • R 3 is selected from hydrogen or C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with one or more fluorine or deuterium; In some embodiments, R 3 is selected from hydrogen or methyl which is optionally substituted with one or more fluorine or deuterium; in some embodiments, R 3 is selected from optionally substituted methyl three deuterium.
  • the structural unit of the compound of Formula I for In some embodiments, the structural unit of the compound of Formula I for
  • R 5 is hydrogen, fluoro, chloro or bromo. In some embodiments, R 5 is hydrogen or fluoro.
  • R 4 , R 6 are each independently selected from hydrogen, fluoro, chloro, bromo, —CHF 2 , —CH 2 F, —CF 3 , —CN or methyl; in some embodiments, R 4 , R 6 are each independently selected from the group consisting of hydrogen, fluorine, chlorine, -CN or methyl.
  • R 4 is selected from the group consisting of hydrogen, fluorine, chlorine, —CHF 2 , —CN, —CF 3 , or methyl. In some embodiments, R 4 is selected from hydrogen.
  • R 6 is selected from hydrogen, fluoro, chloro, -CHF 2 , -CN, -CF 3 or methyl; in some embodiments, R 6 is selected from chloro or -CN.
  • R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, CHF 2 , -CN, -CF 3 or methyl, and at least one of R 4 and R 6 is fluorine or hydrogen. In still another embodiment, at least one of R 4 and R 6 is hydrogen, and the other of R 4 and R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, —CHF 2 , —CN, —CF 3 or base.
  • R 5 is hydrogen or fluoro
  • R 4 , R 6 are each independently selected from hydrogen, fluoro, chloro, or —CN; in some embodiments, R 5 is fluoro, and R 4 , R 6 Each is independently selected from the group consisting of hydrogen, chlorine or -CN; in some embodiments, R 5 is fluoro, R 4 is hydrogen, and R 6 is selected from hydrogen, chloro or -CN; in some embodiments, R 5 is fluoro, R 4 is hydrogen and R 6 is selected from chlorine or -CN.
  • a structural fragment of a compound of Formula I for In some embodiments, a structural fragment of a compound of Formula I for In some embodiments, a structural fragment of a compound of Formula I for
  • a compound of Formula I of the present application or a stereoisomer, tautomer, solvate, hydrate, prodrug or pharmaceutically acceptable salt thereof, is selected from a compound of Formula II or a stereoisomer thereof.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and L are as defined above.
  • a compound of Formula I of the present application or a stereoisomer, tautomer, solvate, hydrate, prodrug or pharmaceutically acceptable salt thereof, is selected from a compound of Formula III or a stereoisomer thereof.
  • R 1 , R 2 , R 5 , R 6 and L are as defined above.
  • a compound of Formula I of the present application or a stereoisomer, tautomer, solvate, hydrate, prodrug or pharmaceutically acceptable salt thereof, is selected from a compound of Formula IV or a stereoisomer thereof.
  • R 1 , R 2 , R 5 and R 6 are as defined above.
  • a compound of Formula I of the present application or a stereoisomer, tautomer, solvate, hydrate, prodrug or pharmaceutically acceptable salt thereof, is selected from a compound of Formula V or a stereoisomer thereof.
  • R 1 , R 2 , R 5 and R 6 are as defined above.
  • a compound of Formula I of the present application is selected from the group consisting of the following compounds or stereoisomers thereof , tautomers, solvates, hydrates, prodrugs or pharmaceutically acceptable salts:
  • the present application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer, tautomer, solvate, hydrate, prodrug or pharmaceutically acceptable salt thereof, of the present application.
  • the pharmaceutical compositions of the present application also include pharmaceutically acceptable excipients.
  • the present application provides a method of inhibiting capsid protein assembly comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I above, or a stereoisomer, tautomer, solvent thereof.
  • the individual is a mammal; in some embodiments, the individual is a human.
  • the present application provides a method of treating a disease which is beneficial for inhibition of capsid protein assembly, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the above formula I or a stereoisomer thereof, an interconversion thereof.
  • a compound of the above formula I or a stereoisomer thereof an interconversion thereof.
  • Isomer, solvate, hydrate, prodrug or pharmaceutically acceptable salt or pharmaceutical composition thereof is administered to a subject in need thereof a therapeutically effective amount of a compound of the above formula I or a stereoisomer thereof, an interconversion thereof.
  • Isomer, solvate, hydrate, prodrug or pharmaceutically acceptable salt or pharmaceutical composition thereof In some embodiments, the individual is a mammal; in some embodiments, the individual is a human.
  • the present application provides a compound of the above formula I, or a stereoisomer, tautomer, solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for inhibiting Use in capsid protein assembly.
  • the present application provides a compound of the above formula I, or a stereoisomer, tautomer, solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation Use in drugs that inhibit capsid protein assembly.
  • the present application provides a compound of the above formula I, or a stereoisomer, tautomer, solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation Use in the prevention or treatment of a drug that benefits from a disease in which capsid protein assembly is inhibited.
  • the present application provides a compound of the above formula I, or a stereoisomer, tautomer, solvate, hydrate, prodrug, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention thereof Or the use in the treatment of a disease that benefits from inhibition of capsid protein assembly.
  • the present application provides a compound of the above formula I, or a stereoisomer, tautomer, solvate, hydrate, prodrug or pharmaceutically acceptable salt thereof, for use in inhibiting capsid protein assembly. Or its pharmaceutical composition.
  • the present application provides a compound of the above formula I, or a stereoisomer, tautomer, solvate, hydrate, prodrug thereof, for use in preventing or treating a disease that benefits from inhibition of capsid protein assembly. Or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
  • the disease that benefits from inhibition of capsid protein assembly refers to a disease caused by hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • the disease that benefits from inhibition of capsid protein assembly refers to a liver disease caused by hepatitis B virus (HBV) infection.
  • HBV hepatitis B virus
  • the treatment which benefits from inhibition of capsid protein assembly, refers to controlling, reducing or eliminating HBV to prevent, alleviate or cure liver disease in an infected patient.
  • the dotted line (----) in the structural unit or group in the present application means a covalent bond.
  • a structural unit including but not limited to
  • the partial segment structure in the present application can be connected to other structures at the left end, and can be connected to other structures at the right end.
  • a dotted line or a solid line indicates a connection key, it will be understood by those skilled in the art by reading the present application, which indicates the connection state of the segment structure with other structures in a directional manner. For example, when L is selected When, it means that L is connected to the groups on both sides. When L is selected When, it means that L is connected to the groups on both sides.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted and the oxo does not occur on the aryl group.
  • an ethyl group “optionally” substituted with halo refers to an ethyl group may be unsubstituted (CH 2 CH 3), monosubstituted (e.g., CH 2 CH 2 F), polysubstituted (e.g. CHFCH 2 F, CH 2 CHF 2, etc.) or completely substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or which cannot be synthesized is introduced.
  • C mn herein is that the moiety has an integer number of carbon atoms in a given range.
  • C1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • C 1-3 means that the group may have 1 carbon atom, 2 carbon atoms, and 3 carbon atoms.
  • any variable eg, R
  • its definition in each case is independent.
  • each R has an independent option.
  • one of the variables is selected from a covalent bond, it means that the two groups to which it is attached are directly linked.
  • L' represents a covalent bond in A-L'-Z, the structure is actually A-Z.
  • the substituent When a bond of a substituent is cross-linked to two atoms on a ring, the substituent may be bonded to any atom on the ring.
  • a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • alkyl refers to a hydrocarbon group of the formula C n H 2n +.
  • the alkyl group can be straight or branched.
  • C 1 - 6 alkyl refers to (e.g., methyl, ethyl, n-propyl, isopropyl, alkyl containing 1 to 6 carbon atoms, n-butyl, isobutyl, sec-butyl, Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl moiety i.e., alkyl
  • alkyl of an alkoxy group, an alkylamino group, a dialkylamino group, an alkylsulfonyl group, and an alkylthio group
  • C 1 - 3 alkyl refers to an alkyl group containing 1-3 carbon atoms (e.g., methyl, ethyl, propyl and isopropyl).
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and can exist as a single ring, bridged ring or spiro ring. Unless otherwise indicated, the carbocyclic ring is typically a 3 to 10 membered ring.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, diamond Alkyl and the like.
  • C 3-4 cycloalkyl includes cyclopropyl and cyclobutyl.
  • treating means administering a compound or formulation described herein to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the present application in which one or more symptoms of a particular disease, condition, or disorder are described herein.
  • the amount of a compound of the present application which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and severity thereof, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art It is determined by its own knowledge and the present disclosure.
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without Many toxic, irritating, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be mentioned.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or a salt thereof and a pharmaceutically acceptable adjuvant.
  • the purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
  • pharmaceutically acceptable excipient refers to those excipients which have no significant irritating effect on the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients 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.
  • solvate refers to a substance formed by combining a compound of the invention with a pharmaceutically acceptable solvent.
  • Pharmaceutically acceptable solvents include water, ethanol, acetic acid, and the like.
  • Solvates include stoichiometric amounts of solvates and non-stoichiometric amounts of solvates.
  • hydrate refers to a solvate comprising a compound disclosed or claimed and a stoichiometric or non-stoichiometric amount of water.
  • the compounds of the invention may also be prepared as prodrugs, such as pharmaceutically acceptable prodrugs. Since prodrugs are known to increase the many desirable properties of the drug (e.g., solubility, bioavailability, preparation, etc.), the compounds of the invention can be delivered in the form of a prodrug. Accordingly, the present invention is intended to encompass prodrugs of currently claimed compounds, methods of delivery thereof, and compositions containing prodrugs.
  • prodrug is intended to include any covalently bonded carrier which, when administered to a mammalian subject, releases the active parent drug of the invention in vivo.
  • the prodrugs of the present invention are prepared by modifying a functional group present in the compound in such a manner that the modification cleaves into the parent compound in a conventional operation or in vivo.
  • the term "individual” includes humans and animals, for example, mammals (e.g., primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, birds, etc.).
  • mammals e.g., primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, birds, etc.
  • the word “comprise” or “comprise” and its English variants such as “comprises” or “comprising” shall be understood to mean an open, non-exclusive meaning, ie “including but not limited to”.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton transfer tautomers include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization.
  • a specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens.
  • Valence tautomers include recombination through some recombination of bonding electrons.
  • the present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but in which one or more atoms are replaced by an atomic weight or mass number different from the atomic mass or mass number normally found in nature.
  • isotopes that may be incorporated into 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 respectively.
  • isotopically-labeled compounds of the present application can be used in compound and/or substrate tissue distribution assays.
  • Deuterated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron emitting 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.
  • Isotopically labeled compounds of the present application can generally be prepared by substituting an isotopically labeled reagent for an unisotopically labeled reagent by procedures similar to those disclosed in the schemes and/or examples disclosed below.
  • substitution with heavier isotopes such as deuterium can provide certain therapeutic advantages resulting from higher metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and thus in some cases
  • the hydrazine substitution may be partial or complete, and the partial hydrazine substitution means that at least one hydrogen is substituted with at least one hydrazine, and all such forms of the compound are included within the scope of the present application.
  • Exemplary deuterated compounds are shown below But it is not limited to this.
  • the compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the asymmetric carbon atom-containing compounds of the present application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using a chiral starting material or a chiral reagent.
  • compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, as solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coating method, a grinding method, an emulsification method, a freeze-drying method, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by admixing the active compound with pharmaceutically acceptable excipients which are well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid adjuvant, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to give tablets. Or the core of the sugar coating. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • the therapeutic dose of a compound of the present application can depend, for example, on the particular use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of the compounds of the present application in the pharmaceutical compositions may not be fixed, depending on a variety of factors including dosage, chemical characteristics (e.g., hydrophobicity) and route of administration.
  • the compound of the present application can be provided for parenteral administration by a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound.
  • Some typical dosages range from about 1 [mu]g/kg to about 1 g/kg body weight per day.
  • the dosage ranges from about 0.01 mg/kg to about 100 mg/kg body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or condition, the general state of health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and the route of administration thereof.
  • An effective dose can be obtained by extrapolation from a dose-response curve derived from an 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, combinations thereof with other chemical synthesis methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the present application.
  • the compounds of formula (I) herein can be prepared by one skilled in the art of organic synthesis by standard procedures in the art using the following routes:
  • the compounds of formula (I) herein can be prepared by one skilled in the art of organic synthesis by standard procedures in the art by the following routes:
  • R 7 is selected from alkyl or cycloalkyl, and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above.
  • Aq represents aqueous; DMF stands for N,N-dimethylformamide; EA stands for ethyl acetate; THF stands for tetrahydrofuran; DCM stands for dichloromethane; LiHMDS stands for lithium hexamethyldisilazane; HATU stands for 2- 7-Oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIPEA stands for N,N-diisopropylethylamine; DMSO stands for dimethyl sulfoxide; Po stands for oral administration.
  • the instrument used for mass spectrometry is AB SCIEX Triple TOF 4600 or AB SCIEX 3200QTRAP.
  • Step A NaH (20.09 g, 837 mmol) was added to a stirred solution of ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (70 g, 419 mmol) in DMF (700 mL) After the addition was completed, the mixture was further stirred under ice bath for 30 minutes. Methyl iodide (71.3 g, 502 mmol) was added dropwise to the above reaction mixture. After the addition was completed, the mixture was stirred for 10 minutes in an ice bath, and then the mixture was transferred to room temperature and stirred for 1 hour. After the reaction is completed, saturated ammonium chloride is added to the above reaction solution, and the mixture is extracted with EA. The obtained organic phase is washed with water and dried over anhydrous sodium sulfate. Ethyl 5-trimethyl-1H-pyrrole-2-carboxylate (74.3 g).
  • Step B LiHDSDS (27.7 g, 166 mL, 166 mmol) was added dropwise to a solution of 1,3,5-trimethyl-1H-pyrrole-2-carboxylate (10 g, 55.2 mmol) at 0 ° C under N 2 and 5-Amino-2-fluorobenzonitrile (9.39 g, 69.0 mmol) in anhydrous THF (400 mL) was stirred. After the dropwise addition was completed, the mixture was stirred at 0 ° C for 30 minutes, the ice bath was removed, and the reaction liquid was naturally raised. Stirring was continued overnight at room temperature.
  • reaction solution was added saturated aqueous ammonium chloride, water and ethyl acetate, was sufficiently stirred, layers were separated, the organic phase washed with water and saturated brine, dried over anhydrous Na 2 SO 4, and concentrated to give a solid 11.75 g of N-(3-cyano-4-fluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide was used directly in the next step.
  • Step C Oxyl chloride monoethyl ester (1.661 g, 12.16 mmol) was added dropwise to N-(3-cyano-4-fluorophenyl)-1,3,5-trimethyl at 0 ° C under N 2 protection.
  • -1H-pyrrole-2-carboxamide 1.1 g, 4.05 mmol
  • DCM 100 mL
  • EtOAc EtOAc
  • reaction solution was slowly poured into 50 g of crushed ice, and then extracted with EA, and the layers were separated, the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography, and dried to give 2-(5-(( 3-cyano-4-fluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetate (1.0 g).
  • Step D An aqueous solution of sodium hydroxide (0.540 g, 13.49 mmol) (25 mL) was added to 2-(5-((3-cyano-4-fluorophenyl)carbamoyl) via a disposable dropper at room temperature. To a stirred solution of 1-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetate (1.67 g, 4.50 mmol) in methanol, the reaction mixture was stirred at room temperature for 10 min.
  • Step A To a 100 mL one-necked flask, ethyl 3-methyl-1H-pyrrole-2-carboxylate (3 g), DMF (20 mL) was added, and sodium hydride (0.705 g) was added to the mixture, and the reaction was carried out for 30 minutes. Methyl iodide (3.34 g) was added dropwise, and the mixture was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, EA was added, washed with water three times, dried and concentrated to give ethyl 1,3-dimethyl-1H-pyrrole-2-carboxylate (2.855 g).
  • Step B In a 100 mL three-necked flask, 1,3-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.2 g), dichloromethane (4 mL) was added, and oxalyl chloride ethyl ester (0.490) was added to the ice bath. g), reaction for 30 minutes. Aluminum trichloride (0.797 g) was added and the reaction was carried out overnight. After completion of the reaction, the reaction solution was added dropwise to a 30 mL ice-water mixture, extracted with ethyl acetate, dried and concentrated to give 4-(2-ethoxy-2-oxoacetyl)-1,3-dimethyl. Ethyl 1H-pyrrole-2-carboxylate (0.345 g) was used directly in the next step.
  • Step C Add 4-(2-ethoxy-2-oxoacetyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.325 g), methanol (2 mL) to a 50 mL vial.
  • the sodium hydroxide (0.122 g) was dissolved in water (2 mL), and the above reaction solution was added dropwise thereto in an ice bath, and the addition was completed in 3 minutes. The reaction was carried out for 5 minutes at room temperature.
  • Step D In a 50 mL single-mouth bottle, 2-(5-(ethoxycarbonyl)-1,4-dimethyl-1H-pyrrol-3-yl)-2-oxoacetic acid (0.27 g), bicyclo [1.1.1] Pentane-1-amine hydrochloride (0.175 g), HATU (0.644 g), N,N-dimethylformamide (5 mL) and N,N-diisopropylethylamine (0.292) g), react at room temperature for 10 h.
  • Step E Add 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-1,3-dimethyl-1H-pyrrole to a 50 mL single-mouth bottle Ethyl 2-carboxylate (0.29 g), sodium hydroxide (0.114 g), methanol (3 mL), water (3 mL), and reacted at 45 ° C for 10 h.
  • Step F In a 50 mL single-mouth bottle, 4-(2-(bicyclo[1.1.1]pent-1-ylamino)-2-oxoacetyl)-1,3-dimethyl-1H-pyrrole- 2-carboxylic acid (0.282 g), toluene (10 ml), and thionyl chloride (0.607 g) were reacted at 115 ° C for 6 h. After completion of the reaction, it was concentrated to give 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-1,3-dimethyl-1H-pyrrole-2- The crude formyl chloride (0.25 g) was used directly in the next reaction.
  • Step G Add 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-1,3-dimethyl-1H-pyrrole to a 50 mL vial 2-formyl chloride (0.25 g), 5-amino-2-fluorobenzonitrile (0.278 g), N,N-dimethylacetamide (5 mL), and reacted at 100 ° C for 3 h. After completion of the reaction, ethyl acetate (30 mL) was added, and water (3*20 mL) was washed three times, dried, concentrated, and dried to give 4-(2-(2-cyclo[1.1.1]pent-1-ylamino)-2. -Oxoacetyl)-N-(3-cyano-4-fluorophenyl)-1,3-dimethyl-1H-pyrrole-2-carboxamide (0.19 g).
  • Step A According to Example 2, in the step A, ethyl 3-pyridyl-2-carboxylate was replaced with ethyl pyrrol-2-carboxylate to prepare 1-methyl-1H-pyrrole-2-carboxylic acid ester.
  • Step B According to Example 2, in step B, ethyl 1-methyl-1H-pyrrole-2-carboxylate was substituted for ethyl 1,3-dimethyl-1H-pyrrole-2-carboxylate to obtain 4- Ethyl (2-ethoxy-2-oxoacetyl)-1-methyl-1H-pyrrole-2-carboxylate.
  • Step C Substituting 4-(2-ethoxy-2-oxoacetyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester for 4-(2-) in step C according to Example 2. Ethyl ethoxy-2-oxoacetyl)-1,3-dimethyl-1H-pyrrole-2-carboxylate to prepare 2-(5-(ethoxycarbonyl)-1-methyl-1H- Pyrrol-3-yl)-2-oxoacetic acid.
  • Step D According to Example 2, in the step D, 2-(5-(ethoxycarbonyl)-1-methyl-1H-pyrrol-3-yl)-2-oxoacetic acid was used instead of 2-(5- Preparation of 4-(2-(bicyclo[1.1.1]pentan-1-yl) by (ethoxycarbonyl)-1,4-dimethyl-1H-pyrrol-3-yl)-2-oxoacetic acid Ethylamino)-2-oxoacetyl)-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester.
  • Step E According to Example 2, 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-1-methyl-1H- Ethyl pyrrol-2-carboxylate in place of 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-1,3-dimethyl-1H-pyrrole- Ethyl 2-carboxylate to give 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-1-methyl-1H-pyrrole-2-carboxylic acid.
  • Step F According to Example 2, 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-1-methyl-1H- Pyrrole-2-carboxylic acid instead of 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid Preparation of 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-1-methyl-1H-pyrrole-2-carbonyl chloride, used directly under One step reaction.
  • Step G According to Example 2, 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-1-methyl-1H- Pyrrole-2-carbonyl chloride in place of 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-1,3-dimethyl-1H-pyrrole-2 -Formyl chloride to prepare 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-N-(3-cyano-4-fluorophenyl)-1 -Methyl-1H-pyrrole-2-carboxamide.
  • Step A According to Example 2, 3-chloro-1H-pyrrole-2-carboxylic acid ethyl ester was replaced with methyl 3-chloro-1H-pyrrole-2-carboxylate in step A to prepare 3-chloro-1-methyl. Methyl-1H-pyrrole-2-carboxylate.
  • Step B According to Example 2, in step B, methyl 3-chloro-1-methyl-1H-pyrrole-2-carboxylate was substituted for ethyl 1,3-dimethyl-1H-pyrrole-2-carboxylate. Methyl 3-chloro-4-(2-ethoxy-2-oxoacetyl)-1-methyl-1H-pyrrole-2-carboxylate was obtained.
  • Step C Substituting methyl 3-chloro-4-(2-ethoxy-2-oxoacetyl)-1-methyl-1H-pyrrole-2-carboxylate in step C according to Example 2 -(2-Ethoxy-2-oxoacetyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester to prepare 2-(4-chloro-5-(methoxycarbonyl) 1-methyl-1H-pyrrol-3-yl)-2-oxoacetic acid.
  • Step D Substituting 2-(4-chloro-5-(methoxycarbonyl)-1-methyl-1H-pyrrol-3-yl)-2-oxoacetic acid in step D for 2 according to Example 2. -(5-(ethoxycarbonyl)-1,4-dimethyl-1H-pyrrol-3-yl)-2-oxoacetic acid to prepare 4-(2-(bicyclo[1.1.1]pentane) Methyl-1-aminoamino)-2-oxoacetyl)-3-chloro-1-methyl-1H-pyrrole-2-carboxylate.
  • Step E According to Example 2, 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-3-chloro-1-methyl was used in Step E Substituting methyl-1H-pyrrole-2-carboxylate for 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-1,3-dimethyl- Preparation of 4-(2-cyclobi[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-3-chloro-1-methyl-ethyl 1H-pyrrole-2-carboxylate 1H-pyrrole-formic acid.
  • Step F According to Example 2, 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-3-chloro-1-methyl was used in Step F Base-1H-pyrrole-carboxylic acid instead of 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-1,3-dimethyl-1H-pyrrole-2 -carboxylic acid to prepare 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-3-chloro-1-methyl-1H-pyrrole-carbonyl chloride, Used directly in the next step.
  • Step G According to Example 2, 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-3-chloro-1-methyl is used in Step G Substituting 1,4-H-pyrrole-carbonyl chloride for 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-1,3-dimethyl-1H-pyrrole 4-(2-(Bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-3-chloro-N-(3-cyano-4-) Fluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide.
  • Step A Add 1,3-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.2g) to a 50mL single-mouth bottle, slowly add chlorosulfonic acid (0.279g), and add in 5 minutes. End. Ethyl acetate was added, washed with water three times, dried and concentrated to give ethyl 4-(chlorosulfonyl)-1,3-dimethyl-1H-pyrrole-2-carboxylate (0.22 g). .
  • Step B Add 4-(chlorosulfonyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.21 g), bicyclo[1.1.1]pentane-1 to a 50 mL single-necked flask. -amine hydrochloride (0.123 g), N,N-dimethylformamide (5 mL).
  • Step C 4-(N-(Bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid was added sequentially to a 50 mL single-necked bottle. Ethyl ester (0.21 g), sodium hydroxide (0.081 g), methanol (3 mL), and water (3 mL) were reacted at 45 ° C for 10 h.
  • Step D Add 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid to a 50 mL single-mouth bottle ( 97.1 mg), thionyl chloride (203 mg), toluene (5 mL), and reacted at 115 ° C for 6 h. After completion of the reaction, it was concentrated to give 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3-dimethyl-1H-pyrrole-2-carbonyl chloride (95 mg) Crude, used directly in the next reaction.
  • Step E Add 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3-dimethyl-1H-pyrrole-2-carbonyl chloride to a 50 mL vial (103 mg), 5-amino-2-fluorobenzonitrile (93 mg), N,N-dimethylacetamide (5 mL), and reacted at 100 ° C for 3 h.
  • Step A According to Example 2, ethyl 1-methylpyrrole-2-carboxylate was replaced with ethyl pyrrol-2-carboxylate in step A to prepare ethyl 1-methylpyrrole-2-carboxylate.
  • Step B According to Example 5, in the step A, ethyl 1-methylpyrrole-2-carboxylate was substituted for ethyl 1,3-dimethyl-1H-pyrrole-2-carboxylate to prepare 4-(chlorosulfonyl) Ethyl-1-methyl-1H-pyrrole-2-carboxylate.
  • Step C Substituting ethyl 4-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate for 4-(chlorosulfonyl)-1,3-diethyl ester according to Example 5 Preparation of ethyl 4-H-pyrrole-2-carboxylate to prepare 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1-methyl-1H-pyrrole-2-carboxylic acid Ethyl ester.
  • Step D According to Example 5, in step C, 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1-methyl-1H-pyrrole-2-carboxylic acid Ethyl ester replaces 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester to prepare 4-( N-(Bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1-methyl-1H-pyrrole-2-carboxylic acid.
  • Step E According to Example 5, in step D, 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1-methyl-1H-pyrrole-2-carboxylic acid Instead of 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid, 4-(N-(di) Ring [1.1.1]pentan-1-yl)sulfamoyl)-1-methyl-1H-pyrrole-2-carbonyl chloride.
  • Step F According to Example 5, 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1-methyl-1H-pyrrole-2-yl was used in Step E Replacement of 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3-dimethyl-1H-pyrrole-2-carbonyl chloride with acid chloride to prepare 4-(N- (Bicyclo[1.1.1]pent-1-yl)sulfamoyl)-N-(3-cyano-4-fluorophenyl)-1-methyl-1H-pyrrole-2-carboxamide.
  • Step A Substituting ethyl 1,3,5-trimethyl-1H-pyrrole-2-carboxylate for ethyl 1,3-dimethyl-1H-pyrrole-2-carboxylate in step A according to Example 5.
  • 13 C-NMR 125 MHz, CDCl 3 ): ⁇ 161.28, 139.79, 128.49, 123.94, 121.38, 60.78, 33.62, 14.31, 11.64, 11.53.
  • Step B Substituting ethyl 4-(chlorosulfonyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxylate for 4-(chlorosulfonyl)-1 according to Example 5 , 3-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, preparation of 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3,5-tri Ethyl methyl-1H-pyrrole-2-carboxylate.
  • Step C According to Example 5, in step C, 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3,5-trimethyl-1H- Ethyl pyrrol-2-carboxylate in place of ethyl 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3-dimethyl-1H-pyrrole-2-carboxylate Preparation of 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxylic acid.
  • Step D According to Example 5, in step D, 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3,5-trimethyl-1H- Pyrrole-2-carboxylic acid instead of 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid, 4- (N-(Bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3,5-trimethyl-1H-pyrrole-2-carbonyl chloride.
  • Step E According to Example 5, in step E, -(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3,5-trimethyl-1H-pyrrole -2-Formyl chloride instead of 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3-dimethyl-1H-pyrrole-2-carbonyl chloride, Preparation 4 -(N-(bicyclo[1.1.1]pent-1-yl)sulfamoyl)-N-(3-cyano-4-fluorophenyl)-1,3,5-trimethyl-1H- Pyrrole-2-carboxamide.
  • Step A Preparation of 4-(N-(bicyclo[1.1.1]pentan-1-) by substituting 3-chloro-4-fluoroaniline for 5-amino-2-fluorobenzonitrile according to Example 7. Aminosulfonyl)-N-(3-chloro-4-fluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide.
  • Step A According to Example 5, in step A, methyl 3-chloro-1-methyl-1H-pyrrole-2-carboxylate was substituted for ethyl 1,3-dimethyl-1H-pyrrole-2-carboxylate. Methyl 3-chloro-4-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate was prepared.
  • Step B Substituting methyl 3-chloro-4-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate for 4-(chlorosulfonyl)-1 in step B according to Example 5, Preparation of 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-3-chloro-1-methyl ethyl 3-dimethyl-1H-pyrrole-2-carboxylate Methyl-1H-pyrrole-2-carboxylate.
  • Step C According to Example 5, in step C, 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-3-chloro-1-methyl-1H-pyrrole
  • Methyl 2-carboxylate replaces ethyl 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3-dimethyl-1H-pyrrole-2-carboxylate, Preparation of 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-3-chloro-1-methyl-1H-pyrrole-2-carboxylic acid.
  • Step D According to Example 5, in step D, 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-3-chloro-1-methyl-1H-pyrrole 2-(N-(Bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3-dimethyl-1H-pyrrole-2-carboxylic acid was replaced by 2-carboxylic acid to prepare 4-( N-(Bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-3-chloro-1-methyl-1H-pyrrole-2-carbonyl chloride.
  • Step E According to Example 5, 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-3-chloro-1-methyl-1H-pyrrole was used in Step E -2-Formyl chloride instead of 4-(N-(bicyclo[1.1.1]pentan-1-yl)sulfamoyl)-1,3-dimethyl-1H-pyrrole-2-carbonyl chloride, Preparation 4 -(N-(bicyclo[1.1.1]pent-1-yl)sulfamoyl)-3-chloro-N-(3-cyano-4-fluorophenyl)-1-methyl-1H-pyrrole -2-carboxamide.
  • Step A To a 50 mL round bottom flask equipped with a condenser, (5-((3-cyano-4-fluorophenyl)carbamoyl)-1,2,4-trimethyl-1H- Pyrrol-3-yl)-2-oxoacetic acid (100 mg, 0.291 mmol), toluene (3 ml) and chlorosulfoxide (104 mg, 0.874 mmol), heated to 90 ° C in an oil bath, stirred for 1 hour, then evaporated under reduced pressure In addition to toluene and the remaining thionyl chloride, a brown solid was obtained.
  • Step A NaH (2.3 g, 96 mmol) was added portionwise to a stirred solution of 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (8 g) in DMF (90 ml). After completion, the reaction was stirred for 30 minutes under an ice bath. Deuterated methyl iodide (8.3 g) was added to the above reaction solution, and the mixture was stirred for 10 minutes under ice cooling, and then the reaction mixture was stirred at room temperature for 1 hour.
  • Step B Under ice bath, oxalyl chloride monoethyl ester (10.89 g) was slowly dropped into ethyl 3,5-dimethyl-1-(methyl-d 3 )-1H-pyrrole-2-carboxylate ( 9.8 g) of DCM (250 ml) stirred solution was added dropwise, then aluminum trichloride (21.27 g, added in portions) was added to the mixture. After the addition was completed, the ice bath was stirred for 5 minutes, and then the reaction solution was allowed to stand at room temperature.
  • Step C An aqueous sodium hydroxide solution (1.2 mol/L, 100 ml) was added dropwise to the solution containing 4-(2-ethoxy-2-oxoacetyl)-3,5-dimethyl-1- (Methyl-d 3 )-1H-pyrrole-2-carboxylic acid ethyl ester (13.5 g) in methanol (200 ml) was added to a stirred solution, and the mixture was stirred at room temperature for 30 minutes, and the reaction was finished. 100 ml of water was added to the reaction solution, and a part of methanol was removed by concentration. 100 ml of ethyl acetate was added to the remaining reaction liquid, and the aqueous phase was separated.
  • Step D Add 2-(5-(ethoxycarbonyl)-2,4-dimethyl-1-(methyl-d 3 )-1H-pyrrol-3-yl) to the reaction flask at room temperature.
  • 2-oxoacetic acid (2.68g), DMF (100ml), HATU (13.29g) and DIPEA (6.95g)
  • stirring at room temperature for 5 minutes then adding bicyclo [1.1.1]pentan-1-amine Hydrochloride (3.54 g), the mixture was stirred at room temperature overnight, and the reaction was completed.
  • Water (100 ml) was added to the reaction mixture, and a large amount of solid was precipitated, filtered, and the filter cake was dried in vacuo (2-(bicyclo[1.1.1.
  • Step E An aqueous sodium hydroxide solution (1.4 mol/L, 60 ml) was added dropwise to (2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)- at room temperature. Addition of 3,5-dimethyl-1-(methyl-d 3)-1H-pyrrole-2-carboxylic acid ethyl ester (9.0 gl) in methanol (80 ml) and tetrahydrofuran (80 ml), heating, heating Stir to 4 ° C for 4 h. After completion of the reaction, 100 ml of water was added to the reaction solution, and a part of methanol was removed by concentration.
  • Step F To the reaction flask, toluene (70 ml) and 4-(2-(bicyclo[1.1.1]pentan-1-ylamino)-2-oxoacetyl)-3,5-di were sequentially added.
  • the solvent was evaporated under reduced pressure.
  • EtOAc EtOAc 3,5-Dimethyl-1-(methyl-d 3 )-1H-pyrrole-2-carbonyl chloride (2.65 g).
  • N,N-dimethylacetamide (30 ml) and 4-(2-(bicyclo[1.1.1]pentan-2-ylamino)-2-oxoacetyl)-3 were added in order.
  • the mixture was heated to 100 ° C for 1 hour. After the completion of the reaction, the reaction mixture was cooled to room temperature, and water (30 ml) was added to the mixture, and the mixture was extracted with ethyl acetate (100 ml ⁇ 2).
  • the absorbance was measured at 450 nm, the inhibition rate was calculated, and the CC50 was calculated.
  • a "-" in the table indicates that no test has been performed.
  • mice Male C57BL/6 mice, 6-8 weeks old, were injected with rAAV8-1.3 HBV virus (adr subtype) into C57BL/6 mice at a dose of 1 ⁇ 10 11 vg. At the 2nd and 4th week after the injection of the virus, the mice were bled with blood, and the serum was separated. The expression levels of HBeAg and HBsAg in the serum and the copy number of HBV DNA were determined to judge whether the model was successfully constructed or not.
  • mice were divided into groups, and a blank control group, a vehicle control group, and a test group were set. Each group of mice was administered by gavage for 2-3 weeks, once a day. During the experiment, blood was collected from the eyelids every other week, serum was separated, DNA content was detected by real-time PCR and quantitative ELISA was used to detect the expression of HBeAg and HBsAg. The specific results are shown in Table 3.
  • mice Male C57BL/6 mice aged 6-8 weeks were used, and the purified recombinant plasmid pHBV1.3 (10 ⁇ g) was dissolved in PBS. Each mouse was injected in a volume of about 10% of its body weight through the tail vein at 3-8 s. Injection into mice. After 24 hours of injection of the plasmid, serum HBV DNA was taken from the eyelids, and the serum DNA of the model mice was selected and grouped into a blank control group, a vehicle control group, and a test group. Each group of mice was administered by intragastric administration for 6 days, once a day. The mouse serum was taken at 1, 3, 5, and 7 days after the injection, and the liver tissue samples were taken from the 7th day. The HBV DNA copy number in the serum and liver of the mice was detected by real-time quantitative PCR. The specific results are shown in Table 4.
  • 300 ⁇ L of the final incubation system contained 30 ⁇ L of human liver microsomes (protein concentration: 0.15 mg/mL), 30 ⁇ L of NADPH + MgCl 2 , 3 ⁇ L of substrate (acetonitrile), and 237 ⁇ L of PBS buffer. Make 2 servings, each serving 0.3 mL. Each tube was first prepared with a total volume of 270 ⁇ L of substrate and enzyme mixture, and NADPH was preincubated at 37 ° C for 5 min, then added with 30 ⁇ L of NADPH + MgCl 2 mixed solution, respectively at 0, 10, 30, 60 min. 50 ⁇ L of the reaction was stopped with 300 ⁇ L of ice-acetonitrile containing an internal standard.
  • Sample preparation 50 ⁇ L of incubation sample, 300 ⁇ L of ice-acetonitrile containing internal standard diazepam, vortexing for 5 min, centrifugation (12000 rpm, 4 ° C) for 10 min. 75 ⁇ L of the supernatant was aspirated into a 96-well plate and diluted with 75 ⁇ L of ultrapure water, and 0.5 ⁇ L was injected for LC-MS/MS analysis. The specific results are shown in Table 5.
  • SD rats weighing 180-220 g, were adapted to 3 to 5 days and randomly divided into 2 groups, 3 in each group, and the test compounds were administered at a dose of 30 mg/kg.
  • test animals SD rats
  • the test animals were fasted for 12 h before administration, and given food for 4 h after administration. Drinking water was free before and after the experiment and during the experiment.

Abstract

本发明属于药物化学领域，涉及一种衣壳蛋白装配抑制剂，具体而言，涉及式I所示的化合物、其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐，其制备方法、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

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2018年2月9日向中国国家知识产权局提交的第201810132621.3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所示的化合物或其立体异构体、互变异构体、溶剂化物、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，及其作为治疗和预防乙型肝炎病毒感染的药物的应用。
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，并且限于两类药剂(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的新靶点即核心抑制剂(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、前基因组RNA(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，研究人员开始开发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。本发明合成了一系列新型衍生物，并对其HBV蛋白组装活性进行研究。
发明概述
本申请涉及式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐，
Figure PCTCN2019074527-appb-000001
其中，
L选自
Figure PCTCN2019074527-appb-000002
Figure PCTCN2019074527-appb-000003
R 1、R 2分别独立地选自氢、氘、-CN、氟、氯、溴、C 1-3烷基或C 3-4环烷基，所述C 1-3烷基或C 3-4环烷基任选地被一个或多个氟或氘取代；
R 3选自氢、C 1-3烷基或C 3-4环烷基，所述C 1-3烷基或C 3-4环烷基任选地被一个或多个氟或氘取代；
R 4、R 5、R 6分别独立地选自氢、氘、氟、氯、溴、-CHF 2、-CH 2F、-CF 3、-CN、C 1-3烷基或C 3-4环烷基，所述C 1-3烷基或C 3-4环烷基任选地被一个或多个氘取代。
另一方面，本申请还提供药物组合物，其包含本申请的式I化合物或其立体异构体、互变异构体、溶剂化物、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，包括对有需要的个体给予治疗有效量的上述式I所示的化合物或其立体异构体、互变异构体、溶剂化物、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，本申请还提供了上述式I化合物或其立体异构体、互变异构体、溶剂化物、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化合物或其立体异构体、互变异构体、溶剂化物、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化合物、或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐、或者其药物组合物。
发明详述
本申请涉及式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上 可接受的盐，
Figure PCTCN2019074527-appb-000004
其中，
L选自
Figure PCTCN2019074527-appb-000005
Figure PCTCN2019074527-appb-000006
R 1、R 2分别独立地选自氢、氘、-CN、氟、氯、溴、C 1-3烷基或C 3-4环烷基，所述C 1-3烷基或C 3-4环烷基任选地被一个或多个氟或氘取代；
R 3选自氢、C 1-3烷基或C 3-4环烷基，所述C 1-3烷基或C 3-4环烷基任选地被一个或多个氟或氘取代；
R 4、R 5、R 6分别独立地选自氢、氘、氟、氯、溴、-CHF 2、-CH 2F、-CF 3、-CN、C 1-3烷基或C 3-4环烷基，所述C 1-3烷基或C 3-4环烷基任选地被一个或多个氘取代。
在一些实施方案中，R 4、R 5、R 6分别独立地选自氢、氘、氟、氯、溴、-CHF 2、-CH 2F、-CF 3、-CN、C 1-3烷基或C 3-4环烷基，所述C 1-3烷基或C 3-4环烷基任选地被一个或多个氘取代，且R 4、R 5、R 6仅其中之一可以选自氟。
在一些实施方案中，L选自
Figure PCTCN2019074527-appb-000007
在一些实施方案中，L选自
Figure PCTCN2019074527-appb-000008
在一些实施方案中，L选自
Figure PCTCN2019074527-appb-000009
在一些实施方案中，R 1、R 2分别独立地选自氢、氘、-CN、氟、氯、溴或C 1-3烷基，所述C 1-3烷基任选地被一个或多个氘取代；在一些实施方案中，R 1、R 2分别独立地选自氢、氘、-CN、氯或C 1-3烷基，所述C 1-3烷基任选地被一个或多个氘取代；在一些实施方案中，R 1、R 2分别独立地选自氢、氘、氯或C 1-3烷基，所述C 1-3烷基任选地被一个或多个氘取代；在一些实施方案中，R 1、R 2分别独立地选自氢、氯、甲基、乙基、丙基或异丙基，所述甲基、乙基、丙基或异丙基任选被一个或多个氘取代；在一些实施方案中，R 1、R 2分别独立地选自氢、 氯、三个氘取代的甲基或甲基；在一些实施方案中，R 1选自氢、氯、三个氘取代的甲基或甲基，R 2选自氢或甲基。
在一些实施方案中，R 3选自氢或C 1-3烷基，所述C 1-3烷基任选地被一个或多个氟或氘取代；在一些实施方案中，R 3选自氢或甲基，所述甲基任选地被一个或多个氟或氘取代；在一些实施方案中，R 3选自任选被三个氘取代的甲基。
在一些实施方案中，式I化合物的结构单元
Figure PCTCN2019074527-appb-000010
为
Figure PCTCN2019074527-appb-000011
在一些实施方案中，式I化合物的结构单元
Figure PCTCN2019074527-appb-000012
为
Figure PCTCN2019074527-appb-000013
在一些实施方案中，R 5是氢、氟、氯或溴。在一些实施方案中，R 5是氢或氟。
在一些实施方案中，R 4、R 6分别独立地选自氢、氟、氯、溴、-CHF 2、-CH 2F、-CF 3、-CN或甲基；在一些实施方案中，R 4、R 6分别独立地选自氢、氟、氯、-CN或甲基。
在一些实施方案中，R 4选自氢、氟、氯、-CHF 2、-CN、-CF 3或甲基。在一些实施方案中，R 4选自氢。
在一些实施方案中，R 6选自氢、氟、氯、-CHF 2、-CN、-CF 3或甲基；在一些实施方案中，R 6选自氯或-CN。
在另一个实施例中，R 6选自氢、氟、氯、CHF 2、-CN、-CF 3或甲基，并且R 4和R 6中的至少一个是氟或氢。在又一个另外的实施例中，R 4和R 6中至少一个是氢，并且R 4和R 6中的另一个选自氢、氟、氯、-CHF 2、-CN、-CF 3或甲基。
在一些实施方案中，R 5是氢或氟，并且R 4、R 6分别独立地选自氢、氟、氯或-CN；在一些实施方案中，R 5是氟，并且R 4、R 6分别独立地选自氢、氯或-CN；在一些实施方案中，R 5是氟，R 4是氢，R 6选自氢、氯或-CN；在一些实施方案中，R 5是氟，R 4是氢，R 6选自氯或-CN。
在一些实施方案中，式I化合物的结构片段
Figure PCTCN2019074527-appb-000014
为
Figure PCTCN2019074527-appb-000015
在一些实施方案中，式I化合物的结构片段
Figure PCTCN2019074527-appb-000016
为
Figure PCTCN2019074527-appb-000017
在一 些实施方案中，式I化合物的结构片段
Figure PCTCN2019074527-appb-000018
为
Figure PCTCN2019074527-appb-000019
Figure PCTCN2019074527-appb-000020
在一些实施方案中，本申请的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐选自式II化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐，
Figure PCTCN2019074527-appb-000021
其中R 1、R 2、R 3、R 4、R 5、R 6和L如上定义。
在一些实施方案中，本申请的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐选自式III化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐，
Figure PCTCN2019074527-appb-000022
其中R 1、R 2、R 5、R 6和L如上定义。
在一些实施方案中，本申请的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐选自式IV化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐，
Figure PCTCN2019074527-appb-000023
其中R 1、R 2、R 5、R 6如上定义。
在一些实施方案中，本申请的式I化合物或其立体异构体、互变异构体、溶剂化物、水合 物、前药或药学上可接受的盐选自式V化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐，
Figure PCTCN2019074527-appb-000024
其中R 1、R 2、R 5、R 6如上定义。
在一些实施方案中，本申请的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐选自以下化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐：
Figure PCTCN2019074527-appb-000025
另一方面，本申请还提供药物组合物，其包含本申请的式I化合物或其立体异构体、互变异构体、溶剂化物、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括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上述式I所示的化合物或其立体异构体、互变异构体、溶剂化物、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，本申请还提供一种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上述式I所示的化合物或其立体异构体、互变异构体、溶剂化物、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，本申请还提供了上述式I化合物或其立体异构体、互变异构体、溶剂化物、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，本申请还提供了上述式I化合物或其立体异构体、互变异构体、溶剂化物、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，本申请还提供了上述式I化合物或其立体异构体、互变异构体、溶剂化物、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化合物或其立体异构体、互变异构体、溶剂化物、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上述式I化合物、或其立体异构体、互变异构体、溶剂化物、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化合物、或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐、或者其药物组合物。
在本申请的部分实施方式中，所述受益于衣壳蛋白装配抑制的疾病是指乙型肝炎病毒(HBV)感染引起的疾病。
在本申请的部分实施方式中，所述受益于衣壳蛋白装配抑制的疾病是指乙型肝炎病毒(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。
本申请中的结构单元或者基团中的虚线(----)表示共价键。
本申请中的某些结构单元或者基团中的共价键未与具体的原子连接时，表示该共价键可 以与该结构单元或者基团中的任意原子连接，只要不违背价键连接规则。因此，例如，结构单元
Figure PCTCN2019074527-appb-000026
包括但不限于
Figure PCTCN2019074527-appb-000027
本申请中部分片段结构可以左端与其他结构连接，并且同时可以右端与其他结构连接。当虚线或实线表示连接键时，本领域的技术人员通过阅读本申请可以理解得到，该虚线或实线方向性地表明了片段结构与其他结构的连接状态。例如，当L选自
Figure PCTCN2019074527-appb-000028
时，表示L与两边的基团连接方式为
Figure PCTCN2019074527-appb-000029
当L选自
Figure PCTCN2019074527-appb-000030
时，表示L与两边的基团连接方式为
Figure PCTCN2019074527-appb-000031
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，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。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
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。
本文中的C m-n，是该部分具有给定范围中的整数个碳原子。例如“C 1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。例如C 1-3是指该基团可具有1个碳原子、2个碳原子、3个碳原子。
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2个R所取代，则每个R都有独立的选项。
当其中一个变量选自共价键时，表示其连接的两个基团直接相连，比如A-L’-Z中L’代表共价键时表示该结构实际上是A-Z。
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任 意原子相键合。例如，结构单元
Figure PCTCN2019074527-appb-000032
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1- 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。又例如，术语“C 1- 3烷基”指含有1至3个碳原子的烷基(例如甲基、乙基、丙基和异丙基)。
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基等。例如，C 3-4环烷基包括环丙基和环丁基。
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防、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)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；
(ii)抑制疾病或疾病状态，即遏制其发展；
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
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“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。
术语“溶剂化物”是指本发明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。
本发明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发明的化合物。因此，本发明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发明的活性母体药物。本发明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。
本发明中，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)。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。例示性的氘代化合物如下所示
Figure PCTCN2019074527-appb-000033
但不限于此。
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
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、***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***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。
在一些实施方案中，本申请通式(I)的化合物可以由有机合成领域技术人员通过以下路线，用本领域的标准方法来制备：
Figure PCTCN2019074527-appb-000034
Figure PCTCN2019074527-appb-000035
在一些实施方案中，本申请通式(I)的化合物可以由有机合成领域技术人员通过以下路线用本领域的标准方法来制备：
Figure PCTCN2019074527-appb-000036
其中R 7选自烷基或环烷基，R 1、R 2、R 3、R 4、R 5、R 6定义同上。
本申请采用下述缩略词：
aq代表含水的；DMF代表N，N-二甲基甲酰胺；EA代表乙酸乙酯；THF代表四氢呋喃；DCM代表二氯甲烷；LiHMDS代表六甲基二硅氮烷锂盐；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；DMSO代表二甲基亚砜；po代表口服。
为清楚起见，进一步用实施例来阐述本发明，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
本发明核磁共振色谱(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 4-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,3,5-三甲基-1H-吡咯-2-甲酰胺
Figure PCTCN2019074527-appb-000037
步骤A：冰浴下，将NaH(20.09g,837mmol)加入到3,5-二甲基-1H-吡咯-2-甲酸乙酯(70g,419mmol)的DMF(700mL)搅拌液中，10分钟后加完毕，混合物继续在冰浴下搅拌反应30分钟。将碘甲烷(71.3g,502mmol)滴加入到上述反应液中，加料完毕继续冰浴下搅拌10分钟，然后将反应液移至室温搅拌1h。反应结束，向上述反应液中加入饱和氯化铵，然后用EA萃取，用水洗涤所得有机相，无水硫酸钠干燥所得有机相，抽滤，浓缩，经硅胶柱层析纯化得1,3,5-三甲基-1H-吡咯-2-甲酸乙酯(74.3g)。
1H-NMR(500MHz,DMSO-d 6):δ5.78(s,1H),4.19(q,J＝7.5Hz,7.0Hz,2H),3.68(s,3H),2.20(s,3H),2.16(s,3H),1.28(t,J＝7.0Hz,3H)； 13C-NMR(125MHz,DMSO-d 6):δ161.71,136.09,128.56,118.79,110.81,59.30,32.96,14.81,14.58,12.56.MS(ESI+,[M+H] +)m/z:182.2.
步骤B：在0℃下，N 2保护下，LiHMDS(27.7g,166mL,166mmol)滴入1,3,5-三甲基-1H-吡咯-2-甲酸乙酯(10g,55.2mmol)和5-氨基-2-氟苯腈(9.39g,69.0mmol)的无水THF(400mL)搅拌液中，滴加完毕后，混合物在0℃搅拌反应30分钟，撤去冰浴，反应液自然升至室温，继续搅拌过夜。反应结束后，向反应液中加入饱和氯化铵水溶液、水及乙酸乙酯，充分搅拌后，分层，有机相分别用水和饱和食盐水洗涤，无水Na 2SO 4干燥，浓缩，得固体11.75g N-(3-氰基-4-氟苯基)-1,3,5-三甲基-1H-吡咯-2-甲酰胺，直接用于下一步。
1H-NMR(500MHz,DMSO-d 6):δ9.89(s,1H),8.16-8.18(m,1H),7.93-7.97(m,1H),7.50(t,J＝9.0Hz,1H),5.76(s,1H),3.57(s,3H),2.18(s,6H)； 13C-NMR(125MHz,DMSO-d 6):δ161.32, 158.41，137.13,133.97,127.10,124.27,123.53,122.63,117.43,114.51,109.68,100.26,32.12,13.19,12.31.MS(ESI+,[M+H] +)m/z：272.3.
步骤C：0℃下，N 2保护下，草酰氯单乙酯(1.661g,12.16mmol)滴入N-(3-氰基-4-氟苯基)-1,3,5-三甲基-1H-吡咯-2-甲酰胺(1.1g,4.05mmol)的DCM(100mL)搅拌液中，再分批加入三氯化铝(1.62g，12.15mmol)后，混合物在0℃继续搅拌30分钟，撤去冰浴，室温下搅拌3天。反应结束后，将反应液缓慢倒入50g碎冰中，然后加入EA萃取，分层，有机相无水硫酸钠干燥，浓缩，经硅胶柱层析纯化，烘干得2-(5-((3-氰基-4-氟苯基)氨基甲酰基)-1,2,4-三甲基-1H-吡咯-3-基)-2-氧代乙酸乙酯(1.0g)。
1H-NMR(500MHz,DMSO-d 6):δ10.58(s,1H),8.20-8.21(m,1H),7.95-7.99(m,1H),7.53-7.57(m,1H),4.34(q,J＝7.0Hz,7.5Hz,2H),3.62(s,3H),2.43(s,3H),2.23(s,3H),1.32(t,J＝7.5Hz,3H)； 13C-NMR(125MHz,DMSO-d 6):δ183.33,166.15,160.16,157.91,142.25,136.32,127.54,124.12,122.53,117.61,115.46,114.35,100.47,62.31,32.51,31.62,30.31,14.24,11.68.MS(ESI+,[M+H] +)m/z：372.3.
步骤D：室温下，将氢氧化钠(0.540g,13.49mmol)的水溶液(25mL)通过一次性滴管加入2-(5-((3-氰基-4-氟苯基)氨基甲酰基)-1,2,4-三甲基-1H-吡咯-3-基)-2-氧代乙酸乙酯(1.67g,4.50mmol)的甲醇搅拌液中，反应液在室温搅拌反应10分钟。反应结束，减压旋转蒸除部分溶剂，用1N HCl水溶液调节反应液pH为2-3，然后加入EA，分层，水洗EA层，无水Na 2SO 4干燥有机相，浓缩有机相得2-(5-((3-氰基-4-氟苯基)氨基甲酰基)-1,2,4-三甲基-1H-吡咯-3-基)-2-氧代乙酸(1.4g)，直接进行下步反应。
MS(ESI-,[M-H] -)m/z：342.2.
步骤E：室温下，向100mL单口圆底烧瓶中依次加入2-(5-((3-氰基-4-氟苯基)氨基甲酰基)-1,2,4-三甲基-1H-吡咯-3-基)-2-氧代乙酸(1.4g,4.08mmol)、DMF(40mL)、HATU(2.016g,5.30mmol)、DIPEA(1.054g,1.424mL,8.16mmol)及二环[1.1.1]戊烷-1-胺盐酸盐(0.536g,4.49mmol)，加料完毕，室温搅拌过夜，反应结束，向反应液中加入水和EA，分层，有机相用水洗涤，无水Na 2SO 4干燥，抽滤，浓缩，硅胶柱层析(PE：EA＝3:2)纯化得4-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,3,5-三甲基-1H-吡咯-2-甲酰胺(0.4g)。
1H-NMR(500MHz,DMSO-d 6)：δ10.50(s,1H),9.18(s,1H),8.20-8.22(m,1H),7.97-8.00(m,1H),7.52-7.56(m,1H),3.60(s,3H),2.48(s,1H),2.41(s,3H),2.25(s,3H),2.07(s,6H)； 13C-NMR(125MHz,DMSO-d 6)：δ188.00,168.12,160.70,159.83,157.82,141.29,136.45,127.49,126.94,124.05,123.06,117.58,116.63,114.38,100.42,53.25,52.68,48.58,32.37,25.27,77.76.MS(ESI-,[M-H] -)m/z：407.4.
实施例2 4-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,3-二甲基-1H-吡咯-2-甲酰胺
Figure PCTCN2019074527-appb-000038
步骤A：100mL单口瓶中，加入3-甲基-1H-吡咯-2-甲酸乙酯(3g)、DMF(20mL)，冰浴下加入氢化钠(0.705g)，反应30分钟。滴加碘甲烷(3.34g)，10分钟滴加完毕，升至室温搅拌1h。反应结束后加入EA，水洗三次，干燥，浓缩，得到1,3-二甲基-1H-吡咯-2-甲酸乙酯(2.855g)，直接用于下一步反应。
1H-NMR(500MHz,DMSO-d 6):δ6.94(s,1H),5.94(s,1H),4.17-4.23(q,J＝21Hz,2H),3.79(s,3H),2.24(s,3H),1.27-1.30(t,J＝14.5Hz,3H)； 13C-NMR(125MHz,DMSO-d 6):δ161.63,129.33,129.20,119.35,110.42,59.57,37.56,14.76,14.62.
步骤B：100mL三口瓶中，依次加入1,3-二甲基-1H-吡咯-2-甲酸乙酯(0.2g)、二氯甲烷(4mL)，冰浴下加入草酰氯单乙酯(0.490g)，反应30分钟。加入三氯化铝(0.797g)，反应过夜。反应结束后将反应液滴加进30mL冰水混合物中，用乙酸乙酯萃取，干燥，浓缩，得到4-(2-乙氧基-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯(0.345g)，直接用于下一步反应。
1H-NMR(500MHz,DMSO-d 6):δ7.91-7.92(d,J＝8Hz,1H),4.31-4.35(q,J＝21.5Hz,2H),4.26-4.30(q,J＝21.5Hz,2H),3.87(s,3H),2.52(s,3H),1.30-1.33(t,J＝14Hz,6H).MS(ESI+,[M+Na] +)m/z：290.3.
步骤C：50mL单口瓶中加入4-(2-乙氧基-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯 (0.325g)、甲醇(2mL)，将氢氧化钠(0.122g)溶于水(2mL)中，于冰浴下滴加进上述反应液，3分钟滴加完毕。室温反应5分钟。反应结束后向反应液中加入水，用2mol/L稀盐酸调节pH至5～6，用乙酸乙酯萃取，干燥，浓缩，得到2-(5-(乙氧基羰基)-1,4-二甲基-1H-吡咯-3-基)-2-氧代乙酸(0.279g),直接用于下一步反应。
MS(ESI-,[M-H] -)m/z：238.2.
步骤D：50mL单口瓶中，加入2-(5-(乙氧基羰基)-1,4-二甲基-1H-吡咯-3-基)-2-氧代乙酸(0.27g)、二环[1.1.1]戊烷-1-胺盐酸盐(0.175g)、HATU(0.644g)、N，N-二甲基甲酰胺(5mL)及N，N-二异丙基乙胺(0.292g)，室温反应10h。反应结束后加入乙酸乙酯，水洗三次，干燥，浓缩，得到4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯(0.291g)粗品，直接用于下一步反应。
MS(ESI+,[M+H] +)m/z：305.1.
步骤E：50mL单口瓶中，加入4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯(0.29g)、氢氧化钠(0.114g)、甲醇(3mL)、水(3mL)，45℃反应10h。反应结束后加入5mL水稀释，用2mol/L稀盐酸调节pH至5～6，用乙酸乙酯洗涤，干燥，浓缩，得到4-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酸(0.282g)粗品，直接用于下一步反应。
MS(ESI-,[M-H] -)m/z：275.2.
步骤F：50mL单口瓶中，加入4-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酸(0.282g)、甲苯(10ml)、氯化亚砜(0.607g)，115℃反应6h。反应结束后浓缩，得到4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酰氯(0.25g)粗品，直接用于下一步反应。
步骤G：50mL单口瓶中，加入4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酰氯(0.25g)、5-氨基-2-氟苯腈(0.278g)、N，N-二甲基乙酰胺(5mL)，100℃反应3h。反应结束后加入乙酸乙酯(30mL)，水(3*20mL)洗三次，干燥，浓缩，烘干后得到4-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1,3-二甲基-1H-吡咯-2-甲酰胺(0.19g)。
1H-NMR(500MHz,DMSO-d 6):δ10.51(s,1H),9.15(s,1H),8.19-8.21(m,1H),8.14(s,1H),7.96-7.99(m,1H),7.83-7.56(m,1H),3.77(s,3H),2.46(s,1H),2.40(s,3H),2.08(s,6H)； 13C-NMR(125MHz,DMSO-d 6):δ183.89,160.42,159.88,157.87,136.39,136.37,136.33,127.86,127.55,127.48,125.14,124.08,117.70,117.54,117.23,114.36,100.53,100.40,52.86,48.76,25.16.MS(ESI-,[M-H] -)m/z：393.3.
实施例3 4-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-2-甲酰胺
Figure PCTCN2019074527-appb-000039
步骤A：根据实施例2，在步骤A中用吡咯-2-甲酸乙酯替代3-甲基-1H-吡咯-2-甲酸乙酯，制备1-甲基-1H-吡咯-2-甲酸乙酯。
1H-NMR(500MHz,DMSO-d 6):δ7.08(t,J＝2Hz,1H),6.83(q,J＝2Hz,1H),6.08(dd,J＝2Hz,1H),4.22(q,J＝7Hz,2H),3.86(s,3H),1.27(t,J＝7Hz,3H)； 13C-NMR(125MHz,DMSO-d 6):δ160.90,130.67,122.29,117.72,108.04,59.75,36.78,14.77.
步骤B：根据实施例2，在步骤B中用1-甲基-1H-吡咯-2-甲酸乙酯替代1,3-二甲基-1H-吡咯-2-甲酸乙酯，制得4-(2-乙氧基-2-氧代乙酰基)-1-甲基-1H-吡咯-2-甲酸乙酯。
MS(ESI +,[M+H] +)m/z：254.2
步骤C：根据实施例2，在步骤C中用4-(2-乙氧基-2-氧代乙酰基)-1-甲基-1H-吡咯-2-甲酸乙酯替代4-(2-乙氧基-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯，制备2-(5-(乙氧基羰基)-1-甲基-1H-吡咯-3-基)-2-氧代乙酸。
MS(ESI -,[M-H] -)m/z：224.3。
步骤D：根据实施例2，在步骤D中用2-(5-(乙氧基羰基)-1-甲基-1H-吡咯-3-基)-2-氧代乙酸替代2-(5-(乙氧基羰基)-1,4-二甲基-1H-吡咯-3-基)-2-氧代乙酸，制备4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-1-甲基-1H-吡咯-2-甲酸乙酯。
1H-NMR(500MHz,DMSO-d6)：δ9.21(s,1H),8.17(s,1H),7.36(s,1H),4.22-4.27(m,2H), 3.92(s,3H),2.45(s,1H),2.07(s,6H),1.29(t,J＝7.5Hz,3H). 13C-NMR(125MHz,DMSO-d6)：δ182.24,163.48,160.43,137.56,124.41,119.27,118.88,60.61,52.84,48.69,37.55,25.16,14.62.MS(ESI+,[M+Na] +)m/z:313.3.
步骤E：根据实施例2，在步骤E中用4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-1-甲基-1H-吡咯-2-甲酸乙酯替代4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯，制备4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-1-甲基-1H-吡咯-2-甲酸。
1H-NMR(500MHz,DMSO-d6)：δ12.74(s,1H),9.18(s,1H),8.14(s,1H),7.29(s,1H),3.91(s,3H),2.45(s,1H),2.07(s,6H). 13C-NMR(125MHz,DMSO-d6)：δ182.36,163.67,161.97,137.37,125.29,119.09,52.84,48.70,37.54,25.16.MS(ESI-,[M-H] -)m/z:261.3.
步骤F：根据实施例2，在步骤F中用4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-1-甲基-1H-吡咯-2-甲酸替代4-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酸，制备4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-1-甲基-1H-吡咯-2-甲酰氯，直接用于下一步反应。
步骤G：根据实施例2，在步骤G中用4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-1-甲基-1H-吡咯-2-甲酰氯替代4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酰氯，制备4-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-2-甲酰胺。
1H-NMR(500MHz,DMSO-d6)：δ10.38(s,1H),9.23(s,1H),8.20-8.23(s,2H),8.02-8.05(m,1H),7.69(d,J＝1.5Hz,1H),7.52(d,J＝9.0Hz,1H),3.96(s,3H),2.46(s,1H),2.08(s,6H). 13C-NMR(125MHz,DMSO-d6)：δ182.32,163.49,159.74,157.68,137.52,136.61,127.83,127.14,124.35,118.95,117.51,115.94,114.44,100.33,52.87,48.73,37.67,25.17.MS(ESI-,[M-H] -)m/z:379.4.
实施例4 4-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-3-氯-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-2-甲酰胺
Figure PCTCN2019074527-appb-000040
Figure PCTCN2019074527-appb-000041
步骤A：根据实施例2，在步骤A中用3-氯-1H-吡咯-2-甲酸甲酯替代3-甲基-1H-吡咯-2-甲酸乙酯，制备3-氯-1-甲基-1H-吡咯-2-甲酸甲酯。
1H-NMR(500MHz,CDCl 3)：δ6.69(s,1H),6.13(s,1H),3.88(s,6H). 13C-NMR(125MHz,CDCl 3)：δ161.04,127.77,120.29,118.74,109.70,51.15,38.35.
步骤B：根据实施例2，在步骤B中用3-氯-1-甲基-1H-吡咯-2-甲酸甲酯替代1,3-二甲基-1H-吡咯-2-甲酸乙酯，制得3-氯-4-(2-乙氧基-2-氧代乙酰基)-1-甲基-1H-吡咯-2-甲酸甲酯。
1H-NMR(500MHz,CDCl 3)：δ7.81(s,1H),4.37-4.41(m,2H),3.96(s,3H),3.93(s,3H),1.42(t,J＝6.5Hz,3H). 13C-NMR(125MHz,CDCl 3)：δ177.49,162.59,160.61,135.26,122.14,117.07,62.41,51.80,39.27,13.98.
步骤C：根据实施例2，在步骤C中用3-氯-4-(2-乙氧基-2-氧代乙酰基)-1-甲基-1H-吡咯-2-甲酸甲酯替代4-(2-乙氧基-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯，制备2-(4-氯-5-(甲氧基羰基)-1-甲基-1H-吡咯-3-基)-2-氧代乙酸。
MS(ESI+,[M+Na] +)m/z:268.0.
步骤D：根据实施例2，在步骤D中用2-(4-氯-5-(甲氧基羰基)-1-甲基-1H-吡咯-3-基)-2-氧代乙酸替代2-(5-(乙氧基羰基)-1,4-二甲基-1H-吡咯-3-基)-2-氧代乙酸，制备4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-3-氯-1-甲基-1H-吡咯-2-甲酸甲酯。
1H-NMR(500MHz,DMSO-d6)：δ9.25(s,1H),8.26(s,1H),3.91(s,3H),3.83(s,3H),2.46(s,1H),2.07(s,6H). 13C-NMR(125MHz,DMSO-d6)：δ182.02,163.75,160.21,137.37,121.60,120.30,115.85,52.84,52.20,48.67,39.00,25.16.MS(ESI+,[M+Na] +)m/z:333.3.
步骤E：根据实施例2，在步骤E中用4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-3-氯-1-甲基-1H-吡咯-2-甲酸甲酯替代4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯，制备4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-3-氯-1-甲基-1H-吡咯-甲酸。
1H-NMR(500MHz,DMSO-d6)：δ13.28(s,1H),9.23(s,1H),8.21(s,1H),3.90(s,3H),2.46(s,1H),2.07(s,6H). 13C-NMR(125MHz,DMSO-d6)：δ182.06,163.86,161.17,136.96,122.53,115.73,111.71,52.84,48.67,39.00,25.15.MS(ESI-,[M-H] -)m/z:295.2.
步骤F：根据实施例2，在步骤F中用4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-3-氯-1- 甲基-1H-吡咯-甲酸替代4-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酸，制备4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-3-氯-1-甲基-1H-吡咯-甲酰氯，直接用于下一步反应。
步骤G：根据实施例2，在步骤G中用4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-3-氯-1-甲基-1H-吡咯-甲酰氯替代4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-1,3-二甲基-1H-吡咯-2-甲酰氯，制备4-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-3-氯-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-2-甲酰胺。
1H-NMR(500MHz,DMSO-d6)：δ10.71(s,1H),9.27(s,1H),8.26(s,1H),8.20-8.21(m,1H),7.97-7.99(m,1H),7.56(t,J＝9.0Hz,1H),3.82(s,3H),2.47(s,1H),2.08(s,6H). 13C-NMR(125MHz,DMSO-d6)：δ181.96,163.65,158.30,136.01,135.61,127.67,126.93,124.17,117.83,115.19,114.66,114.29,100.66,52.85,48.70,37.02,25.17.MS(ESI-,[M-H] -)m/z:413.3.
实施例5 4-(N-(二环[1.1.1]戊-1-基)氨磺酰)-N-(3-氰基-4-氟苯基)-1,3-二甲基-1H-吡咯-2-甲酰胺
Figure PCTCN2019074527-appb-000042
步骤A：50mL单口瓶中，加入1,3-二甲基-1H-吡咯-2-甲酸乙酯(0.2g)，缓缓滴加氯磺酸(0.279g)，5分钟滴加完毕，反应结束。加入乙酸乙酯，水洗三次，干燥，浓缩，得到4-(氯磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯(0.22g)粗品，直接用于下一步反应。
1H-NMR(500MHz,DMSO-d 6):δ7.10(s,1H),4.20-4.24(q,J＝21Hz,2H),3.74(s,3H),2.34(s,3H),1.27-1.30(t,J＝14.5Hz,3H)； 13C-NMR(125MHz,DMSO-d 6):δ161.68,129.90,128.89,126.48,120.01,59.83,37.47,14.72,12.02.MS(ESI+,[M+Na] +)m/z：288.7.
步骤B:50mL单口瓶中，加入4-(氯磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯(0.21g)、二环[1.1.1]戊烷-1-胺盐酸盐(0.123g)、N，N-二甲基甲酰胺(5mL)，室温反应6h。反应结束后加 入乙酸乙酯，水洗三次，干燥，浓缩，得到4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯(0.215g)粗品，直接用于下一步反应。
MS(ESI-,[M-H] -)m/z：311.3.
步骤C:50mL单口瓶中，依次加入4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯(0.21g)、氢氧化钠(0.081g)、甲醇(3mL)、水(3mL)，45℃反应10h。反应结束后加入5mL水稀释，用2mol/L稀盐酸调节pH至5～6，用乙酸乙酯洗涤，干燥，浓缩，得到4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸(97.1mg)粗品，直接用于下一步反应。
MS(ESI-,[M-H] -)m/z：283.2.
步骤D:50mL单口瓶中，加入4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸(97.1mg)、氯化亚砜(203mg)、甲苯(5mL)，115℃反应6h。反应结束后浓缩，得到4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酰氯(95mg)粗品，直接用于下一步反应。
步骤E:50mL单口瓶中，加入4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酰氯(103mg)、5-氨基-2-氟苯腈(93mg)、N，N-二甲基乙酰胺(5mL)，100℃反应3h。反应结束后加入乙酸乙酯，水洗三次，干燥，浓缩，烘干后得到4-(N-(二环[1.1.1]戊-1-基)氨磺酰)-N-(3-氰基-4-氟苯基)-1,3-二甲基-1H-吡咯-2-甲酰胺(65mg)。
1H-NMR(500MHz,DMSO-d 6):δ10.39(s,1H),8.19-8.21(m,2H),7.97-8.00(m,1H),7.68-7.72(t,J＝20.5Hz,1H),7.46-7.56(m,1H),3.76(s,3H),2.30(s,4H),1.79(s,3H)； 13C-NMR(125MHz,DMSO-d 6):δ167.43,157.84,136.44,136.42,132.20,132.02,129.86,129.12,124.21,122.75,120.77,114.37,52.66,48.89,36.10,24.10,10.81.MS(ESI-,[M-H] -)m/z：401.3.
实施例6 4-(N-(二环[1.1.1]戊-1-基)氨磺酰)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-2-甲酰胺
Figure PCTCN2019074527-appb-000043
步骤A：根据实施例2，在步骤A中用吡咯-2-甲酸乙酯替代3-甲基-1H-吡咯-2-甲酸乙酯， 制备1-甲基吡咯-2-甲酸乙酯。
1H-NMR(500MHz,DMSO-d 6):δ7.08(t,J＝2Hz,1H),6.83(q,J＝2Hz,1H),6.08(dd,J＝2Hz,1H),4.22(q,J＝7Hz,2H),3.86(s,3H),1.27(t,J＝7Hz,3H)； 13C-NMR(125MHz,DMSO-d 6):δ160.90,130.67,122.29,117.72,108.04,59.75,36.78,14.77.
步骤B：根据实施例5，在步骤A中用1-甲基吡咯-2-甲酸乙酯替代1,3-二甲基-1H-吡咯-2-甲酸乙酯，制备4-(氯磺酰基)-1-甲基-1H-吡咯-2-甲酸乙酯。
1H-NMR(500MHz,CDCl 3):δ7.49(s,1H),7.39(d,J＝1.5Hz,1H),4.35(q,J＝7.0Hz,2H),4.03(s,3H),1.40(t,J＝7.5Hz,3H)； 13C-NMR(125MHz,CDCl 3):δ159.90,130.73,126.71,124.95,116.16,61.11,37.97,14.24.
步骤C：根据实施例5，在步骤B中用4-(氯磺酰基)-1-甲基-1H-吡咯-2-甲酸乙酯替代4-(氯磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯，制备4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1-甲基-1H-吡咯-2-甲酸乙酯。
MS(ESI -,[M-H] -)m/z：297.2。
步骤D：根据实施例5，在步骤C中用4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1-甲基-1H-吡咯-2-甲酸乙酯替代4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯，制备4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1-甲基-1H-吡咯-2-甲酸。
MS(ESI -,[M-H] -)m/z：269.1。
步骤E：根据实施例5，在步骤D中用4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1-甲基-1H-吡咯-2-甲酸替代4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸，制备4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1-甲基-1H-吡咯-2-甲酰氯。
步骤F：根据实施例5，在步骤E中用4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1-甲基-1H-吡咯-2-甲酰氯替代4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酰氯，制备4-(N-(二环[1.1.1]戊-1-基)氨磺酰)-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-2-甲酰胺。
1H-NMR(500MHz,DMSO-d 6):δ10.35(s,1H),8.22(m,2H),8.02(m,1H),7.58(s,1H),7.53(t,J＝9Hz,1H),7.36(d,J＝1.5Hz,1H),3.93(s,3H),2.32(s,1H),1.82(s,6H)； 13C-NMR(125MHz,DMSO-d 6):δ159.71,159.59,157.70,136.56,136.54,130.84,127.93,126.09,124.47,117.35,114.43,113.27,100.34,100.21,52.71,49.04,37.48,24.12.MS(ESI -,[M-H] -)m/z：387.3。
实施例7 4-(N-(二环[1.1.1]戊-1-基)氨磺酰)-N-(3-氰基-4-氟苯基)-1,3,5-三甲基-1H-吡咯-2-甲酰胺
Figure PCTCN2019074527-appb-000044
步骤A：根据实施例5，在步骤A中用1,3,5-三甲基-1H-吡咯-2-甲酸乙酯替代1,3-二甲基-1H-吡咯-2-甲酸乙酯，制备4-(氯磺酰基)-1,3,5-三甲基-1H-吡咯-2-甲酸乙酯。 1H-NMR(500MHz,CDCl 3):δ4.36(q,J＝7.0Hz,2H),3.85(s,3H),2.60(d,J＝3.0Hz,6H),1.41(t,J＝7.5Hz,3H). 13C-NMR(125MHz,CDCl 3):δ161.28,139.79,128.49,123.94,121.38,60.78,33.62,14.31,11.64,11.53.
步骤B：根据实施例5，在步骤B中用4-(氯磺酰基)-1,3,5-三甲基-1H-吡咯-2-甲酸乙酯替代4-(氯磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯，制备4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3,5-三甲基-1H-吡咯-2-甲酸乙酯。
1H-NMR(500MHz,DMSO-d 6):δ8.34(s,1H),4.25(q,J＝7Hz,2H),3.73(s,3H),2.44(s,3H),2.39(s,3H),2.26(s,1H),1.69(s,6H),1.31(t,J＝7Hz,3H)； 13C-NMR(125MHz,DMSO-d 6):δ161.47,138.71,127.40,120.18,119.93,60.42,52.47,48.80,33.43,24.00,14.63,11.88,11.38。
步骤C：根据实施例5，在步骤C中用4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3,5-三甲基-1H-吡咯-2-甲酸乙酯替代4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯，制备4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3,5-三甲基-1H-吡咯-2-甲酸。
1H-NMR(500MHz,DMSO-d 6):δ12.67(s,1H),8.14(s,1H),3.75(s,3H),2.44(s,3H),2.40(s,3H),2.26(s,1H),1.69(s,6H)； 13C-NMR(125MHz,DMSO-d 6):δ163.01,138.36,127.31,120.76,119.77,52.51,48.87,33.35,23.99,14.63,11.90,11.35.MS(ESI -,[M-H] -)m/z：297.3.
步骤D：根据实施例5，在步骤D中用4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3,5-三甲基-1H-吡咯-2-甲酸替代4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸，制备4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3,5-三甲基-1H-吡咯-2-甲酰氯。
步骤E：根据实施例5，在步骤E中用-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3,5-三甲基-1H-吡咯-2-甲酰氯替代4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酰氯， 制备4-(N-(二环[1.1.1]戊-1-基)氨磺酰)-N-(3-氰基-4-氟苯基)-1,3,5-三甲基-1H-吡咯-2-甲酰胺。
1H-NMR(500MHz,DMSO-d 6):δ10.39(s,1H),8.21(dd,J＝5.5Hz,1H),8.14(s,1H),7.99(m,1H),7.54(dd,J＝9Hz,1H),3.60(s,3H),2.51(m,3H),2.29(s,4H),1.75(s,6H)； 13C-NMR(125MHz,DMSO-d 6):δ160.65,159.83,136.48,136.39,127.65,127.58,125.85,124.20,120.83,119.00,117.63,114.39,100.46,100.33,52.61,48.92,32.48,24.04,11.33,11.11.MS(ESI -,[M-H] -)m/z：415.3.
实施例8 4-(N-(二环[1.1.1]戊-1-基)氨磺酰)-N-(3-氯-4-氟苯基)-1,3,5-三甲基-1H-吡咯-2-甲酰胺
Figure PCTCN2019074527-appb-000045
步骤A：根据实施例7，在步骤E中用3-氯-4-氟苯胺替代5-氨基-2-氟苯腈，制备4-(N-(二环[1.1.1]戊-1-基)氨磺酰)-N-(3-氯-4-氟苯基)-1,3,5-三甲基-1H-吡咯-2-甲酰胺。
1H-NMR(500MHz,DMSO-d 6):δ10.25(s,1H),8.12(d,J＝13.5Hz,1H),7.99(t,J＝3.0Hz,1H),7.61-7.65(m,1H),7.41(t,J＝9.0Hz,1H),3.58(s,1H),3.31(s,1H),2.50(s,3H),2.29(s,1H),2.27(s,3H),1.74(s,3H). 13C-NMR(125MHz,DMSO-d 6):δ160.50,154.78,152.85,136.61,136.16,126.13,121.67,120.54,119.66,118.89,117.47,52.61,48.92,32.43,24.04,11.30.MS(ESI+,[M+H] +)m/z：424.3.
实施例9 4-(N-(二环[1.1.1]戊-1-基)氨磺酰基)-3-氯-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-2-甲酰胺
Figure PCTCN2019074527-appb-000046
步骤A：根据实施例5，在步骤A中用3-氯-1-甲基-1H-吡咯-2-甲酸甲酯替代1,3-二甲基-1H-吡咯-2-甲酸乙酯，制备3-氯-4-(氯磺酰基)-1-甲基-1H-吡咯-2-甲酸甲酯。
1H-NMR(500MHz,DMSO-d6):δ7.48(s,1H),4.00(s,3H),3.96(s,3H). 13C-NMR(125MHz, DMSO-d6)：δ159.92,130.67,124.97,122.25,118.45,52.14,39.45.
步骤B：根据实施例5，在步骤B中用3-氯-4-(氯磺酰基)-1-甲基-1H-吡咯-2-甲酸甲酯替代4-(氯磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯，制备4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-3-氯-1-甲基-1H-吡咯-2-甲酸甲酯。
1H-NMR(500MHz,DMSO-d6)：δ8.48(s,1H),7.72(s,1H),3.88(s,3H),3.83(s,3H),2.29(s,1H),1.75(s,6H). 13C-NMR(125MHz,DMSO-d6)：δ160.09,132.04,122.39,120.80,116.15,52.59,48.60,38.80,24.03.MS(ESI-,[M-H] -)m/z:317.3.
步骤C：根据实施例5，在步骤C中用4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-3-氯-1-甲基-1H-吡咯-2-甲酸甲酯替代4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸乙酯，制备4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-3-氯-1-甲基-1H-吡咯-2-甲酸。
1H-NMR(500MHz,DMSO-d6)：δ13.27(s,1H),8.42(s,1H),7.67(s,1H),3.87(s,3H),2.29(s,1H),1.75(s,6H). 13C-NMR(125MHz,DMSO-d6)：δ161.07,131.56,122.11,121.64,115.93,52.59,48.64,38.79,24.03.MS(ESI-,[M-H] -)m/z:303.1.
步骤D：根据实施例5，在步骤D中用4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-3-氯-1-甲基-1H-吡咯-2-甲酸替代4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酸，制备4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-3-氯-1-甲基-1H-吡咯-2-甲酰氯。
步骤E：根据实施例5，在步骤E中用4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-3-氯-1-甲基-1H-吡咯-2-甲酰氯替代4-(N-(二环[1.1.1]戊烷-1-基)氨磺酰基)-1,3-二甲基-1H-吡咯-2-甲酰氯，制备4-(N-(二环[1.1.1]戊-1-基)氨磺酰基)-3-氯-N-(3-氰基-4-氟苯基)-1-甲基-1H-吡咯-2-甲酰胺。
1H-NMR(500MHz,DMSO-d6)：δ10.62(s,1H),8.49(s,1H),8.20(d,J＝5.0Hz,1H),7.99(t,J＝4.5Hz,1H),7.64(s,1H),7.56(t,J＝9.0Hz,1H),3.79(s,3H),2.32(s,1H),1.80(s,6H). 13C-NMR(125MHz,DMSO-d6)：δ160.08,158.18,136.02,129.80,127.81,126.07,124.34,121.70,117.78,114.30,110.82,100.63,52.69,48.69,36.92,24.09.MS(ESI-,[M-H] -)m/z:421.2.
实施例10 N 4-(二环[1.1.1]戊-1-基)-N 2-(3-氰基-4-氟苯基)-1,3,5-三甲基-1H-吡咯-2,4-二甲酰胺
Figure PCTCN2019074527-appb-000047
Figure PCTCN2019074527-appb-000048
步骤A：向装有冷凝管的50mL圆底烧瓶中，依次加入(5-((3-氰基-4-氟苯基)氨基甲酰基)-1,2,4-三甲基-1H-吡咯-3-基)-2-氧代乙酸(100mg,0.291mmol)、甲苯(3ml)及二氯亚砜(104mg,0.874mmol)，油浴加热至90℃，搅拌1小时后，减压蒸除甲苯及剩余的二氯亚砜，得褐色固体。将此固体溶于N,N-二甲基乙酰胺(3.00ml)，室温下，依次加入二环[1.1.1]戊烷-1-胺盐酸盐(34.8mg,0.291mmol)和DIPEA(94mg,0.728mmol)，室温搅拌过夜。反应结束后向反应液中加入水和EA，充分搅拌后，分层，有机相用无水硫酸钠干燥，抽滤，浓缩，经硅胶柱层析纯化得(N 4-(二环[1.1.1]戊-1-基)-N 2-(3-氰基-4-氟苯基)-1,3,5-三甲基-1H-吡咯-2,4-二甲酰胺(40mg，36.04％)。
1H-NMR(500MHz,DMSO-d6):δ10.20(s,1H),8.18-8.20(m,1H),8.07(s,1H),7.94-7.98(m,1H),7.50-7.54(m,1H),3.56(s,3H),2.43(s,1H),2.28(s,3H),2.20(s,3H),2.05(s,6H)； 13C-NMR(125MHz,DMSO-d6):δ166.01,161.17,159.60,157.60,136.84,133.67,130.14,127.26,124.85,123.73,121.10,118.68,117.51,114.45,100.33,53.02,49.43,32.15,25.07,11.59.MS(ESI-,[M-H] -)m/z：379.4。
实施例11 4-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-甲酰胺
Figure PCTCN2019074527-appb-000049
Figure PCTCN2019074527-appb-000050
步骤A：冰浴下，将NaH(2.3g,96mmol)分批加入到含有3,5-二甲基-1H-吡咯-2-甲酸乙酯(8g)的DMF(90ml)搅拌液中，加毕后，在冰浴下搅拌反应30分钟。将氘代碘甲烷(8.3g)加入到上述反应液中，加料完毕继续冰浴下搅拌10分钟，然后将反应液移至室温搅拌1h。反应结束，向上述反应液中加入饱和氯化铵溶液(20ml)，然后用EA(300ml)萃取，用水30mL*5洗涤有机相，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-羧酸乙酯8.5g。MS(ESI+,[M+H] +)m/z:185.1.
步骤B：冰浴下，将草酰氯单乙酯(10.89g)缓慢滴入含有3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-羧酸乙酯(9.8g)的DCM(250ml)搅拌液中，滴加完毕，然后向混合物中加入三氯化铝(21.27g，分批加入)，加料完毕继续冰浴搅拌5分钟，然后将反应液置于室温搅拌6h小时，反应结束，将反应液倒入碎冰中，用乙酸乙酯(600ml)萃取，分层，有机相分别用水(50ml*3)和饱和食盐水(30ml*3)洗涤，无水硫酸钠干燥，浓缩，柱层析纯化得4-(2-乙氧基-2-氧代乙酰基)-3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-羧酸乙酯(14.5g)。MS(ESI+,[M+H] +)m/z：285.4
步骤C：冰浴下，将氢氧化钠水溶液(1.2mol/L,100ml)滴加入含有4-(2-乙氧基-2-氧代乙酰基)-3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-羧酸乙酯(13.5g)的甲醇(200ml)搅拌液中，滴加完毕，然后将反应液置于室温搅拌30分钟，反应结束，向反应液中加入100ml水，浓缩除去部分甲醇，向剩余反应液中加入100ml乙酸乙酯，分离水相，用1N盐酸调节水相pH＝2左右，有大量固体析出，过滤，干燥得2-(5-(乙氧基羰基)-2,4-二甲基-1-(甲基-d 3)-1H-吡咯-3-基)-2-氧代乙酸(6.89g)。MS(ESI-,[M-H] -)m/z：255.2。
步骤D：室温下，向反应瓶中依次加入2-(5-(乙氧基羰基)-2,4-二甲基-1-(甲基-d 3)-1H-吡咯-3-基)-2-氧代乙酸(2.68g)、DMF(100ml)、HATU(13.29g)及DIPEA(6.95g)，投料完毕继续 室温搅拌5分钟，然后加入双环[1.1.1]戊烷-1-胺盐酸盐(3.54g)，投料完毕，室温搅拌过夜，反应结束，向反应液中加入水(100ml)，有大量固体析出，过滤，滤饼真空干燥得(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-3,5-二甲基-1-(甲基-d3)-1H-吡咯-2-羧酸乙酯(8.0g)。MS(ESI+,[M+H] +)m/z：322.3。
步骤E：室温下，将氢氧化钠水溶液(1.4mol/L,60ml)滴加到(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-羧酸乙酯(9.0gl)的甲醇(80ml)和四氢呋喃(80ml)混合溶液中，加料完毕，加热至40℃，搅拌4h。反应结束，向反应液中加入100ml水，浓缩除去部分甲醇，向剩余反应液中加入100ml乙酸乙酯，分离水相，用1N盐酸调节水相pH＝2左右，有固体析出，抽滤得4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-羧酸(6.4g)。
1H-NMR(500MHz,DMSO-d 6)：δ12.75(s,1H),9.19(s,1H),2.47(s,1H),2.37(s,6H),2.05(s,6H)； 13C-NMR(125MHz,DMSO-d 6)：δ188.22,167.93,163.08,142.73,129.74,121.75,117.40,53.18,52.62,48.54,25.26,12.07.
步骤F：向反应瓶中，依次加入甲苯(70ml)、4-(2-(二环[1.1.1]戊烷-1-基氨基)-2-氧代乙酰基)-3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-羧酸(2.0g)、二氯亚砜(16.22g)，N 2保护下，将混合物加热至115℃，搅拌1小时。反应结束：减压旋蒸除去溶剂，加入10ml甲苯进一步旋蒸浓缩，真空干燥1.0h，得4-(2-(二环[1.1.1]戊-2-基氨基)-2-氧代乙酰基)-3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-碳酰氯(2.65g)。
向反应瓶中，依次加入N,N-二甲基乙酰胺(30ml)、4-(2-(二环[1.1.1]戊-2-基氨基)-2-氧代乙酰基)-3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-碳酰氯(2.65g)、5-氨基-2-氟-苯腈(2.46g,)，N 2保护下，将混合物加热至100℃反应1小时。反应完毕：将反应液降至室温，向反应液中加入水(30ml)，用乙酸乙酯(100mlx2)萃取，合并有机层，饱和氯化钠水洗，抽滤，柱层析得到4-(2-(二环[1.1.1]戊-1-基氨基)-2-氧代乙酰基)-N-(3-氰基-4-氟苯基)-3,5-二甲基-1-(甲基-d 3)-1H-吡咯-2-甲酰胺(200mg)。
1H-NMR(500MHz,DMSO-d 6)：δ10.49(s,1H),9.18(s,1H),8.21-8.22(m,1H),7.98-7.99(m,1H),7.52-7.56(m,1H),2.51(s,1H),2.41(s,3H),2.25(s,3H),2.07(s,6H)； 13C-NMR(125MHz,DMSO-d 6)：δ188.01,168.12,160.70,159.83,157.82,141.30,136.48,127.49,126.90,124.05,123.08,117.58,116.63,114.39,100.42,53.25,52.68,48.59,25.27,11.76.MS(ESI-,[M-H] -)m/z：410.4.
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，不时取出显微镜下观察(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溶解的不同化合物稀释，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。
1.2体外细胞毒性
取处于指数生长期状态良好的HepG2.2.15或HepAD38细胞一瓶，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1及2，其中A表示EC50≤15nM，B表示15nM＜EC50≤100nM，C表示EC50＞100nM。
表1.HepAD38细胞毒性(CC50)、抗HBV活性实验(EC50)结果
化合物编号 EC50(nM) CC50(μM) 化合物编号 EC50(nM) CC50(μM)
实施例1 A ＞100 实施例7 B  
实施例2 A - 实施例8 B -
实施例3 B - 实施例9 B -
实施例4 A - 实施例5 B -
表中“-”表示未进行测试。
表2.HepG2.2.15细胞毒性(CC50)、抗HBV活性实验(EC50)结果
化合物编号 EC50(nM) CC50(μM)
实施例1 A ＞100
实验例2：体内动物药效-AAV小鼠模型评价抗病毒效果
取6-8周龄雄性C57BL/6小鼠，按照1×10 11vg剂量，尾静脉注射rAAV8-1.3HBV病毒(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2-3周，每日1次。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含量和定量ELISA方法检测HBeAg和HBsAg的表达。具体结果见表3。
表3
实施例编号 血清中HBV DNA下降水平(log)
1 1.50
实验例3：HDI小鼠模型评价抗病毒效果
取6-8周龄雄性C57BL/6小鼠，将纯化的重组质粒pHBVl.3(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24h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6天，每日1次。分别于注射后的1、3、5、7天取小鼠血清，第7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。具体结果见表4。
表4
实施例编号 血清中HBV DNA下降水平(log)(30mpk QD)(5d)
1 0.97
实验例4体外人肝微粒体稳定性
300μL最终的温孵体系中，含30μL人肝微粒体(蛋白浓度：0.15mg/mL)，30μL NADPH+MgCl 2，3μL底物(乙腈配制)，237μL PBS缓冲液。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***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。具体结果见表5。
表5
实施例编号 60min剩余量(％)
1 91.8
2 90
实验例5大鼠体内药物代谢动力学
SD大鼠，体重180～220g，适应3～5天后，随机分为2组，每组3只，按30mg/kg剂量分别灌胃受试化合物。
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。
灌胃给药后，于0min、15min、1h、6h于眼眶取血0.2mL左右，EDTA-K 2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(***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。具体结果见表6。
溶媒：Ethanol：Tween 80：PEG400(20:20:60，V/V)。
表6
Figure PCTCN2019074527-appb-000051

Claims (21)

  1. 式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐，
    Figure PCTCN2019074527-appb-100001
    其中，
    L选自
    Figure PCTCN2019074527-appb-100002
    Figure PCTCN2019074527-appb-100003
    R 1、R 2分别独立地选自氢、氘、-CN、氟、氯、溴、C 1-3烷基或C 3-4环烷基，所述C 1-3烷基或C 3-4环烷基任选地被一个或多个氟或氘取代；
    R 3选自氢、C 1-3烷基或C 3-4环烷基，所述C 1-3烷基或C 3-4环烷基任选地被一个或多个氟或氘取代；
    R 4、R 5、R 6分别独立地选自氢、氘、氟、氯、溴、-CHF 2、-CH 2F、-CF 3、-CN、C 1-3烷基或C 3-4环烷基，所述C 1-3烷基或C 3-4环烷基任选地被一个或多个氘取代。
  2. 如权利要求1所述的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐，其中L选自
    Figure PCTCN2019074527-appb-100004
    任选地，L选自
    Figure PCTCN2019074527-appb-100005
    任选地，L选自
    Figure PCTCN2019074527-appb-100006
  3. 如权利要求1所述的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐，其中R 1、R 2分别独立地选自氢、氘、-CN、氟、氯、溴或C 1-3烷基，所述C 1-3烷基任选地被一个或多个氘取代；任选地，R 1、R 2分别独立地选自氢、氘、-CN、氯或C 1-3烷基，所述C 1-3烷基任选地被一个或多个氘取代；任选地，R 1、R 2分别独立地选自氢、氘、氯或C 1-3烷基，所述C 1-3烷基任选地被一个或多个氘取代；任选地，R 1、R 2分别独 立地选自氢、氯、甲基、乙基、丙基或异丙基，所述甲基、乙基、丙基或异丙基任选被一个或多个氘取代；任选地，R 1、R 2分别独立地选自氢、氯、三个氘取代的甲基或甲基；任选地，R 1选自氢、氯、三个氘取代的甲基或甲基，R 2选自氢或甲基。
  4. 如权利要求1所述的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐，其中R 3选自氢或C 1-3烷基，所述C 1-3烷基任选地被一个或多个氟或氘取代；任选地，R 3选自氢或甲基，所述甲基任选地被一个或多个氟或氘取代；任选地，R 3选自任选被三个氘取代的甲基。
  5. 如权利要求1所述的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐，结构单元
    Figure PCTCN2019074527-appb-100007
    为
    Figure PCTCN2019074527-appb-100008
    任选地，结构单元
    Figure PCTCN2019074527-appb-100009
    为
    Figure PCTCN2019074527-appb-100010
  6. 如权利要求1所述的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐，结构片段
    Figure PCTCN2019074527-appb-100011
    为
    Figure PCTCN2019074527-appb-100012
  7. 如权利要求1所述的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐，R 5是氢或氟。
  8. 如权利要求1所述的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐，R 4、R 6分别独立地选自氢、氟、氯、溴、-CHF 2、-CH 2F、-CF 3、-CN或甲基；任选地，R 4、R 6分别独立地选自氢、氟、氯、-CN或甲基。
  9. 如权利要求1所述的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐，R 4选自氢、氟、氯、-CHF 2、-CN、-CF 3或甲基；或者，R 6选自氢、氟、氯、-CHF 2、-CN、-CF 3或甲基，并且R 4和R 6中的至少一个是氟或氢；或者，R 4和R 6中至少一个是氢，并且R 4和R 6中的另一个选自氢、氟、氯、-CHF 2、-CN、-CF 3或甲基。
  10. 如权利要求1所述的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐，R 5是氢或氟，并且R 4、R 6分别独立地选自氢、氟、氯或-CN；任选地，R 5是氟，并且R 4、R 6分别独立地选自氢、氯或-CN；任选地，R 5是氟，R 4是氢，R 6选自氢、 氯或-CN；任选地，R 5是氟，R 4是氢，R 6选自氯或-CN。
  11. 如权利要求1或6所述的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐，结构片段
    Figure PCTCN2019074527-appb-100013
    为
    Figure PCTCN2019074527-appb-100014
    任选地，结构片段
    Figure PCTCN2019074527-appb-100015
    为
    Figure PCTCN2019074527-appb-100016
    Figure PCTCN2019074527-appb-100017
  12. 如权利要求1所述的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐选自式II化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐，
    Figure PCTCN2019074527-appb-100018
  13. 如权利要求1所述的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐选自式III化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐，
    Figure PCTCN2019074527-appb-100019
  14. 如权利要求1所述的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐选自式IV化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐，
    Figure PCTCN2019074527-appb-100020
  15. 如权利要求1所述的式I化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或者药学上可接受的盐选自式V化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐，
    Figure PCTCN2019074527-appb-100021
  16. 以下化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐：
    Figure PCTCN2019074527-appb-100022
  17. 药物组合物，其包含如权利要求1-16任一项所述的化合物或其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐；以及药学上可接受的辅料。
  18. 如权利要求1-16任一项所述的化合物或者其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐，或者如权利要求17所述的药物组合物在制备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，其中受益于衣壳蛋白装配抑制的疾病指乙型 肝炎病毒感染引起的疾病；任选地，其中受益于衣壳蛋白装配抑制的疾病指乙型肝炎病毒感染引起的肝脏疾病。
  19. 如权利要求1-16任一项所述的化合物或者其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐，或者如权利要求17所述的药物组合物在治疗受益于衣壳蛋白装配抑制的疾病中的用途；任选地，其中受益于衣壳蛋白装配抑制的疾病指乙型肝炎病毒感染引起的疾病；任选地，其中受益于衣壳蛋白装配抑制的疾病指乙型肝炎病毒感染引起的肝脏疾病。
  20. 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1-16任一项所述的化合物或者其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐，或者如权利要求17所述的药物组合物；任选地，其中受益于衣壳蛋白装配抑制的疾病指乙型肝炎病毒感染引起的疾病；任选地，其中受益于衣壳蛋白装配抑制的疾病指乙型肝炎病毒感染引起的肝脏疾病。
  21. 用于治疗受益于衣壳蛋白装配抑制的疾病的如权利要求1-16任一项所述的化合物或者其立体异构体、互变异构体、溶剂化物、水合物、前药或药学上可接受的盐，或者如权利要求17所述的药物组合物；任选地，其中受益于衣壳蛋白装配抑制的疾病指乙型肝炎病毒感染引起的疾病；任选地，其中受益于衣壳蛋白装配抑制的疾病指乙型肝炎病毒感染引起的肝脏疾病。
PCT/CN2019/074527 2018-02-09 2019-02-02 衣壳蛋白装配抑制剂、其药物组合物和用途 WO2019154343A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201980007896.7A CN111601788B (zh) 2018-02-09 2019-02-02 衣壳蛋白装配抑制剂、其药物组合物和用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201810132621 2018-02-09
CN201810132621.3 2018-02-09

Publications (1)

Publication Number Publication Date
WO2019154343A1 true WO2019154343A1 (zh) 2019-08-15

Family

ID=67549287

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/074527 WO2019154343A1 (zh) 2018-02-09 2019-02-02 衣壳蛋白装配抑制剂、其药物组合物和用途

Country Status (2)

Country Link
CN (1) CN111601788B (zh)
WO (1) WO2019154343A1 (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021093172A1 (zh) 2019-11-13 2021-05-20 西安新通药物研究有限公司 Hbv抑制剂及其用途
WO2021197486A1 (zh) * 2020-04-03 2021-10-07 东莞市东阳光新药研发有限公司 新型螺环类化合物及其在药物中的应用
US11597716B2 (en) 2018-03-30 2023-03-07 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. N-heterocyclic five-membered ring-containing capsid protein assembly inhibitor, pharmaceutical composition thereof, and use thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022156758A1 (zh) * 2021-01-22 2022-07-28 广东东阳光药业有限公司 新型酰胺吡咯类化合物及其在药物中的用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015011281A1 (en) * 2013-07-25 2015-01-29 Janssen R&D Ireland Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
CN105452220A (zh) * 2013-05-17 2016-03-30 爱尔兰詹森科学公司 氨磺酰基吡咯酰胺衍生物及其作为药物用于治疗乙型肝炎的用途
WO2017156255A1 (en) * 2016-03-09 2017-09-14 Emory University Elimination of hepatitis b virus with antiviral agents

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EA027280B1 (ru) * 2012-08-28 2017-07-31 Янссен Сайенсиз Айрлэнд Юси Сульфамоил-ариламиды и их применение в качестве лекарственных препаратов для лечения гепатита b
US9895349B2 (en) * 2013-04-03 2018-02-20 Janssen Sciences Ireland Us N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B
CA2923712C (en) * 2013-10-23 2021-11-02 Janssen Sciences Ireland Uc Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105452220A (zh) * 2013-05-17 2016-03-30 爱尔兰詹森科学公司 氨磺酰基吡咯酰胺衍生物及其作为药物用于治疗乙型肝炎的用途
WO2015011281A1 (en) * 2013-07-25 2015-01-29 Janssen R&D Ireland Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b
WO2017156255A1 (en) * 2016-03-09 2017-09-14 Emory University Elimination of hepatitis b virus with antiviral agents

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11597716B2 (en) 2018-03-30 2023-03-07 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. N-heterocyclic five-membered ring-containing capsid protein assembly inhibitor, pharmaceutical composition thereof, and use thereof
WO2021093172A1 (zh) 2019-11-13 2021-05-20 西安新通药物研究有限公司 Hbv抑制剂及其用途
JP2022522522A (ja) * 2019-11-13 2022-04-19 西安新通薬物研究股▲フン▼有限公司 Ｈｂｖ抑制剤及びその用途
EP3919474A4 (en) * 2019-11-13 2022-06-01 Xi'An Xintong Pharmaceutical Research Co., Ltd. HBV INHIBITOR AND ITS USE
JP7285027B2 (ja) 2019-11-13 2023-06-01 西安新通薬物研究股▲フン▼有限公司 化合物、その薬学的に許容される塩又は立体異性体、その使用、及び薬物組成物
EP4245372A2 (en) 2019-11-13 2023-09-20 Xi'An Xintong Pharmaceutical Research Co., Ltd. Hbv inhibitor and use thereof
EP4245372A3 (en) * 2019-11-13 2023-11-22 Xi'An Xintong Pharmaceutical Research Co., Ltd. Hbv inhibitor and use thereof
US11903924B2 (en) 2019-11-13 2024-02-20 Xi'an Xintong Pharmaceutical Research Co., Ltd. HBV inhibitor and its use
WO2021197486A1 (zh) * 2020-04-03 2021-10-07 东莞市东阳光新药研发有限公司 新型螺环类化合物及其在药物中的应用
CN113493441A (zh) * 2020-04-03 2021-10-12 广东东阳光药业有限公司 新型螺环类化合物及其在药物中的应用

Also Published As

Publication number Publication date
CN111601788A (zh) 2020-08-28
CN111601788B (zh) 2022-06-14

Similar Documents

Publication Publication Date Title
WO2019185016A1 (zh) 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
WO2019154343A1 (zh) 衣壳蛋白装配抑制剂、其药物组合物和用途
ES2442907T3 (es) Tiazolil dihidropirimidinas sustituidas con bromo-fenilo
JP5197539B2 (ja) ９置換−８−オキソアデニン化合物
WO2005095419A1 (ja) チアゾロピリミジン誘導体
JP2005538062A (ja) 化合物、組成物、および方法
KR20050119652A (ko) 역전사 효소 저해제로서의 벤질-피리다진온
BRPI0809617A2 (pt) Inibidores não-nucleosídicos da transcriptase reversa
WO2020151252A1 (zh) 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
WO2020156494A1 (zh) 含有吡咯并杂环的衣壳蛋白装配抑制剂
WO2019206069A1 (zh) 一种二芳基巨环化合物、药物组合物以及其用途
JP2022549923A (ja) Ｎヘテロ五員環含有カプシドタンパク質集合阻害剤の結晶形及びその使用
WO2021202652A1 (en) Tyrosine kinase 2 inhibitors, preparation methods and medicinal uses thereof
TWI820437B (zh) 亞磺醯基胺基苯甲醯胺與磺醯基胺基苯甲醯胺之衍生物
BR112017005113B1 (pt) Composto de fórmula geral (i), método para preparar o composto de fórmula geral (i), método para preparar um composto de fórmula geral (iv), composição farmacêutica para o tratamento de doenças relacionadas com atividades anormais de jak3 e/ou jak1 quinases, uso do composto, e uso da composição farmacêutica
US20040097539A1 (en) Hsp inductor
WO2018130123A1 (zh) 作为选择性***受体下调剂的五环类化合物及其应用
CN109180649B (zh) 一种含吲哚环的ido抑制剂及其制备方法
WO2022121868A1 (zh) 含酰胺基和杂环烷基的tyk2抑制剂化合物
CN111559982B (zh) 2-(2-取代-4-羟基嘧啶-5-甲酰胺基)乙酸类化合物及其制备方法与用途
CN111662275B (zh) 苯磺酰胺类idh突变体抑制剂、其制备方法和用途
US10611742B2 (en) 4-oxo-4,5-dihydrothiazole derivative, preparation method and use thereof
EA043039B1 (ru) Содержащий n-гетероциклическое пятичленное кольцо ингибитор сборки капсидного белка, его фармацевтическая композиция и их применение
CN114790186A (zh) 作为ep4拮抗剂的稠环化合物及其制备方法和用途
WO2024012449A1 (zh) 含有三氟甲基基团的化合物

Legal Events

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

Ref document number: 19751739

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19751739

Country of ref document: EP

Kind code of ref document: A1