WO2019210880A1 - Dicyclourea nucleocapsid inhibitor and pharmaceutical use thereof - Google Patents

Dicyclourea nucleocapsid inhibitor and pharmaceutical use thereof Download PDF

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Publication number
WO2019210880A1
WO2019210880A1 PCT/CN2019/085559 CN2019085559W WO2019210880A1 WO 2019210880 A1 WO2019210880 A1 WO 2019210880A1 CN 2019085559 W CN2019085559 W CN 2019085559W WO 2019210880 A1 WO2019210880 A1 WO 2019210880A1
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substituted
unsubstituted
group
compound
alkyl
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PCT/CN2019/085559
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French (fr)
Chinese (zh)
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王喆
曾志宏
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上海长森药业有限公司
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Priority to CN201980030320.2A priority Critical patent/CN112074518B/en
Publication of WO2019210880A1 publication Critical patent/WO2019210880A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • A61K31/407—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 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and in particular, the present invention relates to an aryl-cycloamide compound for use in the treatment of hepatitis B and uses thereof.
  • Hepatitis B virus is an enveloped, partially double-stranded DNA (dsDNA), hepatovirus DNA family (Hepadnaviridae) virus. Its genome contains four overlapping reading frames: the pronuclear/nuclear gene, the polymerase gene, the UM and S genes (which encode three envelope proteins), and the X gene.
  • the partially double-stranded DNA genome is transformed into a covalently closed circular DNA (cccDNA) in the host cell nucleus (open loop DNA, rcDNA) and the viral mRNA is transcribed.
  • the pre-genomic RNA which is also encoded by the core protein and Pol, is used as a template for reverse transcription, which regenerates this portion of the dsDNA genome (rcDNA) in the nucleocapsid.
  • HBV has caused epidemics in parts of Asia and Africa, and it is endemic in China. HBV has infected about 2 billion people worldwide, and about 350 million of them have developed chronic infectious diseases. The virus causes hepatitis B disease and chronic infectious diseases are associated with a high increased risk of development of cirrhosis and liver cancer.
  • the spread of hepatitis B virus is derived from exposure to infectious blood or body fluids, while viral DNA is detected in the saliva, tears, and urine of chronic carriers with high-priced DNA in serum.
  • heteroaryldihydropyrimidines have been identified as a class of HBV inhibitors in tissue culture as well as in animal models.
  • a sulfamoyl-arylamide involving anti-HBV activity is also disclosed in WO 2013/006394 (published on Jan. 10, 2013) and WO 2013/096744 (published on June 27, 2013).
  • a compound of the formula A or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
  • the C ring is a substituted or unsubstituted 5-12 membered ring
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl (including monocyclic, polycyclic or bridged ring structures), a substituted or unsubstituted 3-10 membered heterocyclic group having from 1 to 3 hetero atoms selected from N, S and O (including monocyclic, polycyclic or bridged ring structures), substituted or unsubstituted C6-C10 aryl a substituted, unsubstituted or substituted 5- to 5-membered heteroaryl group having from 1 to 3 hetero atoms selected from the group consisting of N, S and O;
  • R 1 , R 2 together with the nitrogen atom to which they are attached constitute a substituted or unsubstituted 3-10 membered heterocyclic group having 1 N and 0-3 heteroatoms selected from N, S and O (including single Ring, ring or bridge ring structure);
  • X is NR 9 ; wherein R 9 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl; wherein the "substituted” means selected from the group consisting of Substituted by one or more (eg, 2, 3, 4, etc.) substituents: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -CN, hydroxy, amino, carboxy;
  • Y is a carbonyl group (-(CO)-);
  • substituted means substituted with one or more (eg, 2, 3, 4, etc.) substituents selected from the group consisting of halogen, C1-C6 alkyl, halo. C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, hydroxy- A C1-C6 alkyl group, an amino group, a carboxyl group, a C6-C10 aryl group, a halogenated C6-C10 aryl group, unsubstituted or substituted with a substituent selected from the group consisting of 1-3 selected from N, S and O 5-10 membered heteroaryl of a hetero atom: halogen, phenyl.
  • substituents selected from the group consisting of 1-3 selected from N, S and O 5-10 membered heteroaryl of
  • the compound is not a compound selected from the group consisting of:
  • the 3-10 membered heterocyclic group is selected from the group consisting of a monocyclic group, a bicyclic group, a fused ring group, a bridged ring group, and a spiro ring group.
  • the C ring is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5-7 membered heteroaryl ring.
  • the B ring is a five-membered five-membered ring.
  • the B ring is a five-membered six-membered ring.
  • the B ring is a six-membered six-membered ring.
  • the B ring is a five-membered and seven-membered ring.
  • the B ring is a saturated ring, a partially unsaturated ring or an aromatic ring.
  • the C ring is a 5-7 membered ring.
  • the C ring is a benzene ring.
  • each of the chiral centers in the compound of formula I is independently R or S.
  • each of R 4 , R 5 and R 6 is independently a substituent selected from the group consisting of hydrogen, halogen, —CN, hydroxy, amino, carboxy, at any position on the C ring. Substituted or unsubstituted C1-C8 alkyl.
  • the compound has the structure shown in Formula I below:
  • W 1 is selected from the group consisting of CR 10 R 11 , CR 10 , O, S, or NR 12 ;
  • W 2 is selected from the group consisting of CR 10 or N;
  • W 3 is CR 10 R 11 , CR 10 , N or NR 12 ;
  • n 0, 1 or 2;
  • the dotted line is a chemical bond or none
  • the compound is selected from the group consisting of the following formula A-1, A-2, A-3 or A-4:
  • W 1 is CR 10 R 11 , S, O or NR 12 ;
  • W 2 is CR 10 or N;
  • W 3 is N or NR 12 ;
  • W 4 is CR 11 or (-(CO)-).
  • the compound has a structure selected from the group consisting of the following groups I, II, III, IV, V, VI, VII, VIII, IXX, XI:
  • R is selected from the group consisting of halogen, C1-C4 alkyl.
  • the C ring is a 5-7 membered ring.
  • the C ring is a saturated ring, a partially unsaturated ring or an aromatic ring.
  • the R 1 is a halogenated or C1-C4 alkyl group substituted by a hydroxy group
  • the R 2 is H.
  • the compound is selected from the compounds described in Table 1.
  • a second aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable thereof a salt, hydrate or solvate; and (2) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises other drugs for preventing and/or treating hepatitis B virus infection.
  • the other drug for preventing and/or treating hepatitis B virus infection may be selected from the group consisting of an immunomodulator (eg, interferon- ⁇ (IFN- ⁇ ), PEGylation interference) Au- ⁇ ) or a stimulant of the innate immune system (such as Toll-like receptor 7 and/or 8 agonists).
  • an immunomodulator eg, interferon- ⁇ (IFN- ⁇ ), PEGylation interference
  • Au- ⁇ e.g, PEGylation interference
  • a stimulant of the innate immune system such as Toll-like receptor 7 and/or 8 agonists
  • the other drug for preventing and/or treating hepatitis B virus infection may be selected from the group consisting of tenofovir, lamivudine, adefovir, entecavir, and telbiv. Set, or a combination thereof.
  • a third aspect of the invention provides a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or Use of a pharmaceutical composition according to the second aspect of the present invention, characterized in that it is used for the preparation of a medicament for preventing and/or treating hepatitis B virus infection.
  • a hepatitis B virus inhibitor comprising the compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutical thereof An acceptable salt, hydrate or solvate.
  • a compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the first aspect of the invention is provided
  • the compound of formula A is a compound of formula XIII-1, and the method comprises the steps of:
  • the compound of formula A is a compound of formula X-2, and the method comprises the steps of:
  • a method for the prophylaxis and/or treatment of hepatitis B comprising the step of administering a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, to a patient in need thereof A construct, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the second aspect of the invention.
  • a method for inhibiting hepatitis B virus in vitro comprising the steps of: the compound of the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutical thereof An acceptable salt, hydrate or solvate that is in contact with the hepatitis B virus to inhibit hepatitis B.
  • the inventors have conducted extensive and intensive research and found a novel class of compounds having excellent therapeutic effects on hepatitis B. On this basis, the inventors completed the present invention.
  • alkyl as used herein includes a straight or branched alkyl group.
  • C 1 -C 8 alkyl represents a straight or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. Wait.
  • alkenyl as used herein, includes a straight or branched alkenyl group.
  • C 2 -C 6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 a butenyl group, or a similar group.
  • alkynyl includes a straight or branched alkynyl group.
  • C 2 -C 6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, or the like.
  • C 3 -C 10 cycloalkyl means a cycloalkyl group having 3-10 carbon atoms. It may be a monocyclic ring such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or the like. It may also be in the form of a double loop, such as a bridged or spiro ring.
  • C 1 -C 8 alkylamino refers to an amine group substituted by a C 1 -C 8 alkyl group, which may be monosubstituted or disubstituted; for example, methylamino, ethylamino, Alanine, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, two Tert-butylamine and the like.
  • C 1 -C 8 alkoxy refers to a straight or branched alkoxy group having from 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propyloxy, butoxy, isobutoxy, tert-butoxy and the like.
  • the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from N, S and O” means having from 3 to 10 atoms and wherein 1-3 of the atoms are selected from A saturated or partially saturated cyclic group of a hetero atom of N, S and O. It may be a single ring or a double ring form, such as a bridge ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
  • C 6 -C 10 aryl refers to an aryl group having 6 to 10 carbon atoms, for example, a phenyl or naphthyl group or the like.
  • the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from N, A cyclic aromatic group of a hetero atom of S and O. It may be a single ring or a fused ring.
  • Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
  • the groups of the present invention may be substituted with a substituent selected from the group consisting of halogen, nitrile group, nitro group, hydroxyl group, amino group, unless otherwise specified as "substituted or unsubstituted". , C 1 -C 6 alkyl-amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 - C 6 alkyl, halo C 2 -C 6 alkenyl, halo C 2 -C 6 alkynyl, halo C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl , C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl
  • halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from the group consisting of F, Cl and Br. "Halo” means substituted with an atom selected from the group consisting of F, Cl, Br, and I.
  • the structural formulae described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetry The central R, S configuration, the (Z) and (E) isomers of the double bond.
  • a single stereochemical isomer of a compound of the invention, or a mixture of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof, is within the scope of the invention.
  • tautomer means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other.
  • proton tautomers ie, proton shifts
  • proton transfer such as 1H-carbazole and 2H-carbazole.
  • Valence tautomers include interconversion through some bonding electron recombination.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a particular ratio.
  • hydrate refers to a complex formed by the coordination of a compound of the invention with water.
  • a compound of the invention refers to a compound of formula (A), and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (A):
  • pharmaceutically acceptable salt refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
  • the B ring, C ring, X, Y, R 1 , R 2 , R 4 , R 5 and R 6 are each independently a group corresponding to each compound in Table 1.
  • the pharmaceutical composition wherein the compound is the main active ingredient can be used for preventing and/or treating (stabilizing, alleviating or curing) hepatitis B virus infection or for preventing and/or treating (stabilizing, alleviating or curing) a hepatitis B virus-related disease ( For example, hepatitis B, progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, terminal liver disease, ethyl liver cancer).
  • hepatitis B progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, terminal liver disease, ethyl liver cancer.
  • compositions of the present invention comprise a safe and effective amount of a compound of the invention and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermixing with the compounds of the invention and between them without significantly reducing the potency of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • vegetable oil such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifier such as Tween
  • a wetting agent such as sodium lauryl sulfate
  • a coloring agent such as a flavoring agent, a stabilizer, an antioxidant, a preservative
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
  • other pharmaceutically acceptable compounds e.g., anti-HBV agents.
  • the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
  • one or more (2, 3, 4, or more) of the other pharmaceutically acceptable compound e.g, an anti-HBV agent
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the compound of the present invention is novel in structure and has an excellent anti-HBV infection effect.
  • the compounds of the invention are very toxic to normal cells.
  • the compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of hepatitis B virus infection.
  • the compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of hepatitis B virus-related diseases (for example, hepatitis B, progressive liver fibrosis, inflammation leading to cirrhosis, and Necrosis, terminal liver disease, ethyl liver cancer).
  • hepatitis B virus-related diseases for example, hepatitis B, progressive liver fibrosis, inflammation leading to cirrhosis, and Necrosis, terminal liver disease, ethyl liver cancer.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “consisting essentially of,” or “consisting of.”
  • step 1
  • Root Example 1 synthesizes the following 100 series of compounds:
  • [C150Bo] represents the concentration of a fluorescently labeled protein
  • A504 represents an absorbance value of a wavelength of 504 nM
  • A280 represents an absorption value of a wavelength of 280 nM
  • M -1 represents the reciprocal of the molar concentration.
  • the mother liquor of the compound was diluted to 6 mM with DMSO, diluted to 600 ⁇ M with 50 mM HEPES, and then further diluted 8 times with 10% DMSO/50 mM HEPES.
  • C150Bo was diluted to 2 ⁇ M with 50 mM HEPES. 37.5 ⁇ L of C150Bo and 2.5 ⁇ L of each concentration of the compound were added to a 96-well reaction plate and mixed, and incubated at room temperature for 15 minutes. 10 ⁇ l of 750 mM NaCl/50 mM HEPES was added to the reaction well, and the final concentration of NaCl was 150 mM.
  • Control wells were assembled with 0% protein, 10 ⁇ L of 50 mM HEPES was added, and the final concentration of NaCl was 0 mM.
  • Control wells were assembled with 100% protein and 10 ⁇ L of 5 M NaCl/50 mM HEPES was added with a final concentration of 1 M NaCl.
  • the final concentration of DMSO was 0.5%, the maximum final concentration of the compound was 30 ⁇ M, and the final concentration of C150Bo was 1.5 ⁇ M. Incubate for 1 hour at room temperature. The fluorescence signal (excitation light 485 nm; emission light 535 nm) was measured.
  • % protein assembly [1- (sample fluorescence value - 1M NaCl fluorescence value) / (0M NaCl fluorescence value - 1M NaCl fluorescence value)] ⁇ 100.
  • the IC 50 value is calculated by the prism software and the equation is as follows:
  • X represents the logarithm of the concentration
  • Y represents the effect value
  • Y is fitted from the bottom to the top with an S-shape
  • Top indicates that Top represents the top of the curve
  • HillSlope represents the absolute value of the maximum slope of the curve.
  • HepG2.2.15 cells (4 x 10 4 cells/well) were plated into 96-well plates and incubated overnight at 37 ° C, 5% CO 2 . The next day, fresh culture medium containing different concentrations of compounds was added to the culture wells. On the fifth day, the old culture solution in the culture well was aspirated and fresh culture medium containing different concentrations of the compound was added.
  • the supernatant in the culture well was collected for extracting HBV DNA from the supernatant, and qPCR was used to detect the HBV DNA content in the supernatant of HepG2.2.15.
  • the culture medium and the Cell-titer Glo reagent were added to the culture well, and the chemiluminescence value of each well was detected by a microplate reader.
  • the activity calculation formula is as follows:
  • X represents the logarithm of the concentration
  • Y represents the effect value
  • Y is fitted from the bottom to the top with an S-shape
  • HillSlope represents the absolute value of the maximum slope of the curve.
  • test compounds The cytotoxicity of the test compounds was tested using HepG2 cells, and these cells were incubated for 4 days in the presence of the test compound. Cell rejuvenation was assessed using the resazurin assay.
  • the compound of the present invention has good anti-HBV nucleocapsid assembly activity and anti-HBV activity in vitro, and has low cytotoxicity.
  • the compounds of the present application have excellent anti-HBV activity.
  • the second column of the table is:
  • +++ means IC 50 ⁇ 1 ⁇ M
  • +++ means EC 50 0.1 ⁇ 100nM
  • the compounds of the present application have excellent anti-HBV activity.

Abstract

The present invention relates to a dicyclourea nucleocapsid inhibitor and the use thereof as a medicament for treating hepatitis B. Specifically, disclosed are a compound that may act as an HBV inhibitor and that has the structure represented by chemical formula (A), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, a hydrate or a solvent thereof. See the description for details of the definitions of each group. The present invention also relates to a pharmaceutical composition containing said compound and the use thereof in the treatment of hepatitis B.

Description

双并环脲类核衣壳抑制剂及其药物用途Biparacyclic urea nucleocapsid inhibitor and its pharmaceutical use 技术领域Technical field
本发明属于医药领域，具体地，本发明涉及用于治疗乙型肝炎的芳基并环酰胺类化合物及其用途。The present invention belongs to the field of medicine, and in particular, the present invention relates to an aryl-cycloamide compound for use in the treatment of hepatitis B and uses thereof.
背景技术Background technique
乙型肝炎病毒(HBV)是一种有包膜的、部分双链DNA(dsDNA)的、嗜肝病毒DNA家族(肝病毒科(Hepadnaviridae))的病毒。它的基因组包含4个重叠阅读框：前核/核基因，聚合酶基因，UM和S基因(它们编码三个包膜蛋白质)，以及X基因。在感染前时，该部分双链DNA基因组在宿主细胞核中(开环DNA，rcDNA)转变为共价闭合环状DNA(cccDNA)并且该病毒mRNA进行转录。一旦被壳体化，该前基因组RNA(pgRNA)(其还为核心蛋白和Pol编码)作为模板用于逆转录，这种逆转录在核衣壳中再生该部分dsDNA基因组(rcDNA)。Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA), hepatovirus DNA family (Hepadnaviridae) virus. Its genome contains four overlapping reading frames: the pronuclear/nuclear gene, the polymerase gene, the UM and S genes (which encode three envelope proteins), and the X gene. At the time of infection, the partially double-stranded DNA genome is transformed into a covalently closed circular DNA (cccDNA) in the host cell nucleus (open loop DNA, rcDNA) and the viral mRNA is transcribed. Once encapsidated, the pre-genomic RNA (pgRNA), which is also encoded by the core protein and Pol, is used as a template for reverse transcription, which regenerates this portion of the dsDNA genome (rcDNA) in the nucleocapsid.
HBV在亚洲和非洲的部分地区造成了流行病，并且它在中国是地方性的。HBV已经在全球感染了大约20亿人，其中大约3.5亿人发展成了慢性传染病。该病毒造成了乙型肝炎疾病并且慢性传染病与肝硬化和肝癌的发展的高增加风险相关联。HBV has caused epidemics in parts of Asia and Africa, and it is endemic in China. HBV has infected about 2 billion people worldwide, and about 350 million of them have developed chronic infectious diseases. The virus causes hepatitis B disease and chronic infectious diseases are associated with a high increased risk of development of cirrhosis and liver cancer.
乙型肝炎病毒的传播来源于暴露于传染性的血液或体液，同时在血清中具有高效价DNA的慢性携带者的唾液、泪液以及尿液中检测到了病毒DNA。The spread of hepatitis B virus is derived from exposure to infectious blood or body fluids, while viral DNA is detected in the saliva, tears, and urine of chronic carriers with high-priced DNA in serum.
虽然目前存在一种有效的并且具有良好耐受性的疫苗，但是直接治疗的选择目前还限于干扰素以及以下的抗病毒药；替诺福韦、拉米夫定、阿德福韦、恩替卡韦以及替比夫定。Although there is currently an effective and well tolerated vaccine, the choice of direct treatment is currently limited to interferon and the following antiviral drugs; tenofovir, lamivudine, adefovir, entecavir and Telbivudine.
此外，杂芳基二氢嘧啶(HAPs)在组织培养以及动物模型中被鉴别作为一类HBV抑制剂。WO 2013/006394(公开于2013年1月10日)和WO 2013/096744(公开于2013年6月27日)还公开了涉及抗HBV活性的氨磺酰基-芳基酰胺。In addition, heteroaryldihydropyrimidines (HAPs) have been identified as a class of HBV inhibitors in tissue culture as well as in animal models. A sulfamoyl-arylamide involving anti-HBV activity is also disclosed in WO 2013/006394 (published on Jan. 10, 2013) and WO 2013/096744 (published on June 27, 2013).
然而，在这些直接的HBV抗病毒药中会遇到的是毒性、致突变性、缺乏选择性、疗效差、生物利用度差以及合成困难等问题。However, problems encountered in these direct HBV antivirals are toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, and difficulty in synthesis.
因此，本领域需要开发具有如效价高、毒性更低等优点的HBV抑制剂。Therefore, there is a need in the art to develop HBV inhibitors having advantages such as high potency and lower toxicity.
发明内容Summary of the invention
本发明的目的是提供一类效价高、毒性更低的HBV抑制剂。It is an object of the present invention to provide a class of HBV inhibitors which are relatively potent and less toxic.
本发明的第一方面，提供了一种化学式A所示的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物，According to a first aspect of the invention, there is provided a compound of the formula A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
Figure PCTCN2019085559-appb-000001
Figure PCTCN2019085559-appb-000001
其中，所述的B环为取代或未取代的8-20元双环并环结构；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；Wherein the B ring is a substituted or unsubstituted 8-20 membered bicyclic ring structure; wherein the substituent refers to one or more hydrogen atoms on the group substituted by a substituent selected from the group consisting of halogen , -CN, hydroxy, amino, carboxy, -(C=O)-substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, Substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or not Substituted 3-10 membered heterocycloalkyl having 1 to 30 hetero atoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted having 1-3 a 5-10 membered heteroaryl group selected from the group consisting of a hetero atom of N, S and O;
C环为取代或未取代的5-12元环；The C ring is a substituted or unsubstituted 5-12 membered ring;
R 1、R 2各自独立地选自下组：氢、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基(包括单环、并环或桥环结构)、取代或未取代的具有1-3个选自N、S和O的杂原子的3-10元杂环基(包括单环、并环或桥环结构)、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基； R 1 and R 2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl (including monocyclic, polycyclic or bridged ring structures), a substituted or unsubstituted 3-10 membered heterocyclic group having from 1 to 3 hetero atoms selected from N, S and O (including monocyclic, polycyclic or bridged ring structures), substituted or unsubstituted C6-C10 aryl a substituted, unsubstituted or substituted 5- to 5-membered heteroaryl group having from 1 to 3 hetero atoms selected from the group consisting of N, S and O;
或R 1、R 2与和它们相连的氮原子共同构成取代或未取代的具有1个N和0-3个选自N、S和O的杂原子的3-10元杂环基(包括单环、并环或桥环结构)； Or R 1 , R 2 together with the nitrogen atom to which they are attached constitute a substituted or unsubstituted 3-10 membered heterocyclic group having 1 N and 0-3 heteroatoms selected from N, S and O (including single Ring, ring or bridge ring structure);
R 4、R 5和R 6各自独立地为位于C环上任意位置的选自下组的取代基：氢、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基； R 4 , R 5 and R 6 are each independently a substituent selected from the group consisting of hydrogen, halogen, -CN, hydroxy, amino, carboxy, -(C=O)-substituted or unsubstituted at any position on the C ring. Substituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkane Amino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having from 1 to 3 heteroatoms selected from the group consisting of N, S and O a 3-10 membered heterocycloalkyl, a substituted or unsubstituted C6-C10 aryl group, and a substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O base;
X为NR 9；其中，R 9为氢、取代或未取代的C1-C8烷基、取代或未取代的C3-C8环烷基；其中，所述“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、-CN、羟基、氨基、羧基； X is NR 9 ; wherein R 9 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl; wherein the "substituted" means selected from the group consisting of Substituted by one or more (eg, 2, 3, 4, etc.) substituents: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -CN, hydroxy, amino, carboxy;
Y为羰基(-(CO)-)；Y is a carbonyl group (-(CO)-);
除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、羟基-C1-C6烷基、氨基、羧基、C6-C10芳基、卤代的C6-C10芳基、未取代或被选自下组的取代基取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基：卤素、苯基。Unless otherwise indicated, the term "substituted" means substituted with one or more (eg, 2, 3, 4, etc.) substituents selected from the group consisting of halogen, C1-C6 alkyl, halo. C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, hydroxy- A C1-C6 alkyl group, an amino group, a carboxyl group, a C6-C10 aryl group, a halogenated C6-C10 aryl group, unsubstituted or substituted with a substituent selected from the group consisting of 1-3 selected from N, S and O 5-10 membered heteroaryl of a hetero atom: halogen, phenyl.
在另一优选例中，所述的化合物不为选自下组的化合物：In another preferred embodiment, the compound is not a compound selected from the group consisting of:
Figure PCTCN2019085559-appb-000002
Figure PCTCN2019085559-appb-000002
在另一优选例中，所述的3-10元杂环基选自下组：单环基、二环基、稠环基、桥环基、螺环基。In another preferred embodiment, the 3-10 membered heterocyclic group is selected from the group consisting of a monocyclic group, a bicyclic group, a fused ring group, a bridged ring group, and a spiro ring group.
在另一优选例中，所述的C环为取代或未取代的苯环，或取代或未取代的5-7元杂芳环。In another preferred embodiment, the C ring is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5-7 membered heteroaryl ring.
在另一优选例中，所述的B环为五元并五元环。In another preferred embodiment, the B ring is a five-membered five-membered ring.
在另一优选例中，所述的B环为五元并六元环。In another preferred embodiment, the B ring is a five-membered six-membered ring.
在另一优选例中，所述的B环为六元并六元环。In another preferred embodiment, the B ring is a six-membered six-membered ring.
在另一优选例中，所述的B环为五元并七元环。In another preferred embodiment, the B ring is a five-membered and seven-membered ring.
在另一优选例中，所述的B环为饱和环、部分不饱和环或芳香环。In another preferred embodiment, the B ring is a saturated ring, a partially unsaturated ring or an aromatic ring.
在另一优选例中，所述的C环为5-7元环。In another preferred embodiment, the C ring is a 5-7 membered ring.
在另一优选例中，所述的C环为苯环。In another preferred embodiment, the C ring is a benzene ring.
在另一优选例中，式I化合物中的各个手性中心各自独立地为R型或S型。In another preferred embodiment, each of the chiral centers in the compound of formula I is independently R or S.
在另一优选例中，所述的R 4、R 5和R 6各自独立地为位于C环上任意位置的选自下 组的取代基：氢、卤素、-CN、羟基、氨基、羧基、取代或未取代的C1-C8烷基。 In another preferred embodiment, each of R 4 , R 5 and R 6 is independently a substituent selected from the group consisting of hydrogen, halogen, —CN, hydroxy, amino, carboxy, at any position on the C ring. Substituted or unsubstituted C1-C8 alkyl.
在另一优选例中，所述的化合物具有如下式I所示的结构：In another preferred embodiment, the compound has the structure shown in Formula I below:
Figure PCTCN2019085559-appb-000003
Figure PCTCN2019085559-appb-000003
其中，W 1选自下组：CR 10R 11、CR 10、O、S、或NR 12； Wherein W 1 is selected from the group consisting of CR 10 R 11 , CR 10 , O, S, or NR 12 ;
W 2选自下组：CR 10或N； W 2 is selected from the group consisting of CR 10 or N;
W 3为CR 10R 11、CR 10、N或NR 12； W 3 is CR 10 R 11 , CR 10 , N or NR 12 ;
n为0、1或2；n is 0, 1 or 2;
虚线为化学键或无；The dotted line is a chemical bond or none;
R 10和R 11各自独立地为的选自下组的取代基：氢、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基； R 10 and R 11 are each independently a substituent selected from the group consisting of hydrogen, halogen, -CN, hydroxy, amino, carboxy, -(C=O)-substituted or unsubstituted C1-C8 alkyl, substituted Or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1 a C8 alkoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocycloalkyl group having 1 to 3 hetero atoms selected from the group consisting of N, S and O, a substituted or unsubstituted C6-C10 aryl group, and a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from the group consisting of N, S and O;
R 12各自独立地为的选自下组的取代基：氢、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基； R 12 is each independently a substituent selected from the group consisting of hydrogen, -CN, hydroxy, amino, carboxy, -(C=O)-substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1 -C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1-C8 alkoxy , substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1 to 3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted a C6-C10 aryl group, and a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from the group consisting of N, S and O;
R 3为位于并环结构上的一个或多个(优选为1、2、3、4或5个)选自下组的取代基：H、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基。 R 3 is one or more (preferably 1, 2, 3, 4 or 5) substituents on the bicyclic structure selected from the group consisting of H, halogen, -CN, hydroxy, amino, carboxy, -( C=O)-substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted Or unsubstituted C1-C8 alkylamino group, substituted or unsubstituted C1-C8 alkoxy group, substituted or unsubstituted C3-C10 cycloalkyl group, substituted or unsubstituted, having 1-3 selected from the group N a 3-10 membered heterocycloalkyl, a substituted or unsubstituted C6-C10 aryl group of a hetero atom of S and O, and a substituted or unsubstituted 1-3 group selected from the group consisting of N, S and O A 5-10 membered heteroaryl of an atom.
在另一优选例中，当n＝2时，所述的化合物具有如下式A2所示的结构：In another preferred embodiment, when n = 2, the compound has the structure shown by the following formula A2:
Figure PCTCN2019085559-appb-000004
Figure PCTCN2019085559-appb-000004
在另一优选例中，R 3为位于并环结构上的一个或多个选自下组的取代基：H、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C4烷基、C1-C4烷基、C2-C4烯基、C2-C4炔基、C1-C4烷胺基、C1-C4烷氧基。 In another preferred embodiment, R 3 is one or more substituents selected from the group consisting of H, halogen, -CN, hydroxy, amino, carboxy, -(C=O)-substituted or Unsubstituted C1-C4 alkyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkylamino, C1-C4 alkoxy.
在另一优选例中，所述的化合物选自下组式A-1、A-2、A-3或A-4：In another preferred embodiment, the compound is selected from the group consisting of the following formula A-1, A-2, A-3 or A-4:
Figure PCTCN2019085559-appb-000005
Figure PCTCN2019085559-appb-000005
W 1为CR 10R 11、S、O或NR 12；W 2为CR 10或N；W 3为N或NR 12；W 4为CR 11或(-(CO)-)。 W 1 is CR 10 R 11 , S, O or NR 12 ; W 2 is CR 10 or N; W 3 is N or NR 12 ; W 4 is CR 11 or (-(CO)-).
在另一优选例中，所述的化合物具有选自下组I、II、III、IV、V、VI、VII、VIII、IXX、XI所示的结构：In another preferred embodiment, the compound has a structure selected from the group consisting of the following groups I, II, III, IV, V, VI, VII, VIII, IXX, XI:
Figure PCTCN2019085559-appb-000006
Figure PCTCN2019085559-appb-000006
Figure PCTCN2019085559-appb-000007
Figure PCTCN2019085559-appb-000007
其中，所述的R选自下组：卤素、C1-C4烷基。Wherein R is selected from the group consisting of halogen, C1-C4 alkyl.
在另一优选例中，所述的C环为5-7元环。In another preferred embodiment, the C ring is a 5-7 membered ring.
在另一优选例中，所述的C环为饱和环、部分不饱和环或芳香环。In another preferred embodiment, the C ring is a saturated ring, a partially unsaturated ring or an aromatic ring.
在另一优选例中，所述的R 1为卤代或被羟基取代的C1-C4烷基，且所述的R 2为H。 In another preferred embodiment, the R 1 is a halogenated or C1-C4 alkyl group substituted by a hydroxy group, and the R 2 is H.
在另一优选例中，所述的化合物选自表1中所述的化合物。In another preferred embodiment, the compound is selected from the compounds described in Table 1.
本发明的第二方面，提供了一种药物组合物，其包含(1)本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物；和(2)药学上可接受的载体。A second aspect of the invention provides a pharmaceutical composition comprising (1) a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable thereof a salt, hydrate or solvate; and (2) a pharmaceutically acceptable carrier.
在另一优选例中，所述药物组合物还包含其它用于预防和/或治疗乙型肝炎病毒感染的药物。In another preferred embodiment, the pharmaceutical composition further comprises other drugs for preventing and/or treating hepatitis B virus infection.
在另一优选例中，所述其它用于预防和/或治疗乙型肝炎病毒感染的药物可选自下组：免疫调节剂(例如干扰素-α(IFN-α)、聚乙二醇化干扰素-α)或先天免疫***的刺激剂(如Toll样受体7和/或8激动剂)。In another preferred embodiment, the other drug for preventing and/or treating hepatitis B virus infection may be selected from the group consisting of an immunomodulator (eg, interferon-α (IFN-α), PEGylation interference) Au-α) or a stimulant of the innate immune system (such as Toll-like receptor 7 and/or 8 agonists).
在另一优选例中，所述其它用于预防和/或治疗乙型肝炎病毒感染的药物可选自下组：替诺福韦、拉米夫定、阿德福韦、恩替卡韦、替比夫定、或其组合。In another preferred embodiment, the other drug for preventing and/or treating hepatitis B virus infection may be selected from the group consisting of tenofovir, lamivudine, adefovir, entecavir, and telbiv. Set, or a combination thereof.
本发明的第三方面，提供了一种如本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物或如本发明第二方面所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗乙型肝炎病毒感染的药物。A third aspect of the invention provides a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or Use of a pharmaceutical composition according to the second aspect of the present invention, characterized in that it is used for the preparation of a medicament for preventing and/or treating hepatitis B virus infection.
本发明的第四方面，提供了一种乙型肝炎病毒抑制剂，所述抑制剂包含本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。According to a fourth aspect of the present invention, a hepatitis B virus inhibitor comprising the compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharmaceutical thereof An acceptable salt, hydrate or solvate.
本发明的第五方面，提供了一种制备如本发明第一方面所述化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物的方法，所示式A化合物为式XIII-1所示的化合物，所述方法包括步骤：According to a fifth aspect of the invention, a compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the first aspect of the invention, is provided In the method, the compound of formula A is a compound of formula XIII-1, and the method comprises the steps of:
Figure PCTCN2019085559-appb-000008
Figure PCTCN2019085559-appb-000008
在惰性溶剂中，用式A1化合物和式A2化合物反应，得到式A化合物。Reaction of a compound of formula A1 with a compound of formula A2 in an inert solvent provides the compound of formula A.
在另一优选例中，所示式A化合物为式X-2所示的化合物，所述方法包括步骤：In another preferred embodiment, the compound of formula A is a compound of formula X-2, and the method comprises the steps of:
Figure PCTCN2019085559-appb-000009
Figure PCTCN2019085559-appb-000009
本发明的第六方面，提供了一种预防和/或治疗乙型肝炎的方法，包括步骤：向所需患者施用本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物或本发明第二方面所述的药物组合物。According to a sixth aspect of the invention, a method for the prophylaxis and/or treatment of hepatitis B, comprising the step of administering a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, to a patient in need thereof A construct, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the second aspect of the invention.
本发明的第七方面，提供了一种体外抑制乙型肝炎病毒的方法，包括步骤：将本发明第一方面所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物，与乙型肝炎病毒接触，从而抑制乙型肝炎。According to a seventh aspect of the invention, a method for inhibiting hepatitis B virus in vitro, comprising the steps of: the compound of the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutical thereof An acceptable salt, hydrate or solvate that is in contact with the hepatitis B virus to inhibit hepatitis B.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
具体实施方式detailed description
本发明人经过广泛而深入的研究，发现了一类对乙型肝炎具有优异的治疗效果的新型化合物。在此基础上，发明人完成了本发明。The inventors have conducted extensive and intensive research and found a novel class of compounds having excellent therapeutic effects on hepatitis B. On this basis, the inventors completed the present invention.
定义definition
如本文所用，术语“烷基”包括直链或支链的烷基。例如C 1-C 8烷基表示具有1-8个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。 The term "alkyl" as used herein includes a straight or branched alkyl group. For example, C 1 -C 8 alkyl represents a straight or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. Wait.
如本文所用，术语“烯基”包括直链或支链的烯基。例如C 2-C 6烯基指具有2-6个碳原子的直链或支链的烯基，例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。 The term "alkenyl" as used herein, includes a straight or branched alkenyl group. For example, C 2 -C 6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 a butenyl group, or a similar group.
如本文所用，术语“炔基”包括直链或支链的炔基。例如C 2-C 6炔基是指具有2-6个碳原子的直链或支链的炔基，例如乙炔基、丙炔基、丁炔基、或类似基团。 The term "alkynyl", as used herein, includes a straight or branched alkynyl group. For example, C 2 -C 6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, or the like.
如本文所用，术语“C 3-C 10环烷基”指具有3-10个碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。 As used herein, the term "C 3 -C 10 cycloalkyl" means a cycloalkyl group having 3-10 carbon atoms. It may be a monocyclic ring such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or the like. It may also be in the form of a double loop, such as a bridged or spiro ring.
如本文所用，术语“C 1-C 8烷胺基”是指被C 1-C 8烷基所取代的胺基，可以是单取代或双取代的；例如，甲胺基、乙胺基、丙胺基、异丙胺基、丁胺基、异丁胺基、叔丁胺基、二甲胺基、二乙胺基、二丙胺基、二异丙胺基、二丁胺基、二异丁胺基、二叔丁胺基等。 As used herein, the term "C 1 -C 8 alkylamino" refers to an amine group substituted by a C 1 -C 8 alkyl group, which may be monosubstituted or disubstituted; for example, methylamino, ethylamino, Alanine, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, two Tert-butylamine and the like.
如本文所用，术语“C 1-C 8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基；例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。 As used herein, the term "C 1 -C 8 alkoxy" refers to a straight or branched alkoxy group having from 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propyloxy, butoxy, isobutoxy, tert-butoxy and the like.
如本文所用，术语“具有1-3个选自N、S和O的杂原子的3-10元杂环烷基”是指具有3-10个原子的且其中1-3个原子为选自N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环，也可以是双环形式，例如桥环或螺环形式。具体的实例可以为氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。As used herein, the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from N, S and O" means having from 3 to 10 atoms and wherein 1-3 of the atoms are selected from A saturated or partially saturated cyclic group of a hetero atom of N, S and O. It may be a single ring or a double ring form, such as a bridge ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
如本文所用，术语“C 6-C 10芳基”是指具有6-10个碳原子的芳基，例如，苯基或萘基等类似基团。 As used herein, the term "C 6 -C 10 aryl" refers to an aryl group having 6 to 10 carbon atoms, for example, a phenyl or naphthyl group or the like.
如本文所用，术语“具有1-3个选自N、S和O的杂原子的5-10元杂芳基”指具有5-10个原子的且其中1-3个原子为选自N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-***基以及(1,2,4)-***基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from N, A cyclic aromatic group of a hetero atom of S and O. It may be a single ring or a fused ring. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
本发明所述的基团除非特别说明是“取代的或未取代的”，否则本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C 1-C 6烷基-胺基、C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、C 1-C 6烷氧基、卤代C 1-C 6烷基、卤代C 2-C 6烯基、卤代C 2-C 6炔基、卤代C 1-C 6烷氧基、烯丙基、苄基、C 6-C 12芳基、C 1-C 6烷氧基-C 1-C 6烷基、C 1-C 6烷氧基-羰基、苯氧羰基、C 2-C 6炔基-羰基、C 2-C 6烯基-羰基、C 3-C 6环烷基-羰基、C 1-C 6烷基-磺酰基等。 The groups of the present invention may be substituted with a substituent selected from the group consisting of halogen, nitrile group, nitro group, hydroxyl group, amino group, unless otherwise specified as "substituted or unsubstituted". , C 1 -C 6 alkyl-amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 - C 6 alkyl, halo C 2 -C 6 alkenyl, halo C 2 -C 6 alkynyl, halo C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl , C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl, C 2 -C 6 alkenyl a carbonyl group, a C 3 -C 6 cycloalkyl-carbonyl group, a C 1 -C 6 alkyl-sulfonyl group or the like.
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from the group consisting of F, Cl and Br. "Halo" means substituted with an atom selected from the group consisting of F, Cl, Br, and I.
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。Unless otherwise stated, the structural formulae described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetry The central R, S configuration, the (Z) and (E) isomers of the double bond. Thus, a single stereochemical isomer of a compound of the invention, or a mixture of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof, is within the scope of the invention.
如本文所用，术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒， 从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。As used herein, the term "tautomer" means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other. For example, proton tautomers (ie, proton shifts) include interconversions by proton transfer, such as 1H-carbazole and 2H-carbazole. Valence tautomers include interconversion through some bonding electron recombination.
如本文所用，术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。As used herein, the term "solvate" refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a particular ratio.
如本文所用，术语“水合物”是指本发明化合物与水进行配位形成的配合物。As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the invention with water.
活性成分Active ingredient
如本文所用，“本发明化合物”指式(A)所示的化合物，并且还包括式(A)化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物：As used herein, "a compound of the invention" refers to a compound of formula (A), and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (A):
Figure PCTCN2019085559-appb-000010
Figure PCTCN2019085559-appb-000010
如本文所用，“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。As used herein, "pharmaceutically acceptable salt" refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. A preferred class of salts are the salts of the compounds of the invention with acids. Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
在另一优选例中，所述的B环，C环，X，Y，R 1、R 2、R 4、R 5和R 6各自独立地为表1中各个化合物所对应的基团。 In another preferred embodiment, the B ring, C ring, X, Y, R 1 , R 2 , R 4 , R 5 and R 6 are each independently a group corresponding to each compound in Table 1.
优选的本发明化合物如表1所示：Preferred compounds of the invention are shown in Table 1:
Figure PCTCN2019085559-appb-000011
Figure PCTCN2019085559-appb-000011
Figure PCTCN2019085559-appb-000012
Figure PCTCN2019085559-appb-000012
Figure PCTCN2019085559-appb-000013
Figure PCTCN2019085559-appb-000013
Figure PCTCN2019085559-appb-000014
Figure PCTCN2019085559-appb-000014
Figure PCTCN2019085559-appb-000015
Figure PCTCN2019085559-appb-000015
Figure PCTCN2019085559-appb-000016
Figure PCTCN2019085559-appb-000016
Figure PCTCN2019085559-appb-000017
Figure PCTCN2019085559-appb-000017
药物组合物和施用方法Pharmaceutical composition and method of administration
由于本发明化合物具有优异的乙型肝炎病毒(HBV)的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)乙型肝炎病毒感染或用于预防和/或治疗(稳定、减轻或治愈)乙型肝炎病毒相关疾病(例如，乙型肝炎、进展性肝纤维化、导致肝硬化的炎症和坏死、末期肝病、乙基肝癌)。Since the compound of the present invention has excellent inhibitory activity against hepatitis B virus (HBV), the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and the present invention The pharmaceutical composition wherein the compound is the main active ingredient can be used for preventing and/or treating (stabilizing, alleviating or curing) hepatitis B virus infection or for preventing and/or treating (stabilizing, alleviating or curing) a hepatitis B virus-related disease ( For example, hepatitis B, progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, terminal liver disease, ethyl liver cancer).
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the invention and a pharmaceutically acceptable excipient or carrier. By "safe and effective amount" it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. In general, the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 200 mg of the compound of the invention per agent. Preferably, the "one dose" is a capsule or tablet.
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2019085559-appb-000018
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By "compatibility" it is meant herein that the components of the composition are capable of intermixing with the compounds of the invention and between them without significantly reducing the potency of the compound. Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid). , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween
Figure PCTCN2019085559-appb-000018
), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous).
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, hard Calcium citrate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合 物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。In addition to these inert diluents, the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
本发明化合物可以单独给药，或者与其他药学上可接受的化合物(例如抗-HBV剂)联合给药。The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的化合物(例如抗-HBV剂)。该其他药学上可接受的化合物(例如抗-HBV剂)中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗HBV感染或HBV相关疾病。When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., anti-HBV agents). One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compound (eg, an anti-HBV agent) may be used simultaneously, separately or sequentially with the compound of the present invention. For the prevention and / or treatment of HBV infection or HBV related diseases.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When a pharmaceutical composition is used, a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight, The dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg. Of course, specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
本发明的主要优点包括：The main advantages of the invention include:
1.本发明的化合物结构新颖且具有优异的抗乙肝病毒感染的作用。1. The compound of the present invention is novel in structure and has an excellent anti-HBV infection effect.
2.本发明的化合物对正常细胞的毒性非常低。2. The compounds of the invention are very toxic to normal cells.
3.本发明化合物以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗乙型肝炎病毒感染。3. The compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of hepatitis B virus infection.
4.本发明化合物以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗乙型肝炎病毒相关疾病(例如，乙型肝炎、进展性肝纤维化、导致肝硬化的炎症和坏死、末期肝病、乙基肝癌)。4. The compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of hepatitis B virus-related diseases (for example, hepatitis B, progressive liver fibrosis, inflammation leading to cirrhosis, and Necrosis, terminal liver disease, ethyl liver cancer).
术语说明Terminology
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise defined.
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。As used herein, when used in reference to a particular recited value, the term "about" means that the value can vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言 之，所述术语也包括“基本上由…构成”、或“由…构成”。As used herein, the terms "containing" or "including" may be open, semi-closed, and closed. In other words, the terms also include "consisting essentially of," or "consisting of."
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。The experimental materials and reagents used in the following examples are available from commercially available sources unless otherwise specified.
以下各个实施例为100类化合物的合成：The following various examples are the synthesis of 100 classes of compounds:
实施例1化合物100a的合成Synthesis of Compound 100a of Example 1
Figure PCTCN2019085559-appb-000019
Figure PCTCN2019085559-appb-000019
步骤1：step 1:
Figure PCTCN2019085559-appb-000020
Figure PCTCN2019085559-appb-000020
将87(50mg)溶于乙腈(3ml)中，加入三乙胺(50mg)加入99(60mg)80度反应。反应结束后，旋干后过柱(heptane：EA＝3:1)10mg。ESI-MS(M+H＝451)87 (50 mg) was dissolved in acetonitrile (3 ml), and triethylamine (50 mg) was added to a mixture of 99 (60 mg). After the reaction was completed, it was spun dry and passed through a column (heptane: EA = 3:1) 10 mg. ESI-MS (M+H=451)
根实施例1的合成方法又合成了如下100类系列化合物：The synthesis method of Root Example 1 synthesizes the following 100 series of compounds:
Figure PCTCN2019085559-appb-000021
Figure PCTCN2019085559-appb-000021
Figure PCTCN2019085559-appb-000022
Figure PCTCN2019085559-appb-000022
Figure PCTCN2019085559-appb-000023
Figure PCTCN2019085559-appb-000023
Figure PCTCN2019085559-appb-000024
Figure PCTCN2019085559-appb-000024
Figure PCTCN2019085559-appb-000025
Figure PCTCN2019085559-appb-000025
Figure PCTCN2019085559-appb-000026
Figure PCTCN2019085559-appb-000026
Figure PCTCN2019085559-appb-000027
Figure PCTCN2019085559-appb-000027
生物学实施例--抗-HBV活性实验Biological Example--Anti-HBV Activity Experiment
实验一：体外抗乙肝病毒核衣壳组装活性试验方法Experiment 1: In vitro anti-HBV nucleocapsid assembly activity test method
主要试剂和原料：Main reagents and raw materials:
C150蛋白为药明康德公司表达和纯化；C150 protein is expressed and purified by WuXi PharmaTech;
Figure PCTCN2019085559-appb-000028
购自赛默飞世尔科技公司。
Figure PCTCN2019085559-appb-000028
Purchased from Thermo Fisher Scientific.
蛋白荧光标记：Protein fluorescent label:
向96孔板每孔加入150μL 2％w/v脱脂牛奶，室温孵育2小时。吸掉脱脂牛奶，用去离子水清洗后烘干，室温保存。将C150蛋白(每管3毫克)用5ml Hitrap脱盐柱脱盐。向每管脱盐后的C150蛋白加入50mM
Figure PCTCN2019085559-appb-000029
荧光染料20μl混合均匀，4℃避光孵育过夜。用Sephadex G-25凝胶过滤去除未与C150结合的荧光染料。计算C150的荧光标记效率，公式如下： 150 μL of 2% w/v skim milk was added to each well of a 96-well plate and incubated for 2 hours at room temperature. Aspirate skim milk, wash it with deionized water, dry it, and store at room temperature. C150 protein (3 mg per tube) was desalted using a 5 ml Hitrap desalting column. Add 50 mM to the C150 protein after desalting each tube
Figure PCTCN2019085559-appb-000029
20 μl of the fluorescent dye was mixed well and incubated overnight at 4 ° C in the dark. The fluorescent dye not bound to C150 was removed by filtration with Sephadex G-25 gel. Calculate the fluorescence labeling efficiency of C150, the formula is as follows:
Figure PCTCN2019085559-appb-000030
Figure PCTCN2019085559-appb-000030
Figure PCTCN2019085559-appb-000031
Figure PCTCN2019085559-appb-000031
Figure PCTCN2019085559-appb-000032
Figure PCTCN2019085559-appb-000032
其中，among them,
Figure PCTCN2019085559-appb-000033
表示荧光标记的浓度；
Figure PCTCN2019085559-appb-000033
Indicates the concentration of the fluorescent label;
[C150Bo]表示荧光标记蛋白的浓度；[C150Bo] represents the concentration of a fluorescently labeled protein;
A504表示波长504nM的吸光值；A504 represents an absorbance value of a wavelength of 504 nM;
A280表示波长280nM的吸光值；A280 represents an absorption value of a wavelength of 280 nM;
M -1表示摩尔浓度的倒数。 M -1 represents the reciprocal of the molar concentration.
化合物稀释：Compound dilution:
将化合物母液用DMSO稀释到6mM，再用50mM HEPES稀释到600μM，然后用10％DMSO/50mM HEPES进一步3倍系列稀释8个浓度。The mother liquor of the compound was diluted to 6 mM with DMSO, diluted to 600 μM with 50 mM HEPES, and then further diluted 8 times with 10% DMSO/50 mM HEPES.
将C150Bo用50mM HEPES稀释到2μM。取37.5μL C150Bo和2.5μL各个浓度的化合物加入到96孔反应板中混匀，室温孵育15分钟。取10μl的750mM NaCl/50mM HEPES加入到反应孔中，NaCl的终浓度为150mM。C150Bo was diluted to 2 μM with 50 mM HEPES. 37.5 μL of C150Bo and 2.5 μL of each concentration of the compound were added to a 96-well reaction plate and mixed, and incubated at room temperature for 15 minutes. 10 μl of 750 mM NaCl/50 mM HEPES was added to the reaction well, and the final concentration of NaCl was 150 mM.
0％蛋白组装对照孔，加入10μL的50mM HEPES，NaCl的终浓度为0mM。Control wells were assembled with 0% protein, 10 μL of 50 mM HEPES was added, and the final concentration of NaCl was 0 mM.
100％蛋白组装对照孔，加入10μL的5M NaCl/50mM HEPES，NaCl的终浓度为1M。Control wells were assembled with 100% protein and 10 μL of 5 M NaCl/50 mM HEPES was added with a final concentration of 1 M NaCl.
DMSO终浓度为0.5％，化合物最高终浓度为30μM，C150Bo终浓度为1.5μM。室温孵育1小时。测量荧光信号(激发光485nm；发射光535nm)。The final concentration of DMSO was 0.5%, the maximum final concentration of the compound was 30 μM, and the final concentration of C150Bo was 1.5 μM. Incubate for 1 hour at room temperature. The fluorescence signal (excitation light 485 nm; emission light 535 nm) was measured.
数据分析data analysis
％蛋白组装＝【1-(样品荧光值–1M NaCl荧光值)/(0M NaCl荧光值-1M NaCl荧光值)】×100.% protein assembly = [1- (sample fluorescence value - 1M NaCl fluorescence value) / (0M NaCl fluorescence value - 1M NaCl fluorescence value)] × 100.
IC 50值通过prism软件计算，方程如下： The IC 50 value is calculated by the prism software and the equation is as follows:
Y＝Bottom+(Top-Bottom)/(1+10 ((LogIC50-X)*HillSlope))； Y=Bottom+(Top-Bottom)/(1+10 ((LogIC50-X)*HillSlope) );
其中，among them,
X表示浓度的对数值，Y表示效应值，Y从底部起始以S型拟合至顶部；X represents the logarithm of the concentration, Y represents the effect value, and Y is fitted from the bottom to the top with an S-shape;
Bottom表示表示曲线的底部；Bottom indicates the bottom of the curve;
Top表示Top表示曲线的顶部；Top indicates that Top represents the top of the curve;
HillSlope表示：曲线的最大斜率的绝对值。HillSlope represents the absolute value of the maximum slope of the curve.
实验二：在HepG2.2.15细胞的抗乙肝病毒活性测定Experiment 2: Determination of anti-HBV activity in HepG2.2.15 cells
主要试剂：Main reagents:
QIAamp 96 DNA血液试剂盒(12)(Qiagen，货号51162)；QIAamp 96 DNA Blood Kit (12) (Qiagen, Cat. No. 51162);
FastStart Universal Probe Master(Roche，货号04914058001)；FastStart Universal Probe Master (Roche, article number 04914058001);
Cell–titer Glo检测试剂(Promega，货号G7573)。Cell–titer Glo detection reagent (Promega, Cat. No. G7573).
化合物稀释：体外抗HBV活性实验和细胞毒性实验所有化合物均3倍系列稀释，8个浓度。受试化合物最终起始浓度为30μM，参照化合物GLS4最终起始浓度为1μM，DMSO终浓度为0.5％。Compound dilution: in vitro anti-HBV activity assay and cytotoxicity assay All compounds were serially diluted 3 times, 8 concentrations. The final starting concentration of the test compound was 30 μM, the final starting concentration of the reference compound GLS4 was 1 μM, and the final concentration of DMSO was 0.5%.
种HepG2.2.15细胞(4×10 4细胞/孔)到96孔板，在37℃，5％CO 2培养过夜。第二天，加入含不同浓度化合物的新鲜培养液到培养孔中。第五天，吸除培养孔中旧的培养液，加入含不同浓度化合物的新鲜培养液。 HepG2.2.15 cells (4 x 10 4 cells/well) were plated into 96-well plates and incubated overnight at 37 ° C, 5% CO 2 . The next day, fresh culture medium containing different concentrations of compounds was added to the culture wells. On the fifth day, the old culture solution in the culture well was aspirated and fresh culture medium containing different concentrations of the compound was added.
第八天，收集培养孔中的上清，用于提取上清中的HBV DNA，qPCR检测HepG2.2.15上清中的HBV DNA含量。收集上清后，再向培养孔中补加培养基和Cell-titer Glo试剂，酶标仪检测各孔的化学发光值。On the eighth day, the supernatant in the culture well was collected for extracting HBV DNA from the supernatant, and qPCR was used to detect the HBV DNA content in the supernatant of HepG2.2.15. After collecting the supernatant, the culture medium and the Cell-titer Glo reagent were added to the culture well, and the chemiluminescence value of each well was detected by a microplate reader.
活性计算公式如下:The activity calculation formula is as follows:
Y＝Bottom+(Top-Bottom)/(1+10 ((LogIC50-X)*HillSlope))； Y=Bottom+(Top-Bottom)/(1+10 ((LogIC50-X)*HillSlope) );
其中，among them,
X表示浓度的对数值，Y表示效应值，Y从底部起始以S型拟合至顶部；X represents the logarithm of the concentration, Y represents the effect value, and Y is fitted from the bottom to the top with an S-shape;
Bottom表示曲线的底部；Bottom represents the bottom of the curve;
Top表示曲线的顶部；Top indicates the top of the curve;
HillSlope表示：曲线的最大斜率的绝对值。HillSlope represents the absolute value of the maximum slope of the curve.
实验三：细胞毒性测定Experiment 3: Determination of cytotoxicity
待测化合物的细胞毒性是使用HepG2细胞进行测试的，将这些细胞在待测化合物存在下孵育4天。使用刃天青测定来评估细胞活力。The cytotoxicity of the test compounds was tested using HepG2 cells, and these cells were incubated for 4 days in the presence of the test compound. Cell rejuvenation was assessed using the resazurin assay.
结果表明：本发明的化合物的体外抗乙肝病毒核衣壳组装活性和抗乙肝病毒活性良好，且细胞毒性低。The results showed that the compound of the present invention has good anti-HBV nucleocapsid assembly activity and anti-HBV activity in vitro, and has low cytotoxicity.
由此可见，本申请的化合物具有优异的抗乙肝病毒活性。Thus, the compounds of the present application have excellent anti-HBV activity.
实验一至实验三的活性数据见表2：The activity data of Experiment 1 to Experiment 3 are shown in Table 2:
表2Table 2
Figure PCTCN2019085559-appb-000034
Figure PCTCN2019085559-appb-000034
其中，所述的表格第二栏中：Among them, the second column of the table is:
+++表示IC 50<1μM； +++ means IC 50 <1 μM;
++表示IC 50为1～100μM； ++ indicates an IC 50 of 1 to 100 μM;
+表示IC 50为>100μM。 + indicates an IC 50 of >100 μM.
表格第三栏中：In the third column of the table:
++++表示EC 50<0.1nM； ++++ means EC 50 <0.1nM;
+++表示EC 50 0.1～100nM； +++ means EC 50 0.1~100nM;
++表示EC 50为100～1000nM； ++ indicates an EC 50 of 100 to 1000 nM;
+表示EC 50为>1000nM。 + indicates an EC 50 of >1000 nM.
由此可见，本申请的化合物具有优异的抗乙肝病毒活性。Thus, the compounds of the present application have excellent anti-HBV activity.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (11)

  1. 一种化学式A所示的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物，a compound of the formula A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
    Figure PCTCN2019085559-appb-100001
    Figure PCTCN2019085559-appb-100001
    其中，所述的B环为取代或未取代的8-20元双环并环结构；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；Wherein the B ring is a substituted or unsubstituted 8-20 membered bicyclic ring structure; wherein the substituent refers to one or more hydrogen atoms on the group substituted by a substituent selected from the group consisting of halogen , -CN, hydroxy, amino, carboxy, -(C=O)-substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, Substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or not Substituted 3-10 membered heterocycloalkyl having 1 to 30 hetero atoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted having 1-3 a 5-10 membered heteroaryl group selected from the group consisting of a hetero atom of N, S and O;
    C环为取代或未取代的5-12元环；The C ring is a substituted or unsubstituted 5-12 membered ring;
    R 1、R 2各自独立地选自下组：氢、取代或未取代的C1-C8烷基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自N、S和O的杂原子的3-10元杂环基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基；或R 1、R 2与和它们相连的氮原子共同构成取代或未取代的具有1个N和0-3个选自N、S和O的杂原子的3-10元杂环基； R 1 and R 2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted, and 1-3 selected from a 3-10 membered heterocyclic group of a hetero atom of N, S and O, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted heteroatom having 1-3 selected from the group consisting of N, S and O 5-10 membered heteroaryl; or R 1 , R 2 together with the nitrogen atom to which they are attached constitute a substituted or unsubstituted 3 having 1 N and 0-3 heteroatoms selected from N, S and O -10 membered heterocyclic group;
    R 4、R 5和R 6各自独立地为位于C环上任意位置的选自下组的取代基：氢、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基； R 4 , R 5 and R 6 are each independently a substituent selected from the group consisting of hydrogen, halogen, -CN, hydroxy, amino, carboxy, -(C=O)-substituted or unsubstituted at any position on the C ring. Substituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkane Amino, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted having from 1 to 3 heteroatoms selected from the group consisting of N, S and O a 3-10 membered heterocycloalkyl, a substituted or unsubstituted C6-C10 aryl group, and a substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O base;
    X为NR 9；其中，R 9为氢、取代或未取代的C1-C8烷基、取代或未取代的C3-C8环烷基；其中，所述“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、-CN、羟基、氨基、羧基； X is NR 9 ; wherein R 9 is hydrogen, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl; wherein the "substituted" means selected from the group consisting of Substituted by one or more (eg, 2, 3, 4, etc.) substituents: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -CN, hydroxy, amino, carboxy;
    Y为羰基(-(CO)-)；Y is a carbonyl group (-(CO)-);
    除非特别说明，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、羟基-C1-C6烷基、 氨基、羧基、C6-C10芳基、卤代的C6-C10芳基、未取代或被选自下组的取代基取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基：卤素、苯基。Unless otherwise indicated, the term "substituted" means substituted with one or more (eg, 2, 3, 4, etc.) substituents selected from the group consisting of halogen, C1-C6 alkyl, halo. C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, oxo, -CN, hydroxy, hydroxy- a C1-C6 alkyl group, an amino group, a carboxyl group, a C6-C10 aryl group, a halogenated C6-C10 aryl group, unsubstituted or substituted with a substituent selected from the group consisting of 1-3 selected from N, S and O 5-10 membered heteroaryl of a hetero atom: halogen, phenyl.
  2. 如权利要求1所述的化合物，其特征在于，所述的化合物具有如下式I所示的结构：The compound of claim 1 wherein said compound has the structure of formula I:
    Figure PCTCN2019085559-appb-100002
    Figure PCTCN2019085559-appb-100002
    其中，W 1选自下组：CR 10R 11、CR 10、O、S、或NR 12； Wherein W 1 is selected from the group consisting of CR 10 R 11 , CR 10 , O, S, or NR 12 ;
    W 2选自下组：CR 10或N； W 2 is selected from the group consisting of CR 10 or N;
    W 3为CR 10R 11、CR 10、N或NR 12； W 3 is CR 10 R 11 , CR 10 , N or NR 12 ;
    n为0、1或2；n is 0, 1 or 2;
    虚线为化学键或无；The dotted line is a chemical bond or none;
    R 10和R 11各自独立地为的选自下组的取代基：氢、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基； R 10 and R 11 are each independently a substituent selected from the group consisting of hydrogen, halogen, -CN, hydroxy, amino, carboxy, -(C=O)-substituted or unsubstituted C1-C8 alkyl, substituted Or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1 a C8 alkoxy group, a substituted or unsubstituted C3-C10 cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocycloalkyl group having 1 to 3 hetero atoms selected from the group consisting of N, S and O, a substituted or unsubstituted C6-C10 aryl group, and a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from the group consisting of N, S and O;
    R 12各自独立地为的选自下组的取代基：氢、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基； R 12 is each independently a substituent selected from the group consisting of hydrogen, -CN, hydroxy, amino, carboxy, -(C=O)-substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1 -C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted C1-C8 alkoxy , substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1 to 3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted a C6-C10 aryl group, and a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from the group consisting of N, S and O;
    R 3为位于并环结构上的一个或多个选自下组的取代基：H、卤素、-CN、羟基、氨基、羧基、-(C＝O)-取代或未取代的C1-C8烷基、取代或未取代的C1-C8烷基、取代或未取代的C2-C6烯基、取代或未取代的C2-C6炔基、取代或未取代的C1-C8烷胺基、取代或未取代的C1-C8烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的具有1-3个选自下组N、S和O的杂原子的3-10元杂环烷基、取代或未取代的C6-C10芳基、和取代或未取代的具有1-3个选自下组N、S和O的杂原子的5-10元杂芳基。 R 3 is one or more substituents selected from the group consisting of H, halogen, -CN, hydroxy, amino, carboxy, -(C=O)-substituted or unsubstituted C1-C8 alkane. , substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted Substituted C1-C8 alkoxy, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted 3-10 membered heterocyclic ring having 1-3 heteroatoms selected from the group consisting of N, S and O An alkyl group, a substituted or unsubstituted C6-C10 aryl group, and a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from the group consisting of N, S and O.
  3. 如权利要求1所述的化合物，其特征在于，所述的C环为5-7元环。The compound of claim 1 wherein said C ring is a 5-7 membered ring.
  4. 如权利要求1所述的化合物，其特征在于，所述的R 1为卤代或被羟基取代的 C1-C4烷基，且所述的R 2为H。 The compound according to claim 1, wherein said R 1 is a halogenated or C1-C4 alkyl group substituted by a hydroxy group, and said R 2 is H.
  5. 如权利要求1所述的化合物，其特征在于，所述的化合物选自下组：The compound of claim 1 wherein said compound is selected from the group consisting of:
    Figure PCTCN2019085559-appb-100003
    Figure PCTCN2019085559-appb-100003
    Figure PCTCN2019085559-appb-100004
    Figure PCTCN2019085559-appb-100004
    Figure PCTCN2019085559-appb-100005
    Figure PCTCN2019085559-appb-100005
    Figure PCTCN2019085559-appb-100006
    Figure PCTCN2019085559-appb-100006
    Figure PCTCN2019085559-appb-100007
    Figure PCTCN2019085559-appb-100007
    Figure PCTCN2019085559-appb-100008
    Figure PCTCN2019085559-appb-100008
    Figure PCTCN2019085559-appb-100009
    Figure PCTCN2019085559-appb-100009
  6. 一种药物组合物，其包含(1)权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物；和(2)药学上可接受的载体。A pharmaceutical composition comprising (1) the compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof; and (2) a pharmaceutically acceptable carrier.
  7. 如权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物或如权利要求6所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗乙型肝炎病毒感染的药物。The use of a compound according to claim 1 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 6 It is characterized by being used for the preparation of a medicament for preventing and/or treating hepatitis B virus infection.
  8. 一种乙型肝炎病毒抑制剂，其特征在于，所述抑制剂包含权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。A hepatitis B virus inhibitor, which comprises the compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt or hydrate thereof Or solvate.
  9. 一种制备如权利要求1所述化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物的方法，所示式A化合物为式XIII-1所示的化合物，所述方法包括步骤：A process for the preparation of a compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of formula A is of formula XIII- The compound shown in 1, the method comprising the steps of:
    Figure PCTCN2019085559-appb-100010
    Figure PCTCN2019085559-appb-100010
    在惰性溶剂中，用式A1化合物和式A2化合物反应，得到式A化合物。Reaction of a compound of formula A1 with a compound of formula A2 in an inert solvent provides the compound of formula A.
  10. 一种预防和/或治疗乙型肝炎的方法，包括步骤：向所需患者施用权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物或权利要求6所述的药物组合物。A method for preventing and/or treating hepatitis B, comprising the steps of: administering a compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, to a patient in need thereof A hydrate or solvate or a pharmaceutical composition according to claim 6.
  11. 一种体外抑制乙型肝炎病毒的方法，其特征在于，包括步骤：将权利要求1所述的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物，与乙型肝炎病毒接触，从而抑制乙型肝炎。A method for inhibiting hepatitis B virus in vitro, comprising the steps of: hydrating the compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, or hydrated Or solvate, in contact with hepatitis B virus, thereby inhibiting hepatitis B.
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