WO2015124064A1 - Thiophène comme inhibiteur du virus de l'hépatite c ou son dérivé variant et son utilisation pour la préparation de médicaments - Google Patents

Thiophène comme inhibiteur du virus de l'hépatite c ou son dérivé variant et son utilisation pour la préparation de médicaments Download PDF

Info

Publication number
WO2015124064A1
WO2015124064A1 PCT/CN2015/072375 CN2015072375W WO2015124064A1 WO 2015124064 A1 WO2015124064 A1 WO 2015124064A1 CN 2015072375 W CN2015072375 W CN 2015072375W WO 2015124064 A1 WO2015124064 A1 WO 2015124064A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
mmol
evaporated
optionally substituted
Prior art date
Application number
PCT/CN2015/072375
Other languages
English (en)
Chinese (zh)
Inventor
陈曙辉
朱文元
王建非
黎健
魏于全
余洛汀
陶鑫
Original Assignee
常州寅盛药业有限公司
四川大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 常州寅盛药业有限公司, 四川大学 filed Critical 常州寅盛药业有限公司
Publication of WO2015124064A1 publication Critical patent/WO2015124064A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to thiophene or a variant derivative thereof and a composition thereof as inhibitors of hepatitis C virus (HCV), and to the use thereof for the preparation of a medicament for treating chronic hepatitis C virus infection.
  • HCV hepatitis C virus
  • the invention relates to a series of compounds as NS5A inhibitors, as well as to compositions and pharmaceutical uses thereof.
  • HCV is one of the major human pathogens, with an estimated 170 million chronic HCV infections worldwide, five times the number of human immunodeficiency virus type 1 infections. People with chronic HCV infection develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. Therefore, chronic H CV infection is the leading cause of death in patients worldwide due to liver disease.
  • HCV is a single-stranded positive-strand RNA virus. It belongs to the genus of the Flaviviridae family. All members of the Flaviviridae are enveloped virions containing a positive-stranded RNA genome that encodes all known virus-specific proteins by translation of a single uninterrupted open reading frame (ORF).
  • ORF open reading frame
  • the nucleotides of the HCV genome and the encoded amino acid sequence are quite heterogeneous. At least 6 major genotypes and more than 50 sub-genotypes have been identified. The main genotypes of HCV are distributed globally. Although a large number of genotypes have been studied for pathogenesis and therapeutic effects, the clinical importance of HCV genetic heterogeneity remains unclear.
  • the HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame encoding a single polyprotein of approximately 3000 amino acids.
  • the polyprotein is cleaved by cellular and viral proteases at multiple sites, resulting in both structural and non-structural (NS) proteins.
  • NS structural and non-structural
  • the formation of mature non-structural proteins is achieved by two viral proteases.
  • the first (NS2) is thought to be a metalloproteinase that cleaves at the NS2-NS3 junction; the second protease is a serine protease that is contained in the N-terminal region of NS3 (also referred to herein as the NS3 protease), which mediates all downstream of NS3. Subsequent cleavage is cis at the NS3-NS4A cleavage site and trans at the NS4A-NS4B, NS4B-NS5A, and NS5A-NA5B sites.
  • the NS4A protein appears to have multiple functions, acting as a cofactor for the NS3 protease and possibly assisting membrane localization of NS3 and other viral replicase components.
  • NS3 protein also showed nucleoside triphosphatase and RNA helicase activities.
  • the function of the two proteins NS4B and NS5A is not fully understood, but plays an important role in the replication of HCV.
  • NS4B is a transmembrane protein involved in the formation of viral replication complexes.
  • NS5A is a phosphorylated protein involved in the replication of viral RNA and the formation of viral particles.
  • NS5B (also known as HCV polymerase) is an RNA-dependent RNA polymerase involved in HCV genomic RNA replication.
  • WO2013095275, WO2012122716, CN102863428A and the like each report a series of compounds as HCV inhibitors, and their effects on activity, solubility and the like need to be improved.
  • E 1 and E 7 independently represent the structural unit represented by the formula (a),
  • R 4 is selected from two or more substituted [chain hydrocarbon groups, hetero chain hydrocarbon groups, chain hydrocarbon hetero groups, cycloalkyl groups, heterocyclic groups, cyclohetero);
  • R 2 , R 5 , R 1a , R 1b , R 3a , R 3b are each independently selected from H, F, Cl, Br, I, CN or optionally substituted [OH, SH, NH 2 , PH 2 , Hydrocarbyl group, heterohydrocarbyl group, hydrocarbyl group, heterohydro group hetero group];
  • n 1 or n 4 are each independently selected from 0 or 1;
  • n 2 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 3 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 5 is selected from 1, 2, 3 or 4;
  • n 1 , n 2 , n 3 or n 4 When n 1 , n 2 , n 3 or n 4 is 0, the corresponding structural unit represents a single bond which only serves as a connection;
  • R 6a , R 6b , R 6c are each independently selected from H, C 1-6 alkyl or alkoxy;
  • n 7 and m 8 are selected from 0, 1, 2;
  • p 1 , p 6 , p 7 are each independently selected from the group consisting of 0, 1 , 2 , 3, 4, 5 or 6;
  • E 4 is selected from the structural unit represented by formula (d) or (e),
  • q 3 , q 4 are each independently selected from 0, 1, 2 or 3;
  • the compound or a pharmaceutically acceptable salt thereof comprises one or more chiral centers.
  • the substructure unit of the above structural unit (b) is as shown in the formula (g),
  • m 5a is selected from 0, 1, 2, 3, 4, 5 or 6;
  • n 6a is selected from 0, 1, 2 or 3, and when m 6a is 0, the corresponding structural unit represents a single bond which only serves as a linking;
  • m 8a is selected from 0, 1, 2, 3, 4, 5 or 6;
  • the substructure unit represented by the above formula (g) is selected from the group consisting of:
  • the substructure unit represented by the above formula (g) is selected from the group consisting of:
  • the structural unit represented by the above formula (c) is selected from the group consisting of:
  • the substructure unit of the structural unit represented by the above formula (d) is as shown in the formula (d-1):
  • the above Z 1 and Z 2 are each independently selected from the following groups which are optionally substituted:
  • the sub-structural unit of the structural unit represented by the above formula (d-1) is selected from the group consisting of:
  • the substructure unit of the structural unit represented by the above formula (e) is selected from the group consisting of:
  • R 4 is selected from the group consisting of two or more of which are substituted:
  • R 4 is selected from the group consisting of two or more of which are substituted:
  • R 4 is selected from the group consisting of two or more of which are substituted:
  • the substructure unit represented by the above formula (a) is selected from the group consisting of:
  • substructure unit represented by the above formula (a) is selected from the group consisting of:
  • the number of carbon atoms in the alkyl group of the above alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, alkylthio group, alkylthioalkyl group, alkoxycarbonyl group and alkoxycarbonylamino group is 1, 4, 5 or 6 for 1, 2, 3, 4, 5 or 6.
  • the compound of formula (I) is selected from the group consisting of:
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and after substitution The compound is stable.
  • it means that two hydrogen atoms are substituted.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • two or more substituted is used in particular, and a “two or more substituted” group means that the group can be attached to the remainder of the molecule by its own two atoms. For example, two or more are replaced Refers to
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • a group or a bond of a substituent may be cross-linked to two atoms on a ring, such a group or substituent may be bonded to any atom on the ring.
  • a group or substituent does not indicate which atom is attached to a compound included in the chemical structural formula, but not specifically mentioned, such a group or substituent may be bonded through any of its atoms.
  • Combinations of groups or substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclodiene.
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic
  • the hydrocarbon radical or a combination thereof may be fully saturated, unitary or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may include divalent or polyvalent radicals having a specified number of carbon atoms (eg, C1 ) -C 10 represents 1 to 10 carbons).
  • the hydrocarbon group includes an aliphatic hydrocarbon group including an chain hydrocarbon group and a cyclic hydrocarbon group, and includes, but not limited to, an alkyl group, an alkenyl group, and an alkynyl group, and the aromatic hydrocarbon group includes, but not limited to, a 6-12 member aromatic hydrocarbon group.
  • alkyl refers to a straight or branched chain of atoms or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.
  • heteroalkyl, heterocyclyl, hydrocarbyl, cyclohetero, heteroalkylhetero, heterocyclylhetero group means a hetero atom or a hetero atom group, a hetero atom or a hetero atom group on a specific group.
  • the so-called heterohydrocarbyl, heterocyclic group is connected to the rest of the molecule through carbon atoms , that is, a hetero atom may be located at any internal position of the group (except that the group is attached to the rest of the molecule); the so-called hydrocarbon heterocycle, cyclohetero is attached to the rest of the molecule through a hetero atom, ie, The atom is located at a position where the group is attached to the rest of the molecule; the so-called heteroalkylhetero, heterocyclyl is attached to the remainder of the molecule through a heteroatom, wherein the heteroatom can be located at any internal position of the group (including This group is attached to the rest of the molecule).
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and the like), by itself or in combination with another term, means a stable straight chain.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the heteroatoms B, O, N and S may be located at any internal position of the heterohydrocarbyl group (except where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkoxy alkylamino
  • alkylthio or thioalkoxy
  • cycloalkyl Unless otherwise specified, the terms “cycloalkyl”, “heterocycloalkyl”, “cyclohetero” or subordinates thereof (such as cycloalkyl, heterocycloalkyl, cycloalkanyl, cycloalkenyl, heterocycloalkenyl)
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • halo or halogen
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, which may be monocyclic or polycyclic (preferably 1 to 3 rings), They are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms.
  • the hetero atom is selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxygenated The nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl
  • aryl groups when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • ring means substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted hetero Aryl.
  • the so-called ring includes a fused ring.
  • the number of atoms on the ring is usually defined as the number of elements of the ring.
  • “5 to 7-membered ring” means 5 to 7 atoms arranged in a circle.
  • the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenylpyridine and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • hetero atom as used herein, unless otherwise specified, includes atoms other than carbon (C) and hydrogen (H), including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), antimony ( Ge), aluminum (Al) and boron (B).
  • leaving group refers to a functional group or atom that can be substituted by another functional group or atom by a substitution reaction (eg, an affinity substitution reaction).
  • a substitution reaction eg, an affinity substitution reaction
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, “amino protecting group”, “hydroxy protecting group” or “thiol protecting group.”
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like.
  • acyl such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxy
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • haloalkyl examples include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl. 3-7 cycloalkyl includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • halo refers to fluoro, chloro, bromo and iodo.
  • heterocycle or “heterocyclyl” means a stable monocyclic or bicyclic or bicyclic heterocyclic ring which may be saturated, partially unsaturated or unsaturated (aromatic), which A carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocyclic rings may be fused to a phenyl ring to form a bicyclic ring.
  • heterocyclic compounds include, but are not limited to, acridinyl, anthracycline, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazole , benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH -carbazolyl, porphyrinyl, chromanyl, chromene, porphyrinyldecahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuran[2 ,3-b]tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthesis methods, and techniques of the art. Preferred embodiments are well known to those skilled in the art, and preferred embodiments include, but are not limited to, embodiments of the invention.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and liquid phase mass spectrometry (LCMS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methyl silane
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, and the silica gel plate used for thin layer chromatography (TLC) adopts the specification of 0.15mm ⁇ 0.2mm.
  • the specification is 0.4mm to 0.5mm.
  • column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, TCI, Alfa, Suiyuan Chemical Accela ChemBio Inc., Beijing Coupling and other companies.
  • the examples can be carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified in the examples.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • a hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon having a volume of about 1 liter.
  • the microwave reaction used a Biotage Initiator 60 microwave reactor unless otherwise specified.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • TLC thin layer chromatography
  • the column chromatography eluent system and the thin layer chromatography developer system used for the purification of the compound include: A: dichloromethane and methanol systems, B: petroleum ether and ethyl acetate systems, C: In the dichloromethane and acetone systems, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.
  • the invention employs the following abbreviations: aq for water; HATU for O-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, etc.
  • CDI carbonyl diimidazole
  • DCM dichloromethane
  • PE petroleum ether
  • DIAD diisopropyl azodicarboxylate
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • EtOAc stands for ethyl acetate
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • CBz stands for benzyloxycarbonyl, an amine protecting group
  • BOC stands for t-butylcarbonyl is an amine protecting group
  • HOAc stands for acetic acid
  • NaCNBH 3 stands for cyanide Sodium borohydride
  • rt stands for room temperature
  • O/N stands for overnight
  • THF stands for tetrahydrofuran
  • Boc 2 O stands for di-tert-butyldicarbonate
  • TFA trifluoroacetic acid
  • DIPEA stands for diisopropylethylamine
  • the compound is either by hand or Software naming, commercially available compounds using the supplier catalog name.
  • the compound of the present invention is highly efficient, low in toxicity, and has achieved remarkable and unexpected progress in activity, half-life, solubility and pharmacokinetics, and is more suitable for pharmaceuticals.
  • Step 1 Synthesis of Compound BB-1-3
  • Step 3 Synthesis of Compound BB-1-5
  • Step 1 Synthesis of Compound BB-2-3
  • Step 1 Synthesis of Compound BB-5-2
  • Step 1 Synthesis of Compound BB-7-1
  • Step 1 Synthesis of Compound BB-9-2
  • Step 1 Synthesis of Compound BB-10-2
  • Compound BB-10-2 can be produced according to Synthesis Steps 1-4 of Reference Example 9 (BB-9). LCMS m/z: 479.1 [M+H] +
  • Compound BB-10 can be produced according to Synthesis Step 5 of Reference Example 9 (BB-9). LCMS m/z: 527.1 [M+H] +
  • Step 1 Synthesis of Compound BB-11-2
  • Compound BB-11-2 can be produced according to Synthesis Steps 1-4 of Reference Example 9 (BB-9). MS m/z: 465.1 [M+H] + .
  • Compound BB-11 can be produced according to Synthesis Step 5 of Reference Example 9 (BB-9). MS m/z: 511.3 [M+H] + .
  • Step 1 Synthesis of Compound BB-12-2
  • Compound BB-12-2 can be produced according to Synthesis Steps 1-4 of Reference Example 9 (BB-9). LCMS m/z: 464.9 [M+H] +
  • Compound BB-12 can be produced according to Synthesis Step 5 of Reference Example 9 (BB-9). LCMS m/z: 488.0 [M+Na] +
  • Compound BB-13-2 can be produced according to Synthesis Steps 1-4 of Reference Example 9 (BB-9). MS m/z: 485.1 [M+H] + .
  • Compound BB-13 can be produced according to Synthesis Step 5 of Reference Example 9 (BB-9). MS m/z: 531.2 [M+H] +
  • BB-14-1 (600 mg, 1.90 mmol) was dissolved in ethyl acetate (5 mL), and hydrogen chloride / ethyl acetate solution (HCl / EA, 4mol/L, 20mL) was added and stirred at room temperature for 3 hours. After completion of the TLC reaction, the solvent was evaporated to give a white solid intermediate (410 mg). The above white solid intermediate (410 mg, 1.63 mmol), N-Moc-L-valine (BB-2-6, 399 mg, 2.09 mmol), diisopropylethylamine (735 mg, 5.70 mmol) was dissolved in DMF (10 mL), HATU (1.08 g, 2.84 mmol) was added.
  • Compound BB-15 can be produced according to Synthesis Step 1 of Reference Example 14 (BB-14).
  • N-Boc-L-proline 400 mg, 1.856 mmol
  • potassium carbonate 510 mg, 3.7 mmol
  • DMF 5 mL
  • ethyl acetate 100 mL was added and the mixture was washed with water (20 mL ⁇ 4) and brine (30 mL).
  • the organic phase was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated, evaporated, mjjjjjjjjjjj g, yield 76%).
  • MS m/z 359.9 [M-Boc+H] + .
  • Step 8 Synthesis of Compound BB-17-9
  • Table 1 Using the compound BB-17-9 as a starting material, according to the synthesis method of the step 9 in Reference Example 17, the compounds BB-18, BB-19, BB-20 in the following table were respectively obtained.
  • Step 1 Synthesis of Compound BB-2-6
  • Step 2 Synthesis of Compound BB-21-1
  • Step 1 Synthesis of Compound BB-22-2
  • Compound BB-23 can be produced according to Synthesis Step 3 of Reference Example 21 (BB-21). MS m/z: 525.0 [M+H] +
  • Step 1 Synthesis of Compound BB-24-2
  • Compound BB-24-2 can be produced according to Synthesis Step 5 of Reference Example 23 (BB-23). MS m/z: 492.9 [M+H] +
  • Compound BB-24 can be produced according to Synthesis Step 3 of Reference Example 21 (BB-21). MS m/z: 539.2 [M+H] +
  • Step 1 Synthesis of Compound BB-25-2
  • Compound BB-25-4 can be produced according to Synthesis Step 5 of Reference Example 23 (BB-23). MS m/z: 465.0 [M+H] +
  • Compound BB-25 can be produced according to Synthesis Step 3 of Reference Example 21 (BB-21). MS m/z: 513.1 [M+H] +
  • Compound BB-26-2 can be produced according to Synthesis Step 5 of Reference Example 23 (BB-23). MS m/z: 422.9 [M+H] +
  • Compound BB-26 can be produced according to Synthesis Step 3 of Reference Example 21 (BB-21). MS m/z: 469.2 [M+H] +
  • Step 1 Synthesis of Compound BB-27-2
  • N-Moc-L-proline (BB-2-6, 10 g, 52.3 mmol) was dissolved in THF (200 ml), cooled to -30 ° C, and triethylamine (11.6 g, 114.9 mmol) and Isobutyl chloroformate (9.36 g, 68.1 mmol). After reacting at -30 ° C for 1 hour, L-serine hydrochloride (BB-27-1, 10.6 g, 68.4 mmol) was further added, and the reaction was continued at -30 ° C for 3 hours, then warmed to room temperature and stirred overnight.
  • BB-27-1 10.6 g, 68.4 mmol
  • Step 5 Synthesis of Compound BB-27
  • Compound BB-27 can be produced according to Synthesis Step 3 of Reference Example 21 (BB-21). MS m/z: 527.3 [M+H] +
  • Step 1 Synthesis of Compound BB-28-2
  • Step 1 Synthesis of Compound BB-29-2
  • Step 1 Synthesis of Compound BB-30
  • Step 1 Synthesis of Compound BB-31-1
  • the compound BB-31-2 (0.72 g, 1.82 mmol) was dissolved in ethyl acetate (10 mL), cooled to 0 ° C, and then evaporated. After completion of the TLC reaction, the solvent was removed under reduced pressure at room temperature to afford a white solid.
  • Step 1 Synthesis of Compound BB-32-1
  • Compound AL_031-1 can be prepared according to step 5 of AL_023.
  • Compound AL_031 can be prepared according to step 6 of AL_023.
  • Step 1 Synthesis of Compound AA_239-1
  • Step 2 Synthesis of Compound AA_239-2
  • Step 3 Synthesis of Compound AA_239-3
  • Step 4 Synthesis of Compound AA_239
  • Step 1 Synthesis of Compound AA_238-1
  • N-iodosuccinimide 13.6 g, 60.36 mmol
  • dichloromethane 50 mL
  • pyridine hydrofluoric acid salt 3.6 g, 36.22
  • a solution of the above-mentioned thione ketone intermediate 5 g, 12.07 mmol
  • dichloromethane 5 ml
  • stirring was continued at -78 ° C for 1 hour, and after completion of the TLC reaction, water (10 mL) was added.
  • Step 2 Synthesis of Compound AA_238-2
  • Step 3 Synthesis of Compound AA_238-3
  • Step 5 Synthesis of Compound AA_238
  • Step 1 Synthesis of Compound AA_241-1
  • Step 2 Synthesis of Compound AA_241-2
  • Step 3 Synthesis of Compound AA_241-3
  • Step 4 Synthesis of Compound AA_241-4
  • Step 5 Synthesis of compound AA_241_A and AA_241_B
  • AA_241_A LCMS m/z: 384.1 [M/2+H] + .
  • AA_241_A LCMS m/z: 384.1 [M/2+H] + .
  • 9,10-Dihydrophenanthrene (AG_082-1, 5 g, 27.74 mmol) was dissolved in dichloromethane (50 mL), and iron powder (78 mg, 1.39 mmol) was added. After cooling to 0 ° C, liquid bromine (9.8 g, 61.03 mmol) was added dropwise. After stirring at room temperature for 8 hours, the reaction was quenched by TLC, and water (10 mL) was then evaporated. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated. 6.2 g, yield 65.9%). NMR (CDCl 3, 400MHz): ⁇ 7.59-7.57 (m, 2H), 7.46-7.41 (m, 4H), 2.88-2.86 (m, 4H).
  • Step 2 Synthesis of compound AG_082_A and AG_082_B
  • Step 1 Synthesis of Compound AA_112-2
  • Step 3 Synthesis of Compound AA_112-4
  • Step 4 Synthesis of Compound AA_112
  • HCV genotype 1a (HCV-1a) and 1b (HCV-1b) stably transfected replicon (replicon)
  • Cell 50 measured values of the anti-HCV compound EC 50 and CC.
  • the genotype 1a replicon is derived from the H77 clone and contains K1691R, K2040R and S2204I adaptive mutations.
  • the genotype 1b replicon is derived from the Con1 clone and contains E1202G, T1280I and K1846T adaptive mutations.
  • the HCV 1a (HCV-1a) and 1b (HCV-1b) genotype subgenomic replication subsystems contain the relevant HCV gene subtype non-structural protein genes, the G418 resistance gene NEO and the luciferase gene, making HCV-related proteins and fluorescein
  • the enzyme can be stably expressed in cells.
  • the level of replication of the HCV replicon can be determined by detecting the level of expression of the luciferase gene. Therefore, this system serves as a model for screening the activity of anti-HCV compounds in vitro.
  • HCV replicon cell lines HCV-1a and HCV-1b cells.
  • Cell culture medium DMEM (Invitrogen, Cat. #11960077) culture medium, plus 10% fetal bovine serum (FBS, Sigma, Cat. #12003C) and 1% double antibody (penicillin 5000 IU / mL, streptomycin 10 mg / mL, Hyclone, Cat. #SV30010).
  • Microplate Spectrophotometer Microplate Spectrophotometer, Molecular Device.
  • the compound powder was dissolved in 100% DMSO. Compounds were then diluted 5 fold at 5 fold and added to the cell plates using an Echo liquid handler. The final concentration of DMSO was guaranteed to be 0.5%. Each compound is doubled. The highest starting concentration is 100, 10 or 1 nM, 5 times dilution, 6 points.
  • HCV-1a or HCV-1b replicon cells Cell culture (HCV-1a or HCV-1b replicon cells):
  • Cells were diluted with culture medium to 8 ⁇ 10 4 / mL, automatic dispenser (Thermo Scientific) The diluted cells were added to 96-well plates (Greiner, Cat. # 655090) (100 ⁇ L / hole-containing compound, 8000cells/hole). The cells were cultured at 37 ° C for 3 days in a 5% CO 2 incubator.
  • luciferase luminescent substrate Bright-Glo incubate for 5 minutes, detect the luciferase activity (wavelength >700nm) with chemiluminescence detection system Envison; analyze the anti-HCV inhibitory activity of the compound according to luciferase data and use Calculate the EC 50 value.
  • EC 50 indicates the in vitro anti-hepatitis C virus activity of the molecule, and an EC 50 of less than 1 uM means that the compound has in vitro activity.
  • Four intervals were divided according to the size of the activity: A (0.001 nM to 0.1 nM); B (0.101 nM to 1.0 nM); C (1.001 nM to 10.0 nM); D (10.001 nM to 100 nM).
  • the value of CC 50 indicates the magnitude of the in vitro toxicity of the molecule, and the larger the value, the smaller the toxicity.
  • the compounds of the invention have excellent anti-hepatitis C virus activity in vitro.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une série de thiophènes comme inhibiteurs du virus de l'hépatite C (VHC) ou leurs dérivés variants et leurs compositions, ainsi que leur application dans la préparation de médicaments contre l'infection chronique causée par le virus de l'hépatite C. La présente invention concerne particulièrement une série de composés employés comme inhibiteurs NS5A et leurs compositions et leurs utilisations pour la préparation de médicaments.
PCT/CN2015/072375 2014-02-21 2015-02-06 Thiophène comme inhibiteur du virus de l'hépatite c ou son dérivé variant et son utilisation pour la préparation de médicaments WO2015124064A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410058355.6A CN104860935A (zh) 2014-02-21 2014-02-21 作为丙肝病毒抑制剂的噻吩或其变体衍生物及其制药用途
CN201410058355.6 2014-02-21

Publications (1)

Publication Number Publication Date
WO2015124064A1 true WO2015124064A1 (fr) 2015-08-27

Family

ID=53877630

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/072375 WO2015124064A1 (fr) 2014-02-21 2015-02-06 Thiophène comme inhibiteur du virus de l'hépatite c ou son dérivé variant et son utilisation pour la préparation de médicaments

Country Status (2)

Country Link
CN (3) CN107954997A (fr)
WO (1) WO2015124064A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105669358A (zh) * 2016-03-17 2016-06-15 中国药科大学 多取代芴衍生物的氟化方法
CN109476677B (zh) * 2016-08-08 2024-06-07 辉诺生物医药科技（杭州）有限公司 抗hcmv病毒化合物
CN108003048A (zh) * 2017-12-07 2018-05-08 滨海吉尔多肽有限公司 一种o-甲基-苏/酪氨酸的制备方法
CN111732570B (zh) * 2020-07-06 2022-11-29 湖北工程学院 具有抗病毒活性的咪唑啉酮及其合成方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102596936A (zh) * 2009-05-13 2012-07-18 吉里德科学公司 抗病毒化合物
CN102791687A (zh) * 2009-12-18 2012-11-21 英特穆恩公司 C型肝炎病毒复制的新型抑制剂
CN102883718A (zh) * 2009-12-24 2013-01-16 顶点制药公司 用于治疗或预防黄病毒感染的类似物

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101558059B (zh) * 2006-08-11 2014-12-03 百时美施贵宝公司 丙型肝炎病毒抑制剂
AU2009322393B2 (en) * 2008-12-03 2017-02-02 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
SG10201402969QA (en) * 2009-03-27 2014-09-26 Merck Sharp & Dohme Inhibitors of hepatitis c virus replication
AU2010253791A1 (en) * 2009-05-29 2011-11-24 Merck Sharp & Dohme Corp. Antiviral compounds composed of three linked Aryl moieties to treat diseases such as Hepatitis C
TWI610916B (zh) * 2012-08-03 2018-01-11 廣東東陽光藥業有限公司 作爲丙型肝炎抑制劑的橋環化合物及其在藥物中的應用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102596936A (zh) * 2009-05-13 2012-07-18 吉里德科学公司 抗病毒化合物
CN102791687A (zh) * 2009-12-18 2012-11-21 英特穆恩公司 C型肝炎病毒复制的新型抑制剂
CN102883718A (zh) * 2009-12-24 2013-01-16 顶点制药公司 用于治疗或预防黄病毒感染的类似物

Also Published As

Publication number Publication date
CN104860935A (zh) 2015-08-26
CN108084172A (zh) 2018-05-29
CN107954997A (zh) 2018-04-24

Similar Documents

Publication Publication Date Title
CN106459009B (zh) 丙肝病毒抑制剂及其制药用途
TWI476190B (zh) Ｃ型肝炎病毒抑制劑
CN111153901A (zh) 一类含氮稠杂环类shp2抑制剂化合物、制备方法和用途
CN109311894B (zh) 作为激酶抑制剂的n-(取代的-苯基)-磺酰胺衍生物
WO2019006291A1 (fr) Composés hétérocycliques utilisés en tant qu'inhibiteurs du vrs
IL302991A (en) Antivirals that are derivatives of the novel spiropyrrolidine
WO2023091561A1 (fr) Nouveaux agents antiviraux dérivés de spiropyrrolidine
WO2006090743A1 (fr) Dérivé de 1-(2h)-isoquinolone
BRPI0918174A2 (pt) composto que apresenta atividade contra o vírus da hepatite c (hcv), sua composição e seu uso
ES2366075T3 (es) Nuevos compuestos como antagonistas de receptores a1 de adenosina.
JP6836693B2 (ja) Ａ２ａ受容体アンタゴニストとしての縮合環誘導体
TW202321251A (zh) 新穎螺環吡咯啶衍生的抗病毒劑
TW201221131A (en) Compounds
KR20190017959A (ko) TGF-βRI 억제제인 벤조트리아졸에서 유도된 α,β-불포화 아미드계 화합물
CN112292374B (zh) 一种新型磷酸肌醇3-激酶抑制剂及其制备方法和用途
CN111163766A (zh) Ahr抑制剂和其用途
TW202031659A (zh) 具抗b型肝炎病毒（hbv）活性之新穎6,7-二氫-4h-吡唑并[1,5-a]吡嗪吲哚-2-羧醯胺
WO2020043173A1 (fr) Composé hétérocyclique utilisé en tant qu'inhibiteur de la protéine kinase 1 interagissant avec le récepteur (rip1)
WO2015124064A1 (fr) Thiophène comme inhibiteur du virus de l'hépatite c ou son dérivé variant et son utilisation pour la préparation de médicaments
CN113527299A (zh) 一类含氮稠环类化合物、制备方法和用途
CN113166136A (zh) C端src激酶抑制剂
CN114805311A (zh) 螺环茚
CN113045569B (zh) 用作ret激酶抑制剂的化合物及其应用
RU2672257C2 (ru) Аналог бензофурана в качестве ингибитора ns4b
ES2574639T3 (es) Furanocarboxamidas sustituidas y su utilización

Legal Events

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

Ref document number: 15752786

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15752786

Country of ref document: EP

Kind code of ref document: A1