WO2018121689A1 - Composé sulfonamide-aryle amide et son utilisation en tant que médicament pour le traitement de l'hépatite b - Google Patents

Composé sulfonamide-aryle amide et son utilisation en tant que médicament pour le traitement de l'hépatite b Download PDF

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WO2018121689A1
WO2018121689A1 PCT/CN2017/119531 CN2017119531W WO2018121689A1 WO 2018121689 A1 WO2018121689 A1 WO 2018121689A1 CN 2017119531 W CN2017119531 W CN 2017119531W WO 2018121689 A1 WO2018121689 A1 WO 2018121689A1
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compound
substituted
unsubstituted
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alkyl
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王喆
王晓光
卢涔宾
范国钦
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上海长森药业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the field of chemical medicine, and in particular, to a sulfonamide-arylamide compound and a pharmaceutical use thereof for treating hepatitis B.
  • 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. Prior to 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.
  • dsDNA partially double-stranded DNA
  • Hepadnaviridae hepatovirus DNA family
  • X gene which encode three envelope proteins
  • 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 and animal models (Weber et al., Antiviral Res. 54:69-78) .
  • 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 first aspect of the invention provides a compound of formula A, or a stereoisomer, cis-trans isomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof ,
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted, and 1-3 are selected from the group consisting of N, a 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted heteroatom of S and O having from 1 to 3 heteroatoms selected from the group consisting of N, S and O a 5-10 membered heteroaryl; or R 1 , R 2 and the nitrogen atom to which they are attached form a substituted or unsubstituted heteroatom having 1 N and 0-3 selected from the group consisting of N, S and O. 3-10 membered heterocycloalkyl;
  • substitution means one or more (for example, 2, 3, 4, etc.) substituents selected from the group consisting of the following groups. Substituted: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 Cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, C6-C10 aryl, halogenated C6-C10 aryl, 5 having from 1 to 3 heteroatoms selected from the group consisting of N, S and O a 10-membered heteroaryl, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;
  • M is O, S, CR 7 R 7' or NR 8 ; wherein R 7 , R 7 ' and R 8 are each independently hydrogen, halogen, -CN, hydroxy, substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 alkoxy group, a substituted or unsubstituted C3-C8 cycloalkyl group; wherein said "substituted” means one or more selected from the group consisting of (for example, 2, 3 , 4, etc. substituted by a substituent: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, -CN, hydroxy, amino, carboxy;
  • Y is a carbonyl group (-(CO)-) or a sulfonyl group (-SO 2 -);
  • X Y cannot be a carbonyl group at the same time, and Y cannot be a sulfonyl group when X is a carbonyl group;
  • Z is N or CR 10 ; wherein R 10 is each independently hydrogen, halogen, -CN, hydroxy, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or not Substituted 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 C6-C10 aryl And a substituted or unsubstituted 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O; wherein said "substituted” refers to a group selected from the group consisting of Or a plurality of (eg, 2, 3, 4, etc.) substituents substituted: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted, and 1-3 are selected from the group consisting of N, a 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted heteroatom of S and O having from 1 to 3 heteroatoms selected from the group consisting of N, S and O a 5-10 membered heteroaryl; or R 1 , R 2 and the nitrogen atom to which they are attached form a substituted or unsubstituted heteroatom having 1 N and 0-3 selected from the group consisting of N, S and O. 3-10 membered heterocycloalkyl;
  • substitution means one or more (for example, 2, 3, 4, etc.) substituents selected from the group consisting of the following groups. Substituted: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 Cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, C6-C10 aryl, halogenated C6-C10 aryl, 5 having from 1 to 3 heteroatoms selected from the group consisting of N, S and O a 10-membered heteroaryl, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;
  • M is NR 8 ; wherein R 8 is a methyl group
  • X is NR 9 ; wherein R 9 is hydrogen;
  • Y is a sulfonyl group (-SO 2 -);
  • Z is N or CR 10 ; wherein R 10 is each independently hydrogen.
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted, and 1-3 are selected from the group consisting of N, a 3-10 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted heteroatom of S and O having from 1 to 3 heteroatoms selected from the group consisting of N, S and O a 5-10 membered heteroaryl; or R 1 , R 2 and the nitrogen atom to which they are attached form a substituted or unsubstituted heteroatom having 1 N and 0-3 selected from the group consisting of N, S and O. 3-10 membered heterocycloalkyl;
  • substitution means one or more (for example, 2, 3, 4, etc.) substituents selected from the group consisting of the following groups. Substituted: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, halogenated C3-C8 Cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, C6-C10 aryl, halogenated C6-C10 aryl, 5 having from 1 to 3 heteroatoms selected from the group consisting of N, S and O a 10-membered heteroaryl, halogenated 5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O;
  • M is NR 8 ; wherein R 8 is a methyl group
  • X is NR 9 ; wherein R 9 is hydrogen;
  • Y is a sulfonyl group (-SO 2 -);
  • Z is CR 10 ; wherein R 10 is hydrogen.
  • R 1 and R 2 are each independently hydrogen, a substituted or unsubstituted C 2 -C 8 alkyl group, a substituted or unsubstituted C 3 -C 4 cycloalkyl group; wherein the "substituted” means Substituted by one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of fluorine, chlorine, bromine, and iodine.
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 2 -C 4 alkyl, substituted or unsubstituted C 3 -C 4 cycloalkyl; wherein said "substituted” means Substituted by one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of fluorine, chlorine, bromine, and iodine.
  • R 3 is hydrogen, fluorine, chlorine, bromine, iodine, -CN, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted C3-C4 cycloalkyl group; "Substituted” means substituted by one or more (eg, 2, 3, 4, etc.) substituents selected from the group consisting of halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, - CN, hydroxyl.
  • R 3 is hydrogen, fluorine, chlorine, bromine or iodine.
  • R 4 , R 5 and R 6 are each independently hydrogen, fluorine, chlorine, bromine, iodine, -CN, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3- C4 cycloalkyl; wherein the "substituted” refers to being substituted with one or more (eg, 2, 3, 4, etc.) substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, C1 -C4 alkyl, halogenated C1-C4 alkyl.
  • R 4 , R 5 and R 6 are each independently hydrogen, fluorine, chlorine, bromine, iodine, -CN, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3- C4 cycloalkyl; wherein said "substituted” refers to being substituted with one or more (e.g., two, three, four, etc.) substituents selected from the group consisting of fluorine, chlorine, bromine, and iodine.
  • M is NR 8 ; wherein R 8 is hydrogen, halogen, -CN, hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, substituted Or unsubstituted C3-C4 cycloalkyl; wherein said "substituted” refers to being substituted with one or more (eg, 2, 3, 4, etc.) substituents selected from the group consisting of halogen, C1 -C4 alkyl, halogenated C1-C4 alkyl, -CN, hydroxy, amino, carboxy.
  • Z is N or CR 10 ; wherein R 10 is each independently hydrogen, fluoro, chloro, bromo, iodo, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3- C4 cycloalkyl; wherein the "substituted” refers to being substituted with one or more (eg, 2, 3, 4, etc.) substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, C1 -C4 alkyl, halogenated C1-C4 alkyl.
  • the compound is selected from the group consisting of:
  • a second aspect of the invention provides a compound according to the first aspect, or a stereoisomer, cis-trans isomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof Preparation method,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the same meanings as defined above;
  • the compound of the formula A is a compound of the formula XIII-3, the method comprising the steps of:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z and M have the same meanings as defined above;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the same meanings as defined above;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the same meanings as defined above.
  • the compound of formula VII-2 can be prepared from the compound of formula 1-2 as a starting material.
  • the preparation method may include the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the same meanings as defined above.
  • the compound of formula V-3 can be prepared from the compound of formula 1-3 as a starting material.
  • the preparation method may include the following steps:
  • R 3 has the same definition as before.
  • the third aspect of the invention provides an intermediate represented by the formula: or a stereoisomer, cis-trans isomer or tautomer thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the same meanings as defined above.
  • a fourth aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (1) the compound of the first aspect, or a stereoisomer, cis-trans isomer or tautomer thereof, or a pharmaceutically acceptable thereof a salt, hydrate or solvate; (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, tenofovir alafenamide (TAF), and Lamiv Ding, adefovir, entecavir and telbivudine.
  • the fifth aspect of the invention provides the compound of the first aspect, or a stereoisomer, cis-trans isomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof or Use of the pharmaceutical composition of the four aspects for the preparation of a medicament for the prevention and/or treatment of hepatitis B virus infection.
  • a sixth aspect of the present invention provides a method for treating hepatitis B, which comprises administering a compound of the first aspect, or a stereoisomer, cis-trans isomer or tautomer thereof, or A pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the fourth aspect.
  • 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.
  • C1-C8 alkyl means a straight or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.
  • alkenyl as used herein, includes a straight or branched alkenyl group.
  • C2-C6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butene Alkenyl, or the like.
  • alkynyl includes a straight or branched alkynyl group.
  • C2-C6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.
  • C3-C10 cycloalkyl refers to a cycloalkyl group having from 3 to 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.
  • C1-C8 alkylamino refers to an amine group substituted by a C1-C8 alkyl group, which may be monosubstituted or disubstituted; for example, methylamino, ethylamino, propylamino, iso Alanine, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di-tert-butylamine, and the like.
  • C1-C8 alkoxy refers to a straight or branched alkoxy group having from 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, isopropoxy Base, butoxy, isobutoxy, tert-butoxy and the like.
  • a 3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O means having from 3 to 10 atoms and wherein 1-3 of the atoms are selected A saturated or partially saturated cyclic group of heteroatoms from the next group 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.
  • C6-C10 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 the group consisting of N, S and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from A cyclic aromatic group of the following group of heteroatoms of N, 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”. , C1-C6 alkyl-amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo C1-C6 alkyl, halo C2-C6 alkenyl , halogenated C2-C6 alkynyl, halogenated C1-C6 alkoxy, allyl, benzyl, C6-C12 aryl, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkoxy a carbonyl group, a phenoxycarbonyl group, a C2-C6 alkynyl-carbonyl group, a C2-C6 alkeny
  • 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 compounds of the invention can be prepared according to methods generally used in the art. It can also be prepared according to the scheme route given below according to the present invention, using conventional synthesis conditions (e.g., reaction temperature or reaction time, etc.). Among them, the reaction temperature and the reaction time can be determined by those skilled in the art based on the conventional reaction conditions of the reaction.
  • the reaction temperature may be -78 ° C to reflux; preferably, it is -20 ° C to reflux or 0 to 100 ° C or the like.
  • the reaction time may be from 0.1 hour to 3 days or from 0.1 hour to 24 hours or from 0.1 hour to 5 hours, and the like.
  • the compound I-1 is subjected to a nitration reaction for a period of time to form a compound II-1;
  • the compound II-1 is subjected to a reduction reaction for a period of time to form a compound III-1;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the same meanings as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the same meanings as defined above.
  • the fluorinating reagent is a nucleophilic fluorinating reagent capable of converting a carbonyl group into a difluoromethylene group, such as DAST, BAST, and Ishikawa reagent 1-fluoropyridine tetrafluoroborate.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the same meanings as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z and M have the same meanings as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 have the same meanings as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Z have the same meanings as defined above.
  • the compound of the formula V-1 can be prepared from the compound of the formula I-1 as a starting material. Specifically, the preparation method may include the following steps:
  • R 1 , R 2 , R 3 and Z have the same meanings as defined above.
  • the compound of the formula VI-1 can be prepared from the compound of the formula I-1 as a starting material. Specifically, the preparation method may include the following steps:
  • R 1 , R 2 , R 3 and Z have the same meanings as defined above.
  • the compound of the formula VII-3 can be prepared from the compound of the formula I-1 as a starting material. Specifically, the preparation method may include the following steps:
  • R 1 , R 2 and R 3 have the same meanings as defined above.
  • the compound of the formula VIII-3 can be prepared from the compound of the formula I-3 as a starting material. Specifically, the preparation method may include the following steps:
  • R 1 , R 2 and R 3 have the same meanings as defined above.
  • 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 compounds of the present invention are novel in structure and have excellent anti-HBV infection effects.
  • the compound of the present invention can effectively inhibit the assembly of the hepatitis B virus nucleocapsid, thereby effectively inhibiting the hepatitis B virus.
  • 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 and necrosis leading to cirrhosis, End stage liver disease, ethyl liver cancer).
  • hepatitis B virus-related diseases for example, hepatitis B, progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, End stage liver disease, ethyl liver cancer.
  • the compounds of the invention exhibit superior solubility properties and good pharmacokinetic properties to the reference compound.
  • the substrate 6 (50 mg) was dissolved in DMF (36 mL), then the compound 7 (20 mg), DIPEA (74 mg) was added to the reaction system, and HATU (78 mg) was added to the reaction system at 0 °C for about 5 hours.
  • the TLC detection of the raw material reaction is complete and new points are generated.
  • 20 mL of saturated brine was added to the reaction system, and ethyl acetate (3*20 mL) was extracted. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness.
  • Color solid compound 8 (5 mg).
  • the substrate 13 (90 mg) was dissolved in DCM (3 mL), the temperature of the system was reduced to 0 °, then the solution of compound 14 (112 mg) in dichloromethane was added to the reaction system, stirred at 0 ° for 30 min, then trichloro Aluminum (144 mg) was added to the reaction system in batches, and the reaction was carried out at 0 ° for 3 h.
  • the reaction of the starting material by TLC was complete and a new point was formed.
  • the substrate 15 (50 mg) was dissolved in tetrahydrofuran (1 mL) and ethanol (3 mL), and then aqueous sodium hydroxide (16 mg) was added to the system, and the mixture was reacted at 30 degrees for 0.5 h. The reaction of the starting material was confirmed by TLC, and a new point was formed. Water (20 mL) was added to the reaction mixture, and the mixture was adjusted to 3-4 EtOAc (EtOAc m. .
  • the substrate 16 (25 mg) was dissolved in DMF (2 mL), then tert-butylamine (6.8 mg), DIPEA (74 mg) was added to the reaction system, and HATU (37 mg) was added to the reaction system at 0 °C, and reacted at about 30 °C for 5 h. , TLC detects the reaction of the raw materials completely, and new points are generated. Saturated brine (20 mL) was added to the reaction mixture, and ethyl acetate (3*20 mL) was evaporated. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. ) A pale red solid compound 17 (5 mg) was isolated.
  • Substrate 17 (15 mg) was dissolved in ethanol (2 mL), then hydroxylamine hydrochloride (13 mg) was added to the reaction system, and the reaction temperature was raised to 60 °C for 10 h. The reaction mixture was dried, and the residue was dissolved in acetonitrile.
  • 1 H-NMR (CDCl 3 , 400 MHz) of 18-1 ⁇ : 1.42 (s, 9H), 3.96 (s, 3H), 6.54-6.57 (m, 1H), 7.16-7.20 (m, 1H), 7.69- 7.72 (m, 1H), 8.02 (s, 1H) 8.53 (d, J 8.0 Hz, 1H).
  • Compound 17a was prepared according to steps 11-15, except that isopropylamine was replaced with isopropylamine.
  • step 16 it is only necessary to replace the compound 17 with the compound 17a, and the other conditions are unchanged, and the target product 18a is obtained by high performance liquid chromatography.
  • Compound 17b was prepared according to steps 11-15, except that ethylamine was used instead of t-butylamine.
  • step 16 it is only necessary to replace the compound 17 with the compound 17b, and the other conditions are unchanged, and the target product 18b) is obtained by high performance liquid chromatography.
  • Compound 17c was prepared according to steps 11-15, except that with trifluoroacetic isopropylamine (CH 3 (CF 3) CHNH 2) instead of t-butylamine.
  • CH 3 (CF 3) CHNH 2 trifluoroacetic isopropylamine
  • step 16 it is only necessary to replace the compound 17 with the compound 17c, and the other conditions are unchanged, and the target product 18c is obtained by high performance liquid chromatography.
  • Compound 17d was prepared according to Steps 11-15, except that instead of t-butylamine, cyclopropylamine was used.
  • step 16 it is only necessary to replace the compound 17 with the compound 17d, and the other conditions are unchanged, and the target product 18d is obtained by high performance liquid chromatography.
  • Compound 19-6b was prepared according to Step 19-A-19-E, except that ethylamine was used instead of t-butylamine.
  • step 19-F it is only necessary to replace the compound 19-6 with the compound 19-6b, and the other conditions are unchanged, and the target product 19b is obtained by high performance liquid chromatography.
  • step 19-A-19-E Preparation of Compound 19-6c, except that isopropylamine was treated with trifluoroacetic (CH 3 (CF 3) CHNH 2) instead of t-butylamine.
  • step 19-F it is only necessary to replace the compound 19-6 with the compound 19-6c, and the other conditions are unchanged, and the target product 19c is obtained by high performance liquid chromatography.
  • Compound 19-6d was prepared according to Step 19-A-19-E, except that the bromoamine was used instead of t-butylamine.
  • step 19-F it is only necessary to replace the compound 19-6 with the compound 19-6d, and the other conditions are unchanged, and the target product 19d is obtained by high performance liquid chromatography.
  • the substrate 28 (80 mg), the compound 29 (50 mg) and DIPEA (70 mg) were dissolved in DMF (5 mL), then HATU (130 mg) was added to the reaction system, then reacted at 40 ° for 8 h, water (20 mL), acetic acid B The ester was extracted (3*20 mL), EtOAc (EtOAc m.
  • the substrate 31 (0.8 g) was dissolved in tetrahydrofuran (12 mL), methanol (3 mL) and water (3 mL), then sodium hydroxide (0.44 g) was added to the system, and the reaction was carried out at 55 ° C for 1 h. , there are new points generated. 1N Hydrochloric acid was adjusted to pH 3-4, and water (20 mL) was added to the reaction mixture, and ethyl acetate (3*20 mL) was evaporated.
  • the substrate 32 (100 mg) was dissolved in DMF (3 mL), then 4-F-3-cyano-aniline (40 mg), DIPEA (84 mg) was added to the reaction system, and TBTU (78 mg) was added to the reaction at 0 degree. The system was reacted at room temperature (30 °C) for 5 h. The TLC detection of the raw materials was complete and a new point was formed. 20 mL of a saturated aqueous solution of sodium chloride was added to the reaction mixture, and ethyl acetate (3*20 mL) was evaporated.
  • the substrate 33 (0.3 g) was dissolved in acetic acid (5 mL), and iron powder (1.0 g) was added to the reaction system at room temperature, and reacted at room temperature for 3 hours.
  • the reaction of the starting material was completely detected by TLC, and the acetic acid was spin-dried to adjust the pH to 9-10.
  • Ethyl acetate (3*45 mL) was extracted, dried and dried, and then purified to give the product.
  • [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.
  • a1 indicates that the IC50 ( ⁇ M) is between 0.001 and 10;
  • A2 indicates that the IC50 ( ⁇ M) is between 10 and 100;
  • A3 indicates that the IC50 ( ⁇ M) is between 100 and 10000;
  • control compound is:
  • solubility and pharmacokinetic properties of the compounds of the present invention were superior to the control compounds as compared to the above control compounds by conventional solubility experiments and pharmacokinetic experiments.

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Abstract

La présente invention concerne un composé sulfonamide-aryle amide et son utilisation en tant que médicament pour le traitement de l'hépatite B. La présente invention concerne particulièrement, un composé en tant qu'inhibiteur de la réplication du VHB et ayant la structure représentée par la formule chimique (A), l'invention concerne également un stéréoisomère, un isomère cis-trans, ou un tautomère de celui-ci, ou un sel, un hydrate ou un solvate pharmaceutiquement acceptable de celui-ci. La définition de chaque groupe est telle que donnée dans la spécification. La présente invention concerne également une composition pharmaceutique comprenant ledit composé, et son utilisation dans le traitement de l'hépatite B.
PCT/CN2017/119531 2016-12-28 2017-12-28 Composé sulfonamide-aryle amide et son utilisation en tant que médicament pour le traitement de l'hépatite b WO2018121689A1 (fr)

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CN111434665B (zh) * 2019-01-11 2023-03-10 上海长森药业有限公司 内环硫脒酰胺-芳基酰胺类化合物及其治疗乙型肝炎的用途
CN113493441A (zh) * 2020-04-03 2021-10-12 广东东阳光药业有限公司 新型螺环类化合物及其在药物中的应用
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CN116768776A (zh) * 2022-03-17 2023-09-19 成都微芯药业有限公司 吡咯酰胺类化合物及其制备方法和用途

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