WO2014194826A1 - Composé phosphoramidate de nucléoside à trois hétérocycles fusionnés circulairement, procédé de préparation et application - Google Patents

Composé phosphoramidate de nucléoside à trois hétérocycles fusionnés circulairement, procédé de préparation et application Download PDF

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WO2014194826A1
WO2014194826A1 PCT/CN2014/079165 CN2014079165W WO2014194826A1 WO 2014194826 A1 WO2014194826 A1 WO 2014194826A1 CN 2014079165 W CN2014079165 W CN 2014079165W WO 2014194826 A1 WO2014194826 A1 WO 2014194826A1
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group
fluorenyl
amino
hydroxy
heteroaryl
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Chinese (zh)
Inventor
王勇
赵立文
毕胜
高毅平
王德忠
陈宏雁
刘阳
张仓
张文萍
郭啸
南阳
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Nanjing Sanhome Pharmaceutical Co Ltd
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Nanjing Sanhome Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • 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

Definitions

  • the invention belongs to the field of medical chemistry, and particularly relates to a class of tricyclic fused heterocyclic nucleoside phosphoramidate compounds, a preparation method thereof, a composition containing the nucleoside phosphoramidate compound, and the compound or composition as a virus infection
  • a therapeutic drug for sexually transmitted diseases particularly as a therapeutic drug for viral hepatitis. Background technique
  • Hepatitis C virus is the leading cause of most non-A, non-B hepatitis. Hepatitis C virus infection is a major health problem leading to chronic liver diseases such as cirrhosis and liver cancer. According to the World Health Organization, there are more than 200 million infected people in the world. Once infected, only about 20% of people can get rid of the virus, and the rest will carry HCV.
  • HCV The genetic structure of HCV and the other two genera of the Flaviviridae, prion and flavivirus, are similar.
  • standard methods of treating HCV infection are interferon and a combination of interferon and ribavirin.
  • interferons had significant side effects such as pan-like symptoms, weight loss, and fatigue, while interferon and ribavirin combination therapy produced considerable Side effects, including hemolysis, anemia, and fatigue.
  • An object of the present invention is to provide a tricyclic fused heterocyclic nucleoside phosphoramidate compound represented by the formula (I) for use in the treatment and/or prevention of HCV infection, a stereoisomer thereof, a prodrug, and a pharmaceutically Acceptable salts, hydrates, solvates,
  • P* represents a chiral phosphorus atom
  • (1) is selected from the group consisting of H and an indenyl group, which is optionally selected from one or more of an indenyl group, an anthracenyloxy group, a phosphonium group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a decyl group, an amino group.
  • R 2 is selected from the group consisting of H, anthracenyl, aminoacyl, aryl and heteroaryl, optionally substituted by one or more fluorenyl, decyloxy, halogen, hydroxy, amino, monodecylamino, Bis-amino, aryl or heteroaryl substituted;
  • R 3 is absent or selected from decyl, alkenyl, alkynyl, decyloxy, halogen, halodecyl, decylamino, decylsulfonyl, decylsulfonylamino, sulfamoyl Sulfhydryl, 3 ⁇ 4 methoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, acylamino, ester, _CN, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, aryl base;
  • D is selected from _ (CR al R a 0-, - (CR al RS -, _S0_, - S0 2 -, - CO-, - N (R b ) -, - N (R b ) - CO- , -CO ⁇ ) -, R al wherein said each is hydrogen, alkyl with halogen, alkyl with haloalkyl, alkenyl or haloalkenyl, or R al, they are attached to form a ring alkyl with C together with The m is 0 or 1, and the R b is absent, hydrogen, sulfhydryl, decylsulfonyl or fluorenylcarbonyl, and each of the Rd, each of which is hydrogen, halogen, fluorenyl, halogenated fluorene group, alkenyl or haloalkenyl, or when Rd, R. 2 are alkyl with time, C with Rd,
  • D 1 is selected from the group consisting of oxygen, sulfur, -S0_, -S0 2 -, -CO-, -N (R d ) -, - (CH) perhaps-, wherein R d is absent, hydrogen, Indenyl or halogenated fluorenyl, said n is 0, 1 or 2, said _ (CH) consult - optionally decyloxy, hydrazino, 3 ⁇ 4, hydroxy, amino, nitro, cyano , a mercapto acyl group, an aminoacyl group, a nonylamino group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group;
  • G and G 1 are each -N- or -CH-;
  • Ring T is selected from:
  • an aromatic ring or a heteroaryl ring which may be substituted with an indenyl group, an alkenyl group, an alkynyl group, a decyloxy group, a halogen, a halogenated fluorenyl group, a halogenated fluorenyl group, a hydroxy group, a nitro group, an amino group, a monodecylamino group, a bis-indolyl group, a decyl acyl group, an aminoacyl group, a decylamino group, an acylamino group, a _CN group, an aryl group or a heteroaryl group;
  • a cyclic anthracene or a heterocyclic anthracene said cycloteronyl or heterocyclic anthracene may be substituted by R 4 , wherein 3 ⁇ 4 is fluorenyl, alkenyl, alkynyl, decyloxy, halogen, halo fluorenyl , halomethoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, decyl acyl, aminoacyl, nonylamino, acylamino, _CN, aryl or heteroaryl.
  • Another object of the present invention is to provide a nucleoside phosphoramidate compound of the formula (I) of the present invention, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof. Methods.
  • a further object of the present invention is to provide a nucleoside phosphoramidate compound, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate or a solvate thereof and a medicament of the formula (I) of the present invention.
  • An acceptable carrier composition and a nucleoside phosphoramidate compound of the formula (I) of the present invention, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate or a solvate thereof Another antiviral composition.
  • a further object of the present invention is to provide a method of inhibiting RNA-dependent RNA viral polymerase, particularly for inhibiting HCV NS5B polymerase.
  • Another object of the invention is also to provide use in the treatment of RNA dependent RNA viral infections, particularly in the treatment of HCV infection.
  • the present invention provides the following technical solutions:
  • the present invention provides a tricyclic fused heterocyclic nucleoside phosphoramidate compound, a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystallization thereof,
  • the compound is as shown in the general formula (I):
  • P* represents a chiral phosphorus atom
  • R 3 is absent or selected from decyl, alkenyl, alkynyl, decyloxy, halogen, halodecyl, decylamino, decylsulfonyl, decylsulfonylamino, sulfamoyl Sulfhydryl, 3 ⁇ 4 methoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, acylamino, ester, _CN, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, aryl base;
  • D is selected from _(CR al R a 0-, -(CH S -, -S0-, - S0 2 -, - CO-, - N(R b )-, - N(R b )- CO -, -CO ⁇ )-, wherein R al , each of which is hydrogen, fluorenyl, halogen, halodecyl, alkenyl or haloalkenyl, or R al , together with the C to which they are attached, constitutes a ring Further, the m is 0 or 1, and the R b is a non-existent hydrogen, a decyl group, a decylsulfonyl group or a fluorenylcarbonyl group, and each of the Rd, each of which is hydrogen, a halogen, a fluorenyl group, or a halogenated group. embankment, alkenyl or haloalkenyl, or when Rd
  • ⁇ is a single key or a double key, two of which are “ ⁇ ” are single keys, or one " ⁇ ” is a single Key, and the other is a double bond;
  • Ring T is selected from:
  • an aromatic ring or a heteroaryl ring which may be substituted with an indenyl group, an alkenyl group, an alkynyl group, a decyloxy group, a halogen, a halogenated fluorenyl group, a halogenated fluorenyl group, a hydroxy group, a nitro group, an amino group, a monodecylamino group, a bis-indolyl group, a decyl acyl group, an aminoacyl group, a decylamino group, an acylamino group, a _CN group, an aryl group or a heteroaryl group;
  • a cyclic anthracene or a heterocyclic anthracene said cyclononan or heterocyclic anthracene may be substituted by R 4 , wherein 3 ⁇ 4 is a fluorenyl, alkenyl, alkynyl, decyloxy, halogen, halogenated fluorenyl group , halomethoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, decyl acyl, aminoacyl, nonylamino, acylamino, _CN, aryl or heteroaryl.
  • the present invention provides a nucleoside phosphoramidate compound of the above formula (I), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate thereof Or crystallized,
  • D is selected from _ (CR al R a 0-, - (CR al R a2 ) complicatS -, -SO-, - S0 2 -, - CO-, - N (R b ) -, - N (R b ) - CO-, -CO -, wherein said IL, each of which is hydrogen, fluorenyl, halogen, halogenated d- 6 fluorenyl, C 2 - 6 alkenyl or halogenated C 2 - 6 alkenyl, or R al And R a2 together with the C to which they are attached constitute a C 3 — s ring fluorenyl group, said m is 0 or 1, said R b being absent, hydrogen, d- 6 fluorenyl, d- 6 fluorenyl sulfonate An acyl group or a d- 6 fluorenylcarbonyl group, each of which is hydrogen, halogen, d- 6
  • D 1 is selected from the group consisting of oxygen, sulfur, _S0-, -S0 2 -, -CO-, -N (R d ) -, _ (CH) philosophical, wherein R d is absent, hydrogen, d- 6 Indenyl, halo d- 6 fluorenyl, said n is 0, 1 or 2, said _ (CH)tician - optionally by ( ⁇ 6 methoxy, d- 6 ⁇ amino, halogen, hydroxy Or an amino group, a nitro group, a cyano group, a d- 6 fluorenyl group, an amino acyl group, a ( -6 ⁇ amino acyl group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group; and the ring T is selected from the group consisting of:
  • An aromatic or heteroaryl ring which may be substituted by R 4 , wherein is d fluorenyl, C 2 -6 alkenyl, C 2 -6 alkynyl, d- 6 decyloxy, halogen , halogenated d- 6 fluorenyl, halogenated d- 6 methoxy, hydroxy, nitro, amino, mono 6 ⁇ amino, bis 6 ⁇ amino, d- 6 decyl acyl, amino acyl, d- 6 Amidinoyl, acylamino, _CN, aryl or heteroaryl;
  • a cyclic anthracene or a heterocyclic anthracene said cycloteronium or heterocycloalkyl hydrocarbon may be substituted by R 4 , wherein 3 ⁇ 4 is ( -6 fluorenyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, d - 6 methoxy, halogen, halogenated d- 6 fluorenyl, halogenated d- 6 methoxy, hydroxy, nitro, amino, mono- 6 ⁇ amino, bis- 6 ⁇ amino, d- 6 decanoyl , aminoacyl, nonylacyl, acylamino, -CN, aryl or heteroaryl.
  • 3 ⁇ 4 is selected from the group consisting of 11 and ( 6 fluorenyl), optionally substituted by one or more d- 6 fluorenyl, d- 6 methoxy, d- 6 ⁇ amino, halogen, hydroxy, amino, nitro, a cyano group, a ( -6- ylhydryl acyl group, an aminoacyl group, a d- 6 hydrazinoyl group, a sulfonyl group, a sulfinyl group, a decyl group, an aryl group or a heteroaryl group;
  • d- 6 fluorenyl C 2 -6 alkenyl, C 2 -6 alkynyl, d- 6 methoxy, halogen, halogenated d- 6 fluorenyl, d- 6 decylamino , D- embankment 6 alkylsulfonyl group, a sulfonylamino group D- embankment 6, sulfamoyl group D- embankment 6, halo (- embankment 6 alkoxy, hydroxy, nitro, amino, mono ( ⁇ 6 amino embankment, Bis( ⁇ - 6 ⁇ amino, amide, ester , _CN C 3 — s cyclodecyl, C 3 — s heterocycloalkyl, aryl, heteroaryl, aryl ( ⁇ 6 fluorenyl).
  • the present invention provides a nucleoside phosphoramidate compound of the above formula (I), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate Object or crystal, of which
  • R 2 is selected from the group consisting of H d- 6 fluorenyl, aminoacyl, aryl and heteroaryl, optionally substituted by one or more ( -6 methoxy, halogen, hydroxy, amino, mono d — 6 ⁇ amino, double d- 6 ⁇ amino, aryl or heteroaryl substituted;
  • R 3 is absent or selected from d- 6 fluorenyl, d- 6 decyloxy, halogen, halogenated d- 6 fluorenyl, halogenated d- 6 methoxy, hydroxy, nitro, amino , 6 ⁇ amino group, bis 6 ⁇ amino group, amide group, ester group, _CN ( 3 - 8 cyclodecyl group, hetero C 3 - s cyclodecyl group, aryl group, heteroaryl group, aryl d- 6 fluorenyl group ;
  • D is selected from _(CR al R a 0- -(CH S - -S0- - S0 2 - -CO- - N(R b )- - N(R b )- CO- -CO -, wherein Each of said ILs is hydrogen, fluorenyl, halogen, halogenated d- 6 fluorenyl, C 2 - 6 alkenyl or halogenated C 2 - 6 alkenyl, or R al R a2 together with the C to which they are attached constitutes C 3 — s ring fluorenyl, said m is 0 or 1, said R b is absent, hydrogen, fluorenyl, decylsulfonyl or fluorenylcarbonyl, said Rd R. 2 each being hydrogen, Halogen, decyl, alkenyl or haloalkenyl, or when Rd R. 2 is a fluorenyl group, C may form a cycl
  • GG 1 is each -N- or -CH-;
  • G is -CH - -N - G 1 is -N-, "" of G is connected to G 1 as a single bond, and D is connected to G as a single bond; only when G is -CH - G 1 is -N -, and when D is -N-, G is connected to G 1 as a single bond, and D is connected to G as a double bond;
  • G is NG 1 is -CH-, G is connected to G 1 as a single bond, and D is connected to G as a single bond;
  • Ring T is selected from:
  • a, five- and six-membered aromatic or heteroaryl rings said five- and six-membered aromatic or heteroaryl rings may be substituted by 3 ⁇ 4, wherein are fluorenyl, alkenyl, alkynyl, decyloxy, halogen, Halogenated fluorenyl, halodecyloxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, decyl acyl, aminoacyl, decylamino, acylamino, _CN, aryl or heteroaryl;
  • cyclohydrocarbon or heterocyclic anthracene said cycloteronium or heterocycloalkyl hydrocarbon may be substituted by R 4 , wherein 3 ⁇ 4 is d- 6 fluorenyl, alkenyl, alkynyl, decyloxy, Halogen, halodecyl, halomethoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, decyl acyl, aminoacyl, hydrazinoyl, acylamino, _CN, aryl or heteroaryl .
  • the present invention provides a tricyclic fused heterocyclic nucleoside phosphoramidate compound of the formula (I), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, Solvent Object or crystal, of which
  • 3 ⁇ 4 is selected from the group consisting of H and d- 6 fluorenyl
  • d- 6 fluorenyl d- 6 methoxy, fluoro, chloro, bromo, halogenated d- 6 fluorenyl, halogenated ( ⁇ -6 methoxy, hydroxy, nitro, amino , ( 6 6 amino group, bis ( ⁇ - 6 ⁇ amino group, acylamino group, ester group,
  • D is selected from _(CR al R a 0-, - (CR al R a2 ) complicatS -, -SO-, - S0 2 -, - CO-, - N(R b )-, - N(R b ) - CO-, -CO ⁇ )-, wherein said IL, each is hydrogen or d- 6 fluorenyl; said m is 0 or 1; said R b is absent, hydrogen, d- 6 ⁇ a d, 6- mercaptosulfonyl or d- 6 fluorenylcarbonyl; each of the R, R.
  • Rd 2 is hydrogen, halogen, fluorenyl, C 2 - 6 alkenyl or halogenated C 2 - 6 alkenyl, or when Rd, are selected from the group firing d- 3, C with Rd, R. 2 constituting the C 3 - 7 cycloalkyl group embankment;
  • D 1 is selected from the group consisting of oxygen, sulfur, _S0-, -S0 2 -, -CO-, -N(R d ) -, _(CH) resort, said R d is absent, hydrogen, sulfhydryl; Said n is 0, 1 or 2;
  • G, G 1 are each -N- or -CH-;
  • Ring T is selected from:
  • (b), C 3 - s cyclononane or heterocyclic anthracene, said cyclononan or heterocycloalkyl hydrocarbon may be substituted by R 4 , wherein is 6 fluorenyl, d- 6 methoxy, halogen, Halogenated d- 6 fluorenyl, halogenated d- 6 methoxy, hydroxy, nitro, amino, mono- 6 ylamino, bis- 6 hydrazine amino, acylamino or _CN.
  • the present invention provides a tricyclic fused heterocyclic nucleoside phosphoramidate compound of the formula (I), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate thereof Solvent or crystal, wherein
  • D 1 is selected from the group consisting of oxygen, sulfur, _S0-, -S0 2 -, -CO-, -N(R d ) -, _(CH) resort, wherein R d is absent, hydrogen or ( 4 ⁇ base; the ⁇ is 0 or 1;
  • G, G 1 are each N or - CH-;
  • the invention provides a tricyclic fused heterocyclic nucleus of formula (I) An amino phosphoramidate compound, a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, wherein is selected from the group consisting of H and d- 6 fluorenyl; and R 2 is selected from d- 6 Anthracenyl, benzyl; R 3 is absent or selected from the group consisting of fluorenyl, d- 6 methoxy, fluoro, chloro, bromo, halogenated d- 6 fluorenyl, halogenated d- 6 methoxy, hydroxy, Nitro, amino, monodecylamino, double d- 6 ⁇ amino, -CN; D is selected from _ (CR al R a2 ) contend0-, - (CR al RS -, -S0-, - S0 2 -, - CO-
  • D 1 is selected from the group consisting of oxygen, sulfur, -S0-, -S0 2 -, -CO-, -NR d -, _ (CH)tician, wherein R d is absent, hydrogen or d- 6 fluorenyl Said n is 0, 1 or 2; G, G 1 are each -N- or -CH-; and ring T is selected from: (a) a five-membered heteroaryl ring or a six-membered heteroaryl ring containing at least one hetero atom, benzene a ring, wherein the five- or six-membered heteroaryl or benzene ring may be substituted by R 4 , wherein ( ⁇ 6 fluorenyl, d- 6 decyloxy, halogen, halogenated ( -6 fluorenyl, halogenated) D- 6 methoxy, hydroxy, nitro, amino, mono ( ⁇ 6 fluorenyl, d- 6 decyloxy,
  • the present invention provides a tricyclic fused heterocyclic nucleoside phosphoramidate compound of the formula (I), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate thereof , solvate or crystalline, is selected from H and d- 4 wherein embankment group;
  • R 2 is selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, cyclopentyl, benzyl;
  • R 3 is Not present, or selected from d- 4 fluorenyl, d- 4 methoxy, fluoro, chloro, bromo;
  • D is selected from _ (CR al R a2 ) contend0-, - (CR al R a2 ) contendS -, -S0-, -S0 2 -, - CO-, - N (R b ) -, - N (R b ) - CO-, -CO ⁇
  • D 1 is selected from the group consisting of oxygen, sulfur, -S0-, -S0 2 -, -CO-, -N (R d ) -, _ (CH)êt -, wherein R d is not Exist, hydrogen or d- 4 fluorenyl, said n is 0 or 1; G, G 1 are each -N- or -CH-; and ring T is selected from: (a), containing at least one N, 0 or a five-membered heteroaryl ring or a six-membered heteroaryl ring or a benzene ring of the S hetero atom, wherein the five- or six-membered heteroaryl ring or benzene ring may be substituted by 3 ⁇ 4, wherein - 6 fluorenyl, d- 6 fluorene , halogen, halogenated d- 6 fluor
  • fluorenyl optionally substituted by one or more fluorenyl, decyloxy, hydrazino, halogen, hydroxy, amino, nitro, cyano, decanoyl, amino An acyl, guanidinoyl, sulfonyl, sulfinyl, fluorenyl, aryl or heteroaryl group;
  • R 2 is selected from the group consisting of H, d- 6 fluorenyl, aminoacyl, aryl and heteroaryl, optionally substituted by one or more fluorenyl, decyloxy, halogen, hydroxy, amino, mono embankment amino, bis embankment amino, aryl or heteroaryl group substituted, e.g. halo ( ⁇ 6 embankment, benzyl;
  • R 3 is absent or selected from decyl, alkenyl, alkynyl, decyloxy, halogen, halodecyl, decylamino, decylsulfonyl, decylsulfonylamino, sulfamoyl Sulfhydryl, 3 ⁇ 4 methoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, acylamino, ester, _CN, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, aryl base;
  • D is selected from _ (CR al R a 0-, - (CR al RS -, _S0_, - S0 2 -, - CO-, - N (R b ) -, - N (R b ) - CO- , -CO ⁇ ) -, R al wherein said each is hydrogen, alkyl with halogen, alkyl with haloalkyl, alkenyl or haloalkenyl, or R al, they are attached to form a ring alkyl with C together with The m is 0 or 1, and the R b is absent, hydrogen, sulfhydryl, decylsulfonyl or fluorenylcarbonyl, and each of the Rd, each of which is hydrogen, halogen, fluorenyl, halogenated fluorene group, alkenyl or haloalkenyl, or when Rd, R. 2 are alkyl with time, C with Rd,
  • G and G 1 are each -N- or -CH-;
  • Ring T is selected from:
  • an aromatic ring or a heteroaryl group for example, may be a 5-membered and a 6-membered aromatic ring or a heteroaryl ring, wherein the aromatic ring or heteroaryl ring may be substituted, wherein is an anthracenyl group, a decyloxy group, a halogen group, a halogenated group Base, halomethoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, acylamino or -CN;
  • a cyclic anthracene or a heterocyclic anthracene said cyclononan or heterocyclic anthracene may be substituted by R 4 , wherein 3 ⁇ 4 is a fluorenyl, alkenyl, alkynyl, decyloxy, halogen, halogenated fluorenyl group , halomethoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, decyl acyl, aminoacyl, nonylamino, acylamino, _CN, aryl or heteroaryl.
  • the present invention provides a tricyclic fused heterocyclic nucleoside phosphoramidate compound of the formula ( ⁇ ), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate Object or crystal, of which
  • 3 ⁇ 4 is selected from the group consisting of H and d- 6 fluorenyl
  • D is selected from - (CR al R a2 ) friendship0-, - (CR al R a2 ) friendshipS -, -S0-, - S0 2 -, - CO-, - N (R b )-, - N (R b ) - CO-, -CO ⁇ ) -, wherein each of R al , R a2 is hydrogen, methyl or ethyl, the m is 0 or 1, and the R b is absent, hydrogen , methyl, ethyl, propyl, isopropyl, cyclopropyl, methylsulfonyl or methylcarbonyl, said Rd, R.
  • C may form a cyclopropyl group with Rd;
  • G is -CH -, -N -, G 1 is -N-, G is connected to G 1 as a single bond, D is connected to G as a single bond; only when G is -CH -, G 1 When -N -, and D is -N-, G is connected to G 1 as a single bond, and D is connected to G as a double bond;
  • Ring T is selected from:
  • the present invention provides a tricyclic fused heterocyclic nucleoside phosphoramidate compound of the formula ( ⁇ ), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or crystal, wherein
  • 3 ⁇ 4 is 11, d- 4 ⁇ base
  • D is selected from - (CR al R a2 ) friendship0-, - (CR al R a2 ) friendshipS -, -S0-, - S0 2 -, - CO-, - N (R b )-, - N (R b ) - CO-, -CO ⁇ ) -, wherein each of R al , R a2 is hydrogen, methyl or ethyl, the m is 0 or 1, and the R b is absent, hydrogen , methyl, ethyl, propyl, isopropyl, cyclopropyl, each of which is hydrogen, fluoro, methyl, ethyl, C 2 - 6 alkenyl or halogenated C 2 - 6 alkenyl , or when Rd, each is methyl or ethyl, C can be combined with Rd, R. 2 constitutes a ring base;
  • G, G 1 are each N or - CH-;
  • Ring T is selected from:
  • the present invention provides a tricyclic fused heterocyclic nucleoside phosphoramidate compound of the formula ( ⁇ ), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate thereof Solvent or crystal, wherein
  • R 2 is selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, cyclopentyl, benzyl;
  • D is selected from -0- - S - -S0- - S0 2 - -CO-, - N (R b ) - - N (R b ) - CO- - C (R cl R c2 ) - wherein R is b is absent, hydrogen, methyl, ethyl, propyl, isopropyl, each of which is hydrogen, fluoro, methyl, ethyl, C 2 - 4 alkenyl, or as Rd R. 2 When each is a methyl group or an ethyl group, C and Rd R. 2 constitutes a ring base;
  • GG 1 is each -N- or -CH-;
  • Ring T is a benzene ring or a cyclohexanyl group, wherein the benzene ring or cyclohexanyl group may be substituted, wherein ( ⁇ 4 fluorenyl group, decyloxy group, halogen, halogenated d- 6 fluorenyl group, halogenated d- 4) Alkoxy, hydroxy, nitro, amino, mono ( -4 ⁇ amino, bis d- 4 -amino, formylamino, acetylamino or _CN
  • the present invention provides the following specific compounds and their diastereomers, prodrugs, and pharmaceutically acceptable
  • a compound of the formula (1) is reacted with phosphorus oxychloride under basic conditions, and then reacted with a compound of the formula (2), followed by addition of pentafluorophenol to obtain a compound of the formula (3);
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I) of the present invention, a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal .
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I), a stereoisomer thereof, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal
  • One or more anti-HCV therapeutic agents comprising a composition selected from the group consisting of HCV NS3 protease inhibitors, HCV NS5B RNA-dependent RNA polymerase inhibitors, nucleoside analogs, interferon ct, pegylated interferon, Ribavirin, levovirin, verramidine, a TLR7 agonist, a TLR9 agonist, a cyclophilin inhibitor, an alpha glucosidase inhibitor, an NS5A inhibitor, and an NS3 helicase inhibitor.
  • the compound of the formula (I), a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof of the present invention may be combined with a pharmaceutically acceptable carrier, diluent or The excipients are mixed to prepare a pharmaceutical preparation suitable for oral or parenteral administration.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
  • the formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.).
  • Administration can be systemic or topical.
  • the orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
  • the formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally employed in the pharmaceutical formulation art.
  • the present invention provides a compound of the formula (I), a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystallization thereof or a pharmaceutical combination of the present invention of the present invention.
  • a method of treating a subject infected with a Flaviviridae virus comprising administering to the subject a compound of formula (I), a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvent Or a compound comprising a compound of the formula (I), a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof, to effectively reduce the amount of the subject The amount of viral load of the virus.
  • the invention provides methods for treating and/or preventing an infection of an RNA virus, such as a Flaviviridae virus, comprising administering to a subject in need thereof a compound of the invention, a stereoisomer thereof, a salt, a hydrate thereof , solvate or crystal or a pharmaceutical composition thereof.
  • the invention provides a method of inhibiting an RNA virus, such as a Flaviviridae virus infection, comprising combining the virus with a therapeutically effective amount of a compound of the invention, a stereoisomer thereof, a salt, a hydrate, a solvent thereof Contact with the crystallization or its pharmaceutical composition.
  • Rhuviridae refers to any virus of the Flaviviridae family, including those that infect humans and non-human animals, such as flaviviruses, plague viruses, and hepatitis C virus.
  • the compounds and compositions of the invention are particularly useful for the therapeutic or prophylactic treatment of HCV.
  • the present invention provides a compound of the formula (I), a stereoisomer, a prodrug, a pharmaceutically acceptable salt, a hydrate, a solvate or a crystal thereof of the present invention for use in the prevention or treatment of a viral infection.
  • a flavivirus-infected disease and in the preparation of a medicament for preventing/treating a viral infection, particularly in the preparation of a medicament for preventing/treating an HCV viral infection, such as an HCV viral hepatitis disease.
  • prodrug refers to any pharmaceutically acceptable form (e.g., an ester, an amide compound) of a compound of the invention when administered to a mammal to provide the active compound.
  • salt refers to a pharmaceutically acceptable salt of a compound of the invention formed with an acid, such as, but not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, Citric acid, Maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, formamidinesulfonic acid or the like.
  • an acid such as, but not limited to, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, Citric acid, Maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, formamidinesulfonic acid or the like.
  • solvate refers to a form of a compound of the invention which forms a solid or liquid complex by coordination with a solvent molecule. Hydrates are a special form of solvates in which they are coordinated with water. Within the scope of the invention, the solvate is preferably a hydrate.
  • crystalline refers to the various solid forms formed by the compounds described herein, including crystalline forms, amorphous forms.
  • mercapto refers to a straight-chain, branched or cyclic saturated hydrocarbon group
  • d-mercapto refers to a saturated hydrocarbon group of 6 or less carbon atoms, including straight-chain or branched d- 6 -fluorenyl. And d- 6 ring fluorenyl.
  • suitable d- 6 thiol groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, positive Pentyl, isopentyl, cyclopentyl, cyclohexyl, n-hexyl.
  • the term includes substituted or unsubstituted indenyl groups which may be optionally substituted by one or more groups selected from the group consisting of fluorenyl, decyloxy, aryloxy, decylamino, arylamino, halogen.
  • C 2 - 6 alkenyl refers to an unsaturated hydrocarbon group containing one or two carbon-carbon double bonds and having from 2 to 6 carbon atoms.
  • C 2 - 4 alkenyl refers to an unsaturated hydrocarbon group containing one or two carbon-carbon double bonds and having from 2 to 4 carbon atoms, and suitable alkenyl groups include, but are not limited to, ethenyl, propenyl.
  • alkynyl refers to a straight or branched chain unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds (C ⁇ C), preferably an alkynyl group having 2 to 6 carbon atoms, more preferably 2 Alkynyl group up to 4 carbon atoms.
  • decyloxy refers to -0-fluorenyl, preferably d- 6 methoxy
  • suitable oxiranyl groups include, but are not limited to, methoxy, ethoxy, and the like.
  • haloindenyl refers to a fluorenyl group substituted with at least one halogen atom, preferably halo ( -6 fluorenyl).
  • mercaptosulfonyl means “mercapto-S0 2 -", preferably d- 6 fluorenyl-so 2 -, suitable fluorenylsulfonyl groups include, but are not limited to, methylsulfonyl, B Sulfonyl.
  • the aromatic ring may be optionally substituted by one or more groups selected from the group consisting of fluorenyl, alkenyl, alkynyl, decyloxy, aryloxy, halogen, halodecyl, halodecyloxy, Hydroxy, nitro, amino, monodecylamino, bis-indolyl, arylamino, decyl acyl, aminoacyl, guanidinoyl, acylamino, _CN, aryl or heteroaryl.
  • heteroaryl ring refers to a 3-10 membered heteroaromatic ring system containing 1-4 heteroatoms selected from N, 0 and S, hetero atoms, and preferably C 3 - 7 membered heteroaromatic ring system,
  • thiophene pyridine
  • imidazole furan
  • pyrrole thiazole
  • 1, 2, 3-triazole 1, 2, 4-triazole
  • 1, 2, 3-thiadiazole 1, 2, 3-thiadiazole
  • oxazole 1, 2, Suitable 4-arodiazoles, 1,3,4-oxadiazoles, etc.
  • suitable heteroaryl rings include, but are not limited to, thiophene, pyridine, imidazole.
  • the term includes both substituted and unsubstituted groups.
  • the heteroaryl ring may be optionally substituted by one or more groups selected from the group consisting of an anthracenyl group, an alkenyl group, an alkynyl group, a decyloxy group, an aryloxy group, a halogen, a halogenated fluorenyl group, a halogenated fluorenyloxy group. , hydroxyl, nitro, amino, single Amidino, bis-indenylamino, arylamino, decyl acyl, aminoacyl, decylamino, acylamino, _CN, aryl or heteroaryl.
  • heterocycle embankment hydrocarbon means having at least one N, 0 or S ring heteroatom embankment hydrocarbons, preferably C 3 - 7 embankment heterocyclic hydrocarbons, including but not limited to heterocyclic embankment pentyl, hexyl heterocycle ⁇ , heterocyclic ⁇ .
  • the cyclic anthracene or heterocyclic anthracene hydrocarbon herein includes both substituted and unsubstituted groups.
  • the cyclononene or heterocycloalkyl hydrocarbon may be optionally substituted by one or more groups selected from the group consisting of: an anthracenyl group, an alkenyl group, an alkynyl group, a decyloxy group, an aryloxy group, a halogen, a halogenated fluorenyl group, 3 ⁇ 4 methoxy, hydroxy, nitro, amino, monodecylamino, bis-indolyl, arylamino, decyl acyl, aminoacyl, hydrazinoyl, acylamino, _CN, aryl or heteroaryl.
  • groups selected from the group consisting of: an anthracenyl group, an alkenyl group, an alkynyl group, a decyloxy group, an aryloxy group, a halogen, a halogenated fluorenyl group, 3 ⁇ 4 methoxy, hydroxy, nitro, amino,
  • amido is "d-decyl-C0N" and suitable amido groups include, but are not limited to, formylamino, acetylamino,
  • the compounds of the present invention contain multiple asymmetric centers and, therefore, can be racemates and racemic mixtures, single enantiomers, diastereomers, diastereomer mixtures, and single diastereomers.
  • (2S)-2-((Pentafluorophenoxy)(9-oxazol-4-yloxy)phosphoryl)amino)propionic acid isopropyl ester (26 mg, 0.1 mmol) was added to the reaction flask, and sealed. Argon protection. Tetrahydrofuran (THF, 1.5 mL) was injected, and t-butylmagnesium chloride (0.3 mL) was injected under ice-cooling, and allowed to react at room temperature for 3 h. Under ice bath, a solution of (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine (70 mg, 0.15 mmol) in THF was injected, and the reaction was completed for 15 h.
  • THF Tetrahydrofuran
  • the compound 3-methoxy-9-oxo-9/-oxaxan (300 mg) obtained in the above step 1.1 was dissolved in dichloromethane (5 mL) in dry ice acetone bath Under nitrogen protection, add BBr 3 (983 mg), stir until the end of the reaction, quench with 1 mL of water, add 10 mL of dichloromethane, wash the organic phase with water, saturated brine, dry dichloromethane, reduce The organic phase was evaporated to give the title compound, m.
  • Step 2 (2S) -2- ((9-oxooxaindole-3-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo-3 , 4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid isopropyl ester
  • N-Boc-3-bromocarbazole (3 g) was dissolved in THF (10 mL), cooled to -78 ° C under nitrogen atmosphere, and n-BuLi (6.5 mL) was added. After stirring at _78 ° C for 1 h, DMF (952 mg) was added thereto. After the addition was completed, the cooling was stopped, the reaction temperature was allowed to rise to room temperature, and quenched with saturated NH 4 C1 (1 mL). The mixture was diluted with EtOAc (EtOAc)EtOAc.
  • 2-Bromo-4-fluoroanisole (5 g) was placed in a reaction flask, then anhydrous THF (80 mL) was added, ice bath, Under the protection of nitrogen, n-butyllithium (20 mL) was slowly added dropwise. After the dropwise addition, the reaction was carried out for 1 hour. Then, trimethyl borate (5.5 mL) was added slowly, stirred at room temperature for 3 h, and monitored by TCL to stop the reaction. The reaction mixture was adjusted to pH 1 with 18% aqueous hydrochloric acid, and then ethyl acetate (200 mL). , white solid, crude product can be directly used in the next reaction.
  • reaction mixture was further reacted at 0 ° C for 1 h, TLC showed the end of the reaction and quenched with methanol (1 mL) The solvent was removed and the crude was purified eluting elut elut elut elut eluting
  • Example 2 4-Hydroxy-9-methyl-9H-carbazole, phosphorus oxychloride, L-alanine ethyl ester hydrochloride, pentafluorophenol and (2' R) -2' prepared by the first step of Example 2.
  • the desired compound was obtained by the same procedure as in Example 1 using deoxy-2'-fluoro-2'-methyluridine as a starting material.
  • Example 2 4-hydroxy-9-methyl-9H-carbazole, phosphorus oxychloride, L-alanine cyclopentyl ester hydrochloride, pentafluorophenol and (2' R) -2 prepared in the first step of Example 2.
  • the target compound was obtained by the same procedure as in Example 1 using '-deoxy-2'-fluoro-2'-methyluridine as a starting material.
  • Example 2 4-hydroxy-9-methyl-9H-carbazole, phosphorus oxychloride, L-alanine benzyl ester hydrochloride, pentafluorophenol and (2' R) -2' prepared in the first step of Example 2.
  • the desired compound was obtained by the same procedure as in Example 1 using deoxy-2'-fluoro-2'-methyluridine as a starting material.
  • Step 2 (2S) -2- ((9-Methyl- ⁇ "carbazole-4-yloxy) ((2R, 3R, 4R, 5R) -5- (2, 4-dioxo) - 3,4-Dihydropyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl)amino)propionic acid neopentyl ester
  • Example 2 4-hydroxy-9-methyl-9H-carbazole, phosphorus oxychloride, L-alanine neopentyl ester hydrochloride, pentafluorophenol and (2' R) -2 prepared in the first step of Example 2.
  • the target compound was obtained by the same procedure as in Example 1 using '-deoxy-2'-fluoro-2'-methyluridine as a starting material.
  • step 4 9 49-trimethyl-9-oxime (1. lg 5 1) carbon tetrachloride 5 ml NBS (lg 5.6 mmol) and azobisisobutyronitrile ( ⁇ The mixture was heated to reflux with EtOAc (EtOAc)EtOAc.
  • EtOAc EtOAc
  • the obtained crude product was placed in a 250 mL single-mouth bottle, and potassium carbonate (910 mg 6.6 mmol), water 20 ml, and P 1 4-dioxane 50 ml were added, and the mixture was heated to 90 ° C for 3 hours, and the reaction was completed. 500 mL), extracted with a sep. funnel, washed with water over 3 EtOAc.
  • step 4 9,9-dimethyl-4-hydroxymethyl-9H-indole (400 mg, 1.7 mmol) was placed in a 50 mL single-mouth bottle, 15 ml of dichloromethane was added, and pyridine chromium chloride was added under ice bath. The acid salt (PCC, 1.2 g, 6 mmol) was evaporated. EtOAc (EtOAc) (EtOAc) Purification by column chromatography gave the title compound.
  • step 5 9,9-dimethyl-4-formyl-911-oxime (20011 ⁇ , 0.95 mmol) was placed in a 50 mL single-mouth bottle, and 15 ml of dichloromethane was added thereto.
  • Oxybenzoic acid mCPBA, 500 mg, 3 mmol
  • ethyl acetate 200 mL was added and extracted with a sep. funnel. After 3 times, it was dried over anhydrous sodium sulfate, filtered, and concentrated, dried, then 15 ml of methanol, K0H (56 mg, lmmol), and reacted at room temperature.
  • step 6 The product obtained in step 6 is 4-hydroxy-9,9-dimethyl-9-indole, phosphorus oxychloride, isopropyl isopropylate hydrochloride, pentafluorophenol and (2' R) -2' Deoxy-2'-fluoro-2'-methyluridine was used as a starting material, and the same procedure as in Example 1 was carried out to obtain the target compound.
  • step 1 was weighed 4-methoxy-9H-carbazole (3. 96 g, 20 mmol), copper acetate (4.0 g, 20 mmol), cyclopropylboronic acid (3.44 g, 40 mmol) and DMAP (7. 32 g, 60 mmol) was placed in a 500 ml eggplant-shaped flask, 200 ml of toluene and 20 ml of sodium bis(trimethylsilyl)amide (NaHMDS) were added, and reacted at 95 ° C for 4 h. After completion of the reaction, it was diluted with ethyl acetate (500 mL). The organic phase was washed with water, brine, dried, filtered,
  • step 9 was weighed and the 9-cyclopropyl-4-methoxy-9H-carbazole (1. 19 g, 5 mmol) was placed in a 250 ml eggplant-shaped flask, and 100 ml of dichloromethane was added thereto at -50 °C.
  • BBr 3 7. 5 excitation 1
  • ethyl acetate 500mL
  • step 3 The product obtained in step 3 is 9-cyclopropyl-4-hydroxy-9H-carbazole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-
  • the target compound was obtained by the same procedure as in Example 1 using deoxy-2'-fluoro-2'-methyluridine as a starting material.
  • 1,3-cyclohexanedione (llg, 0.1 mol), cyclohexanone (10 g, 0.1 mol), xylene 100 ml, p-toluenesulfonic acid 0.45 g (0. Olmol) , adding a water trap, refluxing at 170 ° C for 5 h, after completion of the reaction, cooling to room temperature, concentration and purification by column chromatography to give the title compound.
  • step 3 3, 4, 6, 7, 8, 9-hexahydrodibenzo[b,d]furan-1(2H)-one 5.2 g (0.027 mmol), pair Isopropyltoluene 80 mL, 10%Pa/C3g, was refluxed at 170 ° C for 18 hours under nitrogen atmosphere. After completion of the reaction, the mixture was cooled, filtered, concentrated and purified by column chromatography.
  • the product obtained in the step 2 is 1-hydroxydibenzo[b,d]furan, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride
  • the target compound was obtained by the same procedure as in Example 1 using salt, pentafluorophenol and (2'R) -2'-deoxy-2'-fluoro-2'-methyluridine as starting materials.
  • the m-hydroxybenzoic acid (lg, 7.25 mmol) was dissolved in 20 ML N, N-dimethylacetamide, and thionyl chloride (1.3 g, 10.9 mmol) was added dropwise at 0-4 ° C, and the reaction was carried out at room temperature for 0.5 h. After that, the o-iodoaniline (1.6 g, 7.25 mmol) was added dropwise, and the reaction was completed, and the mixture was evaporated.
  • step 2-derived 3-methoxy-N(2-iodophenyl)methylbenzamide 0.5 g 1.36 1
  • dissolve in DMF 20 ml add Pd (OAc) 2 (50 mg). , 0.22mmol), PPh 3 (70mg 0.267mmol), K 2 C0 3 (0.4g, 2.9mmol), replaced with nitrogen three times, refluxed at 160 ° C for 3h, the reaction was cooled, added with water and ethyl acetate, dried, filtered, Concentrated, purified by column chromatography to give the title compound
  • step 3 In a 100 mL single-mouth bottle, add the product of step 3 to 10-methoxy-5-methylphenanthridine-6(5H)-one (0.15 g 0.6 mmol), HBr/H 2 0 (40%, 5 ml). The reaction of the reaction mixture was carried out, and the mixture was evaporated.
  • step 2 The product obtained in step 2 is 4-hydroxy-9H-indole, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2' R) -2'-deoxy-2'-fluoro-
  • the target compound was obtained by the same procedure as in Example 1 using 2'-methyluridine as a starting material.
  • Step 3 (2S)-2-(((5-Methyl-6-oxo-5,6-dihydrophenanthr-1-yloxy) (((2R, 3R, 4R, 5R)-5) - (2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)phosphoryl Amino) isopropyl propionate
  • the product obtained in the step 2 is 1-hydroxy-5-methylphenanthridine-6(5H)-one, phosphorus oxychloride, L-alanine isopropyl ester hydrochloride, pentafluorophenol and (2'R)-
  • the target compound was obtained by the same procedure as in Example 1 using 2'-deoxy-2'-fluoro-2'-methyluridine as a starting material.
  • the Huh7 lb cell line was supplied by Shanghai WuXi PharmaTech Development Co., Ltd. as a Huh7 cell line containing the HCV lb replicon with a stable luciferase (Luc) reporter. It cloned the HCV non-structural protein gene, neo (G418 resistance) and luciferase reporter gene into pBR vector by gene recombination technology. The vector carrying the HCV replicon was then transfected into huh7 cells, and by G418 resistance screening, the HCV replicon was stably replicated and the related protein and luciferase were stably expressed in huh7 cells. This cell model is used for in vitro screening of anti-HCV compounds.
  • the anti-HCV activity of the compounds was determined by examining the expression level of luciferase. See Lohmann V, et al. 1999. Repl ication of subgenomic hepatitis C virus RNAs in a hepatoma cel l l ine. Science. 285 (5424): 110-113.
  • Cell viability assay Add 30 ⁇ l cell growth fluorescent titration detection reagent per well, incubate the cells for 1 hour at 37 °C, 5% C0 2 incubator, and measure the fluorescence signal value on a spectrophotometer. The data were used for the calculation of compound cytotoxicity. ;
  • Bright-Glo assay Add 100 ⁇ l of luciferase luminescent substrate Bright-Glo per well, and use a chemiluminescence detection system EnVision (PerkinElmer, USA) to detect fluorescence signal values within 5 minutes. The data obtained were used for compound potency calculation.
  • CPD Fluorescence signal value of compound pore
  • CPD Fluorescence signal value of compound pore
  • the compound of the present invention and the control compound prepared in the above Examples 2, 7 and 25 were formulated into 10 mM mother liquor with DMS0, diluted to 10 ⁇ M with DMEM complete culture medium containing 0.5% DMS0, and then diluted 3 times in sequence. , a total of 10 concentrations.
  • the HCVcc reporter virus a full-length HCV mutant transfected with luciferase and GFP, produces a virus with the same infectious ability as JFH-1 wild type, provided by WuXi PharmaTech (Shanghai) New Drug Development Co., Ltd.
  • DMEM medium (DMEM medium), purchased from Invitrogen, USA;
  • Fetal bovine serum purchased from Sigma, USA;
  • L-Glutamine (L(+)-Glutamine), purchased from Invitrogen, USA;
  • Penicillin-streptomycin purchased from Invitrogen, USA;
  • PBS Phosphate buffered sal ine
  • Trypsin purchased from Invitrogen, USA;
  • DMS0 Dimethyl sulfoxide
  • cell lysis buffer purchased from Promega, USA
  • Renillaluciferase test reagent purchased from Promega, USA;
  • Alamar Blue test reagent purchased from Invitrogen, USA.
  • EnVision multi-function microplate reader purchased from Perkin-Elmer, USA.
  • Example 3 Compound preparation: The compound of Example 2, Example 7, Example 25 and the above control compound were added to the HCVcc-reported virus-infected Huh7.5.1 cells, and each compound was provided with double duplicated pores at each concentration; Zero percent effect (ZPE) and 100% effective control group (Hundred percent effect, HPE): The ZPE group replaced the compound with a complete medium containing 0.5% DMSO, and the HPE group was virus-free.
  • ZPE Zero percent effect
  • HPE 100% effective control group
  • Inhibit ion% (RLU ZPE - RLU CPD ) / (RLU ZPE - RLU HPE ) X 100 where RLU. PD is the fluorescence signal value of the test compound well, which is the fluorescence signal value of the ineffective control well, and RLU HPE is the fluorescence signal value of the 100% effective control well.
  • Viabili ty% RFU CPD / RFU X 100
  • the compounds of Examples 2, 7 and 25 of the present invention have excellent antiviral activity and are less cytotoxic to the HCV in vitro cell infection model.

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Abstract

La présente invention concerne un composé phosphoramidate de nucléoside à trois hétérocycles fusionnés circulairement, un procédé de préparation de celui-ci, une composition contenant le composé phosphoramidate de nucléoside à hétérocycles fusionnés, et une application du composé ou de la composition en tant que médicament pour traiter des maladies infectieuses virales, et en particulier, une application du composé ou de la composition en tant que médicament pour traiter l'hépatite virale.
PCT/CN2014/079165 2013-06-06 2014-06-04 Composé phosphoramidate de nucléoside à trois hétérocycles fusionnés circulairement, procédé de préparation et application Ceased WO2014194826A1 (fr)

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CN111763191A (zh) * 2020-06-19 2020-10-13 河北中科金辉药业有限公司 一种dmxaa的制备方法
WO2024023585A3 (fr) * 2022-07-27 2024-03-07 Vandria Sa Dérivés d'urolithine et utilisations thérapeutiques associées
US12351567B2 (en) 2021-01-27 2025-07-08 Vandria Sa Urolithin derivatives and methods of use thereof

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CN111763191A (zh) * 2020-06-19 2020-10-13 河北中科金辉药业有限公司 一种dmxaa的制备方法
US12351567B2 (en) 2021-01-27 2025-07-08 Vandria Sa Urolithin derivatives and methods of use thereof
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WO2024023585A3 (fr) * 2022-07-27 2024-03-07 Vandria Sa Dérivés d'urolithine et utilisations thérapeutiques associées

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