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WO2018019297A1 - Composé isoquinolinone et son utilisation dans la préparation d'un médicament antiviral - Google Patents

Composé isoquinolinone et son utilisation dans la préparation d'un médicament antiviral Download PDF

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Publication number
WO2018019297A1
WO2018019297A1 PCT/CN2017/094946 CN2017094946W WO2018019297A1 WO 2018019297 A1 WO2018019297 A1 WO 2018019297A1 CN 2017094946 W CN2017094946 W CN 2017094946W WO 2018019297 A1 WO2018019297 A1 WO 2018019297A1
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compound
alkyl
group
mmol
rac
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English (en)
Chinese (zh)
Inventor
陈力
翟培彬
邵庆
武进
江涛
李晓闻
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Ginkgo Pharma Co ltd
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Ginkgo Pharma Co ltd
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Priority claimed from CN201610671491.1A external-priority patent/CN107759585A/zh
Application filed by Ginkgo Pharma Co ltd filed Critical Ginkgo Pharma Co ltd
Priority to CA3031021A priority Critical patent/CA3031021A1/fr
Priority to JP2019503692A priority patent/JP2019523261A/ja
Priority to EP17833600.4A priority patent/EP3492467A4/fr
Priority to KR1020197002649A priority patent/KR20190022795A/ko
Priority to US16/319,777 priority patent/US20190381014A1/en
Priority to AU2017304952A priority patent/AU2017304952A1/en
Publication of WO2018019297A1 publication Critical patent/WO2018019297A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • nucleoside drugs reduce hepatitis B virus by inhibiting the synthesis of viral DNA and have no effect on viral RNA.
  • Nucleoside drugs can not cure hepatitis B and can only suppress the replication of hepatitis B virus. Therefore, a drug that simultaneously inhibits the novel mechanism of action of viral DNA and RNA is required to cure hepatitis B.
  • the newly developed core protein inhibitor can simultaneously inhibit the DNA and RNA of the virus, and the therapeutic effect similar to entecavir can be achieved by using the drug alone.
  • hepatitis B In the design of new drugs for the purpose of curing hepatitis B, the mechanism of the newly designed compounds is the same as that of interferon. It is necessary to reactivate the body's own immune system and rely on its own immune system to identify and remove infected liver cells, thus completely curing hepatitis B. Hepatitis B surface antigen and other viral antigens secreted by hepatocytes from patients with chronic hepatitis B interfere with the immune system through signal transduction systems, block the recognition of viruses by immune cells and further limit their antiviral function. In addition, persistent and excessive hepatitis B surface antigens can inactivate the immune system, delete T-cells, and perform functional damage.
  • nucleoside drugs can not reduce hepatitis B surface antigen, and it is necessary to design a new mechanism of action, combined with potent nucleoside drugs, and effectively remove hepatitis B surface antigen and viral DNA in the blood, activate and restore itself. Immune function, which may eventually cure hepatitis B.
  • An object of the present invention is to provide novel isoquinolinone compounds which have an extremely strong activity for inhibiting hepatitis B DNA and a potent inhibitory activity against hepatitis B surface antigen.
  • the structure of this class of compounds will block the pathway of P450 oxidation, increase the bioavailability of the compound, and reduce the toxicity of the compound.
  • These highly active compounds will be combined with nucleoside compounds and TLR7 agonists, which may significantly improve the therapeutic effect and cure rate of hepatitis B in the clinic.
  • the present invention adopts the following technical solutions:
  • R 2 is selected from the group consisting of halogen, C 1-3 alkoxy, deuterated C 1-3 alkoxy, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy , C 4-8 cycloheteroalkyl C 1-6 alkyl, halo C 1-3 alkyloxy, halo C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-6 alkane a group or R 2 and R 3 are bonded by a carbon atom to form a ring;
  • R 5 , R 5 ' independently selected from hydrogen, hydrazine, halogen, methyl, methoxy or R 5 , R 5 'forms a carbocyclic or heterocyclic ring; or R 5 , R 6 form a carbocyclic or heterocyclic ring ring;
  • W is N or CR 7 , wherein R 7 is selected from the group consisting of hydrogen, hydrazine, hydroxy, halogen, C 1-3 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyloxy, ester , carboxyl or cyano;
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the isoquinolinone compound of the formula (I) according to the present invention, a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof, and a pharmaceutically acceptable An acceptable carrier or excipient.
  • the invention provides novel isoquinolinone compounds, which have strong inhibition of hepatitis B DNA activity, EC 50 can be less than 5 nanomolar, and have strong activity for inhibiting hepatitis B surface antigen, and EC 50 is About 10 nanomoles.
  • such compounds have excellent pharmacokinetic properties.
  • the compounds of the invention will block the pathway of P450 oxidation, increase the bioavailability of the compounds, and reduce the toxicity of the compounds.
  • These highly active compounds will be combined with nucleoside compounds and TLR7 agonists, which may significantly improve the therapeutic effect and cure rate of hepatitis B in the clinic.
  • hydrocarbyl refers to a straight, branched or cyclic, saturated or unsaturated substituent consisting essentially of carbon and hydrogen. It is preferably 1 to 20 carbon atoms, more preferably 1 to 12 carbon atoms.
  • alkyl refers to a straight, branched or cyclic saturated hydrocarbon group.
  • cycloalkyl refers to a saturated and/or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group.
  • a single ring can include from 3 to 10 carbon atoms.
  • monocyclic cycloalkane groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • the cycloalkyl group includes an unsubstituted group and a substituent.
  • aryl refers to a 6-10 membered all carbon monocyclic or polycyclic aromatic group including phenyl, naphthyl, biphenyl, and the like.
  • the aryl group can be substituted and unsubstituted.
  • ⁇ is an isotope of hydrogen with an atomic mass twice that of the latter and a stronger binding to carbon.
  • Deuterated “and” ⁇ means that hydrogen is replaced with deuterium at the specified position.
  • a “deuterated substituent” is a substituent in which at least one hydrogen is replaced by deuterium enriched at a specified percentage.
  • heterocyclyl refers to a cyclic group containing at least one heteroatom, wherein the heteroatoms are nitrogen, oxygen, sulfur, sulfur, and the like.
  • the heterocyclic group includes a monoheterocyclic group and a polyheterocyclic group.
  • DIBAL-H Diisobutylaluminum hydride
  • PhN(OTf) 2 N-phenyl bis(trifluoromethanesulfonimide)
  • Compound 26a-rac Compound 22i-rac (186 mg, 0.52 mmol) was dissolved in 20 mL of DMF, and Intermediate 8d (100mg, 0.52mmol) and potassium carbonate (142mg, 1.04mmol). The mixture was heated and stirred at 85 ° C for 3 hours, cooled to room temperature, then added with 60 mL of water, and then extracted with ethyl acetate (50 mL ⁇ 3). The organic layer was combined, washed with saturated sodium chloride, dried and concentrated The next step is to react.
  • Compound 28c-rac Compound 28b-rac (3.40 g, 10.9 mmol) was dissolved in 50 mL of dioxane, and toluene (2.51 g, 54.5 mmol). After cooling to room temperature, 50 mL of a saturated aqueous solution of sodium hydrogencarbonate was added, and then ethyl acetate (50 mL ⁇ 3), and the organic layer was combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated. In the next step.
  • Compound 28f-rac Compound 28e-rac (6.40 g, 13.8 mmol) was dissolved in 40 mL of ethylene glycol dimethyl ether, and tetrachlorophenylhydrazine (3.40 g, 13.8 mmol) was added, and the mixture was stirred under heating at 55 ° C for 3 hours. The mixture was added to a silica gel and purified by column chromatography to give a product 3.20 g. Yield: 50.2%.
  • Compound 30a-rac Compound 28g-rac (85mg, 0.23mmol), compound 6c (89mg, 0.46mmol) and potassium carbonate (63mg, 0.46mmol) were added to 5mL DMF, replaced with nitrogen three times, heated and stirred at 90 °C Reaction for 3 hours. After completion of the reaction, the mixture was diluted with EtOAc (EtOAc m.
  • Compound 31a-rac Compound 28g-rac (65mg, 0.18mmol), compound 7e (55mg, 0.26mmol) and potassium carbonate (50mg, 0.36mmol) were added to 5mL DMF, replaced with nitrogen three times, heated and stirred at 90 °C Reaction for 3 hours. After completion of the reaction, the mixture was diluted with EtOAc (EtOAc m.
  • Compound 52f-rac Compound 52e (0.63 g, 1.84 mmol) was dissolved in 5 mL of dioxane, and 1.0 mL of formic acid and 0.5 mL of triethyl orthoformate were added, and the mixture was stirred under reflux for 48 hours. After completion of the reaction, the solvent was evaporated to dryness.
  • Compound 52h-rac Compound 52g-rac (0.58g, 1.64mmol) and ethyl 2-ethoxymethyleneacetate (0.92g, 4.92mmol) were dissolved in 6mL of ethanol, 2mL water was added, and the reaction was stirred and heated under reflux. After 48 hours, after completion of the reaction, the reaction solvent was dried to give 1.17 g of crude product.
  • Compound 52i-rac Compound 52h-rac (1.17 g, 2.36 mmol) and tetrachlorophenylhydrazine (0.35 g, 1.42 mmol) were dissolved in 15 mL of ethylene glycol dimethyl ether and stirred under reflux for 3 hours. The reaction solvent was spin-dried, and the product was purified by silica gel column chromatography. Yield: 40.9%.
  • Compound 54a-rac Compound 52j-rac (100 mg, 0.25 mmol), Compound 6c (97 mg, 0.50 mmol) and potassium carbonate (103 mg, 0.75 mmol) After adding to 5 mL of DMF, the nitrogen gas was replaced three times, and the reaction was stirred under heating at 90 ° C for 5 hours. After completion of the reaction, the mixture was diluted with EtOAc (EtOAc)EtOAc.
  • Compound I-54-rac Compound 54a-rac (110 mg, 0.22 mmol) was dissolved in 3 mL of tetrahydrofuran, 40 mg of sodium hydroxide and 1 mL of water were added, and the reaction was stirred at 35 ° C for 2 hours. After completion of the reaction, the pH was adjusted to about 2-3 with 1N hydrochloric acid, and extracted with dichloromethane (20 mL ⁇ 3). The organic phase was combined and dried over anhydrous sodium sulfate. Yield: 26.1%.
  • Compound 56a-rac Compound 52j-rac (100 mg, 0.25 mmol), compound 8d (96 mg, 0.50 mmol) and potassium carbonate (103 mg, 0.75 mmol) were added to 5 mL of DMF, replaced with nitrogen three times and heated and stirred at 90 °C. Reaction for 5 hours. After completion of the reaction, it was diluted with water and extracted with ethyl acetate (20 mL ⁇ 3). The organic phase was combined and dried over anhydrous sodium sulfate. Yield: 40.0%.
  • Compound I-56-rac Compound 56a-rac (60 mg, 0.1 mmol) was dissolved in 4 mL of tetrahydrofuran, 25 mg of sodium hydroxide and 1 mL of water were added, and the reaction was stirred at 35 ° C for 2 hours. After the completion of the reaction, the pH was adjusted to about 2-3 with 1N hydrochloric acid, and extracted with dichloromethane (20 mL ⁇ 3). The organic phase was combined, dried over anhydrous sodium sulfate, Yield: 84.7%.
  • the preparations for administration were freshly prepared on the day of administration, and samples were taken for the determination of the actual concentration of the preparation for administration.
  • Group A SD rats were given a single intravenous injection (IV) with a dose of 2 mg ⁇ kg -1
  • group B SD rats were given a single dose (PO) with a dose of 10 mg ⁇ kg -1
  • 0.15 mL of blood was collected from the jugular vein before administration and 5 minutes after administration (intravenous group only), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours.
  • All whole blood samples were centrifuged (5500 rpm) for 10 minutes, and the plasma was separated and stored in a refrigerator at -30 to -10 °C.
  • the concentration of the test compound in the plasma of SD rats was determined by LC-MS/MS analysis.
  • the corresponding pharmacokinetic parameters were calculated using a non-compartmental model in Pharsight Phoenix 7.0. See Tables 2a and 2b for the results.

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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Virology (AREA)
  • Engineering & Computer Science (AREA)
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  • Communicable Diseases (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne un composé d'isoquinolinone tel que présenté dans la formule (I) ou un stéréoisomère, un sel pharmaceutiquement acceptable, un solvate ou un cristal de celui-ci, leur préparation et leur utilisation dans la préparation de médicaments destinés au traitement ou à la prévention de maladies infectieuses virales causées par le virus de l'hépatite B (HBV) et d'autres virus, en particulier l'utilisation de ceux-ci dans des médicaments pour des inhibiteurs de l'antigène de surface HBV et des inhibiteurs de la production d'ADN du HBV. Le composé présente une activité significative pour inhiber l'antigène de surface de l'hépatite B et l'ADN de l'hépatite B, et il est possible d'améliorer significativement la probabilité de durcissement de l'hépatite B par l'administration de celle-ci en combinaison avec des médicaments nucléosidiques ou d'autres médicaments dans le futur, et celui-ci a de bonnes perspectives d'application clinique.
PCT/CN2017/094946 2016-07-29 2017-07-28 Composé isoquinolinone et son utilisation dans la préparation d'un médicament antiviral Ceased WO2018019297A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA3031021A CA3031021A1 (fr) 2016-07-29 2017-07-28 Compose isoquinolinone et son utilisation dans la preparation d'un medicament antiviral
JP2019503692A JP2019523261A (ja) 2016-07-29 2017-07-28 イソキノリノン系化合物及び抗ウイルス剤としての用途
EP17833600.4A EP3492467A4 (fr) 2016-07-29 2017-07-28 Composé isoquinolinone et son utilisation dans la préparation d'un médicament antiviral
KR1020197002649A KR20190022795A (ko) 2016-07-29 2017-07-28 이소퀴놀리논 화합물 및 이의 항바이러스 약물로서의 응용
US16/319,777 US20190381014A1 (en) 2016-07-29 2017-07-28 Isoquinolinone compounds and use thereof in preparation of antiviral drugs
AU2017304952A AU2017304952A1 (en) 2016-07-29 2017-07-28 Isoquinolinone compound and use thereof in preparation of antiviral drugs

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201610626628.1 2016-07-29
CN201610626628 2016-07-29
CN201610671491.1 2016-08-16
CN201610671491.1A CN107759585A (zh) 2016-07-29 2016-08-16 一种异喹啉类化合物及其药用组合物和作为抗病毒药物的应用

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Cited By (66)

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US20170342068A1 (en) 2016-05-27 2017-11-30 Gilead Sciences, Inc. Compounds for the treatment of hepatitis b virus infection
WO2018154466A1 (fr) * 2017-02-21 2018-08-30 Glaxosmithkline Intellectual Property Development Limited Dihydroquinolizinones à utiliser en tant qu'antiviraux
US10189846B2 (en) 2016-06-10 2019-01-29 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
US10239872B2 (en) 2016-07-29 2019-03-26 Newave Pharmaceutical Inc. Therapeutic agents for the treatment of HBV infection
WO2019165374A1 (fr) 2018-02-26 2019-08-29 Gilead Sciences, Inc. Composés de pyrrolizine substitués en tant qu'inhibiteurs de réplication du virus de l'hépatite b
US10428070B2 (en) 2017-12-06 2019-10-01 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
WO2019193533A1 (fr) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides 2'2'-cycliques
WO2019193543A1 (fr) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides 3'3'-cycliques
WO2019195181A1 (fr) 2018-04-05 2019-10-10 Gilead Sciences, Inc. Anticorps et leurs fragments qui se lient à la protéine x du virus de l'hépatite b
WO2019193542A1 (fr) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. Dinucléotides 2'3'-cycliques
US10442804B2 (en) 2017-02-02 2019-10-15 Gilead Sciences, Inc. Compounds for the treatment of hepatitis B virus infection
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CN115521310A (zh) * 2022-10-08 2022-12-27 河南师范大学 异吲哚并异喹啉螺萘酮类化合物的合成方法
WO2025240242A1 (fr) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Polythérapies avec ribavirine
WO2025240246A1 (fr) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Polythérapies avec de la ribavirine
WO2025240243A1 (fr) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Polythérapies comprenant du bulévirtide et un acide nucléique inhibiteur ciblant le virus de l'hépatite b
WO2025240244A1 (fr) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Polythérapies comprenant du bulévirtide et du lonafarnib destinées à être utilisées dans le traitement d'une infection par le virus de l'hépatite d

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