[go: up one dir, main page]

WO2015180593A1 - Dérivés de benzodiallyle hétérocycliques ayant une activité antivirale - Google Patents

Dérivés de benzodiallyle hétérocycliques ayant une activité antivirale Download PDF

Info

Publication number
WO2015180593A1
WO2015180593A1 PCT/CN2015/079652 CN2015079652W WO2015180593A1 WO 2015180593 A1 WO2015180593 A1 WO 2015180593A1 CN 2015079652 W CN2015079652 W CN 2015079652W WO 2015180593 A1 WO2015180593 A1 WO 2015180593A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
independently
ring
group
membered
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2015/079652
Other languages
English (en)
Chinese (zh)
Inventor
张所明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Tangrun Pharmaceuticals Co Ltd
Shanghai Tangrun Pharmaceuticals coltd
Original Assignee
Shanghai Tangrun Pharmaceuticals Co Ltd
Shanghai Tangrun Pharmaceuticals coltd
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 Shanghai Tangrun Pharmaceuticals Co Ltd, Shanghai Tangrun Pharmaceuticals coltd filed Critical Shanghai Tangrun Pharmaceuticals Co Ltd
Publication of WO2015180593A1 publication Critical patent/WO2015180593A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • C07D405/14—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 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
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

Definitions

  • the present invention relates to a class of benzocyclohexadiene derivatives having antiviral activity.
  • a virus is a non-cellular form of parasitic living organism composed of a nucleic acid molecule (DNA or RNA) and a protein or only a protein.
  • Hepatitis C virus HCV
  • HCV Hepatitis C virus
  • RNA virus includes a 5' non-coding region (5'-UTR), an open reading frame (ORF), and a 3' non-coding region (3'-UTR).
  • the ORF translation produces a polypeptide chain that is subsequently processed into at least 10 different proteins, including a shell (core) protein, two envelope proteins (E1 and E2) and non-structural proteins (NS2, NS3, NS4a, NS4b, NS5a and NS5b).
  • Hepatitis C virus NS5a protein is another anti-hepatitis C drug target.
  • the first inhibitor of HCV NS5a protein against this target is BMS-790052, which has strong inhibitory activity against hepatitis C virus and its EC 50 can reach the skin.
  • the molar grade is one of the most potent inhibitors of HCV replication reported so far.
  • Benzocyclohexadiene is a 10-membered fused ring compound containing a hetero atom, such as chromene (also known as benzopyran) or isochromene (isochromene).
  • chromene also known as benzopyran
  • isochromene isochromene
  • thiochromene also known as benzothiopyran
  • isothiochromene also known as isobenzothiopyran
  • the (iso)(thio)chromenes are not important in themselves, but some of their derivatives are important.
  • vitamin E belongs to the dihydride of chromene, that is, a chroma derivative; benzo- ⁇ -pyrone, also known as coumarin, is widely present in plants, and some are active ingredients of Chinese herbal medicine.
  • Benzo- ⁇ -pyrone is also known as chromone.
  • the 2- or 3-position phenyl substituted ketone is the core of an important plant component, and 2-phenyl chromone is called flavonoid. Flavone), 3-phenyl chromone is called isoflavone, and plant components containing such nucleus are commonly referred to as flavonoids.
  • flavonoids There are many reports on (iso)(thio)chromene derivatives in antiviral, antifungal and anticancer effects.
  • the present invention aims to find a novel (iso)(thio)chromene derivative as an inhibitor of HCV NS5a protein for use in anti-hepatitis C virus in order to cope with the resistance and side effects of existing anti-HCV drugs. Appearance.
  • a 1 is O or S
  • a 2 is CR 2
  • a 3 is C(R 7 )(R 8 );
  • a 1 is C(R 9 )(R 10 ), A 3 is CR 2 ;
  • a 1 is C(R 9 )(R 10 ), and
  • a 2 is CR 2 ;
  • Each A 4 is independently a bond or C(O);
  • Z 1 and Z 2 are independently 6 to 10 membered aromatic rings, 5 to 10 members are contained in 1 to 2 heteroaromatic rings selected from N, O and S heteroatoms, 3 to 7 membered cycloalkane rings, and 3 to 7 members. Containing 1 to 2 heterocycloalkyl rings selected from N, O and S heteroatoms, or Z 1 and Z 2 are independently bonded to the ortho R 1 to form a 6 to 10 membered aromatic ring, 5 to 10 members. 1 to 2 heteroaryl rings selected from N, O and S heteroatoms, 3 to 7 membered cycloalkane rings, 3 to 7 members having 1 to 2 heterocycloalkane rings selected from N, O and S heteroatoms, Or, Z 2 is a connection key;
  • Each R 1 is independently H, D or halogen
  • Each R 2 is independently H, D, OH, halogen, CN, amino, (C 1 -C 8 alkyl) 1-2 amino, C 1 -C 8 alkoxycarbonyl, (C 1 -C 8 alkyl) 1-2 aminocarbonyl, C 1 -C 8 alkyldecyl, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkylsulfinyl, C 1 -C 8 alkyl, C 1 -C 8 alkane Oxyl, C 3 -C 10 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, glycosyloxy, or 1 to 5 An oxygen-substituted C 1 -C 8 alkyl group;
  • Each R 3 is independently H, D, OH, halogen, CN, amino, (C 1 -C 8 alkyl) 1-2 amino, C 1 -C 8 alkoxycarbonyl, (C 1 -C 8 alkyl) 1-2 aminocarbonyl, C 1 -C 8 alkyldecyl, C 1 -C 8 alkylsulfonyl, C 1 -C 8 alkylsulfinyl, C 1 -C 8 alkyl, C 1 -C 8 alkane Oxyl, C 3 -C 10 cycloalkyl, C 2 -C 8 heterocycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, glycosyloxy, or 1 to 5 An oxygen-substituted C 1 -C 8 alkyl group;
  • Each R 4 is independently C 1 -C 8 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 7 heterocycloalkyl or C 6 -C 10 aryl;
  • Each R 5 and R 6 is independently H, D, N(R 1 ')(R 2 ') or NHC(O)OR 1 ';
  • R 1 ', R 2 ' are independently H, D, C 1 - a C 8 alkyl group, or R 1 ', R 2 ' together with a N atom to form a 3 to 10 membered heterocyclic ring containing at least one N atom and further containing 0 to 2 hetero atoms selected from N, O and S;
  • Z 1 and Z 2 are independently a 6- to 8-membered aromatic ring, and a 5- to 8-membered heteroaryl ring having 1 to 2 hetero atoms selected from N, O and S hetero atoms, 3 to 3 a 6-membered cycloalkane ring, 3 to 6 members containing 1 to 2 heterocycloalkane rings selected from N, O and S heteroatoms, or Z 1 and Z 2 are independently bonded to the ortho R 1 to form a 6 to 6 8-membered aromatic ring, 5-8 yuan containing 1 to 2 heteroaryl rings selected from N, O and S heteroatoms, 3 to 6-membered cycloalkane rings, 3 to 6 members containing 1 to 2 selected from N, O And a heteroatom ring of the S hetero atom, or Z 2 is a linkage; preferably Z 1 is a benzene ring or Z 1 is bonded to the ortho position R 1 to form a benzene ring, Z 2
  • a 4 is a linkage
  • Z 1 is a benzene ring
  • Z 2 is a linkage
  • R 1 is H
  • formula (I) is formed into formula (Ia);
  • a 4 is a linkage, Z 1 is bonded to the ortho R 1 to form a benzene ring, Z 2 is a linkage, and Z 2 is R 1 is H.
  • (I) is formed into the formula (Ib);
  • a 4 is a linking bond
  • Z 1 is a benzene ring
  • R 1 in the Z 1 ortho is H
  • Z 2 is bonded to the R 1 in the ortho position to form a benzene ring.
  • (I) is formed into the formula (Ic);
  • a 4 is a linkage, Z 1 , Z 2 are respectively bonded to the ortho position R 1 to form a benzene ring, and the general formula (I) is formed into the general formula (Id);
  • each R 2 is independently H, D, OH, halogen, CN, amino, (C 1 -C 6 alkyl) 1-2 amino, C 1 -C 6 alkoxycarbonyl (C 1 -C 6 alkyl) 1-2 aminocarbonyl, C 1 -C 6 alkyl fluorenyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, C 2 -C 6 heterocycloalkyl, C 6 -C 8 aryl, C 6 -C 8 aryloxy, a glycosyloxy group or a C 1 -C 6 alkyl group substituted with 1 to 3 oxygens;
  • each R 2 is independently H, D, OH, halogen, CN, amino, (C 1 -C 4 alkyl) 1-2 amino, C 1 -C 4 alkoxycarbonyl, (C 1 -C 4 Alkyl) 1-2 aminocarbonyl, C 1 -C 4 alkyl fluorenyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkyl, C 1 - C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 aryl, C 6 aryloxy, glycosyloxy, or C substituted by 1 oxygen 1- C 4 alkyl;
  • each R 2 is independently H, D, OH, halogen, CN, amino, (C 1 -C 2 alkyl) 1-2 amino, C 1 -C 2 alkoxycarbonyl, (C 1 -C 2 alkyl) 1-2 aminocarbonyl, C 1 -C 2 alkyl fluorenyl, C 1 -C 2 alkylsulfonyl, C 1 -C 2 alkylsulfinyl, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 5 -C 6 cycloalkyl, C 4 -C 5 heterocycloalkyl, C 6 aryl, C 6 aryloxy, glycosyloxy, or substituted by 1 oxygen C 1 -C 2 alkyl.
  • the glycosyloxy group is a glucosyloxy group, a ribosyloxy group, an arabinosyloxy group, a xylosyloxy group or a fructosy
  • each R 3 is independently H, D, OH, halogen, CN, amino, (C 1 -C 6 alkyl) 1-2 amino, C 1 -C 6 alkoxycarbonyl (C 1 -C 6 alkyl) 1-2 aminocarbonyl, C 1 -C 6 alkyl fluorenyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, C 2 -C 6 heterocycloalkyl, C 6 -C 8 aryl, C 6 -C 8 aryloxy, a glycosyloxy group, or a C 1 -C 6 alkyl group substituted by 1 to 3 oxygens; or R 3 on two adjacent carbon atoms together with 2 carbon atoms to form a C 3 -C 7 carbocyclic ring , or
  • each R 3 is independently H, D, OH, halogen, CN, amino, (C 1 -C 4 alkyl) 1-2 amino, C 1 -C 4 alkoxycarbonyl, (C 1 -C 4 Alkyl) 1-2 aminocarbonyl, C 1 -C 4 alkyl fluorenyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkyl, C 1 - C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 5 heterocycloalkyl, C 6 aryl, C 6 aryloxy, glycosyloxy, or C substituted by 1 oxygen 1 -C 4 alkyl; or R 3 on two adjacent carbon atoms together with the two carbon atoms to which they are bonded form a C 3 -C 6 carbocyclic ring, or two R 3 groups on the same carbon atom
  • One carbon atom forms
  • each R 3 is independently H, D, OH, halogen, CN, amino, (C 1 -C 2 alkyl) 1-2 amino, C 1 -C 2 alkoxycarbonyl, (C 1 -C 2 alkyl) 1-2 aminocarbonyl, C 1 -C 2 alkyl fluorenyl, C 1 -C 2 alkylsulfonyl, C 1 -C 2 alkylsulfinyl, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 5 -C 6 cycloalkyl, C 4 -C 5 heterocycloalkyl, C 6 aryl, C 6 aryloxy, glycosyloxy, or substituted by 1 oxygen C 1 -C 2 alkyl; or R 3 on two adjacent carbon atoms together with the two carbon atoms to which they are attached form a C 3 -C 6 carbocycle, or two R 3 on the same carbon atom are attached thereto One carbon atom forms
  • glycosyloxy group is a glucosyloxy group, a ribosyloxy group, an arabinosyloxy group, a xylosyloxy group or a fructosyloxy group.
  • each R 4 is a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a C 2 -C 6 heterocycloalkyl group or a C 6 -C 8 aryl group;
  • R 5 and R 6 are independently H, D, N(R 1 ')(R 2 ') or NHC(O)OR 1 ';
  • R 1 ', R 2 ' are independently H, D, C 1 -C a 6- alkyl group, or R 1 ', R 2 ' and a N atom together form a 3- to 8-membered heterocyclic ring containing at least one N atom and further containing 0 to 2 hetero atoms selected from N, O and S;
  • R 4 is C 1 -C 4 alkyl, C 5 -C 6 cycloalkyl, C 4 -C 5 heterocycloalkyl or C 6 aryl;
  • R 5 , R 6 are independently H, D , N(R 1 ')(R 2 ') or NHC(O)OR 1 ';
  • R 1 ', R 2 ' are independently H, D, C 1 -C 4 alkyl, or R 1 ', R 2 And a N- to 6-membered heterocyclic ring containing at least one N atom and further containing 0 to 2 hetero atoms selected from N, O and S;
  • R 4 is C 1 -C 2 alkyl, C 5 -C 6 cycloalkyl, C 4 -C 5 heterocycloalkyl or C 6 aryl;
  • R 5 and R 6 are independently H, D, N(R 1 ')(R 2 ') or NHC(O)OR 1 ';
  • R 1 ', R 2 ' are independently H, D, C 1 -C 2 alkyl, or R 1 ', R 2 ' together with the N atom forms a 3- to 6-membered heterocyclic ring containing at least one N atom and further containing 0 to 2 hetero atoms selected from N, O and S.
  • R 7 , R 8 , R 9 and R 10 are independently H, D, or the following substituents which may be optionally substituted by deuterium or halogen: C 1 -C 6 alkane a C 3 -C 7 cycloalkyl group, a C 2 -C 6 heterocycloalkyl group, a 6- to 8-membered aryl group, and a 5- to 8-membered heteroaryl group having 1 to 2 hetero atoms selected from N, O and S hetero atoms.
  • both R 7 and R 8 or both R 9 and R 10 together form a 3 - optionally substituted by deuterium, halogen or 1 to 2 heteroatoms selected from N, O and S.
  • R 7 , R 8 , R 9 , R 10 are independently H, D, or the following substituents which may be optionally substituted by deuterium or halogen: C 1 -C 4 alkyl, C 3 -C 6 a cycloalkyl group, a C 2 -C 6 heterocycloalkyl group, a 6-membered aryl group, a 5- to 6-membered heteroaryl group having 1 to 2 hetero atoms selected from N, O and S, or R 7 and R 8 Or R 9 and R 10 together form a 3- to 8-membered cycloalkane ring which may be optionally substituted by deuterium, halogen or by 1 to 2 heteroatoms selected from N, O and S, or R 7 and R 8 together form an oxo group;
  • R 7 , R 8 , R 9 , R 10 are independently H, D, or the following substituents which may be optionally substituted by deuterium or halogen: C 1 -C 2 alkyl, C 3 -C a 6- cycloalkyl group, a C 2 -C 5 heterocycloalkyl group or a 6-membered aryl group, or both R 7 and R 8 or both R 9 and R 10 together form a ring which may be optionally substituted by hydrazine or halogen. Or a 3- to 6-membered cycloalkane ring inserted from 1 to 2 hetero atoms selected from N, O and S, or both R 7 and R 8 together form an oxo group.
  • R 3 ' is a C 1 -C 8 alkyl group, preferably a C 1 -C 6 alkyl group, more preferably a C 1 -C 4 alkyl group, most preferably a C 1 -C 2 alkyl group.
  • the term “optionally substituted” means that it may or may not be substituted with a substituent; the term “optionally inserted” means that it may be inserted by a hetero atom or may be free of a hetero atom.
  • the term “a 3 to 12 membered cycloalkane ring which may be optionally substituted by deuterium, halogen or substituted by 1 to 2 heteroatoms selected from N, O and S” means a 3 to 12 membered cycloalkane ring.
  • a 3 to 12 membered cycloalkane ring may be inserted by a hetero atom or may be free of a hetero atom; or, at the same time, it may be substituted by hydrazine and/or halogen.
  • each substituent may be arbitrarily selected among the substituent groups, independent of each other, and may be the same or different.
  • each R 1 independently H, D or halogen as an example, it is assumed that when one of R 1 is H, the other R 1 may be H or not H such as D or halogen, two R 1 can be arbitrarily selected in the substituent group without affecting each other.
  • Particular compounds of the invention include the following compounds:
  • Another object of the present invention is to provide a use of the compound of the formula (I) of the present invention for the preparation of a medicament for preventing or treating a viral infection or a medicament for antiviral, the virus being preferably a hepatitis virus, particularly preferably hepatitis C virus.
  • a further object of the present invention is to provide the use of a compound of formula (I) for the treatment of HCV-infected diseases.
  • a further object of the present invention is to provide a method of treating a patient infected with HCV, comprising the step of administering an effective amount of the compound of claim 1 to a patient infected with HCV.
  • a further object of the present invention is to provide a compound of formula (I) for use in combination with an HCV NS3/4a protease inhibitor, an HCV NS5b polymerase inhibitor or other anti-HCV agent for the treatment of HCV infection.
  • Step A heating the starting material A or the intermediate 2 and the bispinacol borate in the catalyst Pd(dppf)Cl 2 and KOAc in a 1,4-dioxane solvent under a nitrogen atmosphere to 80 ° C, The reaction is continued overnight to give Intermediate 1 or Intermediate 3.
  • the mixed solution of the aqueous solution is heated to 80 ° C under a nitrogen atmosphere, and reacted overnight to obtain the target compound represented by the intermediate 2 or the formula (I).
  • 6-Hydroxy-4,4-dimethylbenzoin-2-one (3.4 g, 17.47 mmol) was added to a 100 mL reaction flask, and imidazole (1.42 g, 20.96 mmol) and tert-butyl were added at 0 °C.
  • Dimethylchlorosilane (3.15 g, 20.96 mmol) was stirred at room temperature overnight. The mixture was quenched with EtOAc EtOAc (EtOAc m. -A (4.1g).
  • HCV genotype GT1b replicon cell system was used according to the method described in the literature (Science. 1999 Jul 2; 285 (5424): 110-3 and J. Virol. 2003, Mar; 77(5): 3007-19). Huh7 cells transfected with the HCV 1b replicon) were tested for inhibitory activity of the HCV 1b replicon on compounds 1 to 5.
  • HCV replicon transfected cells Huh7.5.1 cells transfected with HCV replicon (wild type 1b). The transfected cells were seeded in 96-well plates, 8000 cells per well, and cultured at 37 ° C, 5% CO 2 for 24 hours.
  • Sample treatment Different concentrations of Compound 1-5 samples were added to Huh7.5.1 cells transfected with HCV replicon, two duplicate wells were set for each concentration, and no sample control wells were set. The test sample was started from the highest concentration tested, and the POD810 automatic microplate pretreatment system was added to the cells with different concentrations of the compound; the concentration was diluted 3 times; the culture was continued for 72 hours.
  • the fluorescence signal was measured by adding Cell Titer-fluor (Promega), and the obtained data (RFU) was calculated using the GraphPad Prism software to calculate the EC 50 of the compound.
  • A represents EC 50 ⁇ 0.010 nM
  • B represents 0.010 nM ⁇ EC 50 ⁇ 10 nM.
  • the benzohexadiene derivative of the present invention has an excellent anti-hepatitis C virus effect and has a very good industrial application prospect.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention concerne des dérivés de benzodiallyle hétérocycliques représentés par la formule (I), où quand A1 est O ou S, A2 est CR2 et A3 est C(R7)(R8) ; quand A2 est O ou S, A1 est C(R7)(R8) et A3 est CR2 ; quand A3 est O ou S, A1 est C(R7)(R8) et A2 est CR2 ; et Z1, Z2 sont indépendamment ou tous deux liés au R1 voisin pour former ensemble un cycle aromatique, un cycle hétéroaromatique, un cycle naphténique, un cycle hétéronaphténique ou sont des liaisons. Les dérivés de benzodiallyle hétérocycliques selon l'invention manifestent une excellente activité contre le virus de l'hépatite C.
PCT/CN2015/079652 2014-05-30 2015-05-25 Dérivés de benzodiallyle hétérocycliques ayant une activité antivirale Ceased WO2015180593A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410240925.3 2014-05-30
CN201410240925.3A CN105272972B (zh) 2014-05-30 2014-05-30 具有抗病毒活性的苯并杂环己二烯衍生物

Publications (1)

Publication Number Publication Date
WO2015180593A1 true WO2015180593A1 (fr) 2015-12-03

Family

ID=54698080

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/079652 Ceased WO2015180593A1 (fr) 2014-05-30 2015-05-25 Dérivés de benzodiallyle hétérocycliques ayant une activité antivirale

Country Status (2)

Country Link
CN (1) CN105272972B (fr)
WO (1) WO2015180593A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010091413A1 (fr) * 2009-02-09 2010-08-12 Enanta Pharmaceuticals, Inc. Dérivés du dibenzimidazole liés
US20100316607A1 (en) * 2009-06-16 2010-12-16 Yat Sun Or Hepatitis c virus inhibitors
WO2010148006A1 (fr) * 2009-06-16 2010-12-23 Enanta Pharmaceuticals, Inc. Inhibiteurs du virus de l'hépatite c
WO2011031904A1 (fr) * 2009-09-11 2011-03-17 Enanta Pharmaceuticals, Inc Inhibiteurs du virus de l'hépatite c
WO2011081918A1 (fr) * 2009-12-14 2011-07-07 Enanta Pharmaceuticals, Inc Inhibiteurs du virus de l'hépatite c

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120195857A1 (en) * 2010-08-12 2012-08-02 Bristol-Myers Squibb Company Hepatitis C Virus Inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010091413A1 (fr) * 2009-02-09 2010-08-12 Enanta Pharmaceuticals, Inc. Dérivés du dibenzimidazole liés
US20100316607A1 (en) * 2009-06-16 2010-12-16 Yat Sun Or Hepatitis c virus inhibitors
WO2010148006A1 (fr) * 2009-06-16 2010-12-23 Enanta Pharmaceuticals, Inc. Inhibiteurs du virus de l'hépatite c
WO2011031904A1 (fr) * 2009-09-11 2011-03-17 Enanta Pharmaceuticals, Inc Inhibiteurs du virus de l'hépatite c
WO2011081918A1 (fr) * 2009-12-14 2011-07-07 Enanta Pharmaceuticals, Inc Inhibiteurs du virus de l'hépatite c

Also Published As

Publication number Publication date
CN105272972A (zh) 2016-01-27
CN105272972B (zh) 2018-12-11

Similar Documents

Publication Publication Date Title
JP6506880B2 (ja) Ｂ型肝炎ウィルス感染症の治療および予防のための新規な四環式４−オキソ−ピリジン−３−カルボン酸誘導体
JP6212678B1 (ja) 置換された多環性ピリドン誘導体の製造方法およびその結晶
Meguellati et al. B-ring modified aurones as promising allosteric inhibitors of hepatitis C virus RNA-dependent RNA polymerase
RS54713B1 (sr) Inhibitori replikacije virusa hepatitisa c
CN103420991B (zh) 作为丙型肝炎抑制剂的吡咯烷衍生物及其在药物中的应用
CN113943285B (zh) 作为ret抑制剂的化合物
CN113620931A (zh) 一种雄激素受体抑制剂及其用途
EP2350039A1 (fr) Inhibiteurs de la polymérase virale
CN105732602B (zh) 作为ns4b抑制剂的苯并呋喃类似物
JP2017529401A (ja) Ｎｓ４ｂ阻害剤としてのベンゾフラン類似体
CN114901639B (zh) Hbv抑制剂及其用途
CN116239606B (zh) 一种吡咯磺酰类衍生物、及其制备方法与应用
CN114159433B (zh) 苯并噻二唑类化合物在制备抗sars-cov-2新型冠状病毒药物中的应用
CA2694955A1 (fr) Composes de quinolone et coumarine 3,4-disubstitues
CN119139307B (zh) 螺环类化合物在制备3CLpro蛋白酶抑制剂或药物中的用途
WO2015067108A1 (fr) Flavone cyclique ou composé isoflavone et son application
WO2015180593A1 (fr) Dérivés de benzodiallyle hétérocycliques ayant une activité antivirale
CN103980259B (zh) 黄酮类或异黄酮类化合物及其用途
CN103910725B (zh) 一类吡喹酮类似物、其制备方法和用途
CN107074876B (zh) 一类抑制丙肝病毒的大环状杂环化合物及其制备和用途
CN107266529A (zh) 一类抑制丙肝病毒的大环状杂环化合物及其制备和用途
CN112972648A (zh) 一种蛋白酶体抑制剂在抑制新型冠状病毒中的应用
CN101100470B (zh) 四环双吡喃香豆素化合物
CN101896492A (zh) 四环双吡喃香豆素化合物及其抗hiv和抗结核菌用途
WO2025121418A1 (fr) Inhibiteur du virus de l'hépatite c

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: 15799951

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: 15799951

Country of ref document: EP

Kind code of ref document: A1