WO2019154343A1 - Inhibiteur d'assemblage de protéine capsidique, composition pharmaceutique et utilisation associée - Google Patents

Inhibiteur d'assemblage de protéine capsidique, composition pharmaceutique et utilisation associée Download PDF

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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
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Prior art keywords
hydrogen
compound
pharmaceutically acceptable
prodrug
hydrate
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PCT/CN2019/074527
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English (en)
Chinese (zh)
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
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Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN201980007896.7A priority Critical patent/CN111601788B/zh
Publication of WO2019154343A1 publication Critical patent/WO2019154343A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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.

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Abstract

La présente invention se rapporte au domaine de la chimie pharmaceutique, et concerne un inhibiteur d'assemblage de protéine capsidique, et en particulier un composé représenté par la formule I, un stéréoisomère, un tautomère, un solvate, un hydrate, un promédicament ou un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation associé, une composition pharmaceutique correspondante, et une utilisation médicale de ceux-ci, notamment l'utilisation dans le traitement de maladies bénéficiant de l'inhibiteur d'assemblage de protéine capsidique, et en particulier, des maladies provoquées par une infection par le virus de l'hépatite B.
PCT/CN2019/074527 2018-02-09 2019-02-02 Inhibiteur d'assemblage de protéine capsidique, composition pharmaceutique et utilisation associée WO2019154343A1 (fr)

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Cited By (11)

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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
US12116356B2 (en) 2018-03-30 2024-10-15 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. N-heterocyclic five-membered ring-containing capsid protein assembly inhibitor, pharmaceutical composition thereof, and use thereof
WO2021093172A1 (fr) 2019-11-13 2021-05-20 西安新通药物研究有限公司 Inhibiteur du vhb et son utilisation
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 (fr) * 2019-11-13 2022-06-01 Xi'An Xintong Pharmaceutical Research Co., Ltd. Inhibiteur du vhb et son utilisation
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 (fr) 2019-11-13 2023-09-20 Xi'An Xintong Pharmaceutical Research Co., Ltd. Inhibiteur du vhb et son utilisation
EP4245372A3 (fr) * 2019-11-13 2023-11-22 Xi'An Xintong Pharmaceutical Research Co., Ltd. Inhibiteur du vhb et son utilisation
US11903924B2 (en) 2019-11-13 2024-02-20 Xi'an Xintong Pharmaceutical Research Co., Ltd. HBV inhibitor and its use
WO2021197486A1 (fr) * 2020-04-03 2021-10-07 东莞市东阳光新药研发有限公司 Nouveau composé spiro et son utilisation dans un médicament
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

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